Medical Decision-Making and Revascularization in Ischemic Cardiomyopathy
Ischemic cardiomyopathy (ICM) is the most common underlying etiology of heart failure in the United States and is a significant contributor to deaths due to cardiovascular disease worldwide. The diagnosis and management of ICM has advanced significantly over the past few decades, and the evidence for medical therapy in ICM is both compelling and robust. This contrasts with evidence for coronary revascularization, which is more controversial and favors surgical approaches. This review will examine landmark clinical trial results in detail as well as provide a comprehensive overview of the current epidemiology, diagnostic approaches, and management strategies of ICM.
Authors: Chang, Alex J;Liang, Yilin;Hamilton, Steven A;Ambrosy, Andrew P
Med Clin North Am. 2024 May;108(3):553-566. Epub 2023-12-18.
Clinical Outcomes With Electronic Nudges to Increase Influenza Vaccination : A Prespecified Analysis of a Nationwide, Pragmatic, Registry-Based, Randomized Implementation Trial
In the NUDGE-FLU (Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake) trial, electronic letters incorporating cardiovascular (CV) gain-framing and repeated messaging increased influenza vaccination by approximately 1 percentage point. To evaluate the effects of the successful nudging interventions on downstream clinical outcomes. Prespecified exploratory analysis of a nationwide randomized implementation trial. (ClinicalTrials.gov: NCT05542004). The 2022 to 2023 influenza season. 964 870 Danish citizens aged 65 years or older. Usual care or 9 different electronically delivered behavioral nudging letters. Cardiovascular, respiratory, and other clinical end points during follow-up from intervention delivery (16 September 2022) through 31 May 2023. The analysis set included 691 820 participants. Hospitalization for pneumonia or influenza occurred in 3354 of 346 327 (1.0%) participants in the usual care group, 396 of 38 586 (1.0%) in the CV gain-framing group (hazard ratio [HR], 1.06 [95% CI, 0.95 to 1.18]; versus usual care), and 403 of 38 231 (1.1%) in the repeated letter group (HR, 1.09 [CI, 0.98 to 1.21]; versus usual care). In the usual care group, 44 682 (12.9%) participants were hospitalized for any cause, compared with 5002 (13.0%) in the CV gain-framing group (HR, 1.00 [CI, 0.97 to 1.03]; versus usual care) and 4965 (13.0%) in the repeated letter group (HR, 1.01 [CI, 0.98 to 1.04]; versus usual care). A total of 6341 (1.8%) participants died in the usual care group, compared with 721 (1.9%) in the CV gain-framing group (HR, 1.02 [CI, 0.94 to 1.10]; versus usual care) and 646 (1.7%) in the repeated letter group (HR, 0.92 [CI, 0.85 to 1.00]; versus usual care). Prespecified but exploratory analysis, potential misclassification of events in routinely collected registry data, and results may not be generalizable to other health systems or countries with other racial compositions and/or cultural or societal norms. In a prespecified exploratory analysis, modest increases in influenza vaccination rates seen with electronic nudges did not translate into observable improvements in clinical outcomes. Seasonal influenza vaccination should remain strongly recommended. Sanofi.
Authors: Johansen, Niklas Dyrby;Bhatt, Ankeet S;Biering-Sørensen, Tor;et al.
Ann Intern Med. 2024 Apr;177(4):476-483. Epub 2024-03-19.
Donor Electrocardiogram Associations With Cardiac Dysfunction, Heart Transplant Use, and Survival: The Donor Heart Study
Potential organ donors often exhibit abnormalities on electrocardiograms (ECGs) after brain death, but the physiological and prognostic significance of such abnormalities is unknown. This study sought to characterize the prevalence of ECG abnormalities in a nationwide cohort of potential cardiac donors and their associations with cardiac dysfunction, use for heart transplantation (HT), and recipient outcomes. The Donor Heart Study enrolled 4,333 potential cardiac organ donors at 8 organ procurement organizations across the United States from 2015 to 2020. A blinded expert reviewer interpreted all ECGs, which were obtained once hemodynamic stability was achieved after brain death and were repeated 24 ± 6 hours later. ECG findings were summarized, and their associations with other cardiac diagnostic findings, use for HT, and graft survival were assessed using univariable and multivariable regression. Initial ECGs were interpretable for 4,136 potential donors. Overall, 64% of ECGs were deemed clinically abnormal, most commonly as a result of a nonspecific St-T-wave abnormality (39%), T-wave inversion (19%), and/or QTc interval >500 ms (17%). Conduction abnormalities, ectopy, pathologic Q waves, and ST-segment elevations were less common (each present in ≤5% of donors) and resolved on repeat ECGs in most cases. Only pathological Q waves were significant predictors of donor heart nonuse (adjusted OR: 0.39; 95% CI: 0.29-0.53), and none were associated with graft survival at 1 year post-HT. ECG abnormalities are common in potential heart donors but often resolve on serial testing. Pathologic Q waves are associated with a lower likelihood of use for HT, but they do not portend worse graft survival.
Authors: Tapaskar, Natalie;Zaroff, Jonathan;Khush, Kiran K;et al.
JACC Heart Fail. 2024 Apr;12(4):722-736. Epub 2024-01-17.
The Digital Transition: Are Adults Aged 65 Years or Older Willing to Complete Online Forms and Questionnaires in Patient Portals?
Patients are being encouraged to complete forms electronically using patient portals rather than on paper, but willingness of older adults to make this transition is uncertain. The authors analyzed data for 4105 Kaiser Permanente Northern California 2020 Member Health Survey respondents aged 65-85 years who answered a question about willingness to complete online forms and questionnaires using a patient portal. Data weighted to the Kaiser Permanente Northern California membership were used to estimate percentages of older adults willing to complete patient portal forms and questionnaires. Chi-square tests and log-Poisson regression models that included sociodemographic, internet use, and patient portal variables were used to identify factors predictive of willingness. Overall, 59.6% of older adults were willing to complete patient portal forms, 17.6% were not willing, and 22.8% were not sure. Adults aged 75-85 (49.5%) vs 65-74 years (64.8%) and Black (51.9%) and Latino (46.5%) vs White (62.8%) adults were less likely to indicate willingness. In addition to racial and ethnic differences and younger age, higher educational attainment, use of the internet alone (vs internet use with help or not at all), having an internet-enabled computer or tablet, and having sent at least 1 message through the patient portal increased likelihood of being willing. Health care teams should assess older adults’ capabilities and comfort related to completion of patient portal-based forms and support those willing to make the digital transition. Paper forms and oral collection of information should remain available for those unable or unwilling to make this digital transition.
Authors: Gordon, Nancy P;Zhang, Sherry;Lo, Joan C;Li, Christina F
Perm J. 2024 Mar 15;28(1):68-75. Epub 2024-02-06.
Initial antiretroviral therapy regimen and risk of heart failure
Heart failure risk is elevated in people with HIV (PWH). We investigated whether initial antiretroviral therapy (ART) regimens influenced heart failure risk. Cohort study. PWH who initiated an ART regimen between 2000 and 2016 were identified from three integrated healthcare systems. We evaluated heart failure risk by protease inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTI), and integrase strand transfer inhibitor (INSTI)-based ART, and comparing two common nucleotide reverse transcriptase inhibitors: tenofovir disoproxil fumarate (tenofovir) and abacavir. Follow-up for each pairwise comparison varied (i.e. 7 years for protease inhibitor vs. NNRTI; 5 years for tenofovir vs. abacavir; 2 years for INSTIs vs. PIs or NNRTIs). Hazard ratios were from working logistic marginal structural models, fitted with inverse probability weighting to adjust for demographics, and traditional cardiovascular risk factors. Thirteen thousand six hundred and thirty-four PWH were included (88% men, median 40 years of age; 34% non-Hispanic white, 24% non-Hispanic black, and 24% Hispanic). The hazard ratio (95% CI) were: 2.5 (1.5-4.3) for protease inhibitor vs. NNRTI-based ART (reference); 0.5 (0.2-1.8) for protease inhibitor vs. INSTI-based ART (reference); 0.1 (0.1-0.8) for NNRTI vs. INSTI-based ART (reference); and 1.7 (0.5-5.7) for tenofovir vs. abacavir (reference). In more complex models of cumulative incidence that accounted for possible nonproportional hazards over time, the only remaining finding was evidence of a higher risk of heart failure for protease inhibitor compared with NNRTI-based regimens (1.8 vs. 0.8%; P = 0.002). PWH initiating protease inhibitors may be at higher risk of heart failure compared with those initiating NNRTIs. Future studies with longer follow-up with INSTI-based and other specific ART are warranted.
Authors: Silverberg, Michael J;Ambrosy, Andrew P;Go, Alan S;Neugebauer, Romain;Neugebauer, Romain;et al.
AIDS. 2024 Mar 15;38(4):547-556. Epub 2023-11-14.
Rationale and design of NUDGE-FLU-CHRONIC and NUDGE-FLU-2: Two nationwide randomized trials of electronic nudges to increase influenza vaccination among patients with chronic diseases and older adults during the 2023/2024 influenza season
Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively. Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2. NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications. NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023,https://clinicaltrials.gov/study/NCT06030726.
Authors: Johansen, Niklas Dyrby;Bhatt, Ankeet S;Biering-Sørensen, Tor;et al.
Am Heart J. 2024 Mar 07.
Alanine aminotransferase elevation varies by ethnicity among Asian and Pacific Islander children with overweight or obesity
Limited research on alanine aminotransferase (ALT) screening for metabolic dysfunction-associated steatotic liver disease (MASLD) among US Asian/Pacific Islander (PI) children necessitates investigation in this heterogeneous population. Examine ALT elevation among Asian/PI children with overweight or obesity. Elevated ALT prevalence (clinical threshold) and association with body mass index ≥85th percentile were compared among 18 402 Asian/PI and 25 376 non-Hispanic White (NHW) children aged 9-17 years using logistic regression. ALT elevation was more prevalent among Asian/PI (vs. NHW) males with overweight (4.0% vs. 2.7%), moderate (7.8% vs. 5.3%) and severe obesity (16.6% vs. 11.5%), and females with moderate (5.1% vs. 3.0%) and severe obesity (10.2% vs. 5.2%). Adjusted odds of elevated ALT were 1.6-fold and ~2-fold higher for Asian/PI (vs. NHW) males and females (with obesity), respectively. Filipino, Chinese and Southeast Asian males had 1.7-2.1-fold higher odds, but Native Hawaiian/PI (NHPI) and South Asian males did not significantly differ (vs. NHW). Filipina and Chinese females with obesity had >2-fold higher odds, Southeast and South Asian females did not differ and NHPI findings were mixed (vs. NHW). High elevated ALT prevalence among Asian/PI children with overweight and obesity emphasizes the need for MASLD risk assessment and examination of ethnic subgroups.
Authors: Lee, Catherine;Schwimmer, Jeffrey B;Gunderson, Erica P;Goyal, Nidhi P;Darbinian, Jeanne A;Greenspan, Louise C;Lo, Joan C
Pediatr Obes. 2024 Mar 05:e13110.
Cost Effectiveness of Dapagliflozin for Heart Failure Across the Spectrum of Ejection Fraction: An Economic Evaluation Based on Pooled, Individual Participant Data From the DELIVER and DAPA-HF Trials
The sodium glucose cotransporter-2 inhibitors are guideline-recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter-2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking. We conducted a US-based cost-effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3-state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality-adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death. The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01035255 & NCT01920711.
Authors: Bhatt, Ankeet S;Gaziano, Thomas A;et al.
J Am Heart Assoc. 2024 Mar 05;13(5):e032279. Epub 2024-02-23.
Childhood maltreatment and trajectories of cardiometabolic health across the reproductive life span among individuals with a first birth during the Coronary Artery Risk Development in Young Adults Study
Childhood adversity is associated with poor cardiometabolic health in adulthood; little is known about how this relationship evolves through childbearing years for parous individuals. The goal was to estimate differences in cardiometabolic health indicators before, during and after childbearing years by report of childhood maltreatment in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. Including 743 individuals nulliparous at baseline (1985-1986) with one or more pregnancies >20 weeks during follow-up (1986-2022), we fit segmented linear regression models to estimate mean differences between individuals reporting or not reporting childhood maltreatment (physical or emotional) in waist circumference, triglycerides, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, fasting glucose, and body mass index (BMI) prior to, during, and following childbearing years using generalized estimating equations, allowing for interaction between maltreatment and time within each segment, and adjusting for total parity, parental education, and race (Black or white, self-reported). Individuals reporting maltreatment (19%; 141) had a greater waist circumference (post-childbearing: +2.9 cm, 95% CI (0.7, 5.0), higher triglycerides [post-childbearing: +8.1 mg/dL, 95% CI (0.7, 15.6)], and lower HDL cholesterol [post-childbearing: -2.1 mg/dL, 95% CI (-4.7, 0.5)] during all stages compared to those not reporting maltreatment. There were not meaningful differences in blood pressure, fasting glucose, or BMI. Individuals who reported maltreatment did not report faster changes over time. Differences in some aspects of cardiometabolic health between individuals reporting versus not reporting childhood maltreatment were sustained across reproductive life stages, suggesting potentially persistent impacts of childhood adversity.
Authors: Stanhope, Kaitlyn K;Gunderson, Erica P;Suglia, Shakira F;Boulet, Sheree L;Jamieson, Denise J;Kiefe, Catarina I;Kershaw, Kiarri N
Prev Med. 2024 Mar;180:107894. Epub 2024-02-10.
Sex-specific genetic architecture of blood pressure
The genetic and genomic basis of sex differences in blood pressure (BP) traits remain unstudied at scale. Here, we conducted sex-stratified and combined-sex genome-wide association studies of BP traits using the UK Biobank resource, identifying 1,346 previously reported and 29 new BP trait-associated loci. Among associated loci, 412 were female-specific (Pfemale ≤ 5 × 10-8; Pmale > 5 × 10-8) and 142 were male-specific (Pmale ≤ 5 × 10-8; Pfemale > 5 × 10-8); these sex-specific loci were enriched for hormone-related transcription factors, in particular, estrogen receptor 1. Analyses of gene-by-sex interactions and sexually dimorphic effects identified four genomic regions, showing female-specific associations with diastolic BP or pulse pressure, including the chromosome 13q34-COL4A1/COL4A2 locus. Notably, female-specific pulse pressure-associated loci exhibited enriched acetylated histone H3 Lys27 modifications in arterial tissues and a female-specific association with fibromuscular dysplasia, a female-biased vascular disease; colocalization signals included Chr13q34: COL4A1/COL4A2, Chr9p21: CDKN2B-AS1 and Chr4q32.1: MAP9 regions. Sex-specific and sex-biased polygenic associations of BP traits were associated with multiple cardiovascular traits. These findings suggest potentially clinically significant and BP sex-specific pleiotropic effects on cardiovascular diseases.
Authors: Yang, Min-Lee;Xu, Chang;Gupte, Trisha;Hoffmann, Thomas J;Iribarren, Carlos;Zhou, Xiang;Ganesh, Santhi K
Nat Med. 2024 Mar;30(3):818-828. Epub 2024-03-08.
Eligibility and Potential Benefit of Transcatheter Edge-to-Edge Repair in a Contemporary Cohort With Heart Failure: Evidence From a Large Integrated Health Care Delivery System
The eligibility and potential benefit of transcatheter edge-to-edge repair (TEER) in addition to guideline-directed medical therapy to treat moderate-severe or severe secondary mitral regurgitation (MR) has not been reported in a contemporary heart failure (HF) population. Eligibility for TEER based on Food and Drug Administration (FDA) labeling: (1) HF symptoms, (2) moderate-severe or severe MR, (3) left ventricular ejection fraction (LVEF) 20% to 50%, (4) left ventricular end-systolic dimension 7.0 cm, and (5) receiving GDMT (blocker + angiotensin-converting enzyme inhibitor/angiotensin receptor blocker). The proportion (%) of patients eligible for TEER. The hypothetical number needed to treat to prevent or postpone adverse outcomes was estimated using relative risk reductions from published hazard ratios in the registration trial and the observed event rates. We identified 50,841 adults with HF and known LVEF. After applying FDA criteria, 2461 patients (4.8%) were considered eligible for transcatheter mitral valve replacement (FDA+), with the vast majority of patients excluded (FDA-) based on a lack of clinically significant MR (N = 47,279). FDA+ patients had higher natriuretic peptide levels and were more likely to have a prior HF hospitalization compared to FDA- patients. Although FDA+ patients had a more dilated left ventricle and lower LVEF, median (25th-75th) left ventricular end-systolic dimension (cm) was low at 4.4 (3.7-5.1) and only 30.8% had severely reduced LVEF. FDA+ patients were at higher risk of HF-related morbidity and mortality. The estimated number needed to treat to potentially prevent or postpone all-cause hospitalization was 4.4, 8.8 for HF hospitalization, and 5.3 for all-cause death at 24 months in FDA+ patients. There is a low prevalence of TEER eligibility based on FDA criteria primarily due to absence of moderate-severe or severe MR. FDA+ patients are a high acuity population and may potentially derive a robust clinical benefit from TEER based on pivotal studies. Additional research is necessary to validate the scope of eligibility and comparative effectiveness of TEER in real-world populations.
Authors: Ambrosy, Andrew P;Bhatt, Ankeet S;Solomon, Matthew D;Zaroff, Jonathan G;Go, Alan S;Go, Alan S;et al.
Struct Heart. 2024 Mar;8(2):100237. Epub 2023-12-19.
Challenges of fracture risk assessment in Asian and Black women
Bone mineral density (BMD) and fracture risk calculators (eg, the Fracture Risk Assessment Tool [FRAX]) guide primary prevention care in postmenopausal women. BMD scores use non-Hispanic White (NHW) reference data for T-score classification, whereas FRAX incorporates BMD, clinical risk factors, and population differences when calculating risk. This study compares findings among Asian, Black, and NHW women who underwent osteoporosis screening in a US health care system. Retrospective cross-sectional study. Asian, Black, and NHW women aged 65 to 75 years who underwent BMD testing (with no recent fracture, osteoporosis therapy, metastatic cancer, multiple myeloma, metabolic bone disorders, or kidney replacement therapy) were compared across the following measures: femoral neck BMD (FN-BMD) T-score (normal ≥ -1, osteoporosis ≤ -2.5), high FRAX 10-year hip fracture risk (FRAX-Hip ≥ 3%), FRAX risk factors, and diabetes status. Among 3640 Asian women, 23.8% had osteoporosis and 8.7% had FRAX-Hip scores of at least 3% (34.5% among those with osteoporosis). Among 11,711 NHW women, 12.3% had osteoporosis and 17.2% had FRAX-Hip scores of at least 3% (84.8% among those with osteoporosis). Among 1711 Black women, 68.1% had normal FN-BMD, 4.1% had BMD-defined osteoporosis, and 1.8% had FRAX-Hip scores of at least 3% (32.4% among those with osteoporosis). Fracture risk factors differed by group. Diabetes was 2-fold more prevalent in Black and Asian (35% and 36%, respectively) vs NHW (16%) women. A large subset of Asian women have discordant BMD and FRAX scores, presenting challenges in osteoporosis management. Furthermore, FN-BMD and especially FRAX scores identified few Black women at high fracture risk warranting treatment. Studies should examine whether fracture risk assessment can be optimized in understudied racial minority populations, particularly when findings are discordant.
Authors: Lo, Joan C;Chandra, Malini;Yang, Wei;Thompson, Nailah;Lee, Catherine;Ramaswamy, Mohan;Khan, Mehreen;Wheeler, Amber
Am J Manag Care. 2024 Mar;30(3):140-144.
Understanding the role of childhood nurture, abuse, and stability on gestational diabetes in the Coronary Artery Risk Development in Young Adults study (CARDIA)
To estimate associations between facets of the maternal childhood family environment with gestational diabetes (GDM) and to test mediation by pre-pregnancy waist circumference. We used data from CARDIA, a cohort of individuals aged 18-30 years at baseline (1985-86), followed over 30 years (2016). We included participants with one or more pregnancies ≥ 20 weeks after baseline, without pre-pregnancy diabetes. The primary exposure was the Childhood Family Environment Scale (assessed year 15), including the total score and abuse, nurture, and stability subscales as continuous, separate exposures. The outcome was GDM (self-reported at each visit for each pregnancy). We fit log binomial models with generalized estimating equations to calculate risk ratios (RR) and 95% confidence intervals (CI), adjusting for age at delivery, parity, race (Black or White), and parental education. We used regression models with bootstrapped CIs to test mediation and effect modification by excess abdominal adiposity at the last preconception CARDIA visit (waist circumference ≥ 88 cm). We included 1033 individuals (46% Black) with 1836 pregnancies. 130 pregnancies (7.1%) were complicated by GDM. For each 1 point increase on the abuse subscale (e.g., from “rarely or never” to “some or little of the time”) there was a 30% increased risk of GDM (RR: 1.3, 95% CI: 1.0, 1.7). There was evidence of effect modification but not mediation by preconception abdominal adiposity. A more adverse childhood family environment was associated with increased risk of GDM, with a stronger association among individuals with preconception waist circumference ≥ 88 cm.
Authors: Stanhope, Kaitlyn K;Gunderson, Erica P;Suglia, Shakira F;Boulet, Sheree L;Jamieson, Denise J;Kiefe, Catarina I;Kershaw, Kiarri N
Ann Epidemiol. 2024 Mar;91:30-36. Epub 2024-01-23.
Acetazolamide as an Adjunctive Diuretic Therapy for Patients with Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis
Recent evidence suggests that acetazolamide may be beneficial as an adjunctive diuretic therapy in patients with acute decompensated heart failure (HF). We aim to pool all the studies conducted until now and provide updated evidence regarding the role of acetazolamide as adjunctive diuretic in patients with acute decompensated HF. PubMed/Medline, Cochrane Library, and Scopus were searched from inception until July 2023, for randomized and nonrandomized studies evaluating acetazolamide as add-on diuretic in patients with acute decompensated HF. Data about natriuresis, urine output, decongestion, and the clinical signs of congestion were extracted, pooled, and analyzed. Data were pooled using a random effects model. Results were presented as risk ratios (RRs), odds ratios (ORs), or weighted mean differences (WMD) with 95% confidence intervals (95% CIs). Certainty of evidence was assessed using the grading of recommendation, assessment, development, and evaluation (GRADE) approach. A P value of < 0.05 was considered significant in all cases. A total of 5 studies (n = 684 patients) were included with a median follow-up time of 3 months. Pooled analysis demonstrated significantly increased natriuresis (MD 55.07, 95% CI 35.1-77.04, P < 0.00001; I2 = 54%; moderate certainty), urine output (MD 1.04, 95% CI 0.10-1.97, P = 0.03; I2 = 79%; moderate certainty) and decongestion [odds ratio (OR) 1.62, 95% CI 1.14-2.31, P = 0.007; I2 = 0%; high certainty] in the acetazolamide group, as compared with controls. There was no significant difference in ascites (RR 0.56, 95% CI 0.23-1.36, P = 0.20; I2 = 0%; low certainty), edema (RR 1.02, 95% CI 0.52-2.0, P = 0.95; I2 = 45%; very low certainty), raised jugular venous pressure (JVP) (RR 0.86, 95% CI 0.63-1.17, P = 0.35; I2 = 0%; low certainty), and pulmonary rales (RR 0.82, 95% CI 0.44-1.51, P = 0.52; I2 = 25%; low certainty) between the two groups. Acetazolamide as an adjunctive diuretic significantly improves global surrogate endpoints for decongestion therapy but not all individual signs and symptoms of volume overload. This systematic review was prospectively registered on the PROSPERO ( https://www.crd.york.ac.uk/PROSPERO/ ), registration number CRD498330.
Authors: Siddiqi, Ahmed Kamal;Maniya, Muhammad Talha;Alam, Muhammad Tanveer;Ambrosy, Andrew P;Fudim, Marat;Greene, Stephen J;Khan, Muhammad Shahzeb
Am J Cardiovasc Drugs. 2024 Mar;24(2):273-284. Epub 2024-02-28.
TV Viewing From Young Adulthood to Middle Age and Cardiovascular Disease Risk
Few studies have longitudinally examined TV viewing trajectories and cardiovascular disease risk factors. The objective of this study was to determine the association between level and annualized changes in young adult TV viewing and the incidence of cardiovascular disease risk factors from young adulthood to middle age. In 2023, prospective community-based cohort data of 4,318 Coronary Artery Risk Development in Young Adults study participants (1990-1991 to 2015-2016) were analyzed. Individualized daily TV viewing trajectories for each participant were developed using linear mixed models. Every additional hour of TV viewing at age 23 years was associated with higher odds of incident hypertension (AOR=1.16; 95% CI=1.11, 1.22), diabetes (AOR=1.19; 95% CI=1.11, 1.28), high triglycerides (AOR=1.17; 95% CI=1.08, 1.26), dyslipidemia (AOR=1.10; 95% CI=1.03, 1.16), and obesity (AOR=1.12; 95% CI=1.06, 1.17). In addition, each hourly increase in daily TV viewing was associated with higher annual odds of incident hypertension (AOR=1.26; 95% CI=1.16, 1.37), low high-density lipoprotein cholesterol (AOR=1.15; 95% CI=1.03, 1.30), high triglycerides (AOR=1.32; 95% CI=1.15, 1.51), dyslipidemia (AOR=1.22; 95% CI=1.11, 1.34), and obesity (AOR=1.17; 95% CI=1.07, 1.27) over the follow-up period. In this prospective cohort study, higher TV viewing in young adulthood and annual increases in TV viewing were associated with incident hypertension, high triglycerides, and obesity. Young adulthood as well as behaviors across midlife may be important time periods to promote healthful TV viewing behavior patterns.
Authors: Nagata, Jason M;Vittinghoff, Eric;Dooley, Erin E;Lin, Feng;Rana, Jamal S;Sidney, Stephen;Pettee Gabriel, Kelley
Am J Prev Med. 2024 Mar;66(3):427-434. Epub 2023-12-10.
Fate of the unoperated ascending thoracic aortic aneurysm-patient selection and the importance of the denominator
Authors: Solomon, Matthew D;Liang, David H;Miller, D Craig
Eur Heart J. 2024 Mar 01;45(9):733-734.
Racial and Ethnic Variation in Dementia Prevalence in a Diverse Cohort of Adults with Hip Fracture
Authors: Lee, David R;Lo, Joan C;Chandra, Malini;Lee, Catherine;Gilsanz, Paola
J Gen Intern Med. 2024 Mar;39(4):716-719. Epub 2023-12-24.
Identifying Complete Atypical Femur Fractures in Adults with Bisphosphonate Exposure
Authors: Lo, Joan C;Grimsrud, Christopher D
Endocr Pract. 2024 Mar;30(3):278-281. Epub 2023-12-16.
Settling the IRONy of Anemia in Heart Failure: Current Evidence and Future Directions
Authors: Tsangaris, Adamantios;Ambrosy, Andrew P;Tschida, Michael;Alexy, Tamas
J Card Fail. 2024 Feb 22.
Resource Use Among Patients with Transcatheter Cardiac Valve Procedures Admitted to Contemporary Cardiac Intensive Care Units: Insights from CCCTN
Authors: Bhatt, Ankeet S;Berg, David D;Palazzolo, Michael G;Alviar, Carlos L;Bohula, Erin A;Morrow, David A
Eur Heart J Acute Cardiovasc Care. 2024 Feb 16;13(2):245-246.
A PACT for the future: Improving medication adherence in heart failure
Authors: Min, Kyung H;Jackson, Stephanie A;Ambrosy, Andrew P
Eur J Heart Fail. 2024 Feb 12.
Lack of leisure time physical activity and variations in cardiovascular mortality across US communities: a comprehensive county-level analysis (2011-2019)
To investigate the associations between county-level proportions of adults not engaging in leisure-time physical activity (no LTPA) and age-adjusted cardiovascular mortality (AACVM) rates in the overall US population and across demographics. Analysing 2900 US counties from 2011 to 2019, we used the Centers for Disease Control and Prevention (CDC) databases to obtain annual AACVM rates. No LTPA data were sourced from the CDC’s Behavioural Risk Factor Surveillance System survey and county-specific rates were calculated using a validated multilevel regression and poststratification modelling approach. Multiple regression models assessed associations with county characteristics such as socioeconomic, environmental, clinical and healthcare access factors. Poisson generalised linear mixed models were employed to calculate incidence rate ratios (IRR) and additional yearly deaths (AYD) per 100 000 persons. Of 309.9 million residents in 2900 counties in 2011, 7.38 million (2.4%) cardiovascular deaths occurred by 2019. County attributes such as socioeconomic, environmental and clinical factors accounted for up to 65% (adjusted R2=0.65) of variance in no LTPA rates. No LTPA rates associated with higher AACVM across demographics, notably among middle-aged adults (standardised IRR: 1.06; 95% CI (1.04 to 1.07)), particularly women (1.09; 95% CI (1.07 to 1.12)). The highest AYDs were among elderly non-Hispanic black individuals (AYD=68/100 000). Our study reveals a robust association between the high prevalence of no LTPA and elevated AACVM rates beyond other social determinants. The most at-risk groups were middle-aged women and elderly non-Hispanic black individuals. Further, county-level characteristics accounted for substantial variance in community LTPA rates. These results emphasise the need for targeted public health measures to boost physical activity, especially in high-risk communities, to reduce AACVM.
Authors: Abohashem, Shady;Nasir, Khurram;Munir, Malak;Sayed, Ahmed;Aldosoky, Wesam;Abbasi, Taimur;Michos, Erin D;Gulati, Martha;Rana, Jamal S
Br J Sports Med. 2024 Feb 09;58(4):204-212. Epub 2024-02-09.
Development and Validation of the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) Equations
Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.
Authors: Khan, Sadiya S;Go, Alan S;Chronic Kidney Disease Prognosis Consortium and the American Heart Association Cardiovascular-Kidney-Metabolic Science Advisory Group,;et al.
Circulation. 2024 Feb 06;149(6):430-449. Epub 2023-11-10.
Risk of Incident Asthma among Young Asian American, Native Hawaiian, and Pacific Islander Children from Age 3 to 7 years in a Northern California Healthcare System
Incident childhood asthma risk has not been examined among diverse Asian American, Native Hawaiian, and Pacific Islander subgroups. In a large California healthcare system, incident asthma was higher among young Filipino/a, Native Hawaiian/Pacific Islander, and South Asian children compared with non-Hispanic White children, whereas Chinese and Japanese children were similar.
Authors: Arroyo, Anna Chen;Ko, Jimmy;Chandra, Malini;Huang, Polly;Darbinian, Jeanne A;Palaniappan, Latha;Lo, Joan C
J Pediatr. 2024 Feb;265:113802. Epub 2023-10-28.
Medical Therapy Before, During, and After Hospitalization in Medicare Beneficiaries with Heart Failure and Diabetes: The Get With The Guidelines – Heart Failure Registry
Patients hospitalized with heart failure (HF) and diabetes mellitus (DM) are at risk for worsening clinical status. Little is known about the frequency of therapeutic changes during hospitalization. We characterized the use of medical therapies before, during and after hospitalization in patients with HF and DM. We identified Medicare beneficiaries in Get With The Guidelines-Heart Failure (GWTG-HF) hospitalized between July 2014 and September 2019 with Part D prescription coverage. We evaluated trends in the use of 7 classes of antihyperglycemic therapies (metformin, sulfonylureas, GLP-1RA, SGLT2-inhibitors, DPP-4 inhibitors, thiazolidinediones, and insulins) and 4 classes of HF therapies (evidence-based β-blockers, ACEi or ARB, MRA, and ARNI). Medication fills were assessed at 6 and 3 months before hospitalization, at hospital discharge and at 3 months post-discharge. Among 35,165 Medicare beneficiaries, the median age was 77 years, 54% were women, and 76% were white; 11,660 (33%) had HFrEF (LVEF ≤ 40%), 3700 (11%) had HFmrEF (LVEF 41%-49%), and 19,805 (56%) had HFpEF (LVEF ≥ 50%). Overall, insulin was the most commonly prescribed antihyperglycemic after HF hospitalization (n = 12,919, 37%), followed by metformin (n = 7460, 21%) and sulfonylureas (n = 7030, 20%). GLP-1RA (n = 700, 2.0%) and SGLT2i (n = 287, 1.0%) use was low and did not improve over time. In patients with HFrEF, evidence-based beta-blocker, RASi, MRA, and ARNI fills during the 6 months preceding HF hospitalization were 63%, 62%, 19%, and 4%, respectively. Fills initially declined prior to hospitalization, but then rose from 3 months before hospitalization to discharge (beta-blocker: 56%-82%; RASi: 51%-57%, MRA: 15%-28%, ARNI: 3%-6%, triple therapy: 8%-20%; P < 0.01 for all). Prescription rates 3 months after hospitalization were similar to those at hospital discharge. In-hospital optimization of medical therapy in patients with HF and DM is common in participating hospitals of a large US quality improvement registry.
Authors: Bhatt, Ankeet S;Vaduganathan, Muthiah;et al.
J Card Fail. 2024 Feb;30(2):319-328. Epub 2023-09-25.
Uptake of sodium-glucose cotransporter-2 inhibitors in hospitalized patients with heart failure: insights from the veterans affairs healthcare system
The use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) in Veteran Affairs (VA) patients hospitalized with heart failure (HF) has not been previously reported. VA electronic health record data were used to identify patients hospitalized for HF (primary or secondary diagnosis) from 01/2019-11/2022. Patients with SGLT2i allergy, advanced/end-stage chronic kidney disease (CKD), or advanced HF therapies were excluded. We identified factors associated with discharge SGLT2i prescription among hospitalizations in 2022. We also compared SGLT2i and angiotensin receptor-neprilysin inhibitor (ARNI) prescription rates. Hospital-level variation in SGLT2i prescription was assessed via the median odds ratio. A total of 69,680 patients were hospitalized for HF; 10.3% were prescribed SGLT2i at discharge (4.4% newly prescribed, 5.9% continued pre-admission therapy). SGLT2i prescription increased over time and was higher in patients with HFrEF and primary HF. Among 15,762 patients hospitalized in 2022, SGLT2i prescription was more likely in patients with diabetes (adjusted odds ratio [aOR] 2.27; 95% confidence interval [CI]: 2.09-2.47) and ischemic heart disease (aOR 1.14; 95% CI: 1.03-1.26). Patients with increased age (aOR 0.77 per 10 years; 95% CI: 0.73-0.80) and lower systolic blood pressure (aOR 0.94 per 10mmHg; 95% CI: 0.92-0.96) were less likely to be prescribed SGLT2i, and SGLT2i prescription was not more likely in patients with CKD (aOR 1.07; 95% CI 0.98-1.16). The adjusted median odds ratio suggested a 1.8-fold variation in the likelihood that similar patients at 2 random VA sites were prescribed SGLT2i (range 0%-21.0%). In patients with EF ≤40%, 30.9% were prescribed SGLT2i while 26.9% were prescribed ARNI (p<0.01). One-tenth of VA patients hospitalized for HF were prescribed SGLT2i at discharge. Opportunities exist to reduce variation in SGLT2i prescription across hospitals and promote use in patients with CKD and older age.
Authors: Varshney, Anubodh S;Bhatt, Ankeet S;Ambrosy, Andrew P;Sandhu, Alexander T;et al.
J Card Fail. 2024 Jan 26.
Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study
The toxins contributing to uremic symptoms in patients with CKD are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. Cross-sectional. 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not on dialysis. Measurement of 448 known plasma metabolites. The uremic symptoms fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 (KDQOL) instrument. Multivariable adjusted linear regression, Lasso linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least two of the three modeling approaches were deemed “overall” significant. Participant mean eGFR was 43 mL/min/1.73 m2, with 44% self-identifying as female and 41% Non-Hispanic Black. The prevalence of uremic symptoms ranged from 22 – 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom, and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites demonstrated at least a moderate correlation with eGFR (Pearson’s r ≥ 0.5), and some were also associated with risk of developing kidney failure or death in multivariable adjusted Cox regression models. Lack of a second independent cohort for external validation of our findings. Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed.
Authors: Wulczyn, Kendra E;Hsu, Chi-Yuan;CRIC Study Investigators,;et al.
Am J Kidney Dis. 2024 Jan 22.
A polygenic score associated with fracture risk in breast cancer patients treated with aromatase inhibitors
Identifying women at high risk of osteoporotic fracture from aromatase inhibitor (AI) therapy for breast cancer is largely based on known risk factors for healthy postmenopausal women, which might not accurately reflect the risk in breast cancer patients post-AI therapy. To determine whether a polygenic score associated with fracture in healthy women is also significant in women treated with AIs for breast cancer, we used data from a prospective observational cohort of 2152 women diagnosed with hormonal receptor positive breast cancer treated with AIs as the initial endocrine therapy and examined a polygenic score of heel quantitative ultrasound speed of sound (gSOS) in relation to incident osteoporotic fracture after AI therapy during a median 6.1 years of follow up after AI initiation. In multivariable models, patients with the second and third highest tertiles (T) versus the lowest tertile of gSOS had significantly lower risk of fracture (T2: adjusted HR = 0.61, 95% CI: 0.46-0.80; T3: adjusted HR = 0.53, 95% CI: 0.40-0.70). The lower risk of fracture in patients with the highest tertile of gSOS remained significant after further adjustment for BMD at the hip (T3: adjusted HR = 0.62, 95% CI: 0.42-0.91). In conclusion, our analysis showed gSOS as a novel genetic predictor for fracture risk independent of BMD among breast cancer patients treated with AIs. Future studies are warranted to evaluate the performance of incorporating gSOS in prediction models for the risk of AI-related fracture in breast cancer patients.
Authors: Hook, Christine;Lee, Catherine;Lo, Joan C;Kushi, Lawrence H;Kwan, Marilyn L;Yao, Song;et al.
NPJ Breast Cancer. 2024 Jan 20;10(1):9. Epub 2024-01-20.
Hemoglobin A1c and Type 2 Diabetes Incidence Among Adolescents With Overweight and Obesity
With the increase in prediabetes among adolescents with overweight and obesity, identifying those at highest risk for type 2 diabetes (T2D) can support prevention strategies. To assess T2D risk by hemoglobin A1c (HbA1c) levels among adolescents with overweight and obesity. This retrospective cohort study was conducted using data for January 1, 2010, to December 31, 2019, from a large California health care system. The study population comprised adolescents aged 10 to 17 years who had a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) at or above the 85th percentile, had HbA1c measured during 2010 to 2018, and did not have preexisting diabetes. Data abstraction and analyses were conducted from January 1, 2020, to November 16, 2023. Baseline HbA1c, with covariates including BMI category (overweight: 85th to <95th percentile; moderate obesity: 100% to <120% of 95th percentile; or severe obesity: ≥120% of 95th percentile), age, sex, race and ethnicity, and Neighborhood Deprivation Index score. The main outcome was incident T2D during follow-up through 2019, including cumulative incidence and multivariable hazard ratios (HRs) with 95% CIs using Cox proportional hazard regression analyses. This study included 74 552 adolescents with a mean (SD) age of 13.4 (2.3) years. More than half (50.6%) were female; 26.9% of individuals had overweight, 42.3% had moderate obesity, and 30.8% had severe obesity. Individuals identified as Asian or Pacific Islander (17.6%), Black (11.1%), Hispanic (43.6%), White (21.6%), and other or unknown race or ethnicity (6.1%). During follow-up, 698 adolescents (0.9%) developed diabetes, and 626 (89.7%) had T2D; 72 individuals (10.3%) who had type 1, secondary, or other diabetes were censored. The overall T2D incidence was 2.1 (95% CI, 1.9-2.3) per 1000 person-years, with a 5-year cumulative incidence of 1.0% (95% CI, 0.9%-1.1%). Higher baseline HbA1c (from <5.5% to 5.5%-5.6%, 5.7%-5.8%, 5.9%-6.0%, 6.1%-6.2%, and 6.3-6.4%) was associated with higher 5-year cumulative T2D incidence (from 0.3% [95% CI, 0.2%-0.4%] to 0.5% [0.4%-0.7%], 1.1% [0.8%-1.3%], 3.8% [3.2%-4.7%], 11.0% [8.9%-13.7%], and 28.5% [21.9%-36.5%], respectively). In addition, higher baseline HbA1c was associated with greater T2D risk (reference [HbA1c <5.5%]: HR, 1.7 [95% CI, 1.3-2.2], 2.8 [2.1-3.6], 9.3 [7.2-12.1], 23.3 [17.4-31.3], and 71.9 [51.1-101.1], respectively). Higher BMI category, older age, female sex, and Asian or Pacific Islander race (HR, 1.7 [95% CI, 1.3-2.2]), but not Black race or Hispanic ethnicity (compared with White race), were also independent indicators of T2D. In stratified analyses, incremental risk associated with higher HbA1c was greater for Asian or Pacific Islander and White adolescents than for Black and Hispanic adolescents. In this cohort study of adolescents with overweight and obesity, T2D risk increased substantially with baseline HbA1c above 6.0%. Risk varied by BMI, age, sex, and race and ethnicity. These findings suggest that diabetes surveillance in adolescents should be tailored to optimize identification among high-risk subgroups.
Authors: Hoe, Francis M;Darbinian, Jeanne A;Greenspan, Louise C;Lo, Joan C
JAMA Netw Open. 2024 Jan 02;7(1):e2351322. Epub 2024-01-02.
In Search of a Timely, Safe, and Effective Alternative to Hospitalization for Heart Failure
Authors: Gustafson, Shanshan E;Hamilton, Steven A;Ambrosy, Andrew P
JAMA Netw Open. 2024 Jan 02;7(1):e2350454. Epub 2024-01-02.
Comparative safety of tenecteplase vs alteplase for acute ischemic stroke
Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 – 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 – 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.
Authors: Flint, Alexander C;Eaton, Abigail;Melles, Ronald B;Hartman, Jonathan;Cullen, Sean P;Chan, Sheila L;Rao, Vivek A;Nguyen-Huynh, Mai N;Kapadia, Brij;Patel, Nihar U;Klingman, Jeffrey G
J Stroke Cerebrovasc Dis. 2024 Jan;33(1):107468. Epub 2023-11-30.
Inflammatory Conditions During Pregnancy and Risk of Autism and Other Neurodevelopmental Disorders
Maternal inflammation can result from immune dysregulation and metabolic perturbations during pregnancy. Whether conditions associated with inflammation during pregnancy increase the likelihood of autism spectrum disorder (ASD) or other neurodevelopmental disorders (DDs) is not well understood. We conducted a case-control study among children born in California from 2011 to 2016 to investigate maternal immune-mediated and cardiometabolic conditions during pregnancy and risk of ASD (n = 311) and DDs (n = 1291) compared with children from the general population (n = 967). Data on maternal conditions and covariates were retrieved from electronic health records. Maternal genetic data were used to assess a causal relationship. Using multivariable logistic regression, we found that mothers with asthma were more likely to deliver infants later diagnosed with ASD (odds ratio [OR] = 1.62, 95% CI: 1.15-2.29) or DDs (OR = 1.30, 95% CI: 1.02-1.64). Maternal obesity was also associated with child ASD (OR = 1.51, 95% CI: 1.07-2.13). Mothers with both asthma and extreme obesity had the greatest odds of delivering an infant later diagnosed with ASD (OR = 16.9, 95% CI: 5.13-55.71). These increased ASD odds were observed among female children only. Polygenic risk scores for obesity, asthma, and their combination showed no association with ASD risk. Mendelian randomization did not support a causal relationship between maternal conditions and ASD. Inflammatory conditions during pregnancy are associated with risk for neurodevelopmental disorders in children. These risks do not seem to be due to shared genetic risk; rather, inflammatory conditions may share nongenetic risk factors with neurodevelopmental disorders. Children whose mothers have both asthma and obesity during pregnancy may benefit from earlier screening and intervention.
Authors: Croen, Lisa A;Ames, Jennifer L;Qian, Yinge;Alexeeff, Stacey;Ashwood, Paul;Gunderson, Erica P;Wu, Yvonne W;Boghossian, Andrew S;Yolken, Robert;Van de Water, Judy;Weiss, Lauren A
Biol Psychiatry Glob Open Sci. 2024 Jan;4(1):39-50. Epub 2023-10-11.
Advanced Image-Guided Percutaneous Technique Versus Advanced Laparoscopic Surgical Technique for Peritoneal Dialysis Catheter Placement
Timely placement of a functional peritoneal dialysis (PD) catheter is crucial to long-term PD success. Advanced image-guided percutaneous and advanced laparoscopic techniques both represent best practice catheter placement options. Advanced image-guided percutaneous is a minimally invasive procedure that does not require general anesthesia. Retrospective cohort study comparing time from referral to procedure, complication rate, and 1-year catheter survival between placement techniques. Patients who had advanced laparoscopic or advanced image-guided percutaneous PD catheter placement from January 1, 2011 to December 31, 2013 in an integrated Northern California health care delivery system. PD catheter placement using advanced laparoscopic or advanced image-guided percutaneous techniques. One-year PD catheter survival; major, minor, and infectious complications; time from referral to PD catheter placement; and procedure time. Wilcoxon rank sum tests to compare referral and procedure times; χ2/Fisher exact tests to compare complications; and modified least-squares regression to compare adjusted 1-year catheter survival between PD placement techniques. We identified 191 and 238 PD catheters placed through advanced image-guided percutaneous and advanced laparoscopic techniques, respectively. Adjusted 1-year PD catheter survival was 80% (95% CI, 74%-87%) using advanced image-guided percutaneous technique vs 91% (87%-96%) using advanced laparoscopic technique (P = 0.01). Major complications were <1% in both groups. Minor and infectious complications were 45.6% and 38.7% in advanced image-guided percutaneous and advanced laparoscopic techniques, respectively (P = 0.01). Median days from referral to procedure were 12 and 33 for patients undergoing advanced image-guided percutaneous and advanced laparoscopic techniques, respectively (P < 0.001). Median procedure time was 30 and 44.5 minutes for patients undergoing advanced image-guided percutaneous and advanced laparoscopic techniques, respectively (P < 0.001). Retrospective study with practice preference influenced by timing, local expertise, and resources. Both advanced image-guided percutaneous and advanced laparoscopic techniques reported rare major complications and demonstrated excellent (advanced laparoscopic) and acceptable (advanced image-guided percutaneous) 1-year PD catheter survival. For patients referred for PD catheter placement at centers where advanced laparoscopic resources or expertise remain limited, the advanced image-guided percutaneous technique can provide a complementary and timely option to support the utilization of PD. Peritoneal dialysis is a preferred dialysis modality for many patients. However, the lack of available skilled surgeons can limit the placement of the peritoneal dialysis catheter in a timely manner. In the past decade, interventional radiology has developed expertise in placing peritoneal dialysis catheters. Using data from an integrated health care system, we compared the outcome of peritoneal dialysis catheters placed using laparoscopic surgery and interventional radiology techniques. Our results showed excellent 1-year patency of peritoneal dialysis catheters placed using laparoscopic surgery, whereas interventional radiology placement of catheters had lower but acceptable 1-year patency survival, based on best practice guideline criteria. Hence, interventional radiology placement of peritoneal dialysis catheters may be a viable alternative when laparoscopic surgery is not available or feasible.
Authors: Zheng, Sijie;Drasin, Todd;Dybbro, Paul;Darbinian, Jeanne A;Armstrong, Mary Anne;Bhalla, Neelam M
Kidney Med. 2024 Jan;6(1):100744. Epub 2023-10-31.
Asthma exacerbations and eosinophilia in the UK Biobank: a genome-wide association study
Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10-6) in the GERA cohort. In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10-8) in the primary analysis, 116 signals were suggestively significant (p<5×10-6). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes. Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.
Authors: Edris, Ahmed;Voorhies, Kirsten;Lutz, Sharon M;Iribarren, Carlos;Hall, Ian;Wu, Ann Chen;Tobin, Martin;Fawcett, Katherine;Lahousse, Lies
ERJ Open Res. 2024 Jan;10(1). Epub 2024-01-08.
Nudging a Nation – The Danish NUDGE Trial Concept
Danish NUDGE Trial ConceptRandomized encouragement trials randomize to an opportunity to receive treatment instead of to the treatment. Here, Johansen and colleagues combine randomized encouragement trials with several advantages inherent in the Danish health system.
Authors: Johansen, Niklas Dyrby;Vaduganathan, Muthiah;Bhatt, Ankeet S;Biering-Sørensen, Tor
NEJM Evid. 2024 Jan;3(1):EVIDctw2300024. Epub 2023-12-26.
Effective medications can work only in patients who take them: implications for post acute heart failure care
Authors: Cotter, Gad;Ambrosy, Andrew P;Bhatt, Ankeet S;Bhatt, Deepak L;et al.
Eur J Heart Fail. 2024 Jan;26(1):1-4. Epub 2024-01-08.
Echocardiographic Outcomes With Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients
The CLASP IID randomized trial (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial; NCT03706833) demonstrated the safety and effectiveness of the PASCAL system for mitral transcatheter edge-to-edge repair (M-TEER) in patients at prohibitive surgical risk with significant symptomatic degenerative mitral regurgitation (DMR). This study describes the echocardiographic methods and outcomes from the CLASP IID trial and analyzes baseline variables associated with residual mitral regurgitation (MR) ≤1+. An independent echocardiographic core laboratory assessed echocardiographic parameters based on American Society of Echocardiography guidelines focusing on MR mechanism, severity, and feasibility of M-TEER. Factors associated with residual MR ≤1+ were identified using logistic regression. In 180 randomized patients, baseline echocardiographic parameters were well matched between the PASCAL (n = 117) and MitraClip (n = 63) groups, with flail leaflets present in 79.2% of patients. Baseline MR was 4+ in 76.4% and 3+ in 23.6% of patients. All patients achieved MR ≤2+ at discharge. The proportion of patients with MR ≤1+ was similar in both groups at discharge but diverged at 6 months, favoring PASCAL (83.7% vs 71.2%). Overall, patients with a smaller flail gap were significantly more likely to achieve MR ≤1+ at discharge (adjusted OR: 0.70; 95% CI: 0.50-0.99). Patients treated with PASCAL and those with a smaller flail gap were significantly more likely to sustain MR ≤1+ to 6 months (adjusted OR: 2.72 and 0.76; 95% CI: 1.08-6.89 and 0.60-0.98, respectively). The study used DMR-specific echocardiographic methodology for M-TEER reflecting current guidelines and advances in 3-dimensional echocardiography. Treatment with PASCAL and a smaller flail gap were significant factors in sustaining MR ≤1+ to 6 months. Results demonstrate that MR ≤1+ is an achievable benchmark for successful M-TEER. (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID]; NCT03706833).
Authors: Marcoff, Leo;Zaroff, Jonathan G;CLASP IID Pivotal Trial Investigators,;et al.
JACC Cardiovasc Imaging. 2023 Dec 01.
Electronically Delivered Nudges to Increase Influenza Vaccination Uptake in Older Adults With Diabetes: A Secondary Analysis of the NUDGE-FLU Trial
Influenza vaccination is associated with a reduced risk of mortality in patients with diabetes, but vaccination rates remain suboptimal. To assess the effect of electronic nudges on influenza vaccination uptake according to diabetes status. The NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) trial was a nationwide clinical trial of Danish citizens 65 years or older that randomized participants at the household level to usual care or 9 different electronic nudge letters during the 2022 to 2023 influenza season. End of follow-up was January 1, 2023. This secondary analysis of the NUDGE-FLU trial was performed from May to July 2023. Nine different electronic nudge letters designed to boost influenza vaccination were sent in September to October 2022. Effect modification by diabetes status was assessed in a pooled analysis of all intervention arms vs usual care and for individual letters. The primary end point was receipt of a seasonal influenza vaccine. The trial included 964 870 participants (51.5% female; mean [SD] age, 73.8 [6.3] years); 123 974 had diabetes. During follow-up, 83.5% with diabetes vs 80.2% without diabetes received a vaccine (P < .001). In the pooled analysis, nudges improved vaccination uptake in participants without diabetes (80.4% vs 80.0%; difference, 0.37 percentage points; 99.55% CI, 0.08 to 0.66), whereas there was no evidence of effect in those with diabetes (83.4% vs 83.6%; difference, -0.19 percentage points; 99.55% CI, -0.89 to 0.51) (P = .02 for interaction). In the main results of NUDGE-FLU, 2 of the 9 behaviorally designed letters (cardiovascular benefits letter and a repeated letter) significantly increased uptake of influenza vaccination vs usual care; these benefits similarly appeared attenuated in participants with diabetes (cardiovascular gain letter: 83.7% vs 83.6%; difference, 0.04 percentage points; 99.55% CI, -1.52 to 1.60; repeated letter: 83.5% vs 83.6%; difference, -0.15 percentage points; 99.55% CI, -1.71 to 1.41) vs those without diabetes (cardiovascular gain letter: 81.1% vs 80.0%; difference, 1.06 percentage points; 99.55% CI, 0.42 to 1.70; repeated letter: 80.9% vs 80.0%; difference, 0.87 percentage points; 99.55% CI, 0.22 to 1.52) (P = .07 for interaction). In this exploratory subgroup analysis, electronic nudges improved influenza vaccination uptake in persons without diabetes, whereas there was no evidence of an effect in persons with diabetes. Trials are needed to investigate the effect of digital nudges specifically tailored to individuals with diabetes. ClinicalTrials.gov Identifier: NCT05542004.
Authors: Lassen, Mats C Højbjerg;Bhatt, Ankeet S;Biering-Sørensen, Tor;et al.
JAMA Netw Open. 2023 Dec 01;6(12):e2347630. Epub 2023-12-01.
Fracture Risk and Association With TDF Use Among People With HIV in Large Integrated Health Systems
Greater decline in bone health among people with HIV (PWH) has been documented but fracture risk and the impact of specific antiretroviral therapy (ART) regimens remain unclear. Retrospective analyses of electronic health record data from 3 US integrated health care systems. Fracture incidence was compared between PWH aged 40 years or older without prior fracture and demographically matched people without HIV (PWoH), stratified by age, sex, and race/ethnicity. Multivariable Cox proportional hazards models were used to estimate fracture risk associated with HIV infection. The association of tenofovir disoproxil fumarate (TDF) use and fracture risk was evaluated in a subset of PWH initiating ART. Incidence of fracture was higher in PWH [13.6/1000 person-years, 95% confidence interval (CI): 13.0 to 14.3, n = 24,308] compared with PWoH (9.5, 95% CI: 9.4 to 9.7, n = 247,313). Compared with PWoH, the adjusted hazard ratio (aHR) for fracture among PWH was 1.24 (95% CI: 1.18 to 1.31). The association between HIV infection and fracture risk increased with age, with the lowest aHR (1.17, 95% CI: 1.10 to 1.25) among those aged 40-49 years and the highest aHR (1.89, 95% CI: 1.30 to 2.76) among those aged 70 years or older. Among PWH initiating ART (n = 6504), TDF was not associated with significant increase in fracture risk compared with non-TDF regimens (aHR: 1.18, 95% CI: 0.89 to 1.58). Among people aged 40 years or older, HIV infection is associated with increased risk of fractures. Bone health screening from the age of 40 years may be beneficial for PWH. Large cohort studies with longer follow-up are needed to evaluate TDF effect and the potential benefit of early screening.
Authors: Hechter, Rulin C;Lam, Jennifer O;Alexeeff, Stacey;Lo, Joan C;Silverberg, Michael J;Silverberg, Michael J;et al.
J Acquir Immune Defic Syndr. 2023 Dec 01;94(4):341-348.
Postpartum defects in inflammatory response after gestational diabetes precede progression to type 2 diabetes: a nested case-control study within the SWIFT study
Gestational diabetes (GDM) is a distinctive form of diabetes that first presents in pregnancy. While most women return to normoglycemia after delivery, they are nearly ten times more likely to develop type 2 diabetes than women with uncomplicated pregnancies. Current prevention strategies remain limited due to our incomplete understanding of the early underpinnings of progression. To comprehensively characterize the postpartum profiles of women shortly after a GDM pregnancy and identify key mechanisms responsible for the progression to overt type 2 diabetes using multi-dimensional approaches. We conducted a nested case-control study of 200 women from the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy (SWIFT) to examine biochemical, proteomic, metabolomic, and lipidomic profiles at 6-9 weeks postpartum (baseline) after a GDM pregnancy. At baseline and annually up to two years, SWIFT administered research 2-hour 75-gram oral glucose tolerance tests. Women who developed incident type 2 diabetes within four years of delivery (incident case group, n = 100) were pair-matched by age, race, and pre-pregnancy body mass index to those who remained free of diabetes for at least 8 years (control group, n = 100). Correlation analyses were used to assess and integrate relationships across profiling platforms. At baseline, all 200 women were free of diabetes. The case group was more likely to present with dysglycemia (e.g., impaired fasting glucose levels, glucose tolerance, or both). We also detected differences between groups across all omic platforms. Notably, protein profiles revealed an underlying inflammatory response with perturbations in protease inhibitors, coagulation components, extracellular matrix components, and lipoproteins, whereas metabolite and lipid profiles implicated disturbances in amino acids and triglycerides at individual and class levels with future progression. We identified significant correlations between profile features and fasting plasma insulin levels, but not with fasting glucose levels. Additionally, specific cross-omic relationships, particularly among proteins and lipids, were accentuated or activated in the case group but not the control group. Overall, we applied orthogonal, complementary profiling techniques to uncover an inflammatory response linked to elevated triglyceride levels shortly after a GDM pregnancy, which is more pronounced in women who progress to overt diabetes.
Authors: Van, Julie A D;Luo, Yihan;Danska, Jayne S;Dai, Feihan;Alexeeff, Stacey E;Gunderson, Erica P;Rost, Hannes;Wheeler, Michael B
Metabolism. 2023 Dec;149:155695. Epub 2023-10-05.
Impact of COVID-19 in Patients with Heart Failure with Mildly Reduced or Preserved Ejection Fraction Enrolled in the DELIVER Trial
COVID-19 may affect clinical risk in patients with heart failure. DELIVER began before and was conducted during the COVID-19 pandemic. This study aimed to evaluate the association between COVID-19 and clinical outcomes among DELIVER participants. Participants with chronic heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) were randomized to dapagliflozin or placebo across 350 sites in 20 countries. COVID-19 was investigator-reported and the contribution of COVID-19 to death was centrally adjudicated. We assessed (i) the incidence of COVID-19, (ii) event rates before/during the pandemic, and (iii) risks of death after COVID-19 diagnosis compared to risks of death in participants without COVID-19. Further, we performed a sensitivity analysis assessing treatment effects of dapagliflozin vs. placebo censored at pandemic onset. Of 6263 participants, 589 (9.4%) developed COVID-19, of whom 307 (52%) required/prolonged hospitalization. A total of 155 deaths (15% of all deaths) were adjudicated as definitely/possibly COVID-19-related. COVID-19 cases and deaths did not differ by randomized assignment. Death rate in the 12 months following diagnosis was 56.1 (95% confidence interval [CI] 48.0-65.6) versus 6.4 (95% CI 6.0-6.8)/100 participant-years among trial participants with versus without COVID-19 (adjusted hazard ratio [aHR] 8.60, 95% CI 7.18-10.30). Risk was highest 0-3 months following diagnosis (153.5, 95% CI 130.3-180.8) and remained elevated at 3-6 months (12.6, 95% CI 6.6-24.3/100 participant-years). After excluding investigator-reported fatal COVID-19 events, all-cause death rates in the 12 months following diagnosis among COVID-19 survivors (n = 458) remained higher (aHR 2.46, 95% CI 1.83-3.33) than rates for all trial participants from randomization, with censoring of participants who developed COVID-19 at the time of diagnosis. Dapagliflozin reduced cardiovascular death/worsening HF events when censoring participants at COVID-19 diagnosis (HR 0.81, 95% CI 0.72-0.91) and pandemic onset (HR 0.72, 95% CI 0.58-0.89). There were no diabetic ketoacidosis or major hypoglycaemic events within 30 days of COVID-19. DELIVER is one of the most extensive experiences with COVID-19 of any cardiovascular trial, with >75% of follow-up time occurring during the pandemic. COVID-19 was common, with >50% of cases leading to hospitalization or death. Treatment benefits of dapagliflozin persisted when censoring at COVID-19 diagnosis and pandemic onset. Patients surviving COVID-19 had a high early residual risk. ClinicalTrials.gov Identifier NCT03619213.
Authors: Bhatt, Ankeet S;Solomon, Scott D;et al.
Eur J Heart Fail. 2023 Dec;25(12):2177-2188. Epub 2023-10-09.
Stroke Characteristics and Outcomes in Urban Tanzania: Data from the Prospective Lake Zone Stroke Registry
Stroke is a second leading cause of death globally, with an estimated one in four adults suffering a stroke in their lifetime. We aimed to describe the clinical characteristics, quality of care and outcomes in adults with stroke in urban Northwestern Tanzania. We analyzed de-identified data from a prospective stroke registry from Bugando Medical Center in Mwanza, the second largest city in Tanzania, between March 2020 and October 2022. This registry included all adults ≥18 years admitted to our hospital who met the World Health Organization clinical definition of stroke. Information collected included: demographics, risk factors, stroke severity using the National Institutes of Health Stroke Scale, brain imaging, indicators for quality of care, discharge modified Rankin Scale, and in-hospital mortality. We examined independent factors associated with mortality using logistic regression. The cohort included 566 adults, of which 52% (294) were female with a mean age of 65±15 years. The majority had a first-ever stroke 88% (498). Premorbid hypertension was present in 86% (488) but only 41% (200) were taking antihypertensive medications before hospital admission; 6% (32) had HIV infection. Ischemic strokes accounted for 66% (371) but only 6% (22) arriving within 4.5hours of symptom onset. In-hospital mortality was 29% (127). Independent factors associated with mortality were: severe stroke (aOR 1.81, 95% CI: 1.47 – 2.24, p<0.001), moderate to severe stroke (aOR 1.49, 95% CI: 1.22 - 1.84, p<0.001), moderate stroke (aOR 1.80, 95% CI: 1.52 - 2.14, p<0.001), leukocytosis (aOR 1.19, 95% CI: 1.03 - 1.38, p=0.022), lack of health insurance coverage (aOR 1.15, 95% CI 1.02 - 1.29, p=0.025), and not receiving any form of venous thromboembolism prophylaxis (aOR 1.18, 95% CI 1.02 - 1.37, p=0.027). We report a stroke cohort with poor in-hospital outcomes in urban Northwestern Tanzania. Early diagnosis and treatment of hypertension could prevent stroke in this region. More work is needed to raise awareness about stroke symptoms and to ensure that people with stroke receive guidelines-directed therapy.
Authors: Matuja, Sarah Shali;Nguyen, Huynh Mai;Peck, Robert;et al.
Int J Stroke. 2023 Nov 30:17474930231219584.
Gaps in guideline-recommended anticoagulation in patients with atrial fibrillation and elevated thromboembolic risk within an integrated healthcare delivery system
Atrial Fibrillation (AF) is the leading cause of stroke, which can be reduced by 70% with appropriate oral anticoagulation (OAC) therapy. Nationally, appropriate anticoagulation rates for patients with AF with elevated thromboembolic risk are as low as 50% even across the highest stroke risk cohorts. This study aims to evaluate the variability of appropriate anticoagulation rates among patients by sex, ethnicity, and socioeconomic status within the Kaiser Permanente Mid-Atlantic States (KPMAS). This retrospective study investigated 9513 patients in KPMAS’s AF registry with CHADS2 score ≥ 2 over a 6-month period in 2021. Appropriately anticoagulated patients had higher rates of diabetes, prior stroke, and congestive heart failure than patients who were not appropriately anticoagulated. There were no significant differences in anticoagulation rates between males and females (71.8% vs. 71.6%%, [OR] 1.01; 95% CI, 0.93-1.11; P = .76) nor by SES-SVI quartiles. There was a statistically significant difference between Black and White patients (70.8% vs. 73.1%, P = .03) and Asian and White patients (68.3% vs. 71.6%, P = .005). After adjusting for CHADS2, this difference persisted for Black and White participants with CHADS2 scores of ≤3 (62.6% vs. 70.6%, P < .001) and for Asian and White participants with CHADS2 scores > 5 (68.0% vs. 79.3%, P < .001). Black and Asian patients may have differing rates of appropriate anticoagulation when compared with White patients. Characterizing such disparities is the first step towards addressing treatment gaps in AF.
Authors: Malik, Sushmita;Gustafson, Shanshan;Chang, Huai-En R;Tamrat, Yonas;Go, Alan S;Berry, Natalia
BMC Cardiovasc Disord. 2023 Nov 21;23(1):578. Epub 2023-11-21.
Cumulative BMI and incident prediabetes over 30 years of follow-up: The CARDIA study
This study examined how cumulative BMI (cBMI) is associated with incident prediabetes in a biracial observational cohort study followed from young adulthood to middle age. Black and White men and women (n = 4190) from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18 to 30 years in 1985 to 1986 and free of prediabetes or diabetes at baseline, were followed for 30 years. Cox regression was used to determine how cBMI was associated with incident prediabetes after controlling for traditional cardiovascular risk factors. Over 30 years of follow-up, 46.2% of the sample developed prediabetes. Mean cBMI was 801.4 BMI-years for those with prediabetes and 658.3 BMI-years for those without (p < 0.0001). After multivariable adjustment, the hazard rate ratio for the highest cBMI quartile was 2.064 (95% CI: 1.793-2.377) relative to the lowest quartile. The second and third quartiles did not differ from the first quartile, consistent with a nonlinear trend. The cumulative burden of higher weight and longer duration was associated with incident prediabetes, but this association was statistically significant only after a higher threshold was reached. Strategies for prevention of prediabetes in middle age may focus on avoiding overweight in young adulthood to limit duration.
Authors: Schreiner, Pamela J;Bae, Sejong;Allen, Norrina;Liu, Kiang;Reis, Jared P;Wu, Colin;Ingram, Katherine H;Lloyd-Jones, Donald;Lewis, Cora E;Rana, Jamal S
Obesity (Silver Spring). 2023 Nov;31(11):2845-2852. Epub 2023-09-15.
Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management
The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown. To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF. This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023. A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs. Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%). Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.
Authors: Bhatt, Ankeet S;Gaziano, Thomas A;et al.
JAMA Cardiol. 2023 Nov 01;8(11):1041-1048.
Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study
Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype. Prospective cohort study. A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study. Baseline plasma FGF23. Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF] ≥ 50%), HF with reduced EF (HFrEF, EF < 50%) and HF with unknown EF (HFuEF). Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF. During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events. Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes. Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N = 3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.
Authors: Leidner, Alexander S;Go, Alan S;Chronic Renal Insufficiency Cohort (CRIC) study investigators,;et al.
Kidney Med. 2023 Nov;5(11):100723. Epub 2023-09-15.
Proteomics of CKD progression in the chronic renal insufficiency cohort
Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression.
Authors: Dubin, Ruth F;Go, Alan S;Hsu, Chi-Yuan;CKD Biomarkers Consortium,;et al.
Nat Commun. 2023 Oct 10;14(1):6340. Epub 2023-10-10.
Developing Clinical Risk Prediction Models for Worsening Heart Failure Events and Death by Left Ventricular Ejection Fraction
Background There is a need to develop electronic health record-based predictive models for worsening heart failure (WHF) events across clinical settings and across the spectrum of left ventricular ejection fraction (LVEF). Methods and Results We studied adults with heart failure (HF) from 2011 to 2019 within an integrated health care delivery system. WHF encounters were ascertained using natural language processing and structured data. We conducted boosted decision tree ensemble models to predict 1-year hospitalizations, emergency department visits/observation stays, and outpatient encounters for WHF and all-cause death within each LVEF category: HF with reduced ejection fraction (EF) (LVEF <40%), HF with mildly reduced EF (LVEF 40%-49%), and HF with preserved EF (LVEF ≥50%). Model discrimination was evaluated using area under the curve and calibration using mean squared error. We identified 338 426 adults with HF: 61 045 (18.0%) had HF with reduced EF, 49 618 (14.7%) had HF with mildly reduced EF, and 227 763 (67.3%) had HF with preserved EF. The 1-year risks of any WHF event and death were, respectively, 22.3% and 13.0% for HF with reduced EF, 17.0% and 10.1% for HF with mildly reduced EF, and 16.3% and 10.3% for HF with preserved EF. The WHF model displayed an area under the curve of 0.76 and mean squared error of 0.13, whereas the model for death displayed an area under the curve of 0.83 and mean squared error of 0.076. Performance and predictors were similar across WHF encounter types and LVEF categories. Conclusions We developed risk prediction models for 1-year WHF events and death across the LVEF spectrum using structured and unstructured electronic health record data and observed no substantial differences in model performance or predictors except for death, despite differences in underlying HF cause.
Authors: Parikh, Rishi V;Bhatt, Ankeet S;Lee, Keane K;Sax, Dana R;Ambrosy, Andrew P;Ambrosy, Andrew P;et al.
J Am Heart Assoc. 2023 Oct 03;12(19):e029736. Epub 2023-09-30.
Web Exclusive. Annals On Call – Acute Kidney Injury and Chronic Kidney Disease Progression
Authors: Centor, Robert M;Hsu, Chi-Yuan;Muiru, Anthony N
Ann Intern Med. 2023 Oct;176(10):eA220020.
Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease: Secondary Analysis of a Randomized Clinical Trial
Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial. To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity. This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US. Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons. The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state. Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity. In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events. ClinicalTrials.gov Identifier: NCT02787044.
Authors: Hegde, Sheila M;Bhatt, Ankeet S;Vardeny, Orly;et al.
JAMA Netw Open. 2023 Sep 05;6(9):e2331284. Epub 2023-09-05.
Nationwide Utilization of Danish Government Electronic Letter System for Increasing InFLUenza Vaccine Uptake (NUDGE-FLU): Study Protocol for a Nationwide Randomized Implementation Trial
Annual influenza vaccination is widely recommended in older adults and other high-risk groups including patients with cardiovascular disease. The real-world effectiveness of influenza vaccination is limited by suboptimal uptake and effective strategies for increasing vaccination rates are therefore needed. The purpose of this trial is to investigate whether behavioral nudges digitally delivered via the Danish nationwide mandatory governmental electronic letter system can increase influenza vaccination uptake among older adults. The NUDGE-FLU trial is a randomized implementation trial randomizing all Danish citizens aged 65 years and above without an exemption from the Danish mandatory governmental electronic letter system to receive no digitally delivered behavioral nudge (usual care arm) or to receive one of 9 electronic letters (intervention arms) each leveraging different behavioral science strategies. The trial has randomized 964,870 participants with randomization clustered at the household level (n = 691,820 households). Intervention letters were delivered on September 16, 2022, and follow-up is currently ongoing. All trial data are captured using the nationwide Danish administrative health registries. The primary end point is the receipt of an influenza vaccine on or before January 1, 2023. The secondary end point is time to vaccination. Exploratory end points include clinical events such as hospitalization for influenza or pneumonia, cardiovascular events, all-cause hospitalization, and all-cause mortality. The nationwide randomized NUDGE-FLU trial is one of the largest implementation trials ever conducted and will provide important insights into effective communication strategies to maximize vaccination uptake among high-risk groups. Clinicaltrials.gov: NCT05542004, registered September 15, 2022, https://clinicaltrials.gov/ct2/show/NCT05542004.
Authors: Johansen, Niklas Dyrby; Bhatt, Ankeet S; Biering-Sørensen, Tor; et al.
Am Heart J. 2023 Jun;260:58-71. Epub 2023-02-17.
Joint Modeling of Clinical and Biomarker Data in Acute Kidney Injury Defines Unique Subphenotypes with Differing Outcomes
AKI is a heterogeneous syndrome. Current subphenotyping approaches have only used limited laboratory data to understand a much more complex condition. We focused on patients with AKI from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI). We used hierarchical clustering with Ward linkage on biomarkers of inflammation, injury, and repair/health. We then evaluated clinical differences between subphenotypes and examined their associations with cardiorenal events and death using Cox proportional hazard models. We included 748 patients with AKI: 543 (73%) of them had AKI stage 1, 112 (15%) had AKI stage 2, and 93 (12%) had AKI stage 3. The mean age (±SD) was 64 (13) years; 508 (68%) were men; and the median follow-up was 4.7 (Q1: 2.9, Q3: 5.7) years. Patients with AKI subphenotype 1 ( N =181) had the highest kidney injury molecule (KIM-1) and troponin T levels. Subphenotype 2 ( N =250) had the highest levels of uromodulin. AKI subphenotype 3 ( N =159) comprised patients with markedly high pro-brain natriuretic peptide and plasma tumor necrosis factor receptor-1 and -2 and low concentrations of KIM-1 and neutrophil gelatinase-associated lipocalin. Finally, patients with subphenotype 4 ( N =158) predominantly had sepsis-AKI and the highest levels of vascular/kidney inflammation (YKL-40, MCP-1) and injury (neutrophil gelatinase-associated lipocalin, KIM-1). AKI subphenotypes 3 and 4 were independently associated with a higher risk of death compared with subphenotype 2 and had adjusted hazard ratios of 2.9 (95% confidence interval, 1.8 to 4.6) and 1.6 (95% confidence interval, 1.01 to 2.6, P = 0.04), respectively. Subphenotype 3 was also independently associated with a three-fold risk of CKD and cardiovascular events. We discovered four AKI subphenotypes with differing clinical features and biomarker profiles that are associated with longitudinal clinical outcomes.
Authors: Vasquez-Rios, George;Go, Alan S;Nadkarni, Girish N;et al.
Clin J Am Soc Nephrol. 2023 Jun 01;18(6):716-726. Epub 2023-03-28.
Longitudinal biomarkers and kidney disease progression after acute kidney injury
BACKGROUNDLongitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI.METHODSIn a prospective cohort of 656 participants hospitalized with AKI, we measured 7 urine and 2 plasma biomarkers of kidney injury, inflammation, and tubular health at multiple time points from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and we used Cox proportional hazard regressions to determine their associations with a composite outcome of chronic kidney disease (CKD) incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI).RESULTSAfter 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each SD increase in the change of urine KIM-1, MCP-1, and plasma TNFR1 from baseline to 12 months was associated with 2- to 3-fold increased risk for CKD, while the increase in urine uromodulin was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI.CONCLUSIONSustained tissue injury and inflammation, and slower restoration of tubular health, are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help researchers understand and prevent the AKI-to-CKD transition.FUNDINGNIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).
Authors: Wen, Yumeng; Go, Alan S; Parikh, Chirag R; et al.
JCI Insight. 2023 May 08;8(9). Epub 2023-05-08.
Analytical and Biological Variability of a Commercial Modified Aptamer Assay in Plasma Samples of Patients with Chronic Kidney Disease
We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD). Plasma samples were selected from 2 sources: (a) 24 participants from the Chronic Renal Insufficiency Cohort (CRIC) and (b) 49 patients from the Brigham and Women’s Hospital-Kidney/Renal Clinic. We calculated intra-assay variability from both sources and examined short-term biological variability in samples from the Brigham clinic. We also measured correlations of aptamer measurements with traditional biomarker assays. A total of 4656 unique proteins (4849 total aptamer measures) were analyzed in all samples. Median (interquartile range [IQR] intra-assay CV) was 3.7% (2.8-5.3) in CRIC and 5.0% (3.8-7.0) in Brigham samples. Median (IQR) biological CV among Brigham samples drawn from one individual on 2 occasions separated by median (IQR) 7 (4-14) days was 8.7% (6.2-14). CVs were independent of CKD stage, diabetes, or albuminuria but were higher in patients with systemic lupus erythematosus. Rho correlations between aptamer and traditional assays for biomarkers of interest were cystatin C = 0.942, kidney injury model-1 = 0.905, fibroblast growth factor-23 = 0.541, tumor necrosis factor receptors 1 = 0.781 and 2 = 0.843, P < 10-100 for all. Intra-assay and within-subject variability for SomaScan in the CKD setting was low and similar to assay variability reported from individuals without CKD. Intra-assay precision was excellent whether samples were collected in an optimal research protocol, as were CRIC samples, or in the clinical setting, as were the Brigham samples.
Authors: Dubin, Ruth F; Go, Alan S; Ganz, Peter; et al.
J Appl Lab Med. 2023 May 04;8(3):491-503.
The Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: a Prespecified Analysis of the NUDGE-FLU Trial
Influenza vaccines have been demonstrated to effectively reduce the incidence of influenza infection and potentially associated risks of cardiovascular events in patients with cardiovascular disease (CVD). Despite strong guideline and public health endorsements, global influenza vaccination rates in patients with CVD are highly variable. This prespecified analysis of NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) examined the effect of digital behavioral nudges on influenza vaccine uptake based on the presence of CVD. NUDGE-FLU was a randomized, pragmatic, nationwide, register-based trial that included Danish citizens 65 years of age or older during the 2022 to 2023 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 electronic letters with designs based on behavioral concepts. Danish nationwide registers were used to collect baseline and outcome data. The primary end point was receipt of an influenza vaccine on or before January 1, 2023. The effects of the intervention letters were examined according to the presence of CVD and across cardiovascular subgroups that included heart failure, ischemic heart disease, and atrial fibrillation. Of 964 870 NUDGE-FLU participants from 691 820 households, 264 392 (27.4%) had CVD. During follow-up, 83.1% of participants with CVD versus 79.2% of participants without CVD received an influenza vaccination (P<0.001). Compared with usual care, a letter emphasizing the potential cardiovascular benefits of influenza vaccination increased vaccination rates; this effect was consistent in participants with CVD (absolute difference, +0.60 percentage points [99.55% CI, -0.48 to 1.68]) and without CVD (+0.98 percentage points [99.55% CI, 0.27-1.70; P for interaction=0.41). A repeated letter strategy with a reminder follow-up letter 14 days later was also effective in increasing influenza vaccination, irrespective of CVD (CVD: absolute difference, +0.80 percentage points [99.55% CI, -0.27 to 1.86]; no CVD: +0.67 percentage points [99.55% CI, -0.06 to 1.40]; P for interaction=0.77). Effectiveness of both nudging strategies was consistent across all major CVD subgroups. None of the other 7 nudging strategies were effective, regardless of CVD status. Electronic letter interventions emphasizing the potential cardiovascular benefits of influenza vaccination and using a reminder letter strategy were similarly beneficial in increasing influenza vaccination rates among older adults with and without CVD and across cardiovascular subgroups. Electronic nudges may improve influenza vaccine uptake in individuals with CVD. URL: https://www. gov; Unique identifier: NCT05542004.
Authors: Modin, Daniel; Bhatt, Ankeet S; Biering-Sørensen, Tor; et al.
Circulation. 2023 May 02;147(18):1345-1354. Epub 2023-03-05.
Virtual Care Team-Guided Therapeutic Optimization During Hospitalization in Patients with Heart Failure: The IMPLEMENT-HF Study
Scalable and safe approaches for heart failure guideline-directed medical therapy (GDMT) optimization are needed. The authors assessed the safety and effectiveness of a virtual care team guided strategy on GDMT optimization in hospitalized patients with heart failure with reduced ejection fraction (HFrEF). In a multicenter implementation trial, we allocated 252 hospital encounters in patients with left ventricular ejection fraction ≤40% to a virtual care team guided strategy (107 encounters among 83 patients) or usual care (145 encounters among 115 patients) across 3 centers in an integrated health system. In the virtual care team group, clinicians received up to 1 daily GDMT optimization suggestion from a physician-pharmacist team. The primary effectiveness outcome was in-hospital change in GDMT optimization score (+2 initiations, +1 dose up-titrations, -1 dose down-titrations, -2 discontinuations summed across classes). In-hospital safety outcomes were adjudicated by an independent clinical events committee. Among 252 encounters, the mean age was 69 ± 14 years, 85 (34%) were women, 35 (14%) were Black, and 43 (17%) were Hispanic. The virtual care team strategy significantly improved GDMT optimization scores vs usual care (adjusted difference: +1.2; 95% CI: 0.7-1.8; P < 0.001). New initiations (44% vs 23%; absolute difference: +21%; P = 0.001) and net intensifications (44% vs 24%; absolute difference: +20%; P = 0.002) during hospitalization were higher in the virtual care team group, translating to a number needed to intervene of 5 encounters. Overall, 23 (21%) in the virtual care team group and 40 (28%) in usual care experienced 1 or more adverse events (P = 0.30). Acute kidney injury, bradycardia, hypotension, hyperkalemia, and hospital length of stay were similar between groups. Among patients hospitalized with HFrEF, a virtual care team guided strategy for GDMT optimization was safe and improved GDMT across multiple hospitals in an integrated health system. Virtual teams represent a centralized and scalable approach to optimize GDMT.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah; et al.
J Am Coll Cardiol. 2023 May 02;81(17):1680-1693. Epub 2023-03-06.
Approach to Multimorbidity Burden Classification and Outcomes in Older Adults With Heart Failure
The optimal approach to classifying multimorbidity burden in assessing treatment-associated outcomes using real-world data remains uncertain. We assessed whether 2 measurement approaches to characterize multimorbidity influenced observed associations of β-blocker use with outcomes in adults with heart failure (HF). We conducted a retrospective study on adults with HF from 4 integrated health care delivery systems. Multimorbidity burden was characterized by either (1) simple counts of chronic conditions or (2) a weighted multiple chronic conditions score using data from electronic health records. We assessed the impact of these 2 approaches to characterizing multimorbidity on associations between exposure to β-blockers and subsequent all-cause death, hospitalization for HF, and hospitalization for any cause. The study population characterized by a count of chronic conditions included 9988 adults with HF who had a mean (SD) age of 76.4 (12.5) years, with 48.7% women and 24.7% racial/ethnic minorities. The cohort characterized by weighted multiple chronic conditions included 10,082 adults with HF who had a mean (SD) age of 76.4 (12.4) years, 48.9% women, and 25.5% racial/ethnic minorities. The multivariable associations of risks of death or hospitalizations for HF or for any cause associated with incident β-blocker use were similar regardless of how multimorbidity burden was characterized. Simple counts of chronic conditions performed similarly to a weighted multimorbidity score in predicting outcomes using real-world data to examine clinical outcomes associated with β-blocker therapy in HF. Our findings challenge conventional wisdom that more complex measures of multimorbidity are always necessary to characterize patients in observational studies examining therapy-associated outcomes.
Authors: Tisminetzky, Mayra; Gurwitz, Jerry H; Tabada, Grace; Reynolds, Kristi; Smith, David H; Sung, Sue Hee; Goldberg, Robert; Go, Alan S
Med Care. 2023 May 01;61(5):268-278. Epub 2023-03-15.
Novel genetic variants associated with inhaled corticosteroid treatment response in older adults with asthma
Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults. A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases. In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10-5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome. Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.
Authors: Wang, Alberta L; Iribarren, Carlos; Wu, Ann C; et al.
Thorax. 2023 May;78(5):432-441. Epub 2022-05-02.
Changes in Diet Quality, Risk of CKD Progression, and All-Cause Mortality in the CRIC Study
Authors: Sullivan, Valerie K;Hsu, Chi-Yuan;CRIC Study Investigators,;et al.
Am J Kidney Dis. 2023 May;81(5):621-624. Epub 2022-11-29.
Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis
There is considerable variability in the effect of intravenous iron on hard cardiovascular (CV)-related outcomes in patients with heart failure (HF) in randomized controlled trials (RCTs). We use a meta-analytic approach to analyse data from existing RCTs to derive a more robust estimate of the effect size of intravenous iron infusion on CV-related outcomes in patients with HF. PubMed/Medline was searched using the following terms: (‘intravenous’ and ‘iron’ and ‘heart failure’) from inception till 6 November 2022 for RCTs comparing intravenous iron infusion with placebo or standard of care in patients with HF and iron deficiency. Outcomes were the composite of CV mortality and first hospitalization for HF; all-cause mortality; CV mortality; first hospitalization for HF; and total hospitalizations for HF. Random effects risk ratio (RR) with 95% confidence intervals (CIs) were calculated. Ten RCTs with a total of 3438 patients were included. Intravenous iron resulted in a significant reduction in the composite of CV mortality and first hospitalization for HF [RR 0.0.85; 95% CI (0.77, 0.95)], first hospitalization for HF [RR 0.82; 95% CI (0.67, 0.99)], and total hospitalizations for HF [RR 0.74; 95% CI (0.60, 0.91)] but no statistically significant difference in all-cause mortality [RR 0.95; 95% CI. (0.83, 1.09)] or CV mortality [OR 0.89; 95% CI (0.75, 1.05)]. Intravenous iron infusion in patients with HF reduces the composite risk of first hospitalization for HF and CV mortality as well as the risks of first and recurrent hospitalizations for HF, with no effect on all-cause mortality or CV mortality alone.
Authors: Salah, Husam M; Savarese, Gianluigi; Rosano, Giuseppe M C; Ambrosy, Andrew P; Mentz, Robert J; Fudim, Marat
ESC Heart Fail. 2023 Apr;10(2):1473-1480. Epub 2023-02-02.
Association Between Serum Albumin and Outcomes in Heart Failure and Secondary Mitral Regurgitation: The COAPT Trial
Low serum albumin levels are associated with poor prognosis in numerous chronic disease states but the relationship between albumin and outcomes in patients with heart failure (HF) and secondary mitral regurgitation (SMR) has not been described. The randomized COAPT trial evaluated the safety and effectiveness of transcatheter edge-to-edge repair (TEER) with the MitraClipTM plus guideline-directed medical therapy (GDMT) versus GDMT alone in patients with symptomatic HF and moderate-to-severe or severe SMR. Baseline serum albumin levels were measured at enrolment. Among 614 patients enrolled in COAPT, 559 (91.0%) had available baseline serum albumin levels (median 4.0 g/dl, interquartile range 3.7-4.2 g/dl). Patients with albumin <4.0 g/dl compared with ≥4.0 g/dl were older and more likely to have ischaemic cardiomyopathy and a hospitalization within the year prior to enrolment. After multivariable adjustment, patients with albumin <4.0 g/dl had higher 4-year rates of all-cause death (63.7% vs. 47.6%; adjusted hazard ratio 1.34, 95% confidence interval 1.02-1.74; p = 0.032), but there were no significant differences in HF hospitalizations (HFH) or all-cause hospitalizations according to baseline serum albumin level. The relative effectiveness of TEER plus GDMT versus GDMT alone was consistent in patients with low and high albumin levels (pinteraction = 0.19 and 0.35 for death and HFH, respectively). Low baseline serum albumin levels were independently associated with reduced 4-year survival in patients with HF and severe SMR enrolled in the COAPT trial, but not with HFH. Patients treated with TEER derived similarly robust reductions in both death and HFH regardless of baseline albumin level.
Authors: Feng, Kent Y; Ambrosy, Andrew P; Zaroff, Jonathan G; COAPT trial investigators,; et al.
Eur J Heart Fail. 2023 Apr;25(4):553-561. Epub 2023-03-07.
Multi-Marker Risk Assessment in Patients Hospitalized with COVID-19: Results from the American Heart Association COVID-19 Cardiovascular Disease Registry
The pathobiology of inflammation, thrombosis, and myocardial injury associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may be assessed by circulating biomarkers. However, their relative prognostic importance has been incompletely described. We analyzed data from patients hospitalized with COVID-19 from January 2020, to April 2021, at 122 US hospitals in the American Heart Association (AHA) COVID-19 cardiovascular (CV) disease registry. Patients with data for D-dimer, C-reactive protein (CRP), ferritin, natriuretic peptides [NP], or cardiac troponin (cTn) at admission were included. cTn quintiles were indexed to the assay-specific 99th percentile reference limits. Using multivariable logistic regression, we assessed the association between each biomarker by quintile [Q] and odds of in-hospital death and a cardiovascular and thrombotic composite outcome. Of 32,636 registry patients, 26,424 (81%) had admission values for ≥1 of the key biomarkers, of which 4,527 (17%) had admission values for all 5 biomarkers. Each biomarker revealed a significant gradient for in-hospital mortality from Q1 to Q5: D-dimer 14% to 35%, CRP 11%-32%, ferritin 11% to 30%, cTn 13% to 43%, and NPs 7% to 35% (Ptrend for each <.001). After adjustment for other biomarkers and clinical variables, Q5 for NPs (OR:4.67, 95% CI: 3.05-7.14) retained the greatest relative odds for death; cTn (OR:2.68, 95% CI: 2.00-3.59) and NPs (OR:7.14, 95% CI: 4.92-10.37) were associated with the greatest odds of the CV composite. Q5 for D-dimer was associated with the highest risk of thrombotic events (OR: 9.02, 95% CI: 5.36-15.18). Among patients hospitalized with COVID-19, cTn and NPs identified patients at high risk for an in-hospital adverse cardiovascular outcome, while elevations in D-dimer identified patients at risk for thrombotic complications.
Authors: Bhatt, Ankeet S; Daniels, Lori B; de Lemos, James; Goodrich, Erica; Bohula, Erin A; Morrow, David A
Am Heart J. 2023 Apr;258:149-156. Epub 2023-01-18.
Electronic nudges to increase influenza vaccination uptake in Denmark: a nationwide, pragmatic, registry-based, randomised implementation trial
Influenza vaccination rates remain suboptimal despite effectiveness in preventing influenza infection and related complications. We investigated whether behavioural nudges, delivered via a governmental electronic letter system, would increase influenza vaccination uptake among older adults in Denmark. We did a nationwide, pragmatic, registry-based, cluster-randomised implementation trial during the 2022-23 influenza season in Denmark. All Danish citizens aged 65 years or older or turning 65 years by Jan 15, 2023 were included. We excluded individuals living in nursing homes and individuals who had an exemption from the Danish mandatory governmental electronic letter system. Households were randomly assigned (9:1:1:1:1:1:1:1:1:1) to usual care or nine different electronic letters designed on the basis of different behavioural nudging concepts. Data were sourced from nationwide Danish administrative health registries. The primary endpoint was receipt of influenza vaccination on or before Jan 1, 2023. The primary analysis assessed an analytical set of one randomly selected individual per household, and a sensitivity analysis included all randomly assigned individuals and accounted for within-household correlation. The trial is registered with ClinicalTrials.gov, NCT05542004. We identified 1 232 938 individuals aged 65 years or older in Denmark and excluded 56 436 (4·6%) individuals living in nursing homes and 211 632 (17·2%) with an exemption from the electronic letter system. We randomly assigned 964 870 (78·3%) participants across 691 820 households. Compared with usual care, influenza vaccination rates were higher in the group receiving an electronic letter highlighting potential cardiovascular benefits of vaccination (81·00% vs 80·12%; difference 0·89 percentage points [99·55% CI 0·29-1·48]; p<0·0001) and the group receiving repeated letters at randomisation and at day 14 (80·85% vs 80·12%; difference 0·73 percentage points [0·13-1·34]; p=0·0006). These strategies improved vaccination rates across major subgroups including those with and without established cardiovascular disease. The cardiovascular gain-framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season (pinteraction=0·0002). A sensitivity analysis of all randomly assigned individuals accounting for within-household clustering yielded similar findings. Electronically delivered letters highlighting potential cardiovascular benefits of influenza vaccination or sent again as a reminder significantly increased vaccination uptake across Denmark. Although the magnitude of effectiveness was modest, the low-touch, inexpensive, and highly scalable nature of these electronic letters might be informative for future public health campaigns. Sanofi.
Authors: Johansen, Niklas Dyrby; Bhatt, Ankeet S; Biering-Sørensen, Tor; et al.
Lancet. 2023 Apr 01;401(10382):1103-1114. Epub 2023-03-05.
Identification of Recurrent Atrial Fibrillation using Natural Language Processing Applied to Electronic Health Records
This study aimed to develop and apply natural language processing (NLP) algorithms to identify recurrent atrial fibrillation (AF) episodes following rhythm control therapy initiation using electronic health records (EHR). We included adults with new-onset AF who initiated rhythm control therapies (ablation, cardioversion, or antiarrhythmic medication) within two U.S. integrated healthcare delivery systems. A code-based algorithm identified potential AF recurrence using diagnosis and procedure codes. An automated NLP algorithm was developed and validated to capture AF recurrence from electrocardiograms, cardiac monitor reports, and clinical notes. Compared with the reference standard cases confirmed by physicians’ adjudication, the F-scores, sensitivity, and specificity were all above 0.90 for the NLP algorithms at both sites. We applied the NLP and code-based algorithms to patients with incident AF (n = 22, 970) during the 12 months after initiating rhythm control therapy. Applying the NLP algorithms, the percentages of patients with AF recurrence for sites 1 and 2 were 60.7% and 69.9% (ablation), 64.5% and 73.7% (cardioversion), and 49.6% and 55.5% (antiarrhythmic medication), respectively. In comparison, the percentages of patients with code-identified AF recurrence for sites 1 and 2 were 20.2% and 23.7% for ablation, 25.6% and 28.4% for cardioversion, and 20.0% and 27.5% for antiarrhythmic medication, respectively. When compared to a code-based approach alone, this study’s high-performing automated NLP method identified significantly more patients with recurrent AF. The NLP algorithms could enable efficient evaluation of treatment effectiveness of AF therapies in large populations and help develop tailored interventions.
Authors: Zheng, Chengyi; Go, Alan S; An, Jaejin; et al.
Eur Heart J Qual Care Clin Outcomes. 2023 Mar 30.
Development of cardiometabolic risk factors following endocrine therapy in women with breast cancer
Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone-receptor positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone-receptor positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. In 8,985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR: 1.43, 95% CI: 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR: 1.37, 95% CI: 1.05-1.80), dyslipidemia (HR: 1.58, 95% CI: 1.29-1.92) and hypertension (HR: 1.50, 95% CI: 1.24-1.82) compared with non-endocrine therapy users. Hormone-receptor positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.
Authors: Rillamas-Sun, Eileen; Kwan, Marilyn L; Iribarren, Carlos; Neugebauer, Romain; Rana, Jamal S; Nguyen-Huynh, Mai; Kushi, Lawrence H; Greenlee, Heather; et al.
Res Sq. 2023 Mar 22.
Incident Atrial Fibrillation and Risk of Dementia in a Diverse, Community-Based Population
Background Atrial fibrillation (AF) is the most common, clinically relevant arrhythmia in adults and associated with ischemic stroke and premature death. However, data are conflicting on whether AF is independently associated with risk of dementia, particularly in diverse populations. Methods and Results We identified all adults from 2 large integrated health care delivery systems between 2010 and 2017 and performed a 1:1 match of incident AF: no AF by age at index date, sex, estimated glomerular filtration rate category, and study site. Subsequent dementia was identified through previously validated diagnosis codes. Fine-Gray subdistribution hazard models were used to examine the association of incident AF (versus no AF) with risk of incident dementia, adjusting for sociodemographics and comorbidity and accounting for competing risk of death. Subgroup analyses by age, sex, race, ethnicity, and chronic kidney disease status were also performed. Among 196 968 matched adults, mean (SD) age was 73.6 (11.3) years, with 44.8% women, and 72.3% White. Incidence rates (per 100 person-years) for dementia over a median follow-up of 3.3 (interquartile range, 1.7-5.4) years were 2.79 (95% CI, 2.72-2.85) and 2.04 (95% CI, 1.99-2.08) per 100 person-years in persons with versus without incident AF, respectively. In adjusted models, incident AF was associated with a significantly greater risk of diagnosed dementia (subdistribution hazard ratio [sHR], 1.13 [95% CI, 1.09-1.16]). With additional adjustment for interim stroke events, the association of incident AF with dementia remained statistically significant (sHR, 1.10 [95% CI, 1.07-1.15]). Associations were stronger for age <65 (sHR, 1.65 [95% CI, 1.29-2.12]) versus ≥65 (sHR, 1.07 [95% CI, 1.03-1.10]) years (interaction P<0.001); and those without (sHR, 1.20 [95% CI, 1.14-1.26]) versus with chronic kidney disease (sHR, 1.06 [95% CI, 1.01-1.11]; interaction P<0.001). No meaningful differences were seen by sex, race, or ethnicity. Conclusions In a large, diverse community-based cohort, incident AF was associated with a modestly increased risk of dementia that was more prominent in younger patients and those without chronic kidney disease but did not substantially vary across sex, race, or ethnicity. Further studies should delineate mechanisms underpinning these findings, which may inform use of AF therapies.
Authors: Bansal, Nisha; Zelnick, Leila R; An, Jaejin; Harrison, Teresa N; Lee, Ming-Sum; Singer, Daniel E; Fan, Dongjie; Go, Alan S
J Am Heart Assoc. 2023 Mar 21;12(6):e028290. Epub 2023-03-08.
Cardiac Structure and Function and Subsequent Kidney Disease Progression in Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study
The heart-kidney crosstalk is recognized as the cardiorenal syndrome. We examined the association of cardiac function and structure with the risk of kidney failure with replacement therapy (KFRT) in a chronic kidney disease (CKD) population. Prospective observational cohort study. 3,027 participants from the Chronic Renal Insufficiency Cohort Study. Five pre-selected variables that assess different aspects of cardiac structure and function: left ventricular mass index (LVMI), LV volume, left atrial (LA) area, peak tricuspid regurgitation (TR) velocity, and left ventricular ejection fraction (EF) as assessed by echocardiography. Incident KFRT (primary outcome), and annual eGFR slope (secondary outcome). Multivariable Cox models and mixed-effects models. Mean age was 59 (SD 11) years, 54% were men, and mean eGFR was 43 (17) ml/min/1.73m2. Between 2003 and 2018 (median follow-up, 9.9 years), 883 participants developed KFRT. Higher LVMI, LV volume, LA area, peak TR velocity, and lower EF were each statistically significantly associated with an increased risk of KFRT, with corresponding HRs for the highest vs. lowest quartiles (lowest vs. highest for EF) of 1.70 (95%CI, 1.27 to 2.26), 1.50 (1.19 to 1.90), 1.43 (1.11 to 1.84), 1.45 (1.06 to 1.96), and 1.26 (1.03 to 1.56), respectively. For secondary outcome, participants in the highest vs. lowest quartiles (lowest vs. highest for EF) had a statistically significantly faster eGFR decline, except for LA area (ΔeGFR slope per year, -0.57 [95%CI, -0.68 to -0.46] mL/min/1.73m2 for LVMI, -0.25 [-0.35 to -0.15] mL/min/1.73m2 for LV volume, -0.01 [-0.12 to -0.01] mL/min/1.73m2 for LA area, -0.42 [-0.56 to -0.28] mL/min/1.73m2 for peak TR velocity, and -0.11 [-0.20 to -0.01] mL/min/1.73m2 for EF, respectively). The possibility of residual confounding. Multiple aspects of cardiac structure and function were statistically significantly associated with the risk of KFRT. These findings suggest that cardiac abnormalities and incidence of KFRT are potentially on the same causal pathway related to the interaction between hypertension, heart failure, and coronary artery diseases.
Authors: Ishigami, Junichi; Go, Alan S; CRIC Study investigators,; et al.
Am J Kidney Dis. 2023 Mar 17.
Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus
Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.
Authors: Mathieson, Iain; Gunderson, Erica P; Perry, John R B; et al.
Nat Hum Behav. 2023 Mar 02.
Association of Kidney Function With Risk of Adverse Effects of Therapies for Atrial Fibrillation
Atrial fibrillation (AF) is common in chronic kidney disease (CKD) and is treated with rate control medications, antiarrhythmic medications, as well as anticoagulation and procedures, each of which have associated risks. We aimed to evaluate the association of CKD status with the risks of adverse effects after initiation of AF therapies. This was a cohort study of community-based adults who newly initiated rate control medications, antiarrhythmic medications, warfarin, direct oral anticoagulants (DOACs) or received AF procedures in the 1 year after diagnosis of AF. Baseline estimated glomerular filtration rate (eGFR) was calculated using outpatient serum creatinine measures. Adverse effects within 1 year related to each AF therapy or within 1 month of an AF procedure were ascertained from vital sign databases, electrocardiograms (ECGs), and administrative codes. Fine-Gray hazard models were used to study the association of eGFR categories with risk of adverse effects for each AF therapy. Among 115,564 patients with incident AF, lower eGFR (vs. eGFR ≥60 ml/min per 1.73 m2) was significantly associated with higher adjusted risk of adverse effects after initiation of rate control therapies (most commonly hypotension and bradycardia) as follows: eGFR 45-59 (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.07-1.22), 30-44 (HR 1.15, 95% CI 1.06-1.25), and 15-29 (HR 1.29, 95% CI: 1.12-1.47) ml/min per 1.73 m2. Lower eGFR was associated with higher adjusted risk of adverse effects (most commonly prolonged QRS and QTc intervals) after initiation of an antiarrhythmic medication (vs. eGFR >60 ml/min per 1.73 m2) as follows: eGFR 45-59 (HR 1.12, 95% CI 1.01-1.23) and eGFR<15 (HR 1.43, 95% CI 1.01-2.01) ml/min per 1.73 m2. There was a graded association between lower eGFR and risk of major bleeding with warfarin use, with the greatest risk among those with eGFR <15 ml/min per 1.73 m2 (HR of 2.93, 95% CI 1.99-4.30). There was no association of eGFR with major bleeding in patients receiving DOACs. Rates of adverse effects within 1 month of an AF procedure were low among patients with (n = 18) and without (n = 41) CKD and was underpowered for further analyses. In conclusion, lower eGFR was associated with significantly higher risks of adverse effects after initiation of commonly used therapies to treat AF. These data may help inform the complex therapeutic decisions in patients with CKD and AF.
Authors: Bansal, Nisha; Zelnick, Leila R; An, Jaejin; Harrison, Teresa N; Lee, Ming-Sum; Singer, Daniel E; Sung, Sue Hee; Fan, Dongjie; Go, Alan S
Kidney Int Rep. 2023 Mar;8(3):606-618. Epub 2022-12-13.
Assessment of the Risk of Venous Thromboembolism in Nonhospitalized Patients With COVID-19
Patients hospitalized with COVID-19 have higher rates of venous thromboembolism (VTE), but the risk and predictors of VTE among individuals with less severe COVID-19 managed in outpatient settings are less well understood. To assess the risk of VTE among outpatients with COVID-19 and identify independent predictors of VTE. A retrospective cohort study was conducted at 2 integrated health care delivery systems in Northern and Southern California. Data for this study were obtained from the Kaiser Permanente Virtual Data Warehouse and electronic health records. Participants included nonhospitalized adults aged 18 years or older with COVID-19 diagnosed between January 1, 2020, and January 31, 2021, with follow-up through February 28, 2021. Patient demographic and clinical characteristics identified from integrated electronic health records. The primary outcome was the rate per 100 person-years of diagnosed VTE, which was identified using an algorithm based on encounter diagnosis codes and natural language processing. Multivariable regression using a Fine-Gray subdistribution hazard model was used to identify variables independently associated with VTE risk. Multiple imputation was used to address missing data. A total of 398 530 outpatients with COVID-19 were identified. The mean (SD) age was 43.8 (15.8) years, 53.7% were women, and 54.3% were of self-reported Hispanic ethnicity. There were 292 (0.1%) VTE events identified over the follow-up period, for an overall rate of 0.26 (95% CI, 0.24-0.30) per 100 person-years. The sharpest increase in VTE risk was observed during the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% CI, 0.51-0.67 per 100 person-years vs 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days). In multivariable models, the following variables were associated with a higher risk for VTE in the setting of nonhospitalized COVID-19: age 55 to 64 years (HR 1.85 [95% CI, 1.26-2.72]), 65 to 74 years (3.43 [95% CI, 2.18-5.39]), 75 to 84 years (5.46 [95% CI, 3.20-9.34]), greater than or equal to 85 years (6.51 [95% CI, 3.05-13.86]), male gender (1.49 [95% CI, 1.15-1.96]), prior VTE (7.49 [95% CI, 4.29-13.07]), thrombophilia (2.52 [95% CI, 1.04-6.14]), inflammatory bowel disease (2.43 [95% CI, 1.02-5.80]), body mass index 30.0-39.9 (1.57 [95% CI, 1.06-2.34]), and body mass index greater than or equal to 40.0 (3.07 [1.95-4.83]). In this cohort study of outpatients with COVID-19, the absolute risk of VTE was low. Several patient-level factors were associated with higher VTE risk; these findings may help identify subsets of patients with COVID-19 who may benefit from more intensive surveillance or VTE preventive strategies.
Authors: Fang, Margaret C; Reynolds, Kristi; Tabada, Grace H; Prasad, Priya A; Sung, Sue Hee; Parks, Anna L; Garcia, Elisha; Portugal, Cecilia; Fan, Dongjie; Pai, Ashok P; Go, Alan S
JAMA Netw Open. 2023 Mar 01;6(3):e232338. Epub 2023-03-01.
Predictors of Incident Heart Failure Diagnosis Setting: Insights From the Veterans Affairs Healthcare System
Early recognition of heart failure (HF) can reduce morbidity, yet HF is often diagnosed only after symptoms require urgent treatment. The authors sought to describe predictors of HF diagnosis in the acute care vs outpatient setting within the Veterans Health Administration (VHA). The authors estimated whether incident HF diagnoses occurred in acute care (inpatient hospital or emergency department) vs outpatient settings within the VHA between 2014 and 2019. After excluding new-onset HF potentially caused by acute concurrent conditions, they identified sociodemographic and clinical variables associated with diagnosis setting and assessed variation across 130 VHA facilities using multivariable regression analysis. The authors identified 303,632 patients with new HF, with 160,454 (52.8%) diagnosed in acute care settings. In the prior year, 44% had HF symptoms and 11% had a natriuretic peptide tested, 88% of which were elevated. Patients with housing insecurity and high neighborhood social vulnerability had higher odds of acute care diagnosis (adjusted odds ratio: 1.22 [95% CI: 1.17-1.27] and 1.17 [95% CI: 1.14-1.21], respectively) adjusting for medical comorbidities. Better outpatient quality of care (blood pressure control and cholesterol and diabetes monitoring within the prior 2 years) predicted a lower odds of acute care diagnosis. Likelihood of acute care HF diagnosis varied from 41% to 68% across facilities after adjusting for patient-level risk factors. Many first HF diagnoses occur in the acute care setting, especially among socioeconomically vulnerable populations. Better outpatient care was associated with lower rates of an acute care diagnosis. These findings highlight opportunities for timelier HF diagnosis that may improve patient outcomes.
Authors: Tisdale, Rebecca L; Fan, Jun; Calma, Jamie; Cyr, Kevin; Podchiyska, Tanya; Stafford, Randall S; Maron, David J; Hernandez-Boussard, Tina; Ambrosy, Andrew; Heidenreich, Paul A; Sandhu, Alexander T
JACC Heart Fail. 2023 Mar;11(3):347-358. Epub 2023-02-01.
Breast arterial calcification is associated with incident atrial fibrillation among older but not younger post-menopausal women
The goal of this study was to examine the association of breast arterial calcification (BAC) presence and quantity with incident atrial fibrillation (AF) in a large cohort of post-menopausal women. We conducted a longitudinal cohort study among women free of clinically overt cardiovascular disease and AF at baseline (between October 2012 and February 2015) when they attended mammography screening. Atrial fibrillation incidence was ascertained using diagnostic codes and natural language processing. Among 4908 women, 354 incident cases of AF (7%) were ascertained after a mean (standard deviation) of 7 (2) years of follow-up. In Cox regression adjusting for a propensity score for BAC, BAC presence vs. absence was not significantly associated with AF [hazard ratio (HR) = 1.12; 95% confidence interval (CI), 0.89-1.42; P = 0.34]. However, a significant (a priori hypothesized) age by BAC interaction was found (P = 0.02) such that BAC presence was not associated with incident AF in women aged 60-69 years (HR = 0.83; 95% CI, 0.63-1.15; P = 0.26) but was significantly associated with incident AF in women aged 70-79 years (HR = 1.75; 95% CI, 1.21-2.53; P = 0.003). No evidence of dose-response relationship between BAC gradation and AF was noted in the entire cohort or in age groups separately. Our results demonstrate, for the first time, an independent association between BAC and AF in women over age 70 years.
Authors: Iribarren, Carlos; Chandra, Malini; Parikh, Rishi V; Sanchez, Gabriela; Sam, Danny L; Azamian, Farima Faith; Cho, Hyo-Min; Ding, Huanjun; Molloi, Sabee; Go, Alan S
Eur Heart J Open. 2023 Mar;3(2):oead017. Epub 2023-02-28.
Practice Patterns and Outcomes Associated With Anticoagulation Use Following Sepsis Hospitalizations With New-Onset Atrial Fibrillation
Practice patterns and outcomes associated with the use of oral anticoagulation for arterial thromboembolism prevention following a hospitalization with new-onset atrial fibrillation (AF) during sepsis are unclear. Retrospective, observational cohort study of patients ≥40 years of age discharged alive following hospitalization with new-onset AF during sepsis across 21 hospitals in the Kaiser Permanente Northern California health care delivery system, years 2011 to 2018. Primary outcomes were ischemic stroke/transient ischemic attack (TIA), with a safety outcome of major bleeding events, both within 1 year of discharge alive from sepsis hospitalization. Adjusted risk differences for outcomes between patients who did and did not receive oral anticoagulation within 30 days of discharge were estimated using marginal structural models fitted by inverse probability weighting using Super Learning within a target trial emulation framework. Among 82 748 patients hospitalized with sepsis, 3992 (4.8%) had new-onset AF and survived to hospital discharge; mean age was 78±11 years, 53% were men, and 70% were White. Patients with new-onset AF during sepsis averaged 45±33% of telemetry monitoring entries with AF, and 27% had AF present on the day of hospital discharge. Within 1 year of hospital discharge, 89 (2.2%) patients experienced stroke/TIA, 225 (5.6%) had major bleeding, and 1011 (25%) died. Within 30 days of discharge, 807 (20%) patients filled oral anticoagulation prescriptions, which were associated with higher 1-year adjusted risks of ischemic stroke/TIA (5.69% versus 2.32%; risk difference, 3.37% [95% CI, 0.36-6.38]) and no significant difference in 1-year adjusted risks of major bleeding (6.51% versus 7.10%; risk difference, -0.59% [95% CI, -3.09 to 1.91]). Sensitivity analysis of ischemic stroke-only outcomes showed a risk difference of 0.15% (95% CI, -1.72 to 2.03). After hospitalization with new-onset AF during sepsis, oral anticoagulation use was uncommon and associated with potentially higher stroke/TIA risk. Further research to inform mechanisms of stroke and TIA and management of new-onset AF after sepsis is needed.
Authors: Walkey, Allan J; Myers, Laura C; Thai, Khanh K; Kipnis, Patricia; Desai, Manisha; Go, Alan S; Lu, Yun; Clancy, Heather; Devis, Ycar; Neugebauer, Romain; Liu, Vincent X
Circ Cardiovasc Qual Outcomes. 2023 Mar;16(3):e009494. Epub 2023-02-28.
Research Opportunities in Stroke Prevention for Atrial Fibrillation: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop
Atrial fibrillation (AF) is one of the strongest risk factors for ischemic stroke, which is a leading cause of disability and death. Given the aging population, increasing prevalence of AF risk factors, and improved survival in those with cardiovascular disease, the number of individuals affected by AF will continue increasing over time. While multiple proven stroke prevention therapies exist, important questions remain about the optimal approach to stroke prevention at the population and individual patient levels. Our report summarizes the National Heart, Lung, and Blood Institute virtual workshop focused on identifying key research opportunities related to stroke prevention in AF. The workshop reviewed major knowledge gaps and identified targeted research opportunities to advance stroke prevention in AF in the following areas: (1) improving risk stratification tools for stroke and intracranial hemorrhage; (2) addressing challenges with oral anticoagulants; and (3) delineating the optimal roles of percutaneous left atrial appendage occlusion and surgical left atrial appendage closure/excision. This report aims to promote innovative, impactful research that will lead to more personalized, effective use of stroke prevention strategies in people with AF.
Authors: Go, Alan S; Benjamin, Emelia J; et al.
Stroke. 2023 Mar;54(3):e75-e85. Epub 2023-02-27.
Prevalence of Albuminuria Among Adults With Diabetes and Preserved Estimated Glomerular Filtration Rate by Race and Ethnicity
Authors: Nwosu, Uchenna A; Darbinian, Jeanne A; Chen, Kenneth K; Zeng, Billy; Arzumanyan, Hasmik; Lo, Joan C; Zheng, Sijie
Diabetes Care. 2023 Mar 01;46(3):e78-e80.
Outcome prediction in large vessel occlusion ischemic stroke with or without endovascular stroke treatment: THRIVE-EVT
The THRIVE score and the THRIVE-c calculation are validated ischemic stroke outcome prediction tools based on patient variables that are readily available at initial presentation. Randomized controlled trials (RCTs) have demonstrated the benefit of endovascular treatment (EVT) for many patients with large vessel occlusion (LVO), and pooled data from these trials allow for adaptation of the THRIVE-c calculation for use in shared clinical decision making regarding EVT. To extend THRIVE-c for use in the context of EVT, we extracted data from the Virtual International Stroke Trials Archive (VISTA) from 7 RCTs of EVT. Models were built in a randomly selected development cohort using logistic regression that included the predictors from THRIVE-c: age, NIH Stroke Scale (NIHSS) score, presence of hypertension, diabetes mellitus, and/or atrial fibrillation, as well as randomization to EVT and, where available, the Alberta Stroke Program Early CT Score (ASPECTS). Good outcome was achieved in 366/787 (46.5%) of subjects randomized to EVT and in 236/795 (29.7%) of subjects randomized to control (P < 0.001), and the improvement in outcome with EVT was seen across age, NIHSS, and THRIVE-c good outcome prediction. Models to predict outcome using THRIVE elements (age, NIHSS, and comorbidities) together with EVT, with or without ASPECTS, had similar performance by ROC analysis in the development and validation cohorts (THRIVE-EVT ROC area under the curve (AUC) = 0.716 in development, 0.727 in validation, P = 0.30; THRIVE-EVT + ASPECTS ROC AUC = 0.718 in development, 0.735 in validation, P = 0.12). THRIVE-EVT may be used alongside the original THRIVE-c calculation to improve outcome probability estimation for patients with acute ischemic stroke, including patients with or without LVO, and to model the potential improvement in outcomes with EVT for an individual patient based on variables that are available at initial presentation. Online calculators for THRIVE-c estimation are available at www.thrivescore.org and www.mdcalc.com/thrive-score-for-stroke-outcome.
Authors: Flint, Alexander C; Nguyen-Huynh, Mai N; On Behalf Of The Vista-Endovascular Collaboration,; et al.
Int J Stroke. 2023 Mar;18(3):331-337. Epub 2022-04-29.
Sex- and ethnic-specific patterns in the incidence of hip fracture among older US Asian and non-Hispanic White adults
Asian and Pacific Islander (Asian/PI) adults have lower hip fracture incidence than non-Hispanic White (NHW) adults, but data regarding Asian/PI subgroups are limited. We compared hip fracture incidence among older US Asian/PI and NHW populations, including ethnic subgroup differences. Using observational data from a California healthcare system, we identified Asian/PI and NHW adults aged ≥50 years (2000-2019) and followed subjects to 2021 for hip fracture determined by principal/primary hospital diagnosis or by secondary hospital diagnosis with hip/femur procedure codes. Age-adjusted hip fracture incidence was calculated with 95% confidence intervals (CIs). Log-Poisson regression was used to determine fracture incidence rate ratios (IRRs, [CI]; NHW or Chinese as reference) adjusting for age and year. Among 215,359 Asian/PI and 776,839 NHW women, hip fracture incidence was 1.34 (1.28-1.40) and 2.97 (2.94-3.01) per 1000 person-years, respectively, with IRR 0.45 (0.43-0.47). Among 188,328 Asian/PI and 697,046 NHW men, hip fracture incidence was 0.62 (0.58-0.67) and 1.81 (1.78-1.84) per 1000 person-years, respectively, with IRR 0.34 (0.32-0.37). For the four largest Asian/PI subgroups, Filipina women (IRR 0.85 [0.75-0.96]) had lower, and Japanese (IRR 1.36 [1.20-1.54]) and South Asian (IRR 1.36 [1.07-1.72]) women had higher hip fracture incidence compared to Chinese women. Hip fracture incidence was only higher among South Asian (IRR 1.61 [1.21-2.14]) compared to Chinese men. Hip fracture incidence among US Asian/PI adults was 55% (women) and 66% (men) lower than NHW adults, but incidence varied by Asian/PI subgroup. The heterogeneity among Asian/PI adults highlights the importance of examining fracture risk by ethnic subgroup.
Authors: Lo, Joan C; Chandra, Malini; Lee, David R; Darbinian, Jeanne A; Gordon, Nancy P; Zeltser, David W; Grimsrud, Christopher D; Lee, Catherine
J Am Geriatr Soc. 2023 Feb 15.
Effect of Dapagliflozin on Health Status in Patients With Preserved or Mildly Reduced Ejection Fraction
Patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) experience a high burden of symptoms, physical limitations, and poor quality of life; improving health status is a key goal of management. In a prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, we examine effects of dapagliflozin on health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ). The DELIVER trial randomized patients with symptomatic HFmrEF/HFpEF to dapagliflozin 10 mg or placebo. KCCQ was evaluated at randomization, 1, 4, and 8 months; KCCQ Total Symptom Score (TSS) was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles; Cox models examined effects of dapagliflozin on clinical outcomes. We evaluated the effects of dapagliflozin on KCCQ-TSS, Physical Limitations (PLS), Clinical Summary (CSS), and Overall Summary (OSS) domains. Responder analyses compared proportions of dapagliflozin vs placebo-treated patients with clinically meaningful changes in KCCQ. A total of 5,795 patients had baseline KCCQ (median KCCQ-TSS 72.9). The effects of dapagliflozin on reducing cardiovascular death/worsening HF appeared more pronounced in patients with greater baseline symptom burden (lowest-to-highest KCCQ-TSS tertile: HR: 0.70 [95% CI: 0.58-0.84]; 0.81 [95% CI: 0.65-1.01]; 1.07 [95% CI: 0.83-1.37]; Pinteraction = 0.026). Dapagliflozin improved KCCQ-TSS, -PLS, -CSS, and -OSS at 8 months (2.4, 1.9, 2.3, and 2.1 points higher vs placebo; P < 0.001 for all). Dapagliflozin-treated patients experienced improvements in KCCQ-TSS regardless of EF (Pinteraction = 0.85). Fewer dapagliflozin-treated patients had deterioration, and more had improvements in all KCCQ domains at 8 months. The clinical benefits of dapagliflozin in HFmrEF/HFpEF appear especially pronounced in those with greater baseline symptom impairment. Dapagliflozin improved all KCCQ domains and the proportion of patients experiencing clinically meaningful changes in health status. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
Authors: Kosiborod, Mikhail N; Bhatt, Ankeet S; Solomon, Scott D; et al.
J Am Coll Cardiol. 2023 Feb 07;81(5):460-473. Epub 2022-12-14.
Transforming Atrial Fibrillation Research to Integrate Social Determinants of Health: A National Heart, Lung, and Blood Institute Workshop Report
Only modest attention has been paid to the contributions of social determinants of health to atrial fibrillation (AF) risk factors, diagnosis, symptoms, management, and outcomes. The diagnosis of AF provides unique challenges exacerbated by the arrhythmia’s often paroxysmal nature and individuals’ disparate access to health care and technologies that facilitate detection. Social determinants of health affect access to care and management decisions for AF, increasing the likelihood of adverse outcomes among individuals who experience systemic disadvantages. Developing effective approaches to address modifiable social determinants of health requires research to eliminate the substantive inequities in health care delivery and outcomes in AF. The National Heart, Lung, and Blood Institute convened an expert panel to identify major knowledge gaps and research opportunities in the field of social determinants of AF. The workshop addressed the following social determinants: (1) socioeconomic status and access to care; (2) health literacy; (3) race, ethnicity, and racism; (4) sex and gender; (5) shared decision-making in systemically disadvantaged populations; and (6) place, including rurality, neighborhood, and community. Many individuals with AF have multiple adverse social determinants, which may cluster in the individual and in systemically disadvantaged places (eg, rural locations, urban neighborhoods). Cumulative disadvantages may accumulate over the life course and contribute to inequities in the diagnosis, management, and outcomes in AF. Workshop participants identified multiple critical research questions and approaches to catalyze social determinants of health research that address the distinctive aspects of AF. The long-term aspiration of this work is to eradicate the substantive inequities in AF diagnosis, management, and outcomes across populations.
Authors: Benjamin, Emelia J; Go, Alan S; Al-Khatib, Sana M; et al.
JAMA Cardiol. 2023 Feb 01;8(2):182-191.
Predicting Short-term Outcomes After Transcatheter Aortic Valve Replacement for Aortic Stenosis
The approved use of transcatheter aortic valve replacement (TAVR) for aortic stenosis has expanded substantially over time. However, gaps remain with respect to accurately delineating risk for poor clinical and patient-centered outcomes. Our objective was to develop prediction models for 30-day clinical and patient-centered outcomes after TAVR within a large, diverse community-based population. We identified all adults who underwent TAVR between 2013-2019 at Kaiser Permanente Northern California, an integrated healthcare delivery system, and were monitored for the following 30-day outcomes: all-cause death, improvement in quality of life, all-cause hospitalizations, all-cause emergency department (ED) visits, heart failure (HF)-related hospitalizations, and HF-related ED visits. We developed prediction models using gradient boosting machines using linked demographic, clinical and other data from the Society for Thoracic Surgeons (STS)/American College of Cardiology (ACC) TVT Registry and electronic health records. We evaluated model performance using area under the curve (AUC) for model discrimination and associated calibration plots. We also evaluated the association of individual predictors with outcomes using logistic regression for quality of life and Cox proportional hazards regression for all other outcomes. We identified 1,565 eligible patients who received TAVR. The risks of adverse 30-day post-TAVR outcomes ranged from 1.3% (HF hospitalizations) to 15.3% (all-cause ED visits). In models with the highest discrimination, discrimination was only moderate for death (AUC 0.60) and quality of life (AUC 0.62), but better for HF-related ED visits (AUC 0.76). Calibration also varied for different outcomes. Importantly, STS risk score only independently predicted death and all-cause hospitalization but no other outcomes. Older age also only independently predicted HF-related ED visits, and race/ethnicity was not significantly associated with any outcomes. Despite using a combination of detailed STS/ACC TVT Registry and electronic health record data, predicting short-term clinical and patient-centered outcomes after TAVR remains challenging. More work is needed to identify more accurate predictors for post-TAVR outcomes to support personalized clinical decision making and monitoring strategies.
Authors: Savitz, Samuel T; Leong, Thomas; Sung, Sue Hee; Kitzman, Dalane W; McNulty, Edward; Mishell, Jacob; Rassi, Andrew; Ambrosy, Andrew P; Go, Alan S
Am Heart J. 2023 Feb;256:60-72. Epub 2022-11-11.
Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies
The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. Prospective cohort. Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. Cox proportional hazard models. Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.
Authors: Coca, Steven G; Go, Alan S; Parikh, Chirag R; et al.
Am J Kidney Dis. 2023 Feb;81(2):190-200. Epub 2022-09-13.
A prospective study of lifestyle factors and bone health in breast cancer patients who received aromatase inhibitors in an integrated healthcare setting
Fracture and osteoporosis are known side effects of aromatase inhibitors (AIs) for postmenopausal hormone receptor positive (HR+) breast cancer (BC) patients. How modifiable lifestyle factors impact fracture risk in these patients is relatively unknown. We conducted a prospective cohort study to examine the association of lifestyle factors, focusing on physical activity, with risk of incident major osteoporotic fracture and osteoporosis in 2152 HR+ BC patients diagnosed from 2006 to 2013 at Kaiser Permanente Northern California and who received AIs. Patients self-reported lifestyle factors at study entry and at 6-month follow-up. Fracture and osteoporosis outcomes were prospectively ascertained by physician-adjudication and bone mineral density (BMD) values, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from multivariable proportional hazards regression. Models were adjusted for age, menopausal status, race/ethnicity, body mass index (BMI), AJCC stage, breast cancer treatment, prior osteoporosis, and prior major fracture. Over a median 6.1 years of follow-up after AI initiation, 165 women experienced an incident osteoporotic fracture and 243 women had osteoporosis. No associations were found between overall moderate-vigorous physical activity and fracture risk, although < 150 min/week of aerobic exercise in the 6 months after BC diagnosis was associated with increased fracture risk (HR=2.42; 95% CI: 1.34, 4.37) compared with ≥ 150 min/week (meeting physical activity guidelines). Risk was also higher for never or infrequently engaging in aerobic exercise (HR=1.90; 95% CI: 1.05, 3.44). None or infrequent overall moderate-vigorous physical activity in the 6 months before BC diagnosis was associated with increased risk of osteoporosis (HR=1.94; 95% CI: 1.11; 3.37). Moderate-vigorous physical activity during the immediate period after BC diagnosis, particularly aerobic exercise, was associated with lower risk of major osteoporotic fractures in women on AI therapy. Findings may inform fracture prevention in women on AI therapy through non-pharmacologic lifestyle-based strategies.
Authors: Kwan, Marilyn L; Lo, Joan C; Laurent, Cecile A; Roh, Janise M; Tang, Li; Ambrosone, Christine B; Kushi, Lawrence H; Quesenberry, Charles P; Yao, Song
J Cancer Surviv. 2023 Feb;17(1):139-149. Epub 2021-02-09.
Vitamin D Status among Women of Different Asian Subgroups Initiating Osteoporosis Therapy
Among 1866 Asian women (901 Filipina women, 654 Chinese women, and 311 Japanese women) who had vitamin D assessment prior to initiation of osteoporosis therapy, Filipina women had a lower prevalence of vitamin D deficiency compared to Chinese women, despite higher body mass index. In multivariable analyses that adjusted for age, body mass index, and smoking status, the relative risk of low vitamin D was significantly higher for Chinese women (relative risk 1.4, 95% confidence interval 1.1-1.7) but not Japanese women (relative risk 1.2, 95% confidence interval 0.9-1.6). The 40% higher risk of low Vitamin D in Chinese compared to Filipina women emphasizes the importance of disaggregating Asian race when examining nutritional health attributes.
Authors: Ho, Samantha B;Li, Christina F;Chandra, Malini;Lo, Joan C
J Asian Health. 2023 Feb;3(1). Epub 2023-02-24.
Strategic transformations in academic clinical medicine.
Authors: Bhatt, Ankeet S; Deckers, Peter J
Conn Med. 2014 Jun-Jul;78(6):357-61.
Interaction of Body Mass Index on the Association Between N-Terminal-Pro-b-Type Natriuretic Peptide and Morbidity and Mortality in Patients With Acute Heart Failure: Findings From ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).
BACKGROUND: Higher body mass index (BMI) is associated with lower circulating levels of N-terminal-pro-b-type natriuretic peptide (NT-proBNP). The Interaction between BMI and NT-proBNP with respect to clinical outcomes is not well characterized in patients with acute heart failure. METHODS AND RESULTS: A total of 686 patients from the biomarker substudy of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HF ) clinical trial with documented NT-proBNP levels at baseline were included in the present analysis. Patients were classified by the World Health Organization obesity classification (nonobese: BMI <30 kg/m(2), Class I obesity: BMI 30-34.9 kg/m(2), Class II obesity BMI 35-39.9 kg/m(2), and Class III obesity BMI >/=40 kg/m(2)). We assessed baseline characteristics and 30- and 180-day outcomes by BMI class and explored the interaction between BMI and NT-proBNP for these outcomes. Study participants had a median age of 67 years (55, 78) and 71% were female. NT-proBNP levels were inversely correlated with BMI (P<0.001). Higher NT-proBNP levels were associated with higher 180-day mortality (adjusted hazard ratio for each doubling of NT-proBNP, 1.40; 95% confidence interval, 1.16, 1.71; P<0.001), but not 30-day outcomes. The effect of NT-proBNP on 180-day death was not modified by BMI class (interaction P=0.24). CONCLUSIONS: The prognostic value of NT-proBNP was not modified by BMI in this acute heart failure population. NT-proBNP remains a useful prognostic indicator of long-term mortality in acute heart failure even in the obese patient. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00475852.
Authors: Bhatt, Ankeet S; Cooper, Lauren B; Ambrosy, Andrew P; Clare, Robert M; Coles, Adrian; Joyce, Emer; Krishnamoorthy, Arun; Butler, Javed; Felker, G Michael; Ezekowitz, Justin A; Armstrong, Paul W; Hernandez, Adrian F; O'Connor, Christopher M; Mentz, Robert J
J Am Heart Assoc. 2018 Feb 3;7(3). pii: JAHA.117.006740. doi: 10.1161/JAHA.117.006740.
Adverse Remodeling and Reverse Remodeling After Myocardial Infarction.
PURPOSE OF REVIEW: The purpose of this review it to summarize the current literature on remodeling after myocardial infarction, inclusive of pathophysiological considerations, imaging modalities, treatment strategies, and future directions. RECENT FINDINGS: As patients continue to live longer after myocardial infarction (MI), the prevalence of post-MI heart failure continues to rise. Changes in the left ventricle (LV) after MI involve complex interactions between cellular and extracellular components, under neurohormonal regulation. Treatments to prevent adverse LV remodeling and promote reverse remodeling in the post-MI setting include early revascularization, pharmacotherapy aimed at neurohormonal blockade, and device-based therapies that address ventricular dyssynchrony. Despite varying definitions of adverse LV remodeling examined across multiple imaging modalities, the presence of an enlarged LV cavity and/or reduced ejection fraction is consistently associated with poor clinical outcomes. Advances in our knowledge of the neurohormonal regulation of adverse cardiac remodeling have been instrumental in generating therapies aimed at arresting adverse remodeling and promoting reserve remodeling. Further investigation into other specific mechanisms of adverse LV remodeling and pathways to disrupt these mechanisms is ongoing and may provide incremental benefit to current evidence-based therapies.
Authors: Bhatt, Ankeet S; Ambrosy, Andrew P; Velazquez, Eric J
Curr Cardiol Rep. 2017 Aug;19(8):71. doi: 10.1007/s11886-017-0876-4.
Trajectory of Congestion Metrics by Ejection Fraction in Patients With Acute Heart Failure (from the Heart Failure Network).
Differences in the clinical course of congestion by underlying ejection fraction (EF) have not been well-characterized in acute heart failure (AHF). A post hoc analysis was performed using pooled data from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure trials. All patients were admitted for a primary diagnosis of AHF. Patients were grouped as reduced EF /=50%. Multivariable Cox regression analysis was used to assess the association among measures of congestion and the composite of unscheduled outpatient visits, rehospitalization, or death. Mean age was 68 +/- 13 years and 74% were male. Patients with a preserved EF were older, more likely to be female, less likely to have an ischemic etiology of HF, and had a higher prevalence of atrial fibrillation/flutter and chronic obstructive pulmonary disease. Compared with patients with a reduced EF, preserved EF patients had lower amino-terminal pro-b-type natriuretic peptide levels at baseline (i.e., reduced: 5,998 pg/ml [3,009 to 11,414] vs borderline: 4,420 pg/ml [1,740 to 8,057] vs preserved: 3,272 pg/ml [1,687 to 6,536]) and experienced smaller changes during hospitalization. In general, there were few differences between EF groups in the clinical course of congestion as measured by signs and symptoms of HF, body weight change, and net fluid loss. After adjusting for potential confounders, a greater improvement in global visual analog scale was associated with lower risk of unscheduled outpatient visits, rehospitalization, or death at day 60 (hazard ratio 0.94 per 10 mm increase, 95% confidence interval 0.89 to 0.995). This relation did not differ by EF (p = 0.54). In conclusion, among patients hospitalized for AHF, there were few differences in the in-hospital trajectory or prognostic value of routine markers of congestion by EF.
Authors: Ambrosy, Andrew P; Bhatt, Ankeet S; Gallup, Dianne; Anstrom, Kevin J; Butler, Javed; DeVore, Adam D; Felker, G Michael; Fudim, Marat; Greene, Stephen J; Hernandez, Adrian F; Kelly, Jacob P; Samsky, Marc D; Mentz, Robert J
Am J Cardiol. 2017 Jul 1;120(1):98-105. doi: 10.1016/j.amjcard.2017.03.249. Epub 2017 Apr 12.
Achieving a Maximally Tolerated beta-Blocker Dose in Heart Failure Patients: Is There Room for Improvement?
Heart failure (HF) is associated with significant morbidity and mortality. Although initially thought to be harmful in HF, beta-adrenergic blockers (beta-blockers) have consistently been shown to reduce mortality and HF hospitalization in chronic HF with reduced ejection fraction. Proposed mechanisms include neurohormonal blockade and heart rate reduction. A new therapeutic agent now exists to target further heart rate lowering in patients who have been stable on a “maximally tolerated beta-blocker dose,” but this definition and how to achieve it are incompletely understood. In this review, the authors summarize published reports on the mechanisms by which beta-blockers improve clinical outcomes. The authors describe differences in doses achieved in landmark clinical trials and those observed in routine clinical practice. They further discuss reasons for intolerance and the evidence behind using beta-blocker dose and heart rate as therapeutic targets. Finally, the authors offer recommendations for clinicians actively initiating and up-titrating beta-blockers that may aid in achieving maximally tolerated doses.
Authors: Bhatt, Ankeet S; DeVore, Adam D; DeWald, Tracy A; Swedberg, Karl; Mentz, Robert J
J Am Coll Cardiol. 2017 May 23;69(20):2542-2550. doi: 10.1016/j.jacc.2017.03.563.
Can Vaccinations Improve Heart Failure Outcomes?: Contemporary Data and Future Directions.
Heart failure (HF) is a chronic syndrome characterized by acute exacerbations. There is significant overlap between respiratory infections and exacerbation of underlying HF. Vaccination against respiratory infections in patients with HF could serve as a potential cost-effective intervention to improve patients’ quality of life and clinical outcomes. The benefits of influenza vaccination in secondary prevention of ischemic heart disease have been previously studied. However, the evidence for influenza and pneumococcal vaccination specifically in the HF population is less well established. Furthermore, questions around the optimal timing, dose, frequency, and implementation strategies are largely unanswered. This review highlights the current evidence for vaccination against influenza and pneumococcal pneumonia in HF and cardiovascular disease. It summarizes current understanding of the pathophysiologic mechanisms in which vaccination may provide cardioprotection. Finally, it offers opportunities for further investigation on the effects of vaccination in the HF population, spanning basic science, translational research, and large clinical trials.
Authors: Bhatt, Ankeet S; DeVore, Adam D; Hernandez, Adrian F; Mentz, Robert J
JACC Heart Fail. 2017 Mar;5(3):194-203. doi: 10.1016/j.jchf.2016.12.007. Epub 2017 Feb 1.
Curious Crosses: Injection-Induced Lesions.
Authors: Bhatt, Ankeet S; Perkins, Scott; McKinnon, Elizabeth; Perfect, John R
Am J Med. 2017 Jan;130(1):31-33. doi: 10.1016/j.amjmed.2016.08.023. Epub 2016 Sep 9.
Improving operating room turnover time: a systems based approach.
Operating room (OR) turnover time (TT) has a broad and significant impact on hospital administrators, providers, staff and patients. Our objective was to identify current problems in TT management and implement a consistent, reproducible process to reduce average TT and process variability. Initial observations of TT were made to document the existing process at a 511 bed, 24 OR, academic medical center. Three control groups, including one consisting of Orthopedic and Vascular Surgery, were used to limit potential confounders such as case acuity/duration and equipment needs. A redesigned process based on observed issues, focusing on a horizontally structured, systems-based approach has three major interventions: developing consistent criteria for OR readiness, utilizing parallel processing for patient and room readiness, and enhancing perioperative communication. Process redesign was implemented in Orthopedics and Vascular Surgery. Comparisons of mean and standard deviation of TT were made using an independent 2-tailed t-test. Using all surgical specialties as controls (n = 237), mean TT (hh:mm:ss) was reduced by 0:20:48 min (95 % CI, 0:10:46-0:30:50), from 0:44:23 to 0:23:25, a 46.9 % reduction. Standard deviation of TT was reduced by 0:10:32 min, from 0:16:24 to 0:05:52 and frequency of TT>/=30 min was reduced from 72.5to 11.7 %. P < 0.001 for each. Using Vascular and Orthopedic surgical specialties as controls (n = 13), mean TT was reduced by 0:15:16 min (95 % CI, 0:07:18-0:23:14), from 0:38:51 to 0:23:35, a 39.4 % reduction. Standard deviation of TT reduced by 0:08:47, from 0:14:39 to 0:05:52 and frequency of TT>/=30 min reduced from 69.2 to 11.7 %. P < 0.001 for each. Reductions in mean TT present major efficiency, quality improvement, and cost-reduction opportunities. An OR redesign process focusing on parallel processing and enhanced communication resulted in greater than 35 % reduction in TT. A systems-based focus should drive OR TT design.
Authors: Bhatt, Ankeet S; Carlson, Grant W; Deckers, Peter J
J Med Syst. 2014 Dec;38(12):148. doi: 10.1007/s10916-014-0148-4. Epub 2014 Nov 8.
Fewer Hospitalizations for Acute Cardiovascular Conditions During the COVID-19 Pandemic.
BACKGROUND: Although patients with cardiovascular disease face excess risks of severe illness with coronavirus disease-2019 (COVID-19), there may be indirect consequences of the pandemic on this high-risk patient segment. OBJECTIVES: This study sought to examine longitudinal trends in hospitalizations for acute cardiovascular conditions across a tertiary care health system. METHODS: Acute cardiovascular hospitalizations were tracked between January 1, 2019, and March 31, 2020. Daily hospitalization rates were estimated using negative binomial models. Temporal trends in hospitalization rates were compared across the first 3 months of 2020, with the first 3 months of 2019 as a reference. RESULTS: From January 1, 2019, to March 31, 2020, 6,083 patients experienced 7,187 hospitalizations for primary acute cardiovascular reasons. There were 43.4% (95% confidence interval [CI]: 27.4% to 56.0%) fewer estimated daily hospitalizations in March 2020 compared with March 2019 (p < 0.001). The daily rate of hospitalizations did not change throughout 2019 (-0.01% per day [95% CI: -0.04% to +0.02%]; p = 0.50), January 2020 (-0.5% per day [95% CI: -1.6% to +0.5%]; p = 0.31), or February 2020 (+0.7% per day [95% CI: -0.6% to +2.0%]; p = 0.27). There was significant daily decline in hospitalizations in March 2020 (-5.9% per day [95% CI: -7.6% to -4.3%]; p < 0.001). Length of stay was shorter (4.8 days [25th to 75th percentiles: 2.4 to 8.3 days] vs. 6.0 days [25th to 75th percentiles: 3.1 to 9.6 days]; p = 0.003) and in-hospital mortality was not significantly different (6.2% vs. 4.4%; p = 0.30) in March 2020 compared with March 2019. CONCLUSIONS: During the first phase of the COVID-19 pandemic, there was a marked decline in acute cardiovascular hospitalizations, and patients who were admitted had shorter lengths of stay. These data substantiate concerns that acute care of cardiovascular conditions may be delayed, deferred, or abbreviated during the COVID-19 pandemic.
Authors: Bhatt, Ankeet S; Moscone, Alea; McElrath, Erin E; Varshney, Anubodh S; Claggett, Brian L; Bhatt, Deepak L; Januzzi, James L; Butler, Javed; Adler, Dale S; Solomon, Scott D; Vaduganathan, Muthiah
J Am Coll Cardiol. 2020 Jul 21;76(3):280-288. doi: 10.1016/j.jacc.2020.05.038. Epub 2020 May 26.
Post-discharge haemodilution, congestion, and clinical outcomes among patients hospitalized for heart failure with reduced ejection fraction: results from the EVEREST trial.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah; Patel, Ravi B; Fonarow, Gregg C; Subacius, Haris P; Konstam, Marvin A; Zannad, Faiez; Butler, Javed; Greene, Stephen J
Eur J Heart Fail. 2020 Jan;22(1):164-167. doi: 10.1002/ejhf.1651. Epub 2019 Dec 3.
International variation in characteristics and clinical outcomes of patients with type 2 diabetes and heart failure: Insights from TECOS.
International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N=1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF >/=40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF>/=40%. beta-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF>/=40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF>/=40%. These data may inform the design of future international trials.
Authors: Bhatt, Ankeet S; Luo, Nancy; Solomon, Nicole; Pagidipati, Neha J; Ambrosio, Giuseppe; Green, Jennifer B; McGuire, Darren K; Standl, Eberhard; Cornel, Jan H; Halvorsen, Sigrun; Lopes, Renato D; White, Harvey D; Holman, Rury R; Peterson, Eric D; Mentz, Robert J
Am Heart J. 2019 Dec;218:57-65. doi: 10.1016/j.ahj.2019.08.016. Epub 2019 Aug 28.
Influenza Vaccination in Patients With Heart Failure.
Authors: DeVore, Adam D; Bhatt, Ankeet S
Circulation. 2019 Jan 29;139(5):587-589. doi: 10.1161/CIRCULATIONAHA.118.038348.
Reply: Vaccination in Patients With Heart Failure: An Established Recommendation in Patients With Chronic Heart Disease.
Authors: Bhatt, Ankeet S; DeVore, Adam D; Hernandez, Adrian F
JACC Heart Fail. 2019 Jan;7(1):85. doi: 10.1016/j.jchf.2018.11.015.
Loop diuretic adjustments in patients with chronic heart failure: Insights from HF-ACTION.
BACKGROUND: The relationship between diuretic use or change in diuretic use and outcomes in chronic heart failure (HF) remains poorly defined. We evaluated the association between diuretic use and changes in health status, exercise capacity, and clinical events in a large randomized trial of subjects with HF. METHODS: HF-ACTION randomized 2,331 outpatients with HF and ejection fraction .05). A dose increase was associated with decrease in 6-minute walk distance (-4.25 m, SE 1.12 m, P<.001) and change in Kansas City Cardiomyopathy Questionnaire overall score (-0.56 m, SE 0.24 m, P=.02). There were no between-group differences for all-cause death or hospitalization comparing continuous use versus never use (adjusted HR 0.91; 95% CI 0.72-1.15; P=.432). CONCLUSIONS: The initiation or discontinuation of diuretics over a 6-month time frame was not associated with a difference in mortality, hospitalizations, exercise, or health status outcomes, but a dose increase in HF patients was associated with worse exercise and health status outcomes.
Authors: Fudim, Marat; O'Connor, Christopher M; Mulder, Hillary; Coles, Adrian; Bhatt, Ankeet S; Ambrosy, Andrew P; Kraus, William E; Pina, Ileana L; Whellan, David J; Mentz, Robert J
Am Heart J. 2018 Nov;205:133-141. doi: 10.1016/j.ahj.2018.06.017. Epub 2018 Jul 29.
Vaccination Trends in Patients With Heart Failure: Insights From Get With The Guidelines-Heart Failure.
OBJECTIVES: This study sought to evaluate and contribute to the limited data on U.S. hospital practice patterns with respect to respiratory vaccination in patients hospitalized with heart failure (HF). BACKGROUND: Respiratory infection is a major driver of morbidity in patients with HF, and many influenza and pneumococcal infections may be prevented by vaccination. METHODS: This study evaluated patients hospitalized at centers participating in the Get With The Guidelines-HF (GWTG-HF) registry from October 2012 to March 2017. The proportion of patients receiving vaccination was described for influenza and pneumococcal vaccination, respectively. The association of hospital-level vaccination rates with individual GWTG-HF performance measures and defect-free care was evaluated using multivariable modeling. RESULTS: This study evaluated 313,761 patients discharged from 392 hospitals during the study period. The proportion of patients receiving influenza vaccination was 68% overall and declined from 70% in 2012 to 2013 to 66% in 2016 to 2017 (p < 0.001), although this was not statistically significant after adjustment (odds ratio: 1.05 per flu season; 95% confidence interval [CI]: 0.94 to 1.18). The proportion of patients receiving pneumococcal vaccination was 66% overall and decreased over the study period from 71% in 2013 to 60% in 2016 (p < 0.001), remaining significant after adjustment (odds ratio: 0.75 per calendar year; 95% CI: 0.67 to 0.84). Hospitals with higher vaccination rates were more likely to discharge patients with higher performance on defect-free care and individual GWTG-HF performance measures (p < 0.001). In a subset of patients with linked Medicare claims, vaccinated patients had similar rates of 1-year all-cause mortality (adjusted hazard ratio: 0.96 [95% CI: 0.89 to 1.03] for influenza vaccination; adjusted hazard ratio: 0.95 [95% CI: 0.89 to 1.01] for pneumococcal vaccination) compared with those not vaccinated. CONCLUSIONS: Nearly 1 in 3 patients hospitalized with HF at participating hospitals were not vaccinated for influenza or pneumococcal pneumonia, and vaccination rates did not improve from 2012 to 2017. Hospitals that exhibited higher vaccination rates performed well with respect to other HF quality of care measures. Vaccination status was not associated with differences in clinical outcomes. Further randomized controlled data are needed to assess the relationship between vaccination and outcomes.
Authors: Bhatt, Ankeet S; Liang, Li; DeVore, Adam D; Fonarow, Gregg C; Solomon, Scott D; Vardeny, Orly; Yancy, Clyde W; Mentz, Robert J; Khariton, Yevgeniy; Chan, Paul S; Matsouaka, Roland; Lytle, Barbara L; Pina, Ileana L; Hernandez, Adrian F
JACC Heart Fail. 2018 Oct;6(10):844-855. doi: 10.1016/j.jchf.2018.04.012. Epub 2018 Aug 8.
Prevalent digoxin use and subsequent risk of death or hospitalization in ambulatory heart failure patients with a reduced ejection fraction-Findings from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized controlled trial.
BACKGROUND: Despite more than 200 years of clinical experience and a pivotal trial, recently published research has called into question the safety and efficacy of digoxin therapy in heart failure (HF). METHODS: HF-ACTION (ClinicalTrials.gov Number: NCT00047437) enrolled 2331 outpatients with HF and an EF
Authors: Ambrosy, Andrew P; Bhatt, Ankeet S; Stebbins, Amanda L; Wruck, Lisa M; Fudim, Marat; Greene, Stephen J; Kraus, William E; O'Connor, Christopher M; Pina, Ileana L; Whellan, David J; Mentz, Robert J
Am Heart J. 2018 May;199:97-104. doi: 10.1016/j.ahj.2018.02.004. Epub 2018 Feb 11.
Discovery and care innovation amidst a pandemic.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah
Eur J Heart Fail. 2020 Dec;22(12):2202-2204. doi: 10.1002/ejhf.2070. Epub 2020 Dec 14.
Innovation in Ambulatory Care of Heart Failure in the Era of Coronavirus Disease 2019.
Despite steady progress over the past 3 decades in advancing drug and device therapies to reduce morbidity and mortality in heart failure with reduced ejection fraction, large registries of usual care demonstrate incomplete use of these evidence-based therapies in clinical practice. Potential strategies to improve guideline-directed medical therapy include leveraging non-physician clinicians, solidifying transitions of care, incorporating telehealth solutions, and engaging in comprehensive comorbid disease management via multidisciplinary team structures. These approaches may be particularly relevant in an era of Coronavirus Disease 2019 and associated need for social distancing, further limiting contact with traditional ambulatory clinic settings.
Authors: Leiva, Orly; Bhatt, Ankeet S; Vaduganathan, Muthiah
Heart Fail Clin. 2020 Oct;16(4):433-440. doi: 10.1016/j.hfc.2020.06.004. Epub 2020 Jun 19.
Clinical Outcomes in Young US Adults Hospitalized With COVID-19.
Authors: Cunningham, Jonathan W; Vaduganathan, Muthiah; Claggett, Brian L; Jering, Karola S; Bhatt, Ankeet S; Rosenthal, Ning; Solomon, Scott D
JAMA Intern Med. 2020 Sep 9. pii: 2770542. doi: 10.1001/jamainternmed.2020.5313.
A Man in His 30s With a New Continuous Murmur and Fever.
Authors: Li, Selena; Bhatt, Ankeet S; O'Gara, Patrick T
JAMA Cardiol. 2020 Aug 1;5(8):e203255. doi: 10.1001/jamacardio.2020.3255. Epub 2020 Aug 19.
Growing Mismatch Between Evidence Generation and Implementation in Heart Failure.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah; Butler, Javed
Am J Med. 2020 May;133(5):525-527. doi: 10.1016/j.amjmed.2019.11.032. Epub 2020 Jan 17.
Angiotensin-neprilysin inhibition in de novo heart failure – starting off strong.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah; Butler, Javed
Eur J Heart Fail. 2020 Feb;22(2):313-314. doi: 10.1002/ejhf.1675. Epub 2019 Dec 16.
Clinical Outcomes in Patients With Heart Failure Hospitalized With COVID-19.
OBJECTIVES: The purpose of this study was to evaluate in-hospital outcomes among patients with a history of heart failure (HF) hospitalized with coronavirus disease-2019 (COVID-19). BACKGROUND: Cardiometabolic comorbidities are common in patients with severe COVID-19. Patients with HF may be particularly susceptible to COVID-19 complications. METHODS: The Premier Healthcare Database was used to identify patients with at least 1 HF hospitalization or 2 HF outpatient visits between January 1, 2019, and March 31, 2020, who were subsequently hospitalized between April and September 2020. Baseline characteristics, health care resource utilization, and mortality rates were compared between those hospitalized with COVID-19 and those hospitalized with other causes. Predictors of in-hospital mortality were identified in HF patients hospitalized with COVID-19 by using multivariate logistic regression. RESULTS: Among 1,212,153 patients with history of HF, 132,312 patients were hospitalized from April 1, 2020, to September 30, 2020. A total of 23,843 patients (18.0%) were hospitalized with acute HF, 8,383 patients (6.4%) were hospitalized with COVID-19, and 100,068 patients (75.6%) were hospitalized with alternative reasons. Hospitalization with COVID-19 was associated with greater odds of in-hospital mortality as compared with hospitalization with acute HF; 24.2% of patients hospitalized with COVID-19 died in-hospital compared to 2.6% of those hospitalized with acute HF. This association was strongest in April (adjusted odds ratio [OR]: 14.48; 95% confidence interval [CI]:12.25 to 17.12) than in subsequent months (adjusted OR: 10.11; 95% CI: 8.95 to 11.42; pinteraction <0.001). Among patients with HF hospitalized with COVID-19, male sex (adjusted OR: 1.26; 95% CI: 1.13 to 1.40) and morbid obesity (adjusted OR: 1.25; 95% CI: 1.07 to 1.46) were associated with greater odds of in-hospital mortality, along with age (adjusted OR: 1.35; 95% CI: 1.29 to 1.42 per 10 years) and admission earlier in the pandemic. CONCLUSIONS: Patients with HF hospitalized with COVID-19 are at high risk for complications, with nearly 1 in 4 dying during hospitalization.
Authors: Bhatt, Ankeet S; Jering, Karola S; Vaduganathan, Muthiah; Claggett, Brian L; Cunningham, Jonathan W; Rosenthal, Ning; Signorovitch, James; Thune, Jens J; Vardeny, Orly; Solomon, Scott D
JACC Heart Fail. 2021 Jan;9(1):65-73. doi: 10.1016/j.jchf.2020.11.003.
Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory.
The treatment of heart failure with reduced ejection fraction (HFrEF) has changed considerably over time, particularly with the sequential development of therapies aimed at antagonism of maladaptive biologic pathways, including inhibition of the sympathetic nervous system and the renin-angiotensin aldosterone system. The sequential nature of earlier HFrEF trials allowed the integration of new therapies tested against the background therapy of the time. More recently, multiple heart failure therapies are being evaluated simultaneously, and the number of therapeutic choices for treating HFrEF has grown considerably. In addition, implementation science has lagged behind discovery science in heart failure. Furthermore, given there are currently >200 ongoing clinical trials in heart failure, further complexities are anticipated. In an effort to provide a decision-making framework in the current era of expanding therapeutic options in HFrEF, the Heart Failure Collaboratory convened a multi-stakeholder group, including patients, clinicians, clinical investigators, the U.S. Food and Drug Administration, industry, and payers who met at the U.S. Food and Drug Administration campus on March 6, 2020. This paper summarizes the discussions and expert consensus recommendations.
Authors: Bhatt, Ankeet S; Abraham, William T; Lindenfeld, JoAnn; Bristow, Michael; Carson, Peter E; Felker, G Michael; Fonarow, Gregg C; Greene, Stephen J; Psotka, Mitchell A; Solomon, Scott D; Stockbridge, Norman; Teerlink, John R; Vaduganathan, Muthiah; Wittes, Janet; Fiuzat, Mona; O'Connor, Christopher M; Butler, Javed
JACC Heart Fail. 2021 Jan;9(1):1-12. doi: 10.1016/j.jchf.2020.10.014. Epub 2020 Dec 9.
Bias in natriuretic peptide-guided heart failure trials: time to improve guideline adherence using alternative approaches.
Treatment of patients with heart failure with reduced ejection fraction (HFrEF) with currently available therapies reduces morbidity and mortality. However, implementation of these therapies is a problem with only few patients achieving guideline-recommended maximal doses of therapy. In an effort to improve guideline adherence and uptitration, several trials have investigated a biomarker-guided strategy (using natriuretic peptide targets in specific), but although conceptually promising, these trials failed to show a consistent beneficial effect on outcomes. In this review, we discuss different methodological issues that may explain the failure of these trials and offer potential solutions. Moreover, alternative approaches to increase heart failure guideline adherence are evaluated.
Authors: Stienen, Susan; Bhatt, Ankeet; Ferreira, Joao Pedro; Vaduganathan, Muthiah; Januzzi, James; Adams, Kirkwood; Tardif, Jean-Claude; Rossignol, Patrick; Zannad, Faiez
Heart Fail Rev. 2021 Jan;26(1):11-21. doi: 10.1007/s10741-020-10004-6.
Practice pattern of use of high sensitivity troponin in the outpatient settings.
BACKGROUND: High-sensitivity troponin assays (hs-Tn) detect lower serum concentrations than prior-generation assays and help guide acute coronary syndrome (ACS) evaluation in emergency departments. Outpatient hs-Tn utilization is not well described. HYPOTHESIS: Outpatient providers use hs-TnT to triage patients with suspected ACS. METHODS: We compared the volume of outpatient prior-generation troponin tests in the pre-hsTn implementation period (January 2015-March 2018) with outpatient hs-TnT volume in the post-implementation period (April 2018-January 2020). Triage patterns were compared between patients with hs-TnT>/=99th vs <99th percentile, using two-sample t tests. In patients triaged home, adverse events were compared between patients with hs-TnT>/=99th vs <99th percentile, using log-rank tests. RESULTS: Across a large tertiary healthcare system, a mean of 80 prior-generation tests/month were ordered during the pre-hsTn implementation period compared with 12 hs-TnT tests/month in the post-implementation period. Prior-generation orders rose by 1.72 tests/month during pre-implementation, vs a decline of 2.74 hs-TnT tests/month during post-implementation (P < .001). Among 129 hs-TnT orders, most were placed by cardiologists (54%) and primary care providers (32%). Patient symptoms at the time of troponin ordering included dyspnea (34%) and chest pain (33%), although 25% were asymptomatic. Among symptomatic patients (n = 74), those with hs-TnT > 99th percentile were more likely to be sent to the ED (RR, 3.36; 95% CI, 1.22-9.25; P = .002). Among patients sent home (n = 66), those with hs-TnT > 99th percentile had more adverse events by 6 months (3.3% vs 22.2% RR, 6.67; 95% CI, 1.04-42.9; P = .026). CONCLUSIONS: In this healthcare system, outpatient troponin utilization significantly declined since hs-TnT implementation. Some providers use hs-TnT to triage patients with suspected ACS to the ED; others test asymptomatic patients and some send patients home despite high hs-TnT values.
Authors: Ferro, Enrico G; Bhatt, Ankeet S; Zhou, Guohai; Fiumara, Karen; Wasfy, Jason H; Sequist, Thomas D; Morrow, David A; Scirica, Benjamin M
Clin Cardiol. 2020 Dec;43(12):1573-1578. doi: 10.1002/clc.23482. Epub 2020 Oct 22.
Reply: Are We Missing Something in the Management of Acute Coronary Syndromes in COVID-19-Negative Patients?
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah
J Am Coll Cardiol. 2020 Nov 24;76(21):2574-2575. doi: 10.1016/j.jacc.2020.09.548.
Conduct of Clinical Trials in the Era of COVID-19: JACC Scientific Expert Panel.
The coronavirus disease-2019 (COVID-19) pandemic has profoundly changed clinical care and research, including the conduct of clinical trials, and the clinical research ecosystem will need to adapt to this transformed environment. The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory and the Academic Research Consortium, composed of academic investigators from the United States and Europe, patients, the U.S. Food and Drug Administration, the National Institutes of Health, and industry members. A series of meetings were convened to address the challenges caused by the COVID-19 pandemic, review options for maintaining or altering best practices, and establish key recommendations for the conduct and analysis of clinical trials for cardiovascular disease and heart failure. This paper summarizes the discussions and expert consensus recommendations.
Authors: Psotka, Mitchell A; Abraham, William T; Fiuzat, Mona; Filippatos, Gerasimos; Lindenfeld, JoAnn; Ahmad, Tariq; Bhatt, Ankeet S; Carson, Peter E; Cleland, John G F; Felker, G Michael; Januzzi, James L Jr; Kitzman, Dalane W; Leifer, Eric S; Lewis, Eldrin F; McMurray, John J V; Mentz, Robert J; Solomon, Scott D; Stockbridge, Norman; Teerlink, John R; Vaduganathan, Muthiah; Vardeny, Orly; Whellan, David J; Wittes, Janet; Anker, Stefan D; O'Connor, Christopher M
J Am Coll Cardiol. 2020 Nov 17;76(20):2368-2378. doi: 10.1016/j.jacc.2020.09.544.
Accuracy of ICD-10 Diagnostic Codes to Identify COVID-19 Among Hospitalized Patients.
Authors: Bhatt, Ankeet S; McElrath, Erin E; Claggett, Brian L; Bhatt, Deepak L; Adler, Dale S; Solomon, Scott D; Vaduganathan, Muthiah
J Gen Intern Med. 2021 Aug;36(8):2532-2535. doi: 10.1007/s11606-021-06936-w. Epub 2021 Jun 7.
Virtual optimization of guideline-directed medical therapy in hospitalized patients with heart failure with reduced ejection fraction: the IMPLEMENT-HF pilot study.
AIMS: Implementation of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains incomplete. Non-cardiovascular hospitalization may present opportunities for GDMT optimization. We assessed the efficacy and durability of a virtual, multidisciplinary ‘GDMT Team’ on medical therapy prescription for HFrEF. METHODS AND RESULTS: Consecutive hospitalizations in patients with HFrEF (ejection fraction
Authors: Bhatt, Ankeet S; Varshney, Anubodh S; Nekoui, Mahan; Moscone, Alea; Cunningham, Jonathan W; Jering, Karola S; Patel, Parth N; Sinnenberg, Lauren E; Bernier, Thomas D; Buckley, Leo F; Cook, Bryan M; Dempsey, Jillian; Kelly, Julie; Knowles, Danielle M; Lupi, Kenneth; Malloy, Rhynn; Matta, Lina S; Rhoten, Megan N; Sharma, Krishan; Snyder, Caroline A; Ting, Clara; McElrath, Erin E; Amato, Mary G; Alobaidly, Maryam; Ulbricht, Catherine E; Choudhry, Niteesh K; Adler, Dale S; Vaduganathan, Muthiah
Eur J Heart Fail. 2021 Jul;23(7):1191-1201. doi: 10.1002/ejhf.2163. Epub 2021 Apr 13.
Influenza vaccination: a ‘shot’ at INVESTing in cardiovascular health.
The link between viral respiratory infection and non-pulmonary organ-specific injury, including cardiac injury, has become increasingly appreciated during the current coronavirus disease 2019 (COVID-19) pandemic. Even prior to the pandemic, however, the association between acute infection with influenza and elevated cardiovascular risk was evident. The recently published results of the NHLBI-funded INfluenza Vaccine to Effectively Stop CardioThoracic Events and Decompensated (INVESTED) trial, a 5200 patient comparative effectiveness study of high-dose vs. standard-dose influenza vaccine to reduce cardiopulmonary events and mortality in a high-risk cardiovascular population, found no difference between strategies. However, the broader implications of influenza vaccine as a strategy to reduce morbidity in high-risk patients remain extremely important, with randomized controlled trial and observational data supporting vaccination in high-risk patients with cardiovascular disease. Given a favourable risk-benefit profile and widespread availability at generally low cost, we contend that influenza vaccination should remain a centrepiece of cardiovascular risk mitigation and describe the broader context of underutilization of this strategy. Few therapeutics in medicine offer seasonal efficacy from a single administration with generally mild, transient side effects, and exceedingly low rates of serious adverse effects. Infection control measures such as physical distancing, hand washing, and the use of masks during the COVID-19 pandemic have already been associated with substantially curtailed incidence of influenza outbreaks across the globe. Appending annual influenza vaccination to these measures represents an important public health and moral imperative.
Authors: Bhatt, Ankeet S; Vardeny, Orly; Udell, Jacob A; Joseph, Jacob; Kim, KyungMann; Solomon, Scott D
Eur Heart J. 2021 May 21;42(20):2015-2018. doi: 10.1093/eurheartj/ehab133.
For vaptans, as for life, balance is better.
Authors: Bhatt, Ankeet S; Yanamandala, Mounica; Konstam, Marvin A
Eur J Heart Fail. 2021 May;23(5):751-753. doi: 10.1002/ejhf.2042. Epub 2020 Nov 18.
Incidence and Outcomes of Pneumonia in Patients With Heart Failure.
BACKGROUND: The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). OBJECTIVES: This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials. METHODS: The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide). RESULTS: In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58). CONCLUSIONS: The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711).
Authors: Shen, Li; Jhund, Pardeep S; Anand, Inder S; Bhatt, Ankeet S; Desai, Akshay S; Maggioni, Aldo P; Martinez, Felipe A; Pfeffer, Marc A; Rizkala, Adel R; Rouleau, Jean L; Swedberg, Karl; Vaduganathan, Muthiah; Vardeny, Orly; van Veldhuisen, Dirk J; Zannad, Faiez; Zile, Michael R; Packer, Milton; Solomon, Scott D; McMurray, John J V
J Am Coll Cardiol. 2021 Apr 27;77(16):1961-1973. doi: 10.1016/j.jacc.2021.03.001.
Reply: Improving Heart Failure Therapeutics: Thinking Outside the Pillbox?
Authors: Bhatt, Ankeet S; Fiuzat, Mona; Lindenfeld, JoAnn; O'Connor, Christopher M; Butler, Javed
JACC Heart Fail. 2021 Apr;9(4):320-321. doi: 10.1016/j.jchf.2021.01.005.
Characteristics of clinical trials evaluating cardiovascular therapies for Coronavirus Disease 2019 Registered on ClinicalTrials.gov: a cross sectional analysis.
Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. METHODS: ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. RESULTS: A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). CONCLUSIONS: A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.
Authors: Varshney, Anubodh S; Wang, David E; Bhatt, Ankeet S; Blood, Alexander; Sharkawi, Musa A; Siddiqi, Hasan K; Vaduganathan, Muthiah; Monteleone, Peter P; Patel, Manesh R; Jones, W Schuyler; Lopes, Renato D; Mehra, Mandeep R; Bhatt, Deepak L; Kochar, Ajar
Am Heart J. 2021 Feb;232:105-115. doi: 10.1016/j.ahj.2020.10.065. Epub 2020 Oct 26.
Treatment Effects of Sacubitril/Valsartan Compared With Valsartan by Ejection Fraction in Patients With Recent Hospitalization.
Authors: Bhatt, Ankeet S; Claggett, Brian L; Packer, Milton; Lefkowitz, Martin P; Zile, Michael R; McMurray, John J V; Solomon, Scott D; Vaduganathan, Muthiah
J Card Fail. 2021 Sep;27(9):1027-1030. doi: 10.1016/j.cardfail.2021.05.020. Epub 2021 Jun 13.
Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial.
AIMS: Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on beta-blocker and mineralocorticoid receptor antagonist (MRA) use and dosing in a large randomized clinical trial. METHODS AND RESULTS: Patients with full data on medication use were included. We examined beta-blocker and MRA use in patients randomized to sacubitril/valsartan vs. enalapril through 12-month follow-up. New initiations and discontinuations of beta-blocker and MRA were compared between treatment groups. Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of beta-blocker and MRA at any dose was 87% and 56%, respectively. Mean doses of beta-blocker and MRA were similar between treatment groups at baseline and at 6-month and 12-month follow-up. New initiations through 12-month follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for beta-blockers [37 (9.0%) vs. 42 (10.2%), P = 0.56] and MRA [127 (7.6%) vs. 143 (9.2%), P = 0.10]. Among patients on MRA therapy at baseline, there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12 months [125 (6.2%) vs. 187 (9.0%), P = 0.001]. Discontinuations of beta-blockers were not significantly different between groups in follow-up (2.2% vs. 2.6%, P = 0.26). CONCLUSIONS: Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose down-titration of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah; Claggett, Brian L; Liu, Jiankang; Packer, Milton; Desai, Akshay S; Lefkowitz, Martin P; Rouleau, Jean L; Shi, Victor C; Zile, Michael R; Swedberg, Karl; Vardeny, Orly; McMurray, John J V; Solomon, Scott D
Eur J Heart Fail. 2021 Sep;23(9):1518-1524. doi: 10.1002/ejhf.2259. Epub 2021 Jun 21.
Evidence-Based Prescribing and Polypharmacy for Patients With Heart Failure.
Authors: Bhatt, Ankeet S; Choudhry, Niteesh K
Ann Intern Med. 2021 Aug;174(8):1165-1166. doi: 10.7326/M21-1427. Epub 2021 Jun 29.
Hospitalization of Patients With (But Not for) Heart Failure: An Opportunity for Accelerated Guideline-Directed Medical Therapy Optimization?
Authors: Varshney, Anubodh S; Bhatt, Ankeet S; Vaduganathan, Muthiah
J Card Fail. 2021 Aug;27(8):910-912. doi: 10.1016/j.cardfail.2021.04.004.
Prioritizing Dissemination and Implementation Science in Cardiometabolic Medicine: CONNECTing the Dots.
Authors: Bhatt, Ankeet S; Solomon, Scott D; Vaduganathan, Muthiah
JAMA. 2021 Jul 27;326(4):311-313. doi: 10.1001/jama.2021.9847.
Prognostic Value of Natriuretic Peptides and Cardiac Troponins in COVID-19.
Authors: Cunningham, Jonathan W; Claggett, Brian L; Jering, Karola S; Vaduganathan, Muthiah; Bhatt, Ankeet S; Rosenthal, Ning; Solomon, Scott D
Circulation. 2021 Jul 13;144(2):177-179. doi: 10.1161/CIRCULATIONAHA.121.054969. Epub 2021 May 17.
Coronavirus Disease-2019 and Heart Failure: A Scientific Statement From the Heart Failure Society of America.
Authors: Bhatt, Ankeet S; Adler, Eric D; Albert, Nancy M; Anyanwu, Anelechi; Bhadelia, Nahid; Cooper, Leslie T; Correa, Ashish; Defilippis, Ersilia M; Joyce, Emer; Sauer, Andrew J; Solomon, Scott D; Vardeny, Orly; Yancy, Clyde; Lala, Anuradha
J Card Fail. 2022 Jan;28(1):93-112. doi: 10.1016/j.cardfail.2021.08.013. Epub 2021 Sep 1.
Adherence to Evidence-Based Therapies in Heart Failure: Deepening the Implementation Divide.
Authors: Bhatt, Ankeet S
JACC Heart Fail. 2021 Dec;9(12):887-889. doi: 10.1016/j.jchf.2021.07.007. Epub 2021 Sep 8.
Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US.
Importance: The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals. Objective: To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label. Design, Setting, and Participants: Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021. Main Outcomes and Measures: Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Results: Of an estimated 4682098 adults, the mean (SE) age was 66.3 (0.8) years, 1995037 (42.6%) were women, and 748045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643161 (95% CI, 534433-751888; LVEF of 41% to 50%) to 1838756 (95% CI, 1527911-2149601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69268 (95% CI, 57558-80978) worsening HF events (LVEF of 41% to 50%) to 182592 (95% CI, 151725-213460) worsening HF events (LVEF of 41% to 60%). Conclusions and Relevance: The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180000 worsening HF events, depending on the definition of normal LVEF.
Authors: Vaduganathan, Muthiah; Claggett, Brian L; Greene, Stephen J; Aggarwal, Rahul; Bhatt, Ankeet S; McMurray, John J V; Fonarow, Gregg C; Solomon, Scott D
JAMA Cardiol. 2021 Dec 1;6(12):1415-1423. doi: 10.1001/jamacardio.2021.3651.
Epidemiology of Cardiogenic Shock in Hospitalized Adults With COVID-19: A Report From the American Heart Association COVID-19 Cardiovascular Disease Registry.
Authors: Varshney, Anubodh S; Omar, Wally A; Goodrich, Erica L; Bhatt, Ankeet S; Wolley, Ann E; Gong, Jingyi; Senman, Balimkiz C; Silva, Danuzia; Levangie, Michael W; Berg, David D; Yeh, Robert W; de Lemos, James A; Morrow, David A; Kazi, Dhruv S; Bohula, Erin A
Circ Heart Fail. 2021 Dec;14(12):e008477. doi: 10.1161/CIRCHEARTFAILURE.121.008477. Epub 2021 Nov 18.
De Novo vs Acute-on-Chronic Presentations of Heart Failure-Related Cardiogenic Shock: Insights from the Critical Care Cardiology Trials Network Registry.
BACKGROUND: Heart failure-related cardiogenic shock (HF-CS) accounts for an increasing proportion of cases of CS in contemporary cardiac intensive care units. Whether the chronicity of HF identifies distinct clinical profiles of HF-CS is unknown. METHODS AND RESULTS: We evaluated admissions to cardiac intensive care units for HF-CS in 28 centers using data from the Critical Care Cardiology Trials Network registry (2017-2020). HF-CS was defined as CS due to ventricular failure in the absence of acute myocardial infarction and was classified as de novo vs acute-on-chronic based on the absence or presence of a prior diagnosis of HF, respectively. Clinical features, resource use, and outcomes were compared among groups. Of 1405 admissions with HF-CS, 370 had de novo HF-CS (26.3%), and 1035 had acute-on-chronic HF-CS (73.7%). Patients with de novo HF-CS had a lower prevalence of hypertension, diabetes, coronary artery disease, atrial fibrillation, and chronic kidney disease (all P < 0.01). Median Sequential Organ Failure Assessment (SOFA) scores were higher in those with de novo HF-CS (8; 25th-75th: 5-11) vs acute-on-chronic HF-CS (6; 25th-75th: 4-9, P < 0.01), as was the proportion of Society of Cardiovascular Angiography and Intervention (SCAI) shock stage E (46.1% vs 26.1%, P < 0.01). After adjustment for clinical covariates and preceding cardiac arrest, the risk of in-hospital mortality was higher in patients with de novo HF-CS than in those with acute-on-chronic HF-CS (adjusted hazard ratio 1.36, 95% confidence interval 1.05-1.75, P=0.02). CONCLUSIONS: Despite having fewer comorbidities, patients with de novo HF-CS had more severe shock presentations and worse in-hospital outcomes. Whether HF disease chronicity is associated with time-dependent compensatory adaptations, unique pathobiological features and responses to treatment in patients presenting with HF-CS warrants further investigation.
Authors: Bhatt, Ankeet S; Berg, David D; Bohula, Erin A; Alviar, Carlos L; Baird-Zars, Vivian M; Barnett, Christopher F; Burke, James A; Carnicelli, Anthony P; Chaudhry, Sunit-Preet; Daniels, Lori B; Fang, James C; Fordyce, Christopher B; Gerber, Daniel A; Guo, Jianping; Jentzer, Jacob C; Katz, Jason N; Keller, Norma; Kontos, Michael C; Lawler, Patrick R; Menon, Venu; Metkus, Thomas S; Nativi-Nicolau, Jose; Phreaner, Nicholas; Roswell, Robert O; Sinha, Shashank S; Jeffrey Snell, R; Solomon, Michael A; Van Diepen, Sean; Morrow, David A
J Card Fail. 2021 Oct;27(10):1073-1081. doi: 10.1016/j.cardfail.2021.08.014.
The cardiovascular legacy of the COVID-19 pandemic.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah
Eur Heart J. 2022 Sep 1;43(33):3179-3181. doi: 10.1093/eurheartj/ehac256.
Prioritizing prevention of de novo and worsening chronic heart failure.
Authors: Bhatt, Ankeet S; Fonarow, Gregg C; Greene, Stephen J
Eur J Heart Fail. 2022 Apr;24(4):653-656. doi: 10.1002/ejhf.2464. Epub 2022 Mar 15.
Epidemiology of Acute Heart Failure in Critically Ill Patients With COVID-19: An Analysis From the Critical Care Cardiology Trials Network.
BACKGROUND: Acute heart failure (HF) is an important complication of coronavirus disease 2019 (COVID-19) and has been hypothesized to relate to inflammatory activation. METHODS: We evaluated consecutive intensive care unit (ICU) admissions for COVID-19 across 6 centers in the Critical Care Cardiology Trials Network, identifying patients with vs without acute HF. Acute HF was subclassified as de novo vs acute-on-chronic, based on the absence or presence of prior HF. Clinical features, biomarker profiles and outcomes were compared. RESULTS: Of 901 admissions to an ICU due to COVID-19, 80 (8.9%) had acute HF, including 18 (2.0%) with classic cardiogenic shock (CS) and 37 (4.1%) with vasodilatory CS. The majority (n=45) were de novo HF presentations. Compared to patients without acute HF, those with acute HF had higher cardiac troponin and natriuretic peptide levels and similar inflammatory biomarkers; patients with de novo HF had the highest cardiac troponin levels. Notably, among patients critically ill with COVID-19, illness severity (median Sequential Organ Failure Assessment, 8 [IQR, 5-10] vs 6 [4-9]; P=0.025) and mortality rates (43.8% vs 32.4%; P=0.040) were modestly higher in patients with vs those without acute HF. CONCLUSIONS: Among patients critically ill with COVID-19, acute HF is distinguished more by biomarkers of myocardial injury and hemodynamic stress than by biomarkers of inflammation.
Authors: Berg, David D; Alviar, Carlos L; Bhatt, Ankeet S; Baird-Zars, Vivian M; Barnett, Christopher F; Daniels, Lori B; Defilippis, Andrew P; Fagundes, Antonio Jr; Katrapati, Praneeth; Kenigsberg, Benjamin B; Guo, Jianping; Keller, Norma; Lopes, Mathew S; Mody, Anika; Papolos, Alexander I; Phreaner, Nicholas; Sedighi, Romteen; Sinha, Shashank S; Toomu, Sandeep; Varshney, Anubodh S; Morrow, David A; Bohula, Erin A
J Card Fail. 2022 Apr;28(4):675-681. doi: 10.1016/j.cardfail.2021.12.020. Epub 2022 Jan 17.
Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.
Authors: Salah, Husam M; Verma, Subodh; Santos-Gallego, Carlos G; Bhatt, Ankeet S; Vaduganathan, Muthiah; Khan, Muhammad Shahzeb; Lopes, Renato D; Al'Aref, Subhi J; McGuire, Darren K; Fudim, Marat
J Cardiovasc Transl Res. 2022 Mar 15. pii: 10.1007/s12265-022-10220-5. doi: 10.1007/s12265-022-10220-5.
Reply: Bounded Rationality and Clinical Guidance Documents for Heart Failure.
Authors: Ostrominski, John W; Hirji, Sameer; Bhatt, Ankeet S; Vaduganathan, Muthiah
JACC Heart Fail. 2022 Mar;10(3):213-214. doi: 10.1016/j.jchf.2022.01.002.
Personalizing Comprehensive Disease-Modifying Therapy: Obstacles and Opportunities.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah; Ibrahim, Nasrien E
JACC Heart Fail. 2022 Feb;10(2):85-88. doi: 10.1016/j.jchf.2021.10.008. Epub 2021 Dec 8.
Relationship Between Myocardial Injury During Index Hospitalization for SARS-CoV-2 Infection and Longer-Term Outcomes.
Background Myocardial injury in patients with COVID-19 is associated with increased mortality during index hospitalization; however, the relationship to long-term sequelae of SARS-CoV-2 is unknown. This study assessed the relationship between myocardial injury (high-sensitivity cardiac troponin T level) during index hospitalization for COVID-19 and longer-term outcomes. Methods and Results This is a prospective cohort of patients who were hospitalized at a single center between March and May 2020 with SARS-CoV-2. Cardiac biomarkers were systematically collected. Outcomes were adjudicated and stratified on the basis of myocardial injury. The study cohort includes 483 patients who had high-sensitivity cardiac troponin T data during their index hospitalization. During index hospitalization, 91 (18.8%) died, 70 (14.4%) had thrombotic complications, and 126 (25.6%) had cardiovascular complications. By 12 months, 107 (22.2%) died. During index hospitalization, 301 (62.3%) had cardiac injury (high-sensitivity cardiac troponin T>==14 ng/L); these patients had 28.6%, 32.2%, and 33.2% mortality during index hospitalization, at 6 months, and at 12 months, respectively, compared with 4.1%, 4.9%, and 4.9% mortality for those with low-level positive troponin and 0%, 0%, and 0% for those with undetectable troponin. Of 392 (81.2%) patients who survived the index hospitalization, 94 (24%) had at least 1 readmission within 12 months, of whom 61 (65%) had myocardial injury during the index hospitalization. Of 377 (96%) patients who were alive and had follow-up after the index hospitalization, 211 (56%) patients had a documented, detailed clinical assessment at 6 months. A total of 78 of 211 (37.0%) had ongoing COVID-19-related symptoms; 34 of 211 (16.1%) had neurocognitive decline, 8 of 211 (3.8%) had increased supplemental oxygen requirements, and 42 of 211 (19.9%) had worsening functional status. Conclusions Myocardial injury during index hospitalization for COVID-19 was associated with increased mortality and may predict who are more likely to have postacute sequelae of COVID-19. Among patients who survived their index hospitalization, the incremental mortality through 12 months was low, even among troponin-positive patients.
Authors: Weber, Brittany; Siddiqi, Hasan; Zhou, Guohai; Vieira, Jefferson; Kim, Andy; Rutherford, Henry; Mitre, Xhoi; Feeley, Monica; Oganezova, Karina; Varshney, Anubodh S; Bhatt, Ankeet S; Nauffal, Victor; Atri, Deepak S; Blankstein, Ron; Karlson, Elizabeth W; Di Carli, Marcelo; Baden, Lindsey R; Bhatt, Deepak L; Woolley, Ann E
J Am Heart Assoc. 2022 Jan 4;11(1):e022010. doi: 10.1161/JAHA.121.022010. Epub 2021 Dec 31.
Cost and Value in Contemporary Heart Failure Clinical Guidance Documents.
OBJECTIVES: This study sought to evaluate the frequency and nature of cost/value statements in contemporary heart failure (HF) clinical guidance documents (CGDs). BACKGROUND: In an era of rising health care costs and expanding therapeutic options, there is an increasing need for formal consideration of cost and value in the development of HF CGDs. METHODS: HF CGDs published by major professional cardiovascular organizations between January 2010 and February 2021 were reviewed for the inclusion of cost/value statements. RESULTS: Overall, 33 documents were identified, including 5 (15%) appropriate use criteria, 7 (21%) clinical practice guidelines, and 21 (64%) expert consensus documents. Most CGDs (27 of 33; 82%) included at least 1 cost/value statement, and 20 (61%) CGDs included at least 1 cost/value-related citation. Most of these statements were found in expert consensus documents (77.7%). Three (9%) documents reported estimated costs of recommended interventions, but only 1 estimated out-of-pocket cost. Of 179 cost/value-related statements observed, 116 (64.8%) highlighted the economic impact of HF or HF-related care, 6 (3.4%) advocated for cost/value issues, 15 (8.4%) reported gaps in cost/value evidence, and 42 (23.5%) supported clinical guidance recommendations. Over time, patterns of inclusion of statements and citations of cost/value have been largely stable. CONCLUSIONS: Although most contemporary HF CGDs contain at least 1 cost/value statement, most CGDs focus on the high economic impact of HF and its related care; explicit inclusion of cost/value to support clinical guidance recommendations remains infrequent. These results highlight key opportunities for the integration of formalized cost/value considerations in future HF-focused CGDs.
Authors: Ostrominski, John W; Hirji, Sameer; Bhatt, Ankeet S; Butler, Javed; Fiuzat, Mona; Fonarow, Gregg C; Heidenreich, Paul A; Januzzi, James L Jr; Lam, Carolyn S P; Maddox, Thomas M; O'Connor, Christopher M; Vaduganathan, Muthiah
JACC Heart Fail. 2022 Jan;10(1):1-11. doi: 10.1016/j.jchf.2021.08.002. Epub 2021 Nov 10.
Building a Curriculum for the Cardiovascular Implementation Scientist.
Authors: Bhatt, Ankeet S; Lee, Simin; Vaduganathan, Muthiah
J Am Coll Cardiol. 2022 Sep 6;80(10):1023-1027. doi: 10.1016/j.jacc.2022.06.028.
Sacubitril/valsartan use patterns among older adults with heart failure in clinical practice: a population-based cohort study of >25 000 Medicare beneficiaries.
AIMS: Sacubitril/valsartan is strongly supported in guidelines for the management of heart failure, but suboptimal adherence and treatment non-persistence may limit the population-level benefit that this therapy might otherwise offer. METHODS AND RESULTS: We identified a cohort of Medicare beneficiaries (2014-2017) initiating sacubitril/valsartan after >/=6 months of continuous enrolment. We assessed adherence as the proportion of days covered (PDC) and proportion of patients non-persistent (having no prescription available) at 180 days after initiation. We fit a multivariable negative binomial model with a count of adherent days to evaluate independent factors associated with of sacubitril/valsartan adherence. Among 27 063 new sacubitril/valsartan users, most (n = 17 663, 65%) were prescribed low-dose at 24 mg/26 mg and most (n = 19 984, 74%) were switched from prior angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) rather than being RASi treatment naive. Median 180-day PDC was 86% (25th-75th percentiles 58-98%). Black patients, those with high comorbid disease burden (>/=8 comorbidities), and patients with recent hospitalization within 30 days had fewer adherent days, while those treated with preceding ACEi/ARB had more adherent days. Thirty-four percent of patients did not have an active sacubitril/valsartan prescription at day 180. Among these, few had preceding dose down-titrations (6% among patients on 49 mg/51 mg and 9% among patients on 97 mg/103 mg) and 68% did not have a subsequent ACEi/ARB prescription. Among patients who remained persistent, dose up-titrations occurred in 29% of patients who started on 24 mg/26 mg and 27% of patients on 49 mg/51 mg. CONCLUSIONS: Overall adherence to sacubitril/valsartan among Medicare beneficiaries is acceptable, but is lower in Black patients, those with higher comorbidities or those who started therapy after recent hospitalization. While broad implementation of guideline-directed medical therapy is a key priority, additional focused efforts to improve adherence early after hospitalization and among at-risk patients are needed in parallel.
Authors: Bhatt, Ankeet S; Vaduganathan, Muthiah; Solomon, Scott D; Schneeweiss, Sebastian; Lauffenburger, Julie C; Desai, Rishi J
Eur J Heart Fail. 2022 Sep;24(9):1506-1515. doi: 10.1002/ejhf.2572. Epub 2022 Jun 22.
Vaccines, Antibodies and Donors: Varying Attitudes and Policies Surrounding COVID-19 and Heart Transplantation.
INTRODUCTION: There are varied opinions in the United States regarding many aspects of care related to COVID-19. The purpose of this study was to examine the opinions of health care personnel and the policies of heart transplant centers concerning practices for the prevention and treatment of COVID-19 in donors and recipients of heart transplants. METHODS: Two anonymous, electronic web-based surveys were developed: 1 was administered to health care personnel through a mailing list maintained by the Heart Failure Society of America (HFSA); another was administered to U.S. medical adult and pediatric heart transplant (HT) program directors. Individual and group e-mails were sent with an embedded link to the respective surveys in February 2022. RESULTS: A total of 176 individuals (8.6%) responded to the survey administered through the HFSA. Of medical directors of transplant programs, 78 (54% response rate) completed a separate survey on their centers’ policies. Although 95% (n = 167) of individuals indicated vaccination against COVID-19 should be required prior to HT, only 67% (n = 52) of centers mandated that practice. Similarly, 61% of individuals thought vaccination should be required prior to HT for caregivers, but only 13% of transplant centers mandated caregiver vaccination. Of the centers, 63% reported considering donors despite histories of recent COVID-19 infection (within 3 months), and 47% considered donors with current positive polymerase chain reaction tests. Regarding post-transplant care, only 22% of programs routinely measured antibodies to COVID-19, and 71% used tixagevimab/cilgavimab (Evusheld) for pre-exposure prophylaxis. CONCLUSIONS: There were significant differences between individual preferences and centers’ practices with respect to COVID-19 management of candidates for and recipients of HT. Additionally, there was wide variation in policies among centers, reflecting the need for further study to inform consistent guidance and recommendations across centers to optimize equitable care for this high-risk patient population.
Authors: Defilippis, Ersilia M; Allen, Larry A; Bhatt, Ankeet S; Joseph, Susan; Kittleson, Michelle; Vardeny, Orly; Drazner, Mark H; Lala, Anuradha
J Card Fail. 2022 Jun 16. pii: S1071-9164(22)00537-1. doi: 10.1016/j.cardfail.2022.05.009.
Epidemiology and Management of ST-Segment-Elevation Myocardial Infarction in Patients With COVID-19: A Report From the American Heart Association COVID-19 Cardiovascular Disease Registry.
Background Early reports from the COVID-19 pandemic identified coronary thrombosis leading to ST-segment-elevation myocardial infarction (STEMI) as a complication of COVID-19 infection. However, the epidemiology of STEMI in patients with COVID-19 is not well characterized. We sought to determine the incidence, diagnostic and therapeutic approaches, and outcomes in STEMI patients hospitalized for COVID-19. Methods and Results Patients with data on presentation ECG and in-hospital myocardial infarction were identified from January 14, 2020 to November 30, 2020, from 105 sites participating in the American Heart Association COVID-19 Cardiovascular Disease Registry. Patient characteristics, resource use, and clinical outcomes were summarized and compared based on the presence or absence of STEMI. Among 15 621 COVID-19 hospitalizations, 54 (0.35%) patients experienced in-hospital STEMI. Among patients with STEMI, the majority (n=40, 74%) underwent transthoracic echocardiography, but only half (n=27, 50%) underwent coronary angiography. Half of all patients with COVID-19 and STEMI (n=27, 50%) did not undergo any form of primary reperfusion therapy. Rates of all-cause shock (47% versus 14%), cardiac arrest (22% versus 4.8%), new heart failure (17% versus 1.4%), and need for new renal replacement therapy (11% versus 4.3%) were multifold higher in patients with STEMI compared with those without STEMI (P<0.050 for all). Rates of in-hospital death were 41% in patients with STEMI, compared with 16% in those without STEMI (P<0.001). Conclusions STEMI in hospitalized patients with COVID-19 is rare but associated with poor in-hospital outcomes. Rates of coronary angiography and primary reperfusion were low in this population of patients with STEMI and COVID-19. Adaptations of systems of care to ensure timely contemporary treatment for this population are needed.
Authors: Bhatt, Ankeet S; Varshney, Anubodh S; Goodrich, Erica L; Gong, Jingyi; Ginder, Curtis; Senman, Balimkiz C; Johnson, Matthew; Butler, Kayleigh; Woolley, Ann E; de Lemos, James A; Morrow, David A; Bohula, Erin A
J Am Heart Assoc. 2022 May 3;11(9):e024451. doi: 10.1161/JAHA.121.024451. Epub 2022 Apr 26.
Extracting patient-level data from the electronic health record: Expanding opportunities for health system research
Epidemiological studies of interstitial lung disease (ILD) are limited by small numbers and tertiary care bias. Investigators have leveraged the widespread use of electronic health records (EHRs) to overcome these limitations, but struggle to extract patient-level, longitudinal clinical data needed to address many important research questions. We hypothesized that we could automate longitudinal ILD cohort development using the EHR of a large, community-based healthcare system. We applied a previously validated algorithm to the EHR of a community-based healthcare system to identify ILD cases between 2012-2020. We then extracted disease-specific characteristics and outcomes using fully automated data-extraction algorithms and natural language processing of selected free-text. We identified a community cohort of 5,399 ILD patients (prevalence = 118 per 100,000). Pulmonary function tests (71%) and serologies (54%) were commonly used in the diagnostic evaluation, whereas lung biopsy was rare (5%). IPF was the most common ILD diagnosis (n = 972, 18%). Prednisone was the most commonly prescribed medication (911, 17%). Nintedanib and pirfenidone were rarely prescribed (n = 305, 5%). ILD patients were high-utilizers of inpatient (40%/year hospitalized) and outpatient care (80%/year with pulmonary visit), with sustained utilization throughout the post-diagnosis study period. We demonstrated the feasibility of robustly characterizing a variety of patient-level utilization and health services outcomes in a community-based EHR cohort. This represents a substantial methodological improvement by alleviating traditional constraints on the accuracy and clinical resolution of such ILD cohorts; we believe this approach will make community-based ILD research more efficient, effective, and scalable.
Authors: Farrand, Erica; Collard, Harold R; Guarnieri, Michael; Minowada, George; Block, Lawrence; Lee, Mei; Iribarren, Carlos
PLoS One. 2023;18(3):e0280342. Epub 2023-03-10.
Evaluating Implementation Approaches in Heart Failure: Ripe for rEVOLUTION
Authors: Bhatt, Ankeet S; Slade, Justin J
JACC Heart Fail. 2023 Jan;11(1):15-18. Epub 2022-12-07.
A common IGF1R gene variant predicts later life breast cancer risk in women with preeclampsia
Preeclampsia has been inconsistently associated with altered later life risk of cancer. This study utilizes the Nurses’ Health Study 2 (NHS2) to determine if the future risk of breast and non-breast cancers in women who experience preeclampsia is modified by carrying a protective variant of rs2016347, a functional insulin-like growth factor receptor-1 (IGF1R) single nucleotide polymorphism. This retrospective cohort study completed within the NHS2 evaluated participants enrolled in 1989 and followed them through 2015, with a study population of 86,751 after exclusions. Cox proportional hazards models both with and without the impact of rs2016347 genotype were used to assess the risk of invasive breast cancer, hormone receptor-positive (HR+) breast cancer, and non-breast cancers. Women with preeclampsia had no change in risk of all breast, HR+?breast, or non-breast cancers when not considering genotype. However, women carrying at least one T allele of rs2016347 had a lower risk of HR+?breast cancer, HR�0.67, 95% CI: 0.47-0.97, P?=?0.04, with interaction term P?=?0.06. For non-breast cancers as a group, women carrying a T allele had an HR�0.76, 95% CI: 0.53-1.08, P?=?0.12, with interaction term P?=?0.26. This retrospective cohort study found that women with preeclampsia who carry a T allele of IGF1R rs2016347 had a reduced future risk of developing HR+?breast cancer, and a reduced but not statistically significant decreased risk of non-breast cancers suggesting a possible role for the IGF-1 axis in the development of cancer in these women.
Authors: Powell, Mark; Fuller, Sophia; Gunderson, Erica; Benz, Christopher
Breast Cancer Res Treat. 2023 Jan;197(1):149-159. Epub 2022-11-04.
Predicting Post-Sepsis Cardiovascular Events with Death as a Competing Risk
Authors: Myers, Laura C; Lee, Catherine; Go, Alan S; Liu, Vincent X; Walkey, Allan J; et al.
Ann Am Thorac Soc. 2023 Jan;20(1):145-148.
Cardiovascular Disease Risk Factors Among Middle-Aged and Older Adult Vietnamese American Members of a Northern California Health Plan
There is increasing recognition that cardiovascular disease (CVD) risk factors vary by Asian subgroups. We examined CVD risk factor prevalence among Vietnamese adults in a northern California health plan. We used electronic health record data to examine smoking, overweight/obesity (body mass index ≥23.0 kg/m2), obesity (body mass index ≥27.5 kg/m2), prediabetes, diabetes, and hypertension among middle-aged (n = 12 757; aged 45-64 years) and older (n = 3418; aged 65-84 years) Vietnamese adults, including 37.8% whose preferred language was Vietnamese. Findings were compared with East Asian adults. Current smoking prevalence was 20.3% for middle-aged men, 7.0% for older men, and <1% for women in both age groups. Obesity prevalence was 12.0% for older men, 17.9% for middle-aged men, and 10% for women in both age groups. Among middle-aged men and women, 20.9% and 17.0% had hypertension and 13.5% and 8.5% had diabetes, respectively. Among older men and women, 64.0% and 60.0% had hypertension and 32.8% and 29.3% had diabetes, respectively. In both age groups, Vietnamese language preference was associated with higher risk of smoking (men only) and of diabetes and hypertension (women only). Compared with East Asian adults, Vietnamese adults had lower obesity prevalence but similar prevalence of diabetes, prediabetes, and hypertension. Vietnamese men were more likely and Vietnamese women less likely than East Asian adults to be current smokers. Study results suggest that more research on health conditions, lifestyle, and social factors among Vietnamese American adults is needed to develop culturally competent interventions to reduce CVD risk in this growing ethnic group.
Authors: Haysbert, Donna B; Lo, Joan C; Ramalingam, Nirmala D; Gordon, Nancy P
Public Health Rep. 2023 Jan-Feb;138(1):123-130. Epub 2022-02-20.
Asthma and COVID-19 Outcomes: A Prospective Study in a Large Health Care Delivery System
Previous studies on the outcomes of asthma and COVID-19 have shown inconsistent results. This study aimed to elucidate the association between asthma and COVID-19 outcomes. We conducted a prospective study with a large health plan to compare the incidence of COVID-19 infection, hospitalization and ICU admission in a cohort of 41,282 patients with asthma and a 1:1 age-, sex-, and race-ethnicity-matched cohort without asthma across the following pandemic periods: pre-Delta (03/01/2020 to 05/31/2021), Delta (06/01/2021 to 12/31/2021), and Omicron (01/01/2022 to 08/13/2022). Demographic factors, comorbidities, COVID-19 test results, inpatient utilization, and COVID-19 vaccination status were collected from electronic health records. Subjects with asthma were more likely than controls to undergo COVID-19 testing during the three pandemic periods and were less likely to test positive in the Omicron period (fully adjusted odds ratio=0.92; 95% CI=0.86-0.98; p=0.01). Relative to controls, patients with asthma had an increased risk of hospitalization for COVID-19 (fully adjusted hazard ratio=1.33; 95% CI=1.08-1.64; p=0.01) and borderline significant (p=0.05) higher rates of ICU admissions in the pre-delta period but not during the delta or Omicron periods. The increased risk of COVID-19 hospitalization associated with asthma was more pronounced in patients with severe asthma and in women compared with men. None of the associations were significantly modified by vaccination status. Asthma was associated with a lower risk of COVID-19 infection but only during the Omicron period. Asthma was an independent risk factor for hospitalization for COVID-19 in the pre-delta period and this association was stronger for severe asthma and in women.
Authors: Finkas, Lindsay K;Ramesh, Navneet;Block, Lawrence S;Yu, Bing Q;Lee, Mei-Tsung;Lu, Meng;Skarbinski, Jacek;Iribarren, Carlos
J Asthma Allergy. 2023;16:1041-1051. Epub 2023-09-26.
Elevated Serum Androstenedione Level in a Patient With Ectopic Adrenocorticotropic Hormone Syndrome
Ectopic Cushing syndrome can be challenging to diagnose when its presentation is atypical. Herein, we highlight features of ectopic adrenocorticotropic hormone (ACTH) syndrome in a patient with worsening hypertension, hypokalemia, ACTH-dependent hypercortisolism, and disproportionate elevation in serum androstenedione levels. A 59-year-old woman presented with rapidly progressing hypertension, severe hypokalemia, confusion, and weakness. Her medical history included well-controlled hypertension receiving amlodipine 5 mg/day, which worsened 3 months prior to admission requiring losartan and spironolactone therapy, with twice daily potassium supplementation. Physical examination was notable for bruising, muscle wasting, thin extremities, facial fullness, and abdominal adiposity despite body mass index 17 kg/m2. Laboratory evaluation showed potassium 2.6 mEq/L (3.5-5.3), morning cortisol >50 mcg/dL (8-25), 24-hour urine cortisol 8369 mcg/day (<50), ACTH 308 pg/mL (<46), androstenedione 398 ng/dL (20-75), dehydroepiandrosterone sulfate 48 mcg/dL (≤430), and testosterone 11 ng/dL (≤4.5) levels. A 3.8-cm carcinoid right lung tumor was identified, and resection was performed with clean margins. Cortisol, androstenedione, and potassium levels rapidly normalized postoperatively and blood pressure returned to baseline, well-controlled on amlodipine. Our case illustrates disproportionate elevation in androstenedione levels despite normal dehydroepiandrosterone sulfate and testosterone in a woman with ectopic ACTH syndrome. Limited reports have observed similar discordance in androgen profiles in ectopic versus pituitary ACTH hypersecretion, potentially attributable to differential activation of androgen biosynthesis. Adrenal androgen assessment may help differentiate pituitary versus ectopic ACTH secretion in which androstenedione is elevated, but studies are needed to determine whether disproportionate androstenedione elevation reliably predicts the origin of ACTH excess.
Authors: Zhang, Sherry;Lo, Joan C;Jaffe, Marc G;Arzumanyan, Hasmik
AACE Clin Case Rep. 2023 Sep-Oct;9(5):142-145. Epub 2023-04-23.
Implementation and effectiveness of a physician-focused peer support program
The practice of medicine faces a mounting burnout crisis. Physician burnout leads to worse mental health outcomes, provider turnover, and decreased quality of care. Peer support, a viable strategy to combat burnout, has been shown to be well received by physicians. This study evaluates the Peer Outreach Support Team (POST) program, a physician-focused peer support initiative established in a 2-hospital system, using descriptive statistical methodologies. We evaluate the POST program using the Practical Robust Implementation and Sustainability Model (PRISM) framework to describe important contextual factors including characteristics of the intervention, recipients, implementation and sustainability infrastructure, and external environment, and to assess RE-AIM outcomes including reach, effectiveness, adoption, implementation, and maintenance. This program successfully trained 59 peer supporters across 11 departments in a 2-hospital system over a 3-year period. Trained supporters unanimously felt the training was useful and aided in general departmental culture shift (100% of respondents). After 3 years, 48.5% of physician survey respondents across 5 active departments had had a peer support interaction, with 306 successful interactions recorded. The rate of interactions increased over the 3-year study period, and the program was adopted by 11 departments, representing approximately 60% of all physicians in the 2-hospital system. Important implementation barriers and facilitators were identified. Physician recipients of peer support reported improved well-being, decreased negative emotions and stigma, and perceived positive cultural changes within their departments. We found that POST, a physician-focused peer support program, had widespread reach and a positive effect on perceived physician well-being and departmental culture. This analysis outlines a viable approach to support physicians and suggests future studies considering direct effectiveness measures and programmatic adaptations. Our findings can inform and guide other healthcare systems striving to establish peer support initiatives to improve physician well-being.
Authors: Tolins, Molly L;Rana, Jamal S;Lippert, Suzanne;LeMaster, Christopher;Kimura, Yusuke F;Sax, Dana R
PLoS One. 2023;18(11):e0292917. Epub 2023-11-01.
CKD stage-specific utility of two equations for predicting 1-year risk of ESKD
The Kidney Failure Risk Equation (KFRE) and Kaiser Permanente Northwest (KPNW) models have been proposed to predict progression to ESKD among adults with CKD within 2 and 5 years. We evaluated the utility of these equations to predict the 1-year risk of ESKD in a contemporary, ethnically diverse CKD population. We conducted a retrospective cohort study of adult members of Kaiser Permanente Northern California (KPNC) with CKD Stages 3-5 from January 2008-September 2015. We ascertained the onset of ESKD through September 2016, and calculated stage-specific estimates of model discrimination and calibration for the KFRE and KPNW equations. We identified 108,091 eligible adults with CKD (98,757 CKD Stage 3; 8,384 CKD Stage 4; and 950 CKD Stage 5 not yet receiving kidney replacement therapy), with mean age of 75 years, 55% women, and 37% being non-white. The overall 1-year risk of ESKD was 0.8% (95%CI: 0.8-0.9%). The KFRE displayed only moderate discrimination for CKD 3 and 5 (c = 0.76) but excellent discrimination for CKD 4 (c = 0.86), with good calibration for CKD 3-4 patients but suboptimal calibration for CKD 5. Calibration by CKD stage was similar to KFRE for the KPNW equation but displayed worse calibration across CKD stages for 1-year ESKD prediction. In a large, ethnically diverse, community-based CKD 3-5 population, both the KFRE and KPNW equation were suboptimal in accurately predicting the 1-year risk of ESKD within CKD stage 3 and 5, but more accurate for stage 4. Our findings suggest these equations can be used in1-year prediction for CKD 4 patients, but also highlight the need for more personalized, stage-specific equations that predicted various short- and long-term adverse outcomes to better inform overall decision-making.
Authors: Zheng, Sijie;Parikh, Rishi V;Tan, Thida C;Pravoverov, Leonid;Patel, Jignesh K;Horiuchi, Kate M;Go, Alan S
PLoS One. 2023;18(11):e0293293. Epub 2023-11-01.
Association of diabetes with coronary artery calcium in South Asian adults and other race/ethnic groups: The multi-ethnic study of atherosclerosis and the mediators of atherosclerosis in South Asians living in America study
South Asian (SA) persons have increased risks for diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD). We examined whether the association of DM with subclinical atherosclerosis assessed by coronary artery calcium (CAC) differs in SA versus other ethnic groups. We studied adults from the Multi-Ethnic Study of Atherosclerosis and the Mediators of Atherosclerosis in South Asians Living in America studies without ASCVD. CAC was examined among those normoglycemic, pre-DM and DM. Logistic regression examined pre-DM and DM with the odds of any CAC > 0 and CAC ≥ 100. Among 7562 participants, CAC > 0 and CAC ≥ 100 in those with DM was highest in non-Hispanic White (NHW) (80% and 48%) and SA (72% and 41%) persons. Adjusted Ln (CAC + 1) was highest in NHW (3.68 ± 0.21) and SA (3.60 ± 0.23) (p < .01) DM patients. SA and NHW adults with DM (vs normoglycemic) had highest odds of CAC > 0 (2.13 and 2.27, respectively, p < .01). For CAC ≥ 100, SA and Chinese adults had the highest odds (2.28 and 2.27, respectively, p < .01). Fasting glucose and glycated hemoglobin were most strongly associated with CAC among SA. Diabetes mellitus most strongly relates to any CAC in SA and NHW adults and CAC ≥ 100 in SA and Chinese adults, helping to explain the relation of DM with ASCVD in these populations.
Authors: Premyodhin, Ned;Fan, Wenjun;Arora, Millie;Budoff, Matthew J;Kanaya, Alka M;Kandula, Namratha;Palaniappan, Latha;Rana, Jamal S;Younus, Masood;Wong, Nathan D
Diab Vasc Dis Res. 2023 Sep-Oct;20(5):14791641231204368.
The evolving role of data & safety monitoring boards for real-world clinical trials
Clinical trials provide the “gold standard” evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources – data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor. Three examples of real-world trials that leverage different types of data sources – wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived. Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity. Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials.
Authors: Bunning, Bryan J;Go, Alan;Desai, Manisha;et al.
J Clin Transl Sci. 2023;7(1):e179. Epub 2023-08-02.
Performance of the pooled cohort equation in South Asians: insights from a large integrated healthcare delivery system
South Asian ethnicity is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk and has been identified as a “risk enhancer” in the 2018 American College of Cardiology/American Heart Association Guidelines. Risk estimation and statin eligibility in South Asians is not well understood; we studied the accuracy of 10-years ASCVD risk prediction by the pooled cohort equation (PCE), based on statin use, in a South Asian cohort. This is a retrospective cohort study of Kaiser Permanente Northern California South Asian members without existing ASCVD, age range 30-70, and 10-years follow up. ASCVD events were defined as myocardial infarction, ischemic stroke, and cardiovascular death. The cohort was stratified by statin use during the study period: never; at baseline and during follow-up; and only during follow-up. Predicted probability of ASCVD, using the PCE was calculated and compared to observed ASCVD events for low < 5.0%, borderline 5.0 to < 7.5%, intermediate 7.5 to < 20.0%, and high ≥ 20.0% risk groups. A total of 1835 South Asian members were included: 773 never on statin, 374 on statins at baseline and follow-up, and 688 on statins during follow-up only. ASCVD risk was underestimated by the PCE in low-risk groups: entire cohort: 1.8 versus 4.9%, p < 0.0001; on statin at baseline and follow-up: 2.58 versus 8.43%, p < 0.0001; on statin during follow-up only: 2.18 versus 7.77%, p < 0.0001; and never on statin: 1.37 versus 2.09%, p = 0.12. In this South Asian cohort, the PCE underestimated risk in South Asians, regardless of statin use, in the low risk ASCVD risk category.
Authors: Mantri, Neha M; Merchant, Maqdooda; Rana, Jamal S; Go, Alan S; Pursnani, Seema K
BMC Cardiovasc Disord. 2022 Dec 23;22(1):566. Epub 2022-12-23.
Reply to M.S. Ewer et al
Authors: Greenlee, Heather; Rillamas-Sun, Eileen; Cheng, Richard; Iribarren, Carlos; Rana, Jamal S; Nguyen-Huynh, Mai; Kushi, Lawrence H; Kwan, Marilyn L
J Clin Oncol. 2022 Dec 10;40(35):4159-4160. Epub 2022-07-25.
Investigating the Association Between Telemedicine Use and Timely Follow-Up Care After Acute Cardiovascular Hospital Encounters
Telemedicine use increased dramatically during the COVID-19 pandemic; however, questions remain as to how telemedicine use impacts care. The purpose of this study was to examine the association of increased telemedicine use on rates of timely follow-up and unplanned readmission after acute cardiovascular hospital encounters. We examined hospital encounters for acute coronary syndrome, arrhythmia disorders, heart failure (HF), and valvular heart disease from a large U.S., multisite, integrated academic health system among patients with established cardiovascular care within the system. We evaluated 14-day postdischarge follow-up and 30-day all-cause unplanned readmission rates for encounters from the pandemic “steady state” period from May 24, 2020 through December 31, 2020, when telemedicine use was high and compared them to those of encounters from the week-matched period in 2019 (May 26, 2019, through December 31, 2019), adjusting for patient and encounter characteristics. The study population included 6,026 hospital encounters. In the pandemic steady-state period, 40% of follow-ups after these encounters were conducted via telemedicine vs 0% during the week-matched period in 2019. Overall, 14-day follow-up rates increased from 41.7% to 44.9% (adjusted difference: +2.0 percentage points [pp], 95% CI: -1.1 to +5.1 pp, P = 0.20). HF encounters experienced the largest improvement from 50.1% to 55.5% (adjusted difference: +6.5 pp, 95% CI: +0.5 to +12.4 pp, P = 0.03). Overall 30-day all-cause unplanned readmission rates fell slightly, from 18.3% to 16.9% (adjusted difference -1.6 pp; 95% CI: -4.0 to +0.8 pp, P = 0.20). Increased telemedicine use during the COVID-19 pandemic was associated with earlier follow-ups, particularly after HF encounters. Readmission rates did not increase, suggesting that the shift to telemedicine did not compromise care quality.
Authors: Tang, Mitchell; Holmgren, A Jay; McElrath, Erin E; Bhatt, Ankeet S; Varshney, Anubodh S; Lee, Simin G; Vaduganathan, Muthiah; Adler, Dale S; Huckman, Robert S
JACC Adv. 2022 Dec;1(5):100156. Epub 2022-12-30.
High-sensitivity troponin I is associated with cardiovascular outcomes but not with breast arterial calcification among postmenopausal women
Prior studies support the utility of high sensitivity troponin I (hsTnI) for cardiovascular disease (CVD) risk stratification among asymptomatic populations; however, only two prior studies examined women separately. The association between hsTnI and breast arterial calcification is unknown. Cohort study of 2896 women aged 60-79 years recruited after attending mammography screening between 10/2012 and 2/2015. BAC status (presence versus absence) and quantity (calcium mass mg) was determined using digital mammograms. Pre-specified endpoints were incident coronary heart disease (CHD), ischemic stroke, heart failure and its subtypes and all CVD. After 7.4 (SD = 1.7) years of follow-up, 51 CHD, 30 ischemic stroke and 46 heart failure events were ascertained. At a limit of detection of 1.6 ng/L, 98.3 of the cohort had measurable hsTnI concentration. HsTnI in the 4-10 ng/L range were independently associated of CHD (adjusted hazard ratio[aHR] = 2.78; 95% CI, 1.48-5.22; p = 0.002) and all CVD (aHR = 2.06; 95% CI, 1.37-3.09; p = 0.0005) and hsTnI over 10 ng/L was independently associated with CHD (aHR = 4.75; 95% CI, 1.83-12.3; p = 0.001), ischemic stroke (aHR = 3.81; 95% CI, 1.22-11.9; p = 0.02), heart failure (aHR = 3.29; 95% CI, 1.33-8.13; p = 0.01) and all CVD (aHR = 4.78; 95% CI, 2.66-8.59; p < 0.0001). No significant association was found between hsTnI and BAC. Adding hsTnI to a model containing the Pooled Cohorts Equation resulted in significant and clinical important improved calibration, discrimination (Δ Cindex = 6.5; p = 0.02) and reclassification (bias-corrected clinical NRI = 0.18; 95% CI, -0.13-0.49 after adding hsTnI categories). Our results support the consideration of hsTnI as a risk enhancing factor for CVD in asymptomatic women that could drive preventive or therapeutic decisions.
Authors: Iribarren, Carlos; Chandra, Malini; Lee, Catherine; Sanchez, Gabriela; Sam, Danny L; Azamian, Farima Faith; Cho, Hyo-Min; Ding, Huanjun; Wong, Nathan D; Molloi, Sabee
Int J Cardiol Cardiovasc Risk Prev. 2022 Dec;15:200157. Epub 2022-11-01.
Decreasing Trends in Reintervention and Readmission After Endovascular Aneurysm Repair in a Multiregional Implant Registry
As endovascular aortic aneurysm repair (EVAR) matures into its third decade, measures such as long-term reintervention and readmission have become a focus of quality improvement efforts. Within a large United States integrated health care system, we describe time trends in the rates of long-term reinterventions utilization measures. Data from a United States multiregional EVAR registry was used to perform a descriptive study of 3891 adults who underwent conventional infrarenal EVAR for infrarenal abdominal aortic aneurysm between 2010 and 2019. Three-year follow-up was 96.7%. Outcomes included 1-, 3-, and 5-year graft revision (defined as a procedure involving placement of a new endograft component), secondary interventions (defined as a procedure necessary for maintenance of EVAR integrity [eg, coil embolization and balloon angioplasty/stenting]), conversion to open, interventions for type II endoleaks alone, and 90-day readmission. Crude cause-specific reintervention probabilities were calculated by operative year using the Aalen-Johansen estimator, with death as a competing risk and December 31, 2020 as the study end date. Excluding interventions for type II endoleak alone, 1-year secondary intervention incidence decreased from 5.9% for EVARs in 2010 to 2.0% in 2019 (P < .001) and 3-year incidence decreased from 7.2% to 3.6% from 2010 to 2017 (P = .03). The 3-year incidences of graft revision (mean incidence, 3.4%) and conversion to open remained fairly stable (mean incidence, 0.6%) over time. The 3-year incidence of interventions for type II endoleak alone also decreased from 3.4% in 2010 to 0.7% in 2017 (P = .01). Ninety-day readmission rates decreased from 19.3% for index EVAR in 2010 to 9.2% in 2019 (P = .03). Comprehensive data from a multiregional health care system demonstrates decreasing long-term secondary intervention and readmission rates over time in patients undergoing EVAR. These trends are not explained by evolving management of type II endoleaks and suggest improving graft durability, patient selection, or surgical technique. Further study is needed to define implant and anatomic predictors of different types of long-term reintervention.
Authors: Le, Sidney T; Prentice, Heather A; Harris, Jessica E; Hsu, Jeffrey H; Rehring, Thomas F; Nelken, Nicolas A; Hajarizadeh, Homayon; Chang, Robert W
J Vasc Surg. 2022 Dec;76(6):1511-1519. Epub 2022-06-14.
Adverse events after initiating angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy in individuals with heart failure and multimorbidity
Current clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. However, evidence is lacking on whether routine follow-up testing reduces therapy-related adverse events in adults with heart failure and if multimorbidity influences the association between laboratory testing and these adverse events. We conducted a retrospective cohort study among adults with heart failure from 4 US integrated health care delivery systems. Multimorbidity was defined using counts of chronic conditions. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACEI or ARB therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression. We identified 3629 matched adults with heart failure initiating ACEI or ARB therapy between January 1, 2005, and December 31, 2012. Follow-up testing was not significantly associated with 30-day all-cause mortality (adjusted hazard ratio [aHR] 0.45, 95% confidence interval [CI] 0.14; 1.39) and hospitalization with hyperkalemia (aHR 0.73, 95% CI, 0.33; 1.61). However, follow-up testing was significantly associated with hospitalization with acute kidney injury (aHR, 1.40, 95% CI, 1.01; 1.94). Interaction between multimorbidity burden and follow-up testing was not statistically significant in any of the outcome models examined. Routine laboratory monitoring after ACEI or ARB therapy initiation was not associated with risk of 30-day all-cause mortality or hospitalization with hyperkalemia across the spectrum of multimorbidity burden in a cohort of patients with heart failure.
Authors: Tisminetzky, Mayra; Gurwitz, Jerry H; Tabada, Grace; Reynolds, Kristi; Fortmann, Stephen P; Garcia, Elisha; Pham, Thu; Goldberg, Robert; Go, Alan S
Am J Med. 2022 Dec;135(12):1468-1477. Epub 2022-09-02.
Heart failure during the COVID-19 pandemic: clinical, diagnostic, management, and organizational dilemmas
The coronavirus 2019 (COVID-19) infection pandemic has affected the care of patients with heart failure (HF). Several consensus documents describe the appropriate diagnostic algorithm and treatment approach for patients with HF and associated COVID-19 infection. However, few questions about the mechanisms by which COVID can exacerbate HF in patients with high-risk (Stage B) or symptomatic HF (Stage C) remain unanswered. Therefore, the type of HF occurring during infection is poorly investigated. The diagnostic differentiation and management should be focused on the identification of the HF phenotype, underlying causes, and subsequent tailored therapy. In this framework, the relationship existing between COVID and onset of acute decompensated HF, isolated right HF, and cardiogenic shock is questioned, and the specific management is mainly based on local hospital organization rather than a standardized model. Similarly, some specific populations such as advanced HF, heart transplant, patients with left ventricular assist device (LVAD), or valve disease remain under investigated. In this systematic review, we examine recent advances regarding the relationships between HF and COVID-19 pandemic with respect to epidemiology, pathogenetic mechanisms, and differential diagnosis. Also, according to the recent HF guidelines definition, we highlight different clinical profile identification, pointing out the main concerns in understudied HF populations.
Authors: Palazzuoli, Alberto; Ambrosy, Andrew P; Chioncel, Ovidiu; et al.
ESC Heart Fail. 2022 Dec;9(6):3713-3736. Epub 2022-09-16.
A large genome-wide association study of QT interval length utilizing electronic health records
QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants. Conditional analysis identified 15 additional variants, 3 of which were novel. Little, if any, difference was seen when adjusting for putative QT interval lengthening medications genome-wide. Using multiple measurements in Genetic Epidemiology Research on Adult Health and Aging increased variance explained by 163%, and we show that the ≈6 measurements in Genetic Epidemiology Research on Adult Health and Aging was equivalent to a 2.4× increase in sample size of a design with a single measurement. The array heritability was estimated at ≈17%, approximately half of our estimate of 36% from family correlations. Heritability enrichment was estimated highest and most significant in cardiovascular tissue (enrichment 7.2, 95% CI = 5.7-8.7, P = 2.1e-10), and many of the novel variants included expression quantitative trait loci in heart and other relevant tissues. Comparing our results to other cardiac function traits, it appears that QT interval has a multifactorial genetic etiology.
Authors: Hoffmann, Thomas J; Lu, Meng; Oni-Orisan, Akinyemi; Lee, Catherine; Risch, Neil; Iribarren, Carlos
Genetics. 2022 Nov 30;222(4).
Characteristics and Outcomes of Suspected Digoxin Toxicity and Immune Fab Treatment Over the Past Two Decades-2000-2020
The role of digoxin in clinical practice has narrowed over time. Data on digoxin toxicity trends and outcomes are variable and lack granularity for treatment outcomes. This study aimed to address data gaps in digoxin toxicity trends and outcomes in patients treated with or without digoxin immune fab (DIF). This single-center analysis examined patients with signs/symptoms concerning digoxin toxicity, defined as hospital admission or emergency department visit with elevated digoxin serum concentrations (>2 ng/ml) and/or a primary diagnosis code of digoxin toxicity and/or DIF order. Between 2000 and 2020, 727 patients were identified with signs concerning for digoxin toxicity with a mortality rate of 12.7% during admission and 42.7% at 1 year. DIF was ordered in 9% of cases. Incidence of digoxin toxicity per 1,000 patients with a digoxin prescription and frequency of DIF treatment fluctuated over time without a clear trend toward increase or reduction. DIF-treated patients demonstrated a heavier co-morbidity burden and lower presenting heart rates (median 53 [39.5 to 69.5] vs 77 [64.0 to 91.5] beats/min, p <0.001), worse renal function (median estimated glomerular filtration rate, 30.3 [14.8 to 48.6] vs 40.0 [24.2 to 61.2] ml/min/1.73 m2, p = 0.013), and higher potassium (median 4.5 [4.0 to 5.3] vs 4.3 [3.9 to 4.8] mEq/L, p = 0.022). Compared with a matched cohort, DIF-treated patients experienced a nonsignificant, numerically lower in-hospital mortality (8.2% vs 15.8%, p = 0.199) and 30-day all-cause hospitalization (14.3% vs 24.7%, p = 0.112) and similar 6-month and 1-year hospitalization and mortality. In conclusion, digoxin toxicity remains a pertinent public health issue despite reduction in digoxin utilization. DIF therapy is used in a medically complex population with a high-acuity illness at presentation and is associated with nonsignificant trends toward reduced in-hospital mortality and early readmission that are attenuated over time.
Authors: Peters, Anthony E; Chiswell, Karen; Hofmann, Paul; Ambrosy, Andrew; Fudim, Marat
Am J Cardiol. 2022 Nov 15;183:129-136. Epub 2022-09-09.
Prevalence of sleep-related problems and risks in a community-dwelling older adult population: a cross-sectional survey-based study
Despite evidence of adverse health consequences of inadequate restorative sleep for older adults, assessment of sleep quantity, quality, and use of sleep aids is not routinely done. We aimed to characterize sleep problems, sleep risks, and advice received about sleep in a community-dwelling older adult population, overall and in subgroups with health conditions and functional difficulties. This cross-sectional study used weighted self-report data for 5074 Kaiser Permanente Northern California members aged 65-79y who responded to a 2017 or 2020 Member Health Survey. We estimated usual amount of sleep (< 6, 6 to < 7, ≥7 hours) and prevalence of sleep problems (frequent insomnia, frequent daytime fatigue, poor quality sleep, and potential sleep apnea (OSA) symptoms (frequent very loud snoring, apnea episodes)) for older adults overall, by self-rated health, and in subgroups reporting hypertension, diabetes, heart disease, frequent problems with balance/walking, and frequent memory problems. We also estimated percentages who regularly used sleep aids and had discussed sleep adequacy with a healthcare professional in the past year. Approximately 30% of older adults usually got less than the recommended ≥7 hours sleep per day, and 9% experienced frequent daytime fatigue, 13% frequent insomnia, 18% frequent insomnia/poor quality sleep, and 8% potential OSA symptoms. Prevalence of frequent insomnia was higher among women than men (16% vs. 11%). Higher percentages of those in fair/poor health and those with frequent balance/walking and memory problems reported sleeping < 6 hours per day and having all four types of sleep problems. Nearly 20% of all older adults (22% of women vs. 17% of men) and 45% of those with frequent insomnia (no sex difference) reported regular sleep aid use. Only 10% of older adults reported discussing sleep with a healthcare professional whereas > 20% reported discussing diet and exercise. Large percentages of older adults experience sleep problems or get less sleep than recommended for optimal sleep health. Older patients should routinely be assessed on multiple components of sleep health (sleep hygiene, quantity, quality, problems, and sleep aid use) and educated about sleep hygiene and the importance of getting adequate restorative sleep for their overall health and wellbeing.
Authors: Gordon, Nancy P; Yao, Jimmy H; Brickner, Leslea A; Lo, Joan C
BMC Public Health. 2022 Nov 08;22(1):2045. Epub 2022-11-08.
Health Literacy and Treatment Satisfaction Among Patients with Venous Thromboembolism
Venous thromboembolism (VTE) treatment requires complex management, and patients with limited health literacy (HL) may perceive higher burden and lower benefits associated with their treatment. To examine the association of HL with treatment satisfaction among patients with VTE. Retrospective cohort study PARTICIPANTS: Kaiser Permanente Southern and Northern California members who were taking oral anticoagulants (OAC) for incident VTE between 2015 and 2018 were surveyed. Main Measures HL was assessed using a 3-item HL assessment and dichotomized as having adequate or limited HL. High treatment burden and low treatment benefit were defined as Anti-Clot Treatment Scale (ACTS) scores below the 25th percentile of the distributions for ACTS Burdens and Benefits survey components, respectively. Using Poisson regression, multivariable adjusted risk ratios (RR) and 95% confidence intervals (CI) were calculated for the association of HL with high treatment burden and low treatment benefits. Among 2154 respondents, 397 (18.4%) had limited HL. Patients with limited vs adequate HL were older (47.9% vs 27.5% aged ≥ 75 years, p<0.001), more likely to use a non-English language when discussing their health (10.8% vs 1.7%, p<0.001), to have less than high school education (10.1% vs 1.7%, p<0.001), and to self-rate their health as fair or poor (47.6% vs 25.5%, p<0.001). After multivariable adjustment, patients with limited HL were more likely to have higher perceived treatment burden (RR 1.24, 95% CI 1.07, 1.45) and lower perceived treatment benefits (RR 1.21, 95% CI 1.08, 1.37). Limited HL was associated with lower OAC treatment satisfaction, though absolute differences in satisfaction scores were small. Further examination of the intersection of HL with VTE treatment satisfaction and compliance among older and non-English speaking patients is warranted.
Authors: Mefford, Matthew T; Zhou, Hui; Fan, Dongjie; Fang, Margaret C; Prasad, Priya A; Go, Alan S; Portugal, Cecilia; Chang, John M; Reynolds, Kristi
J Gen Intern Med. 2022 Nov 03.
Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning
Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.
Authors: Lahti, Jari; Starr, John M; Räikkönen, Katri; et al.
Mol Psychiatry. 2022 Nov;27(11):4419-4431. Epub 2022-08-16.
The race coefficient in glomerular filtration rate-estimating equations and its removal
To review new publications about the use of the race coefficient in glomerular filtration rate (GFR)-estimating equations since this topic was last reviewed a year ago in Current Opinion in Nephrology and Hypertension . Accounting for race (or genetic ancestry) does improve the performance of GFR-estimating equations when serum creatinine (SCr) is used as the filtration marker but not when cystatin C is used. The National Kidney Foundation (NKF)-American Society of Nephrology (ASN) Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease recommended immediate adoption of a new refitted SCr-based equation without race and increased use of cystatin C. This report has created consensus but the endorsed new SCr equation without race underestimates GFR in Black Americans and overestimates GFR in non-Black Americans, which may result in diminished ability to detect racial disparities. The approach recommended by the NKF-ASN Task Force represents a compromise attempting to balance a number of competing values, including racial justice, benefit of classifying more Black Americans as having (more severe) chronic kidney disease, accuracy compared with measured GFR, and financial cost. The full implications of adopting the race-free refitted CKD-EPI SCr equation are yet to be known.
Authors: Hsu, Chi-Yuan; Go, Alan S
Curr Opin Nephrol Hypertens. 2022 Nov 01;31(6):527-533. Epub 2022-08-26.
Aspirin for Primary and Secondary Prevention of Mortality, Cardiovascular Disease, and Kidney Failure in the Chronic Renal Insufficiency Cohort (CRIC) Study
Chronic kidney disease is a risk enhancing factor for cardiovascular disease (CVD) and mortality, and the role of aspirin use is unclear in this population. We investigated the risk and benefits of aspirin use in primary and secondary prevention of CVD in the Chronic Renal Insufficiency Cohort Study. Prospective observational cohort. 3,664 Chronic Renal Insufficiency Cohort participants. Aspirin use in patients with and without preexisting CVD. Mortality, composite and individual CVD events (myocardial infarction, stroke, and peripheral arterial disease), kidney failure (dialysis and transplant), and major bleeding. Intention-to-treat analysis and multivariable Cox proportional hazards model to examine associations of time varying aspirin use. The primary prevention group was composed of 2,578 (70.3%) individuals. Mean age was 57 ± 11 years, 46% women, 42% Black, and 47% had diabetes. The mean estimated glomerular filtration rate was 45 mL/min/1.73 m2. Median follow-up was 11.5 (IQR, 7.4-13) years. Aspirin was not associated with all-cause mortality in those without preexisting cardiovascular disease (CVD) (HR, 0.84; 95% CI, 0.7-1.01; P = 0.06) or those with CVD (HR, 0.88; 95% CI, 0.77-1.02, P = 0.08). Aspirin was not associated with a reduction of the CVD composite in primary prevention (HR, 0.97; 95% CI, 0.77-1.23; P = 0.79) and in secondary prevention because the original study design was not meant to study the effects of aspirin. This is not a randomized controlled trial, and therefore, causality cannot be determined. Aspirin use in chronic kidney disease patients was not associated with reduction in primary or secondary CVD events, progression to kidney failure, or major bleeding.
Authors: Taliercio, Jonathan J; Go, Alan S; CRIC study Investigators,; et al.
Kidney Med. 2022 Nov;4(11):100547. Epub 2022-10-04.
Physical activity trajectories, autonomic balance and cognitive function: The Coronary Artery Risk Development in Young Adults (CARDIA) study
Physical activity (PA) plays an important role in cognitive health. However, the underlying mechanisms are not fully understood. Cardiac autonomic balance is influenced by PA and implicated in dementia pathogenesis. We examined whether autonomic balance mediates the association between PA and cognitive function. The sample included 1939 participants from the Coronary Artery Risk Development in Young Adults study who completed cognitive testing after 30-year follow-up (baseline: mean age 25.2 ± 3.5y; 58% women; 43% Black). Moderate to vigorous intensity PA (MVPA) was obtained in 7 consecutive examinations over 20 years (Year 0-Year 20). Cardiac autonomic balance was assessed at Year 20 via resting heart rate (RHR), standard deviation normal to normal (SDNN) and root mean square of successive differences (RMSSD). We used group-based trajectory modeling to identify homogenous MVPA trajectory groups, and formal mediation analysis to test whether autonomic function indices mediate the association between MVPA trajectories and cognition. We identified three distinct PA trajectory patterns: (1) Below MVPA guidelines (n = 1122; 57.9%); (2) Meeting MVPA guidelines (n = 652; 33.6%); and (3) Exceeding MVPA guidelines (n = 165; 8.5%). Meeting and exceeding MVPA guidelines were related to better autonomic balance overall, and to improved semantic fluency performance. Statistically, the association between higher MVPA level and verbal ability was mediated by SDNN and RMSSD, but not by RHR. In our sample of young and middle-aged adults, higher MVPA levels over time were associated with better cardiac autonomic function, which explained some of the associations between PA trajectories and better cognition.
Authors: Gafni, Tal; Gabriel, Kelley Pettee; Shuval, Kerem; Yaffe, Kristine; Sidney, Steve; Weinstein, Galit
Prev Med. 2022 Nov;164:107291. Epub 2022-10-07.
Polygenic risk score and statin relative risk reduction for primary prevention of myocardial infarction in a real-world population
Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Covariate-adjusted Cox regression models were used to compare the risk of cardiovascular outcomes between statin users and matched nonusers. Statin effectiveness on incident myocardial infarction showed no gradient with increasing 10-year Pooled Cohort Equations atherosclerotic cardiovascular disease (ASCVD) risk across low, borderline, intermediate, and high ASCVD risk score groups. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (hazard ratio (HR) 0.41, 95% confidence interval (CI), 0.31-0.53; P = 1.5E-11), intermediate in the intermediate polygenic risk score group (HR 0.56, 95% CI, 0.47-0.66; P = 8.4E-12), and smallest in the low polygenic risk score group (HR 0.67, 95% CI, 0.47-0.97; P = 0.03; P for high vs. low = 0.01). ASCVD risk and statin low-density lipoprotein cholesterol (LDL-C) lowering did not differ across polygenic risk score groups. In patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of LDL-C lowering. Our findings extend prior work by identifying a subset (i.e., self-identified White individuals with low CHD polygenic risk scores) with attenuated clinical benefit from statins.
Authors: Oni-Orisan, Akinyemi; Haldar, Tanushree; Cayabyab, Mari A S; Ranatunga, Dilrini K; Hoffmann, Thomas J; Iribarren, Carlos; Krauss, Ronald M; Risch, Neil
Clin Pharmacol Ther. 2022 Nov;112(5):1070-1078. Epub 2022-08-24.
Association of Thoracic Aortic Aneurysm Size With Long-term Patient Outcomes: The KP-TAA Study
The risk of adverse events from ascending thoracic aorta aneurysm (TAA) is poorly understood but drives clinical decision-making. To evaluate the association of TAA size with outcomes in nonsyndromic patients in a large non-referral-based health care delivery system. The Kaiser Permanente Thoracic Aortic Aneurysm (KP-TAA) cohort study was a retrospective cohort study at Kaiser Permanente Northern California, a fully integrated health care delivery system insuring and providing care for more than 4.5 million persons. Nonsyndromic patients from a regional TAA safety net tracking system were included. Imaging data including maximum TAA size were merged with electronic health record (EHR) and comprehensive death data to obtain demographic characteristics, comorbidities, medications, laboratory values, vital signs, and subsequent outcomes. Unadjusted rates were calculated and the association of TAA size with outcomes was evaluated in multivariable competing risk models that categorized TAA size as a baseline and time-updated variable and accounted for potential confounders. Data were analyzed from January 2018 to August 2021. TAA size. Aortic dissection (AD), all-cause death, and elective aortic surgery. Of 6372 patients with TAA identified between 2000 and 2016 (mean [SD] age, 68.6 [13.0] years; 2050 female individuals [32.2%] and 4322 male individuals [67.8%]), mean (SD) initial TAA size was 4.4 (0.5) cm (828 individuals [13.0% of cohort] had initial TAA size 5.0 cm or larger and 280 [4.4%] 5.5 cm or larger). Rates of AD were low across a mean (SD) 3.7 (2.5) years of follow-up (44 individuals [0.7% of cohort]; incidence 0.22 events per 100 person-years). Larger initial aortic size was associated with higher risk of AD and all-cause death in multivariable models, with an inflection point in risk at 6.0 cm. Estimated adjusted risks of AD within 5 years were 0.3% (95% CI, 0.3-0.7), 0.6% (95% CI, 0.4-1.3), 1.5% (95% CI, 1.2-3.9), 3.6% (95% CI, 1.8-12.8), and 10.5% (95% CI, 2.7-44.3) in patients with TAA size of 4.0 to 4.4 cm, 4.5 to 4.9 cm, 5.0 to 5.4 cm, 5.5 to 5.9 cm, and 6.0 cm or larger, respectively, in time-updated models. Rates of the composite outcome of AD and all-cause death were higher than for AD alone, but a similar inflection point for increased risk was observed at 6.0 cm. In a large sociodemographically diverse cohort of patients with TAA, absolute risk of aortic dissection was low but increased with larger aortic sizes after adjustment for potential confounders and competing risks. Our data support current consensus guidelines recommending prophylactic surgery in nonsyndromic individuals with TAA at a 5.5-cm threshold.
Authors: Solomon, Matthew D; Lee, Catherine; Chang, Robert; Go, Alan S; Kaiser Permanente Northern California Center for Thoracic Aortic Disease ,; et al.
JAMA Cardiol. 2022 Nov 01;7(11):1160-1169.
Black and White Adults With CKD Hospitalized With Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study
Few studies have investigated racial disparities in acute kidney injury (AKI), in contrast to the extensive literature on racial differences in the risk of kidney failure. We sought to study potential differences in risk in the setting of chronic kidney disease (CKD). Prospective cohort study. We studied 2,720 self-identified Black or White participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study from July 1, 2013, to December 31, 2017. Self-reported race (Black vs White). Hospitalized AKI (≥50% increase from nadir to peak serum creatinine). Cox regression models adjusting for demographics (age and sex), prehospitalization clinical risk factors (diabetes, blood pressure, cardiovascular disease, estimated glomerular filtration rate, proteinuria, receipt of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers), and socioeconomic status (insurance status and education level). In a subset of participants with genotype data, we adjusted for apolipoprotein L1 gene (APOL1) high-risk status and sickle cell trait. Black participants (n = 1,266) were younger but had a higher burden of prehospitalization clinical risk factors. The incidence rate of first AKI hospitalization among Black participants was 6.3 (95% CI, 5.5-7.2) per 100 person-years versus 5.3 (95% CI, 4.6-6.1) per 100 person-years among White participants. In an unadjusted Cox regression model, Black participants were at a modestly increased risk of incident AKI (HR, 1.22 [95% CI, 1.01-1.48]) compared with White participants. However, this risk was attenuated and no longer significant after adjusting for prehospitalization clinical risk factors (adjusted HR, 1.02 [95% CI, 0.83-1.25]). There were only 11 AKI hospitalizations among individuals with high-risk APOL1 risk status and 14 AKI hospitalizations among individuals with sickle cell trait. Participants were limited to research volunteers and potentially not fully representative of all CKD patients. In this multicenter prospective cohort of CKD patients, racial disparities in AKI incidence were modest and were explained by differences in prehospitalization clinical risk factors.
Authors: Muiru, Anthony N; Go, Alan S; CRIC Study Investigators,; et al.
Am J Kidney Dis. 2022 Nov;80(5):610-618.e1. Epub 2022-04-08.
Prepregnancy Protein Source and BCAA Intake Are Associated with Gestational Diabetes Mellitus in the CARDIA Study
Diet quality and protein source are associated with type 2 diabetes, however relationships with GDM are less clear. This study aimed to determine whether prepregnancy diet quality and protein source are associated with gestational diabetes mellitus (GDM). Participants were 1314 Black and White women without diabetes, who had at least one birth during 25 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study. The CARDIA A Priori Diet Quality Score (APDQS) was assessed in the overall cohort at enrollment and again at Year 7. Protein source and branched-chain amino acid (BCAA) intake were assessed only at the Year 7 exam (n = 565). Logistic regression analysis was used to determine associations between prepregnancy dietary factors and GDM. Women who developed GDM (n = 161) were more likely to have prepregnancy obesity and a family history of diabetes (p < 0.05). GDM was not associated with prepregnancy diet quality at enrollment (Year 0) (odds ratio [OR]: 1.01; 95% confidence interval [CI] 0.99, 1.02) or Year 7 (odds ratio [OR]: 0.97; 95% confidence interval [CI] 0.94, 1.00) in an adjusted model. Conversely, BCAA intake (OR:1.59, 95% CI 1.03, 2.43) and animal protein intake (OR: 1.06, 95% CI 1.02, 1.10) as a proportion of total protein intake, were associated with increased odds of GDM, while proportion of plant protein was associated with decreased odds of GDM (OR: 0.95, 95% CI 0.91, 0.99). In conclusion, GDM is strongly associated with source of prepregnancy dietary protein intake but not APDQS in the CARDIA study.
Authors: Gadgil, Meghana D; Ingram, Katherine H; Appiah, Duke; Rudd, Jessica; Whitaker, Kara M; Bennett, Wendy L; Shikany, James M; Jacobs, David R; Lewis, Cora E; Gunderson, Erica P
Int J Environ Res Public Health. 2022 Oct 29;19(21). Epub 2022-10-29.
Marijuana use and DNA methylation-based biological age in young adults
Marijuana is the third most commonly used drug in the USA and efforts to legalize it for medical and recreational use are growing. Despite the increase in use, marijuana’s effect on aging remains understudied and understanding the effects of marijuana on molecular aging may provide novel insights into the role of marijuana in the aging process. We therefore sought to investigate the association between cumulative and recent use of marijuana with epigenetic age acceleration (EAA) as estimated from blood DNA methylation. A random subset of participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study with available whole blood at examination years (Y) 15 and Y20 underwent epigenomic profiling. Four EAA estimates (intrinsic epigenetic age acceleration, extrinsic epigenetic age acceleration, PhenoAge acceleration, and GrimAge acceleration) were calculated from DNA methylation levels measured at Y15 and Y20. Ever use and cumulative marijuana-years were calculated from the baseline visit to Y15 and Y20, and recent marijuana use (both any and number of days of use in the last 30 days) were calculated at Y15 and Y20. Ever use of marijuana and each additional marijuana-year were associated with a 6-month (P < 0.001) and a 2.5-month (P < 0.001) higher average in GrimAge acceleration (GAA) using generalized estimating equations, respectively. Recent use and each additional day of recent use were associated with a 20-month (P < 0.001) and a 1-month (P < 0.001) higher GAA, respectively. A statistical interaction between marijuana-years and alcohol consumption on GAA was observed (P = 0.011), with nondrinkers exhibiting a higher GAA (β = 0.21 [95% CI 0.05, 0.36], P = 0.008) compared to heavy drinkers (β = 0.05 [95% CI - 0.09, 0.18], P = 0.500) per each additional marijuana-year. No associations were observed for the remaining EAA estimates. These findings suggest cumulative and recent marijuana use are associated with age-related epigenetic changes that are related to lifespan. These observed associations may be modified by alcohol consumption. Given the increase in use and legalization, these findings provide novel insight on the effect of marijuana use on the aging process as captured through blood DNA methylation.
Authors: Nannini, Drew R; Greenland, Philip; Hou, Lifang; et al.
Clin Epigenetics. 2022 Oct 26;14(1):134. Epub 2022-10-26.
Prevalence of prediabetes and diabetes vary by ethnicity among U.S. Asian adults at healthy weight, overweight, and obesity ranges: an electronic health record study
Asian adults develop Type 2 diabetes at a lower body mass index (BMI) compared to other racial/ethnic groups. We examined the variation in prevalence of prediabetes and diabetes among Asian ethnic groups within weight strata by comparing middle-aged Chinese, Filipino, South Asian, and White adults receiving care in the same integrated healthcare delivery system. Our retrospective cross-sectional U.S. study examined data from 283,110 (non-Hispanic) White, 33,263 Chinese, 38,766 Filipino, and 17,959 South Asian adults aged 45-64 years who were members of a Northern California health plan in 2016 and had measured height and weight. Prediabetes and diabetes were classified based on laboratory data, clinical diagnoses, or diabetes pharmacotherapy. Age-standardized prevalence of prediabetes and diabetes were compared by race/ethnicity within healthy weight, overweight, and obesity categories, using standard BMI thresholds for White adults (18.5 to < 25, 25 to < 30, ≥ 30 kg/m2) and lower BMI thresholds for Asian adults (18.5 to < 23, 23 to < 27.5, ≥ 27.5 kg/m2). Prevalence ratios (PRs) were used to compare the prevalence of diabetes and prediabetes for Asian groups to White adults in each weight category, adjusted for age and BMI. Across all weight categories, diabetes prevalence was higher for Asian than White adults, and among Asian groups it was highest for Filipino and South Asian adults. Compared to White, PRs for South Asian men/women at healthy BMI were 1.8/2.8 for prediabetes and 5.9/8.0 for diabetes, respectively. The PRs for Filipino men/women at healthy BMI were 1.8/2.6 for prediabetes and 5.0/7.5 for diabetes, respectively. For Chinese men/women at healthy BMI, the PRs for prediabetes (2.1/2.9) were similar to Filipino and South Asian, but the PRs for diabetes were lower (2.1/3.4). Chinese, Filipino, and South Asian adults have higher prevalence of prediabetes and diabetes than White adults in all weight categories, despite using lower BMI thresholds for weight classification in Asian groups. Within Asian ethnic groups, Filipino and South Asian adults had considerably higher diabetes prevalence than Chinese adults. Our data emphasize the disproportionate metabolic risk among middle-aged Asian adults and underscore the need for diabetes screening among high-risk Asian groups at healthy BMI levels.
Authors: Vicks, William S; Lo, Joan C; Guo, Lynn; Rana, Jamal S; Zhang, Sherry; Ramalingam, Nirmala D; Gordon, Nancy P
BMC Public Health. 2022 Oct 22;22(1):1954. Epub 2022-10-22.
Adverse Pregnancy Outcomes: The Missing Link in Discovering the Role of Lactation in Cardiovascular Disease Prevention
Authors: Lane, Abbi; Lewis, Cora E; Gunderson, Erica P
J Am Heart Assoc. 2022 10 18;11(20):e027707. Epub 2022-10-17.
Association of Obesity With Cognitive Decline in Black and White Americans
There are disparities in the prevalence of obesity by race and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and if the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared to normal weight, and that the impact of obesity on cognitive decline is more pronounced in Black adults compared to their White counterparts. We pooled data from 28,867 participants free of stroke and dementia (mean, standard deviation [SD]: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from six cohorts. The primary outcome was annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, standard deviation [SD] 10) at a participant’s first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the six cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15). Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; P<0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; P=0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; P=0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; P<0.001). There was no evidence that race modified the association between BMI and global cognitive decline (P=0.34). These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.
Authors: Quaye, Emmanuel; Windham, B Gwen; Levine, Deborah A; et al.
Neurology. 2022 Oct 18.
Variation in Heart Failure Risk by HIV Severity and Sex in People With HIV Infection
HIV is an independent risk factor for heart failure (HF). However, the association of HIV severity with incident HF and the potential interaction with sex are incompletely understood. Integrated health care system. We conducted a cohort study of people with HIV (PWH) and matched people without HIV (PWoH), all aged ≥ 21 years and with no previous HF. Poisson regression was used to compare incident HF by HIV status, with PWH stratified by severity of HIV infection [defined by recent (<6 months) CD4 count, nadir CD4 count, or recent HIV RNA level]. Models were adjusted for sociodemographic characteristics, substance use, and HF risk factors. Analyses were conducted for men and women combined, then by sex. The study included 38,868 PWH and 386,569 PWoH (mean baseline age = 41.0 ± 10.8 years; 88% men). Compared with PWoH, incident HF risk was higher among PWH with lower recent CD4 [200-499 cells/µL, adjusted rate ratio (aRR) = 1.82, 95% confidence interval (CI) = 1.50 to 2.21 and <200 cells/µL, aRR = 3.26 (2.47 to 4.30)] and a low nadir CD4 [<200 cells/µL, aRR = 1.56 (1.37 to 1.79)] but not among PWH with normal CD4 [≥500 cells/µL, aRR = 1.14 (0.90 to 1.44)]. Higher incident HF risk was observed among PWH at all HIV RNA levels, with greater HF risk at higher HIV RNA levels. The excess HF risk associated with low CD4 (recent or nadir) and high HIV RNA was stronger among women than men (P interactions=0.05, 0.08, and 0.01, respectively). Given the association of HIV severity with HF, optimizing HIV treatment and management may be important for HF prevention among PWH.
Authors: Lam, Jennifer O; Ambrosy, Andrew P; Go, Alan S; Silverberg, Michael J; et al.
J Acquir Immune Defic Syndr. 2022 Oct 01;91(2):175-181.
Thromboembolism after treatment with 4-factor prothrombin complex concentrate or plasma for warfarin-related bleeding
Limited data exist in large, representative populations about whether the risk of thromboembolic events varies after receiving four-factor human prothrombin complex concentrate (4F-PCC) versus treatment with human plasma for urgent reversal of oral vitamin K antagonist therapy. We conducted a multicenter observational study to compare the 45-day risk of thromboembolic events in adults with warfarin-associated major bleeding after treatment with 4F-PCC (Kcentra®) or plasma. Hospitalized patients in two large integrated healthcare delivery systems who received 4F-PCC or plasma for reversal of warfarin due to major bleeding from January 1, 2008 to March 31, 2020 were identified and were matched 1:1 on potential confounders and a high-dimensional propensity score. Arterial and venous thromboembolic events were identified up to 45 days after receiving 4F-PCC or plasma from electronic health records and adjudicated by physician review. Among 1119 patients receiving 4F-PCC and a matched historical cohort of 1119 patients receiving plasma without a recent history of thromboembolism, mean (SD) age was 76.7 (10.5) years, 45.6% were women, and 9.4% Black, 14.6% Asian/Pacific Islander, and 15.7% Hispanic. The 45-day risk of thromboembolic events was 3.4% in those receiving 4F-PCC and 4.1% in those receiving plasma (P = 0.26; adjusted hazard ratio 0.76; 95% confidence interval 0.49-1.16). The adjusted risk of all-cause death at 45 days post-treatment was lower in those receiving 4F-PCC compared with plasma. Among a large, ethnically diverse cohort of adults treated for reversal of warfarin-associated bleeding, receipt of 4F-PCC was not associated with an excess risk of thromboembolic events at 45 days compared with plasma therapy.
Authors: Go, Alan S; Solomon, Matthew D; REVERSAL Study,; et al.
J Thromb Thrombolysis. 2022 Oct;54(3):470-479. Epub 2022-08-19.
A population-based meta-analysis of circulating GFAP for cognition and dementia risk
Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings. Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer’s disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models. Meta-analyses indicated that higher circulating GFAP associated with lower general cognition (ß = -0.09, [95% confidence interval [CI]: -0.15 to -0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52-4.01)) and Alzheimer’s disease dementia (HR: 2.54 [95% CI: 1.42-4.53]) over up to 15-years of follow-up. Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.
Authors: Gonzales, Mitzi M; Bryan, R Nick; Satizabal, Claudia L; et al.
Ann Clin Transl Neurol. 2022 Oct;9(10):1574-1585. Epub 2022-09-03.
Fluid Restriction Recommendations in Heart Failure Dry as a Bone or Quench Your Thirst?
Authors: Merlo, Aurelie; Mezue, Kenechukwu; Ambrosy, Andrew P
J Card Fail. 2022 10;28(10):1531-1533. Epub 2022-08-15.
Identifying modifiable obesogenic behaviors among Latino adolescents in primary pediatric care.
Latino adolescents engage in more obesogenic behaviors, including sedentary behaviors and sugary drink consumption, than White adolescents. However, it is unclear whether engagement in obesogenic behaviors differs within the Latino population. Cross-sectional data were examined from Latino adolescents ages 13-17 with a well-child visit (2016-2019) in an integrated healthcare system. Adolescents self-reported on four daily obesogenic behaviors: 1) consuming < 5 servings of fruits/vegetables; 2) drinking > 1 juice/soda; 3) exercising/playing sports < 60 min; and 4) > 2 h screen time. A composite variable of >/= 3 self-reported behaviors was constructed. Multivariable logistic regression was used to examine associations between obesogenic behaviors with age category (13-15 or 16-17 years), sex, household language preference (English/Spanish), neighborhood deprivation index (NDI quartiles), and body mass index (BMI). Among 77,514 Latino adolescents (mean age 14.7 +/- 1.4; 50 % female), 23 % lived in Spanish-speaking households, 43 % resided in census tracts with the highest (most deprived) NDI quartile, and 45 % had an overweight or obese BMI. Older (vs younger) adolescents had higher odds of insufficient fruit/vegetable intake (OR 1.20; CI 1.17-1.24), greater sedentary behavior (OR 1.51; 1.46-1.56), and reporting > 2 h screen time (OR 1.07; 1.03-1.11). Adolescents in the 4th (vs 1st) NDI quartile (OR 1.34; 1.26-1.42) and those with obesity (vs healthy weight) (OR 1.55; 1.42-1.70 for class 3 obesity) had higher odds of >/= 3 obesogenic behaviors. In conclusion, among Latino adolescents, older age, obesity, and living in more deprived neighborhoods were associated with greater obesogenic behaviors. Identifying adolescents more likely to engage in obesogenic behaviors can inform targeted lifestyle interventions.
Authors: Rodriguez LA; Gopalan A; Darbinian JA; Chandra M; Greenspan LC; Howell A; Lo JC
Prev Med Rep. 2022 Jul 30;29:101939. doi: 10.1016/j.pmedr.2022.101939. eCollection 2022 Oct.
Evaluating Digital Technologies for Implementation Science
Authors: Bhatt, Ankeet S
J Card Fail. 2022 10;28(10):1497-1499. Epub 2022-08-20.
Effect of Medically Tailored Meals on Clinical Outcomes in Recently Hospitalized High-Risk Adults
Inability to adhere to nutritional recommendations is common and linked to worse outcomes in patients with nutrition-sensitive conditions. The purpose of this study is to evaluate whether medically tailored meals (MTMs) improve outcomes in recently discharged adults with nutrition-sensitive conditions compared with usual care. Remote pragmatic randomized trial. Adults with heart failure, diabetes, or chronic kidney disease being discharged home between April 27, 2020, and June 9, 2021, from 5 hospitals within an integrated health care delivery system. Participants were prerandomized to 10 weeks of MTMs (with or without virtual nutritional counseling) compared with usual care. The primary outcome was all-cause hospitalization within 90 days after discharge. Exploratory outcomes included all-cause and cause-specific health care utilization and all-cause death within 90 days after discharge. A total of 1977 participants (MTMs: n=993, with 497 assigned to also receive virtual nutritional counseling; usual care: n=984) were enrolled. Compared with usual care, MTMs did not reduce all-cause hospitalization at 90 days after discharge [adjusted hazard ratio, aHR: 1.02, 95% confidence interval (CI), 0.86-1.21]. In exploratory analyses, MTMs were associated with lower mortality (aHR: 0.65, 95% CI, 0.43-0.98) and fewer hospitalizations for heart failure (aHR: 0.53, 95% CI, 0.33-0.88), but not for any emergency department visits (aHR: 0.95, 95% CI, 0.78-1.15) or diabetes-related hospitalizations (aHR: 0.75, 95% CI, 0.31-1.82). No additional benefit was observed with virtual nutritional counseling. Provision of MTMs after discharge did not reduce risk of all-cause hospitalization in adults with nutrition-sensitive conditions. Additional large-scale randomized controlled trials are needed to definitively determine the impact of MTMs on survival and cause-specific health care utilization in at-risk individuals.
Authors: Go, Alan S; Ambrosy, Andrew P; Lee, Keane K; Lo, Joan C; KP NOURISH Study Investigators,; et al.
Med Care. 2022 Oct 01;60(10):750-758. Epub 2022-08-15.
Ischemic Stroke in Patients With Asymptomatic Severe Carotid Stenosis Without Surgical Intervention-Reply
Authors: Chang, Robert W; Nguyen-Huynh, Mai N; Avins, Andrew L
JAMA. 2022 09 27;328(12):1257.
Race, Interleukin-6, TMPRSS6 Genotype, and Cardiovascular Disease in Patients With Chronic Kidney Disease
Background Differences in death rate and cardiovascular disease (CVD) between Black and White patients with chronic kidney disease is attributed to sociocultural factors, comorbidities, genetics, and inflammation. Methods and Results We examined the interaction of race, plasma IL-6 (interleukin-6), and TMPRSS6 genotype as determinants of CVD and mortality in 3031 Chronic Renal Insufficiency Cohort study participants. The primary outcomes were all-cause mortality and a composite of incident myocardial infarction, peripheral artery disease, stroke, and heart failure. During the median follow-up of 10 years, Black patients with chronic kidney disease experienced a significantly higher mortality (34% versus 26%) and CVD composite (41% versus 28%) compared with White patients. After adjustment, TMPRSS6 genotype did not associate with the outcomes. The adjusted hazard ratio for mortality (4.11 [2.48-6.80], P<0.001) and CVD composite (2.52 [1.96-3.24], P<0.001) were higher for the highest versus lowest IL-6 quintile. The adjusted hazards for death per 1-quintile increase in IL-6 in White and Black individuals were 1.53 (1.42-1.64) versus 1.29 (1.20-1.38) (P<0.001), respectively. For CVD composite they were 1.61 (1.50-1.74) versus 1.30 (1.22-1.39) (P<0.001), respectively. In Cox proportional hazard models that included IL-6, there was no longer a racial disparity for death (1.01 [0.87-1.16], P=0.92), but significant unexplained mediation remained for CVD (1.24 [1.07-1.43]; P=0.004). Path models that included IL-6, diabetes, and urine albumin to creatinine ratio were able to identify variables responsible for racial disparity in mortality and CVD. Conclusions Racial differences in mortality and CVD among patients with chronic kidney disease could be explained by good-fitting path models that include selected mediator variables including diabetes and plasma IL-6.
Authors: Barrows, Ian R; Go, Alan; CRIC Study Investigators *,; et al.
J Am Heart Assoc. 2022 Sep 20;11(18):e025627. Epub 2022-09-14.
Absence of long-term changes in urine biomarkers after AKI: findings from the CRIC study
Mechanisms by which AKI leads to CKD progression remain unclear. Several urine biomarkers have been identified as independent predictors of progressive CKD. It is unknown whether AKI may result in long-term changes in these urine biomarkers, which may mediate the effect of AKI on CKD progression. We selected 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥ 1.5) among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. We matched the best non-AKI hospitalization (unique patients) for each AKI hospitalization using pre-hospitalization characteristics including eGFR and urine protein/creatinine ratio. Biomarkers were measured in banked urine samples collected at annual CRIC study visits. Urine biomarker measurements occurred a median of 7 months before and 5 months after hospitalization. There were no significant differences in the change in urine biomarker-to-creatinine ratio between the AKI and non-AKI groups: KIM-1/Cr + 9% vs + 7%, MCP-1/Cr + 4% vs + 1%, YKL-40/Cr + 7% vs -20%, EGF/Cr -11% vs -8%, UMOD/Cr -2% vs -7% and albumin/Cr + 17% vs + 13% (all p > 0.05). In this cohort of adults with CKD, AKI did not associate with long-term changes in urine biomarkers.
Authors: McCoy, Ian E; Liu, Kathleen D; Hsu, Chi-Yuan; et al.
BMC Nephrol. 2022 09 13;23(1):311. Epub 2022-09-13.
Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
Authors: Wang, Zhe; Siggeirsdottir, Kristin; Hoed, Marcel den; et al.
Nat Genet. 2022 Sep;54(9):1332-1344. Epub 2022-09-07.
Prevalence of Atherosclerotic Risk Factors Among Children and Young Adults With Arterial Ischemic Stroke
Arterial ischemic stroke (AIS) incidence has decreased overall in recent decades yet has increased in young adults. The potential associations with atherosclerotic risk factors (ARFs) remain unknown. To assess the ages at which ARFs may be risk factors associated with AIS. A nested case-control study was conducted within Kaiser Permanente Northern California (KPNC) from January 1, 2000, through December 31, 2014. Data were analyzed from 2019 to 2022. Cases were identified using diagnostic codes and radiology reports. A total of 2 to 3 controls per case, matched on age and enrollment dates, were randomly identified and confirmed as stroke-free by medical record review. Only ARFs documented prior to stroke diagnosis (or the same date in controls) were considered to ensure the same period of observation. Comparisons were stratified by decade of life. Cases and controls were selected from the KPNC population (4.7 million children and 7.5 million young adults). Medical record review was conducted of all children (aged 29 days to 19 years) and a sample of young adults (aged 20-49 years) with International Classification of Diseases, Ninth Revision code or radiology text string search suggestive of AIS. Stroke-free controls were randomly selected. Hypertension, hyperlipidemia, diabetes, obesity, and smoking history. Odds of AIS. In all analyses, cases and controls were compared using logistic regression. A total of 141 pediatric cases (69 [48.9%] aged 29 days to 9 years; 72 [51.1%] aged 10-19 years) and 364 pediatric controls (168 [46.2%] aged 0-9 years; 196 [53.8%] aged 10-19 years) and 455 young adult cases (71 [15.6%] aged 20-29 years; 144 [31.6%] aged 30-39 years; and 240 [52.7%] aged 40-49 years) and 1018 young adult controls (121 [11.9%] aged 20-29 years; 298 [29.3%] aged 30-39 years; and 599 [58.8%] aged 40-49 years) were identified. The percent of the cases that were male or female did not differ from the percent in the control group. The odds ratio (OR) of having any ARFs on AIS was 1.87 (95% CI, 0.72-4.88) for age range 0 to 9 years; OR, 1.00 (95% CI, 0.51-1.99) for age range 10 to 19 years; OR, 2.3 (95% CI, 1.17- 4.51) for age range 20 to 29 years; OR, 3.57 (95% CI, 2.34-5.45) for age range 30 to 39 years; and OR, 4.91 (95% CI, 3.52-6.86) for age range 40 to 49 years. The risk associated with multiple ARFs was OR, 5.29 (95% CI, 0.47-59.4) for age range 0 to 9 years; OR, 2.75 (95% CI, 0.77-9.87) for age range 10 to 19 years; OR, 7.33 (95% CI, 1.92-27.9) for age range 20 to 29 years; OR, 9.86 (95% CI, 4.96-19.6) for age range 30 to 39 years; and OR, 9.35 (95% CI, 6.31-13.8) for age range 40 to 49 years. The ARF findings by both definitions were significant in all young adult groups. Atherosclerosis was the presumed etiology in 0% of cases in the age group 0 to 9 years, 1.4% in the age group 10 to 19 years, 8.5% in the age group 20 to 29 years, 21.5% in the age group 30 to 39 years, and 42.5% in the age group 40 to 49 years. Although atherosclerosis may not be a common cause of AIS in children or in early young adulthood, findings of this study suggest that ARFs associated with stroke in older adults are present in childhood and increase with age. Efforts to reduce these risk factors should begin as early as possible.
Authors: Poisson, Sharon N; Hills, Nancy K; Sidney, Stephen; Fullerton, Heather J
JAMA Neurol. 2022 Sep 01;79(9):901-910.
Natural History of Asymptomatic Moderate Carotid Artery Stenosis in a Large Community-Based Cohort
Moderate carotid artery stenosis is a poorly defined risk factor for ischemic stroke. As such, practice recommendations are lacking. In this study, we describe the long-term risk of stroke in patients with moderate asymptomatic stenosis in an integrated health care system. All adult patients with asymptomatic moderate (50%-69%) internal carotid artery stenosis between 2008 and 2012 were identified, with follow-up through 2017. The primary outcome was acute ischemic stroke attributed to the ipsilateral carotid artery. Stroke rates were calculated using competing risk analysis. Secondary outcomes included disease progression, ipsilateral intervention, and long-term survival. Overall, 11 614 arteries with moderate stenosis in 9803 patients were identified. Mean age was 74.2±9.9 years with 51.4% women. Mean follow-up was 5.1±2.9 years. There were 180 ipsilateral ischemic strokes (1.6%) identified (crude annual risk, 0.31% [95% CI, 0.21%-0.41%]), of which thirty-one (17.2%) underwent subsequent intervention. Controlling for death and intervention as competing risks, the cumulative incidence of stroke was 1.2% (95% CI, 1.0%-1.4%) at 5 years and 2.0% (95% CI, 1.7%-2.4%) at 10 years. Of identified strokes, 50 (27.8%) arteries had progressed to severe stenosis or occlusion. During follow-up, there were 17 029 carotid studies performed in 5951 patients, revealing stenosis progression in 1674 (14.4%) arteries, including 1614 (13.9%) progressing to severe stenosis and 60 (0.5%) to occlusion. The mean time to stenosis progression was 2.6±2.1 years. Carotid intervention occurred in 708 arteries (6.1%). Of these, 66.1% (468/708) had progressed to severe stenosis. The overall mortality rate was 44.5%, with 10.5% of patients lost to follow-up. In this community-based sample of patients with asymptomatic moderate internal carotid artery stenosis followed for an average of 5 years, the cumulative incidence of stroke is low out to 10 years. Future research is needed to optimize management strategies for this population.
Authors: Gologorsky, Rebecca C; Lancaster, Elizabeth; Tucker, Lue-Yen; Nguyen-Huynh, Mai N; Rothenberg, Kara A; Avins, Andrew L; Kuang, Hui C; Chang, Robert W
Stroke. 2022 Sep;53(9):2838-2846. Epub 2022-06-08.
Prolactin and maternal metabolism in women with a recent GDM pregnancy and links to future T2D: the SWIFT study
Prolactin is a multifaceted hormone known to regulate lactation. In women with gestational diabetes mellitus (GDM) history, intensive lactation has been associated with lower relative risk of future type 2 diabetes (T2D). However, the role of prolactin in T2D development and maternal metabolism in women with a recent GDM pregnancy has not been ascertained. We examined the relationships among prolactin, future T2D risk, and key clinical and metabolic parameters. We utilized a prospective GDM research cohort (the SWIFT study) and followed T2D onset by performing 2-hour 75-g research oral glucose tolerance test (OGTT) at study baseline (6-9 weeks postpartum) and again annually for 2 years, and also by retrieving clinical diagnoses of T2D from 2 years through 10 years of follow up from electronic medical records. Targeted metabolomics and lipidomics were applied on fasting plasma samples collected at study baseline from 2-hour 75-g research OGTTs in a nested case-control study (100 future incident T2D cases vs 100 no T2D controls). Decreasing prolactin quartiles were associated with increased future T2D risk (adjusted odds ratio 2.48; 95% CI, 0.81-7.58; P = 0.05). In women who maintained normoglycemia during the 10-year follow-up period, higher prolactin at baseline was associated with higher insulin sensitivity (P = 0.038) and HDL-cholesterol (P = 0.01), but lower BMI (P = 0.001) and leptin (P = 0.002). Remarkably, among women who developed future T2D, prolactin was not correlated with a favorable metabolic status (all P > 0.05). Metabolomics and lipidomics showed that lower circulating prolactin strongly correlated with a T2D-high risk lipid profile, with elevated circulating neutral lipids and lower concentrations of specific phospholipids/sphingolipids. In women with recent GDM pregnancy, low circulating prolactin is associated with specific clinical and metabolic parameters and lipid metabolites linked to a high risk of developing T2D.
Authors: Zhang, Ziyi; Piro, Anthony L; Allalou, Amina; Alexeeff, Stacey E; Dai, Feihan F; Gunderson, Erica P; Wheeler, Michael B
J Clin Endocrinol Metab. 2022 Aug 18;107(9):2652-2665.
Health-related quality of life associated with warfarin and direct oral anticoagulants in venous thromboembolism
Venous thromboembolism (VTE) is commonly treated with oral anticoagulants, including warfarin or direct oral anticoagulants (DOACs). Although DOACs are associated with favorable treatment satisfaction, few studies have assessed whether quality of life differs between DOAC and warfarin users. We invited adults enrolled in two California-based integrated health care delivery systems and with a history of VTE between January 1, 2015 and June 30, 2018 to complete a survey on their experience with anticoagulants. Health-related quality of life (QOL) was assessed using the RAND 36-item Short Form Health Survey (SF-36), which measures QOL in 2 general component scores (physical and mental). We used multivariable linear regression to compare mean QOL component scores between DOAC-users and warfarin-users, adjusting for patient and clinical characteristics. Overall, 2230 patients (43.1 % women and 31.8 % >75 years of age) taking anticoagulants answered at least 1 question on the SF-36, 975 taking DOACs and 1255 taking warfarin. After adjustment for patient-level factors, there were no significant differences in either physical component scores (39.2 v 38.3, p = 0.24) or mental component scores (48.5 v 49.0, p = 0.42) between DOAC and warfarin users. Health-related QOL did not significantly differ between DOAC and warfarin users with a history of VTE.
Authors: Fang, Margaret C; Go, Alan S; Prasad, Priya A; Zhou, Hui X; Parks, Anna L; Fan, Dongjie; Portugal, Cecilia; Sung, Sue Hee; Reynolds, Kristi
Thromb Res. 2022 Aug;216:97-102. Epub 2022-06-28.
Vitamin K Status and Cognitive Function in Adults with Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort
Vitamin K is linked to cognitive function, but studies in individuals with chronic kidney disease (CKD), who are at risk for vitamin K insufficiency and cognitive impairment, are lacking. The cross-sectional association of vitamin K status biomarkers with cognitive performance was evaluated in ≥55-y-old adults with CKD (N = 714, 49% female, 44% black). A composite score of a cognitive performance test battery, calculated by averaging the z scores of the individual tests, was the primary outcome. Vitamin K status was measured using plasma phylloquinone and dephospho-uncarboxylated matrix Gla protein [(dp)ucMGP]. Participants with low plasma (dp)ucMGP, reflecting higher vitamin K status, had better cognitive performance than those in the two higher (dp)ucMGP categories based on the composite outcome (P = 0.03), whereas it did not significantly differ according to plasma phylloquinone categories (P = 0.08). Neither biomarker was significantly associated with performance on individual tests (all P > 0.05). The importance of vitamin K to cognitive performance in adults with CKD remains to be clarified.
Authors: Shea, M Kyla; He, Jiang; Cric Study Investigators ,; et al.
Curr Dev Nutr. 2022 Aug;6(8):nzac111. Epub 2022-06-24.
Heart Failure with Iron Deficiency across the Left Ventricular Ejection Fraction Continuum – Need to Redefine?
Authors: Sawicki, Konrad Teodor; Ambrosy, Andrew P
J Card Fail. 2022 08;28(8):1264-1266. Epub 2022-02-11.
Moderate-to-vigorous intensity physical activity from young adulthood to middle age and metabolic disease: a 30-year population-based cohort study
To determine the association between moderate-to-vigorous intensity physical activity (MVPA) trajectories (course over age and time) through the adult life course and onset of metabolic disease (diabetes and dyslipidaemia). We analysed prospective community-based cohort data of 5115 participants in the Coronary Artery Risk Development in Young Adults study, who were black and white men and women aged 18-30 years at baseline (1985-1986) at four urban sites, collected through 30 years of follow-up. Individualised MVPA trajectories were developed for each participant using linear mixed models. Lower estimated MVPA score at age 18 was associated with a 12% (95% CI 6% to 18%) higher odds of incident diabetes, a 4% (95% CI 1% to 7%) higher odds of incident low high-density lipoprotein (HDL) and a 6% (95% CI 2% to 11%) higher odds of incident high triglycerides. Each additional annual 1-unit reduction in the MVPA score was associated with a 6% (95% CI 4% to 9%) higher annual odds of diabetes incidence and a 4% (95% CI 2% to 6%) higher annual odds of high triglyceride incidence. Analysing various MVPA trajectory groups, participants who were in the most active group at age 18 (over 300 min/week), but with sharp declines in midlife, had higher odds of high low-density lipoprotein and low HDL incidence, compared with those in the most active group at age 18 with subsequent gains. Given recent trends in declining MVPA across the life course and associated metabolic disease risk, young adulthood is an important time period for interventions to increase and begin the maintenance of MVPA.
Authors: Nagata, Jason M; Vittinghoff, Eric; Pettee Gabriel, Kelley; Garber, Andrea K; Moran, Andrew E; Rana, Jamal S; Reis, Jared P; Sidney, Stephen; Bibbins-Domingo, Kirsten
Br J Sports Med. 2022 Aug;56(15):847-853. Epub 2021-09-14.
Associations of Clinical and Social Risk Factors With Racial Differences in Premature Cardiovascular Disease
Racial differences in cardiovascular disease (CVD) are likely related to differences in clinical and social factors. The relative contributions of these factors to Black-White differences in premature CVD have not been investigated. In Black and White adults aged 18 to 30 years at baseline in the CARDIA study (Coronary Artery Risk Development in Young Adults), the associations of clinical, lifestyle, depression, socioeconomic, and neighborhood factors across young adulthood with racial differences in incident premature CVD were evaluated in sex-stratified, multivariable-adjusted Cox proportional hazards models using multiply imputed data assuming missing at random. Percent reduction in the β estimate (log-hazard ratio [HR]) for race quantified the contribution of each factor group to racial differences in incident CVD. Among 2785 Black and 2327 White participants followed for a median 33.9 years (25th-75th percentile, 33.7-34.0), Black (versus White) adults had a higher risk of incident premature CVD (Black women: HR, 2.44 [95% CI, 1.71-3.49], Black men: HR, 1.59 [1.20-2.10] adjusted for age and center). Racial differences were not statistically significant after full adjustment (Black women: HR, 0.91 [0.55-1.52], Black men: HR 1.02 [0.70-1.49]). In women, the largest magnitude percent reduction in the β estimate for race occurred with adjustment for clinical (87%), neighborhood (32%), and socioeconomic (23%) factors. In men, the largest magnitude percent reduction in the β estimate for race occurred with an adjustment for clinical (64%), socioeconomic (50%), and lifestyle (34%) factors. In CARDIA, the significantly higher risk for premature CVD in Black versus White adults was statistically explained by adjustment for antecedent multilevel factors. The largest contributions to racial differences were from clinical and neighborhood factors in women, and clinical and socioeconomic factors in men.
Authors: Shah, Nilay S; Sidney, Stephen; Jacobs, David R; Khan, Sadiya S; et al.
Circulation. 2022 Jul 19;146(3):201-210. Epub 2022-05-24.
Modest effect of statins on fasting glucose in a longitudinal electronic health record based cohort
Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels. Using electronic health record (EHR) data from a large and diverse longitudinal cohort, we defined long-term statin exposure in two ways: the cumulative years of statin use (cumulative supply) and the years’ supply-weighted sum of doses (cumulative dose). Simvastatin, lovastatin, atorvastatin and pravastatin were included in the analysis. The relationship between statin exposure and FG was examined using linear regression with mixed effects modeling, comparing statin users before and after initiating statins and statin never-users. We examined 593,130 FG measurements from 87,151 individuals over a median follow up of 20 years. Of these, 42,678 were never-users and 44,473 were statin users with a total of 730,031 statin prescriptions. FG was positively associated with cumulative supply of statin but not comulative dose when both measures were in the same model. While statistically significant, the annual increase in FG attributable to statin exposure was modest at only 0.14 mg/dl, with only slight and non-significant differences among statin types. Elevation in FG level is associated with statin exposure, but the effect is modest. The results suggest that the risk of a clinically significant increase in FG attributable to long-term statin use is small for most individuals.
Authors: Haldar, Tanushree; Oni-Orisan, Akinyemi; Hoffmann, Thomas J; Schaefer, Catherine; Iribarren, Carlos; Krauss, Ronald M; Medina, Marisa W; Risch, Neil
Cardiovasc Diabetol. 2022 Jul 14;21(1):132. Epub 2022-07-14.
Analysis of Worsening Heart Failure Events in an Integrated Health Care System
There is growing interest to disentangle worsening heart failure (WHF) from location of care and move away from hospitalization as a surrogate for acuity. The purpose of this study was to describe the incidence of WHF events across the care continuum from ambulatory encounters to hospitalizations. We studied calendar year cohorts of adults with diagnosed heart failure (HF) from 2010-2019 within a large, integrated health care delivery system. Electronic health record (EHR) data were accessed for outpatient encounters, emergency department (ED) visits/observation stays, and hospitalizations. WHF was defined as ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Symptoms and signs were ascertained using natural language processing. We identified 103,138 eligible individuals with mean age 73.6 ± 13.7 years, 47.5% women, and mean left ventricular ejection fraction of 51.4% ± 13.7%. There were 1,136,750 unique encounters including 743,039 (65.4%) outpatient encounters, 224,670 (19.8%) ED visits/observation stays, and 169,041 (14.9%) hospitalizations. A total of 126,008 WHF episodes were identified, including 34,758 (27.6%) outpatient encounters, 28,301 (22.5%) ED visits/observation stays, and 62,949 (50.0%) hospitalizations. The annual incidence (events per 100 person-years) of WHF increased from 25 to 33 during the study period primarily caused by outpatient encounters (7 to 10) and ED visits/observation stays (4 to 7). The 30-day rate of hospitalizations for WHF ranged from 8.2% for outpatient encounters to 12.4% for hospitalizations. ED visits/observation stays and outpatient encounters account for approximately one-half of WHF events, are driving the underlying growth in HF morbidity, and portend a poor short-term prognosis.
Authors: Ambrosy, Andrew P; Go, Alan S; et al.
J Am Coll Cardiol. 2022 Jul 12;80(2):111-122.
Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study
Cardiovascular health (CVH) from young adulthood is strongly associated with an individual’s future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05). Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.
Authors: Zheng, Yinan; Chen, Dongquan; Lloyd-Jones, Donald; et al.
Circulation. 2022 07 12;146(2):94-109. Epub 2022-06-02.
Considerations in Controlling for Urine Concentration for Biomarkers of Kidney Disease Progression After Acute Kidney Injury
Biomarkers of acute kidney injury (AKI) are often indexed to urine creatinine (UCr) or urine osmolarity (UOsm) to control for urine concentration. We evaluated how these approaches affect the biomarker-outcome association in patients with AKI. The Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Study was a cohort of hospitalized patients with and without AKI between 2009 and 2015. Using Cox proportional hazards regression, we assessed the associations and predictions (C-statistics) of urine biomarkers with a composite outcome of incident chronic kidney disease (CKD) and CKD progression. We used 4 approaches to account for urine concentration: indexing and adjusting for UCr and UOsm. Among 1538 participants, 769 (50%) had AKI and 300 (19.5%) developed composite CKD outcome at median follow-up of 4.7 years. UCr and UOsm during hospitalization were inversely associated with the composite CKD outcome. The associations and predictions with CKD were significantly strengthened after indexing or adjusting for UCr or UOsm for urine kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1) in patients with AKI. There was no significant improvement with indexing or adjusting UCr or UOsm for albumin, neutrophil gelatinase-associated lipocalin (NGAL), and chitinase 3-like 1 (YKL-40). Uromodulin’s (UMOD) inverse association with the outcome was significantly blunted after indexing but not adjusting for UCr or UOsm. UCr and UOsm during hospitalization are inversely associated with development and progression of CKD. Indexing or adjusting for UCr or UOsm strengthened associations and improved predictions for CKD for only some biomarkers. Incorporating urinary concentration should be individualized for each biomarker in research and clinical applications.
Authors: Wen, Yumeng; Go, Alan S; Parikh, Chirag R; et al.
Kidney Int Rep. 2022 Jul;7(7):1502-1513. Epub 2022-04-06.
Factors Associated with Age-Related Declines in Cardiorespiratory Fitness from Early Adulthood Through Midlife: CARDIA
This study aimed to describe maximal and submaximal cardiorespiratory fitness from early adulthood to midlife and examine differences in maximal fitness at age 20 yr and changes in fitness overtime by subcategories of sociodemographic, behavioral, and health-related factors. Data include 5018 Coronary Artery Risk Development in Young Adults participants (mean (SD) age, 24.8 (3.7) yr; 53.3% female; and 51.4% Black participants) who completed at least one maximal graded exercise test at baseline and/or the year 7 and 20 exams. Maximal and submaximal fitness were estimated by exercise duration and heart rate at the end of stage 2. Multivariable adjusted linear-mixed models were used to estimate fitness trajectories using age as the mechanism for time after adjustment for covariates. Fitness trajectories from ages 20 to 50 yr in 5-yr increments were estimated overall and by subgroups determined by each factor after adjustment for duration within the less favorable category. Mean (95% confidence interval) maximal fitness at age 20 and 50 yr was 613 (607-616) and 357 (350-362) s; submaximal heart rate during this period also reflected age-related fitness declines (126 (125-127) and 138 (137-138) bpm). Compared with men, women had lower maximal fitness at age 20 yr (P < 0.001), which persisted over follow-up (P < 0.001); differences were also found by race within sex strata (all P < 0.001). Differences in maximal fitness at age 20 yr were noted by socioeconomic, behavioral, and health-related status in young adulthood (all P < 0.05), which persisted over follow-up (all P < 0.001) and were generally consistent in sex-stratified analyses. Targeting individuals experiencing accelerated fitness declines with tailored intervention strategies may provide an opportunity to preserve fitness throughout midlife to reduce lifetime cardiovascular disease risk.
Authors: Pettee Gabriel, Kelley; Sternfeld, Barbara; Sidney, Stephen; et al.
Med Sci Sports Exerc. 2022 Jul 01;54(7):1147-1154. Epub 2022-02-08.
Oxidative Stress and Menopausal Status: The Coronary Artery Risk Development in Young Adults Cohort Study
Background: Low endogenous estrogen concentrations after menopause may contribute to higher oxidative stress and greater cardiovascular disease (CVD) risk. However, differences in oxidative stress between similarly aged premenopausal and postmenopausal women are not well-characterized on a population level. We hypothesized that urinary isoprostane concentrations, a standard measure of systemic oxidative stress, are higher in women who have undergone menopause compared to premenopausal women. Methods and Results: We examined differences in urinary 8-isoprostane (iPF2α-III) and 2,3-dinor-8-isoprostane (iPF2α-III-M) indexed to urinary creatinine between 279 postmenopausal and 196 premenopausal women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, using linear regression with progressive adjustment for sociodemographic factors and traditional CVD risk factors. Unadjusted iPF2α-III-M concentrations were higher among postmenopausal compared to premenopausal women (Median [25th, 75th percentile]: 1762 [1178, 2974] vs. 1535 [1067, 2462] ng/g creatinine; p = 0.01). Menopause was associated with 25.5% higher iPF2α-III-M (95% confidence interval [6.5-47.9]) adjusted for age, race, college education, and field center. Further adjustments for tobacco use (21.2% [2.9-42.6]) and then CVD risk factors (18.8% [0.1-39.6]) led to additional partial attenuation. Menopause was associated with higher iPF2α-III in Black but not White women. Conclusions: We conclude that postmenopausal women had higher oxidative stress, which may contribute to greater CVD risk. ClinicalTrials.gov Identifier: NCT00005130.
Authors: Heravi, Amir S; Guallar, Eliseo; Post, Wendy S; et al.
J Womens Health (Larchmt). 2022 07;31(7):1057-1065. Epub 2022-06-08.
Long-Term Cardiovascular Effects of COVID-19: Emerging Data Relevant to the Cardiovascular Clinician
COVID-19 is now a global pandemic and the illness affects multiple organ systems, including the cardiovascular system. Long-term cardiovascular consequences of COVID-19 are not yet fully characterized. This review seeks to consolidate available data on long-term cardiovascular complications of COVID-19 infection. Acute cardiovascular complications of COVID-19 infection include myocarditis, pericarditis, acute coronary syndrome, heart failure, pulmonary hypertension, right ventricular dysfunction, and arrhythmia. Long-term follow-up shows increased incidence of arrhythmia, heart failure, acute coronary syndrome, right ventricular dysfunction, myocardial fibrosis, hypertension, and diabetes mellitus. There is increased mortality in COVID-19 patients after hospital discharge, and initial myocardial injury is associated with increased mortality. Emerging data demonstrates increased incidence of cardiovascular illness and structural changes in recovered COVID-19 patients. Future research will be important in understanding the clinical significance of these structural abnormalities, and to determine the effect of vaccines on preventing long-term cardiovascular complications.
Authors: Tobler, Diana L; Pruzansky, Alix J; Naderi, Sahar; Ambrosy, Andrew P; Slade, Justin J
Curr Atheroscler Rep. 2022 07;24(7):563-570. Epub 2022-05-04.
ReducinG stroke by screening for UndiAgnosed atRial fibrillation in elderly inDividuals (GUARD-AF): Rationale and Design of the GUARD-AF Randomized Trial of Screening for Atrial Fibrillation with a 14-day Patch-Based Continuous ECG Monitor
Screening for atrial fibrillation (AF) is attractive because AF independently raises the risk of ischemic stroke, this risk is largely reversible by long-term oral anticoagulant therapy (OAC), and many patients with AF remain undiagnosed and untreated. Recent trials of one-time brief screening for AF have not produced a significant increase in the proportion of patients diagnosed with AF. Trials of longer-term screening have demonstrated an increase in AF diagnoses, primarily paroxysmal AF. To date, however, no trials have demonstrated that screening for AF results in lower rates of stroke. Clinical practice guidelines conflict in their level of support for screening for AF. The GUARD-AF individually randomized trial is designed to test whether screening for AF in individuals age 70 years or greater using a 2-week single-lead electrocardiographic patch monitor can identify patients with undiagnosed AF and lead to treatment with OAC, resulting in a reduced rate of stroke in the screened population. The trial’s efficacy end point is hospitalization for stroke (either ischemic or hemorrhagic) and the trial’s safety end point is hospitalization for a bleeding event. End points will be ascertained via Medicare claims or electronic health records at 2.5 years after study start. Enrollment is based in primary care practices and the OAC decision for screen-detected cases is left to the patient and their physician. The initial planned target sample size was 52,000, with 26,000 allocated to either screening or to usual care. Trial enrollment was severely hampered by the novel coronavirus disease 2019 (COVID-19) pandemic and stopped at a total enrollment of 11,931 participants. Of 5,965 randomized to the screening arm, 5,713 patients (96%) returned monitors with analyzable results. Incidence of screen-detected and clinically detected AF and associated stroke and bleeding outcomes will be ascertained. GUARD-AF is the largest AF screening randomized trial using a longer-term patch-based continuous electrocardiographic monitor. The results will contribute important information on the yield of patch-based AF screening, the “burden” of AF detected (percent time in AF, longest episode), and physicians’ OAC decisions as a function of AF burden. GUARD-AF’s stroke and bleed results will contribute to pooled trial analyses of AF screening, thereby informing future studies and guidelines.
Authors: Singer, Daniel E; Atlas, Steven J; Go, Alan S; Lopes, Renato D; Lubitz, Steven A; McManus, David D; Revkin, James H; Mills, Donna; Crosson, Lori A; Lenane, Judith C; Aronson, Ronald S
Am Heart J. 2022 07;249:76-85. Epub 2022-04-25.
Association between Current and Cumulative Cannabis use and Heart Rate. The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Resting heart rate can predict cardiovascular disease. Heart rate increases with tobacco smoking, but its association with cannabis use is unclear. We studied the association between current and cumulative cannabis use and heart rate. We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a large prospective cohort of 5115 Black and white women and men followed over 30 years. We explored the association between cannabis exposure and heart rate, adjusted for demographic factors, cardiovascular risk factors, alcohol and other illicit drug use, physical activity, and beta-blockers, in mixed longitudinal models censoring participants with cardiovascular disease. CARDIA participants contributed to 35,654 individual examinations over 30 years. At the Year 30 examination, 471 out of 3269 (14%) currently used cannabis. In multivariable adjusted models, compared to no current use, using cannabis 5 times per month was associated with lower heart rate of -0.7 beats per minute (95% confidence interval: -1.0 to -0.3), and daily use with lower heart rate of -2.1 beats per minute (95% confidence interval: -3.0 to -1.3, overall P < .001). Cumulative exposure to cannabis use was not associated with heart rate. Recent current cannabis use was associated with lower resting heart rate. The findings appeared to be transient because past cumulative exposure to cannabis was not associated with heart rate. This adds to the growing body of evidence suggesting a lack of deleterious association of cannabis use at a level typical of the general population on surrogate outcomes of cardiovascular disease.
Authors: Jakob, Julian; Stalder, Odile; Kali, Tali; Pruvot, Etienne; Pletcher, Mark J; Rana, Jamal S; Sidney, Stephen; Auer, Reto
Am J Med. 2022 07;135(7):871-878.e14. Epub 2022-03-02.
Ethnic diversity and burden of polycystic ovary syndrome among US adolescent females
Polycystic Ovary Syndrome (PCOS) is a common female endocrine disorder presenting as early as adolescence. Recent data suggest that Asians may be at increased risk. This study examines PCOS prevalence by race/ethnicity in a large, diverse population of adolescent females. This retrospective study included 244,642 females (ages 13-17) with well-child visits during 2012-2018 in a Northern California healthcare system. Race/ethnicity and Asian ethnicity were classified using self-reported data. Body mass index was classified as healthy, overweight, and moderate/severe obesity. PCOS was determined by clinical diagnosis within one year of the visit. The overall prevalence of PCOS was 0.7% and increased substantially with weight. Among those with obesity, PCOS prevalence was 4.2, 2.9, 2.4, 2.1% in Asian/Pacific Islander (PI), Hispanic/Latina, Non-Hispanic White, Black adolescents and 7.8, 6.7, 5.7, 3.4% in South Asian, Chinese, Filipina, Native Hawaiian/PI adolescents, respectively. Compared to White adolescents, Asian/PIs had two-fold higher risk of PCOS, and Hispanic/Latinas had 1.3-fold higher risk. Compared to Chinese adolescents, South Asians had 1.7-fold higher risk, while Native Hawaiian/PIs had half the risk. The increased burden of diagnosed PCOS in Asian/PI and Hispanic/Latina adolescents, especially those with obesity, calls for further examination and clinical surveillance of at-risk populations.
Authors: Khil, Jaclyn; Darbinian, Jeanne A; Guo, Lynn; Greenspan, Louise C; Ramalingam, Nirmala D; Lo, Joan C
J Pediatr Endocrinol Metab. 2022 Jun 27;35(6):821-825. Epub 2022-05-23.
Association of Estimated GFR Calculated Using Race-Free Equations With Kidney Failure and Mortality by Black vs Non-Black Race
At a given estimated glomerular filtration rate (eGFR), individuals who are Black have higher rates of mortality and kidney failure with replacement therapy (KFRT) compared with those who are non-Black. Whether the recently adopted eGFR equations without race preserve racial differences in risk of mortality and KFRT at a given eGFR is unknown. To assess whether eGFR equations with and without race and cystatin C document racial differences in risk of KFRT and mortality in populations including Black and non-Black participants. Retrospective individual-level data analysis of 62 011 participants from 5 general population and 3 chronic kidney disease (CKD) US-based cohorts with serum creatinine, cystatin C, and follow-up for KFRT and mortality from 1988 to 2018. Chronic Kidney Disease Epidemiology Collaboration equation with serum creatinine (eGFRcr with and without race), cystatin C (eGFRcys without race), or both markers (eGFRcr-cys without race). The prevalence of decreased eGFR at baseline and hazard ratios of KFRT and mortality in Black vs non-Black participants were calculated, adjusted for age and sex. Analyses were performed within each cohort and with random-effect meta-analyses of the models. Among 62 011 participants (20 773 Black and 41 238 non-Black; mean age, 63 years; 53% women), the prevalence ratio (95% CI; percent prevalences) of eGFR less than 60 mL/min/1.73 m2 comparing Black with non-Black participants was 0.98 (95% CI, 0.93-1.03; 11% vs 12%) for eGFRcr with race, 0.95 (95% CI, 0.91-0.98; 17% vs 18%) for eGFRcys, and 1.2 (95% CI, 1.2-1.3; 13% vs 11%) for eGFRcr-cys but was 1.8 (95% CI, 1.7-1.8; 15% vs 9%) for eGFRcr without race. During a mean follow-up of 13 years, 8% and 4% of Black and non-Black participants experienced KFRT and 34% and 39% died, respectively. Decreased eGFR was associated with significantly greater risk of both outcomes for all equations. At an eGFR of 60 mL/min/1.73 m2, the hazard ratios for KFRT comparing Black with non-Black participants were 2.8 (95% CI, 1.6-4.9) for eGFRcr with race, 3.0 (95% CI, 1.5-5.8) for eGFRcys, and 2.8 (95% CI, 1.4-5.4) for eGFRcr-cys vs 1.3 (95% CI, 0.8-2.1) for eGFRcr without race. The 5-year absolute risk differences for KFRT comparing Black with non-Black participants were 1.4% (95% CI, 0.2%-2.6%) for eGFRcr with race, 1.1% (95% CI, 0.2%-1.9%) for eGFRcys, and 1.3% (95% CI, 0%-2.6%) for eGFRcr-cys vs 0.37% (95% CI, -0.32% to 1.05%) for eGFRcr without race. Similar patterns were observed for mortality. In this retrospective analysis of 8 US cohorts including Black and non-Black individuals, the eGFR equation without race that included creatinine and cystatin C, but not the eGFR equation without race that included creatinine without cystatin C, demonstrated racial differences in the risk of KFRT and mortality throughout the range of eGFR. The eGFRcr-cys equation may be preferable to the eGFRcr equation without race for assessing racial differences in the risk of KFRT and mortality associated with low eGFR.
Authors: Gutiérrez, Orlando M; Go, Alan S; Chronic Kidney Disease Prognosis Consortium,; et al.
JAMA. 2022 06 21;327(23):2306-2316.
Framingham and American College of Cardiology/American Heart Association Pooled Cohort Equations, High-Sensitivity Troponin T, and N-Terminal Pro-Brain-Type Natriuretic Peptide for Predicting Atherosclerotic Cardiovascular Events Across the Spectrum of Kidney Dysfunction
Background Contemporary guidelines recommend using atherosclerotic cardiovascular disease screening tools to guide primary prevention. The performance of these scores is not well known in patients with moderate to advanced chronic kidney disease, particularly in combination with clinically available cardiac biomarkers including N-terminal pro-brain-type natriuretic peptide and high-sensitivity troponin T (hsTnT). Methods and Results We studied 1027 participants from the Chronic Renal Insufficiency Cohort without self-reported atherosclerotic cardiovascular disease who were not taking aspirin or statins at enrollment. Framingham Risk Score, Pooled Cohort Equation, N-terminal pro-brain-type natriuretic peptide, and hsTnT were measured at baseline. Outcomes included fatal and nonfatal myocardial infarction, stroke, and cardiac death. We calculated 10-fold cross-validated Harrell’s C-indices for each risk score and cardiac biomarker alone and in combination. The C-index (95% CI) for discrimination of atherosclerotic cardiovascular disease was 0.72 (0.67, 0.77) for the Framingham Risk Score, and 0.72 (0.67, 0.76) for the Pooled Cohort Equation. HsTnT had comparable discrimination to each risk score, and improved the discrimination of each (change in Framingham 0.029, 95% CI 0.003, 0.055; change in Pooled Cohort Equation 0.027, 95% CI 0.002, 0.052). N-terminal pro-brain-type natriuretic peptide had poorer discrimination than the risk scores and did not significantly improve their discrimination (change in Framingham 0.009, 95% CI -0.001, 0.018; change in Pooled Cohort Equation 0.011, 95% CI -0.001, 0.024). Conclusions The Framingham Risk Score and Pooled Cohort Equation demonstrated moderate discrimination for atherosclerotic cardiovascular disease in patients with chronic kidney disease. HsTnT, but not N-terminal pro-brain-type natriuretic peptide, improved their discrimination overall. Until chronic kidney disease-specific atherosclerotic cardiovascular disease risk scores can be developed, it may be worth considering how to incorporate hsTnT into existing clinical risk scores.
Authors: Lidgard, Benjamin; Zelnick, Leila R; Go, Alan; O'Brien, Kevin D; Bansal, Nisha; CRIC Study Investigators *,
J Am Heart Assoc. 2022 06 07;11(11):e024913. Epub 2022-05-27.
Multimorbidity Burden and Incident Heart Failure Among People With and Without HIV: The HIV-HEART Study
To examine the association between multimorbidity burden and incident heart failure (HF) among people with HIV (PWH) and people without HIV (PWoH). The HIV-HEART study is a retrospective cohort study that included adult PWH and PWoH aged 21 years or older at Kaiser Permanente between 2000 and 2016. Multimorbidity burden was defined by the baseline prevalence of 22 chronic conditions and was categorized as 0-1, 2-3, and 4 or more comorbidities on the basis of distribution of the overall population. People with HIV and PWoH were followed for a first HF event, all-cause death, or up to the end of follow-up on December 31, 2016. Using Cox proportional hazard regression, hazard ratios and 95% CIs were calculated to examine the association between multimorbidity burden and incident HF among PWH and PWoH, separately. The prevalences of 0-1, 2-3, and 4 or more comorbidities were 83.3%, 13.0%, and 3.7% in PWH (n=38,868), and 82.2%, 14.3%, and 3.5% in PWoH (n=386,586), respectively. After multivariable adjustment, compared with people with 0-1 comorbidities, the hazard ratios of incident HF associated with 2-3 and 4 or more comorbidities were 1.33 (95% CI, 1.04-1.71) and 2.41 (95% CI, 1.78-3.25) in PWH and 2.10 (95% CI, 1.92-2.29) and 4.09 (95% CI, 3.64-4.61) in PWoH, respectively. Multimorbidity was associated with a higher risk of incident HF among PWH and PWoH, with more prominent associations in PWoH and certain patient subgroups. The identification of specific multimorbidity patterns that contribute to higher HF risk in PWH may lead to future preventative strategies.
Authors: Mefford, Matthew T; Silverberg, Michael J; Leong, Thomas K; Hechter, Rulin C; Towner, William J; Go, Alan S; Horberg, Michael; Hu, Haihong; Harrison, Teresa N; Sung, Sue Hee; Reynolds, Kristi
Mayo Clin Proc Innov Qual Outcomes. 2022 Jun;6(3):218-227. Epub 2022-05-03.
Risk of heart failure with preserved versus reduced ejection fraction in women with breast cancer
While clinical heart failure (HF) is recognized as an adverse effect from breast cancer (BC) treatment, sparse data exist on specific HF phenotypes in affected BC survivors. We examined risk of HF by left ventricular ejection fraction (LVEF) status in women with a history of BC. 14,804 women diagnosed with all stages of invasive BC from 2005 to 2013 and with no history of HF were matched 1:5 to 74,034 women without BC on birth year, race, and ethnicity. LVEF values were extracted from echocardiography studies within 30 days before through 90 days after the HF clinical encounter. HF was stratified into HF with preserved ejection fraction (HFpEF, LVEF ≥ 45%) and HF with reduced ejection fraction (HFrEF, LVEF < 45%). Cumulative incidence rates (CIRs) were estimated with competing risk of overall death. Hazard ratios (HR) were calculated by multivariable Cox proportional hazards regression. Mean time to HF diagnosis was 5.31 years (range 0.03-13.03) in cases and 5.25 years (range 0.01-12.94) in controls. 10-year CIRs were 1.2% and 0.9% for overall HF, 0.8% and 0.7% for HFpEF, and 0.4% and 0.2% for HFrEF in cases and controls, respectively. In fully adjusted models, an overall significant increased risk of HF in cases versus controls was observed (HR: 1.31, 95% CI 1.14, 1.51). The increased risk was seen for both HFrEF (HR: 1.59, 95% CI 1.22, 2.08) and HFpEF (HR: 1.22; 95% CI 1.03, 1.45). BC survivors experienced higher risk of HF compared with women without BC, and the risk persisted across LVEF phenotypes. Systematic cardio-oncology surveillance should be considered to mitigate this risk in BC patients.
Authors: Kwan, Marilyn L; Cheng, Richard K; Iribarren, Carlos; Shen, Hanjie; Laurent, Cecile A; Roh, Janise M; Hershman, Dawn L; Kushi, Lawrence H; Greenlee, Heather; Rana, Jamal S
Breast Cancer Res Treat. 2022 Jun;193(3):669-675. Epub 2022-04-16.
Prognostic Value of Echocardiography for Heart Failure and Death in Adults with Chronic Kidney Disease
Adults with chronic kidney disease (CKD) are at increased risk of heart failure (HF) morbidity and mortality. Despite well-characterized abnormalities in cardiac structure in CKD, it remains unclear how to optimally leverage echocardiography to risk stratify CKD patients. We evaluated associations between echocardiographic parameters and risk of HF hospitalization and death using Cox proportional hazard models and forward selection with integrated discrimination improvement (IDI). The study included 3,505 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. Mean age was 59 ± 11 years, HF prevalence was 10%, and mean left ventricular (LV) ejection fraction (LVEF) was 54 ± 9%. During median 11 (interquartile range: 8-12) years of follow-up, event rates per 100-person years for HF hospitalizations and death, respectively, were 9.4 (95% Confidence Interval [CI]: 7.9-11.3) and 8.9 (95% CI: 7.6-10.5) for participants with LVEF <40%, 3.5 (95% CI: 3.0-4.2) and 4.6 (95% CI: 4.0-5.2) for patients with LVEF 40% to 49%, and 1.9 (95% CI: 1.7-2.1) and 3.1 (95% CI: 2.9-3.3) for patients with LVEF >50%. The rate of HF hospitalizations and deaths increased with lower eGFR across all LVEF categories. LV mass index, LVEF, and LV geometry had the strongest association with outcomes but provided modest incremental prognostic value to a baseline clinical model (IDI = 0.14 and ΔAUC = 0.017 for HF hospitalization, IDI = 0.12 and ΔAUC = 0.008 for death). Baseline echocardiographic parameters are independently associated with increased risk of subsequent HF morbidity and mortality but provide only marginal incremental prognostic utility beyond clinical characteristics in the setting of CKD.
Authors: Fitzpatrick, Jesse K; Ambrosy, Andrew P; Parikh, Rishi V; Tan, Thida C; Bansal, Nisha; Go, Alan S; CRIC Study Investigators,,
Am Heart J. 2022 06;248:84-96. Epub 2022-03-10.
Acute Kidney Injury Associates with Long-Term Increases in Plasma TNFR1, TNFR2, and KIM-1: Findings from the CRIC study
Some markers of inflammation-TNF receptors 1 and 2 (TNFR1 and TNFR2)-are independently associated with progressive CKD, as is a marker of proximal tubule injury, kidney injury molecule 1 (KIM-1). However, whether an episode of hospitalized AKI may cause long-term changes in these biomarkers is unknown. Among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study, we identified 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥1.5). For each AKI hospitalization, we found the best matched non-AKI hospitalization (unique patients), using prehospitalization characteristics, including eGFR and urine protein/creatinine ratio. We measured TNFR1, TNFR2, and KIM-1 in banked plasma samples collected at annual CRIC study visits before and after the hospitalization (a median of 7 months before and 5 months after hospitalization). In the AKI and non-AKI groups, we found similar prehospitalization median levels of TNFR1 (1373 pg/ml versus 1371 pg/ml, for AKI and non-AKI, respectively), TNFR2 (47,141 pg/ml versus 46,135 pg/ml, respectively), and KIM-1 (857 pg/ml versus 719 pg/ml, respectively). Compared with matched study participants who did not experience AKI, study participants who did experience AKI had greater increases in TNFR1 (23% versus 10%, P<0.01), TNFR2 (10% versus 3%, P<0.01), and KIM-1 (13% versus -2%, P<0.01). Among patients with CKD, AKI during hospitalization was associated with increases in plasma TNFR1, TNFR2, and KIM-1 several months after their hospitalization. These results highlight a potential mechanism by which AKI may contribute to more rapid loss of kidney function months to years after the acute insult.
Authors: McCoy, Ian E; Liu, Kathleen D; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators,; et al.
J Am Soc Nephrol. 2022 06;33(6):1173-1181. Epub 2022-03-16.
Multiomics Analysis Identifies BIRC3 as a Novel Glucocorticoid Response-Associated Gene
Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics data sets are available to interrogate their biological effects. We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets. Variants with P values less than 10-4 from a previous ICS-response genome-wide association study were reranked on the basis of integrative scores determined from (1) glucocorticoid receptor- and (2) RNA polymerase II-binding regions inferred from ChIP-Seq data for 3 airway cell types, (3) glucocorticoid response element motifs, (4) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic data sets, and (5) expression quantitative trait loci from GTEx. Candidate variants were tested for association with ICS response and asthma in 6 independent studies. Four variants had significant (q value < 0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high linkage disequilibrium (r2 ≥ 0.8) near glucocorticoid receptor-binding sites by the gene BIRC3. Variants were also BIRC3 expression quantitative trait loci in lung, and 2 were within/near putative glucocorticoid response element motifs. BIRC3 had increased RNA polymerase II occupancy and gene expression, with glucocorticoid exposure in 2 ChIP-Seq and 13 transcriptomic data sets. Some BIRC3 variants in the 52-variant locus were associated (P < .05) with ICS response in 3 independent studies and others with asthma in 1 study. BIRC3 should be prioritized for further functional studies of ICS response.
Authors: Kan, Mengyuan; Lu, Meng X; Himes, Blanca E; et al.
J Allergy Clin Immunol. 2022 06;149(6):1981-1991. Epub 2021-12-28.
Usage of long-acting muscarinic antagonists and biologics as add-on therapy for patients in the United States with moderate-to-severe asthma
Many asthma patients remain uncontrolled on inhaled corticosteroids (ICS) and long-acting beta agonists (LABAs), but guidance for selecting add-on therapies, including long-acting muscarinic antagonists (LAMAs) or biologics, is limited. We describe how prescribing practices for add-on LAMA and biologic therapy have changed with increased treatment options and revised treatment guidelines. We further identify differences in treatment initiation and discontinuation rates by patient characteristics, including concomitant COPD. This retrospective cohort study analyzed insurance claims in the IBM Marketscan database for adult US asthma patients treated with medium- or high-dose ICS/LABA between 2012 and 2019 (n = 277,373). We used negative binomial regression models to evaluate LAMA and biologic initiation rates and their association with patient characteristics, and survival analysis methods for assessing discontinuation rates. Between 2012 and 2019, LAMA and biologic uptake increased approximately 5-fold and 20-fold, respectively. LAMA initiation was significantly higher among patients with concomitant COPD, a group typically unstudied in clinical trials, versus those with asthma only (rate ratio of 5.90, 95% CI: 5.76-6.04). High-dose ICS/LABA treatment and the need for oral corticosteroid (OCS) bursts had stronger associations with biologic initiation. Probability of discontinuation (i.e. non-persistence) in the first year was 40.5% and 22.7% for those initiating LAMAs and biologics, respectively, with higher LAMA discontinuation rates among patients with asthma only versus those with concomitant COPD. Our results provide insights into how clinicians apply treatment guidelines for initiating add-on LAMA and biologic therapies in moderate-to-severe asthma patients and highlight patients who have an unmet treatment need after discontinuation.
Authors: Spain, C Victor; Dayal, Parul; Ding, Yingjie; Iribarren, Carlos; Omachi, Theodore A; Chen, Hubert
J Asthma. 2022 06;59(6):1237-1247. Epub 2021-05-22.
Cardiac Biomarkers and Risk of Atherosclerotic Cardiovascular Disease in Patients with CKD
Several cardiac biomarkers of cardiac stress, inflammation, and fibrosis (N-terminal pro brain-type natriuretic peptide [NT-proBNP], high-sensitivity troponin T [hsTnT], growth differentiation factor 15 [GDF-15], and soluble ST2 [sST2]) have been associated with atherosclerotic disease in the general population. We hypothesized that these cardiac biomarkers may also be associated with the atherosclerotic cardiovascular disease in patients with CKD. We analyzed levels of NT-proBNP, hsTnT, GDF-15, and sST2 in a cohort of 2732 participants with mild to moderate CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. Outcomes included incident atherosclerotic disease, defined as the first instance of myocardial infarction, stroke, or peripheral vascular disease. We used Cox proportional hazard models to the test the association of each cardiac biomarker with risk of incident atherosclerotic disease, adjusting for multiple possible confounders. When modeled continuously (per SD increase in the log-transformed biomarker), NT-proBNP, hsTnT, GDF-15, and sST2 were significantly associated with incident atherosclerotic disease after adjustment for multiple potential confounders: (NT-proBNP HR, 1.51; 95% CI, 1.27 to 1.81; hsTnT HR, 1.61; 95% CI, 1.38 to 1.89; GDF-15 HR, 1.44; 95% CI, 1.19 to 1.73; and sST2 HR, 1.19; 95% CI, 1.04 to 1.36). NT-proBNP, hsTnT, GDF-15, and sST2 were significantly associated with incident atherosclerotic cardiovascular disease in patients with CKD. These associations may highlight important mechanisms for the development of atherosclerotic disease in CKD.
Authors: Lidgard, Benjamin; He, Jiang; CRIC Study Investigators*,; et al.
Kidney360. 2022 05 26;3(5):859-871. Epub 2022-03-02.
Incidence of Ischemic Stroke in Patients With Asymptomatic Severe Carotid Stenosis Without Surgical Intervention
Optimal management of patients with asymptomatic severe carotid stenosis is uncertain, due to advances in medical care and a lack of contemporary data comparing medical and surgical treatment. To estimate stroke outcomes among patients with medically treated asymptomatic severe carotid stenosis who did not undergo surgical intervention. Retrospective cohort study that included 3737 adult participants with asymptomatic severe (70%-99%) carotid stenosis diagnosed between 2008 and 2012 and no prior intervention or ipsilateral neurologic event in the prior 6 months. Participants received follow-up through 2019, and all were members of an integrated US regional health system serving 4.5 million members. Imaging diagnosis of asymptomatic carotid stenosis of 70% to 99%. Occurrence of ipsilateral carotid-related acute ischemic stroke. Censoring occurred with death, disenrollment, or ipsilateral intervention. Among 94 822 patients with qualifying imaging studies, 4230 arteries in 3737 (mean age, 73.8 [SD 9.5 years]; 57.4% male) patients met selection criteria including 2539 arteries in 2314 patients who never received intervention. The mean follow-up in this cohort was 4.1 years (SD 3.6 years). Prior to any intervention, there were 133 ipsilateral strokes with a mean annual stroke rate of 0.9% (95% confidence interval [CI], 0.7%-1.2%). The Kaplan-Meier estimate of ipsilateral stroke by 5 years was 4.7% (95% CI, 3.9%-5.7%). In a community-based cohort of patients with asymptomatic severe carotid stenosis who did not undergo surgical intervention, the estimated rate of ipsilateral carotid-related acute ischemic stroke was 4.7% over 5 years. These findings may inform decision-making regarding surgical and medical treatment for patients with asymptomatic severe carotid artery stenosis.
Authors: Chang, Robert W; Tucker, Lue-Yen; Rothenberg, Kara A; Lancaster, Elizabeth; Faruqi, Rishad M; Kuang, Hui C; Flint, Alexander C; Avins, Andrew L; Nguyen-Huynh, Mai N
JAMA. 2022 05 24;327(20):1974-1982.
Risk of Cardiovascular Disease in Women With and Without Breast Cancer: The Pathways Heart Study
To examine cardiovascular disease (CVD) and mortality risk in women with breast cancer (BC) by cancer therapy received relative to women without BC. The study population comprised Kaiser Permanente Northern California members. Cases with invasive BC diagnosed from 2005 to 2013 were matched 1:5 to controls without BC on birth year and race/ethnicity. Cancer treatment, CVD outcomes, and covariate data were from electronic health records. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs of CVD incidence and mortality by receipt of chemotherapy treatment combinations, radiation therapy, and endocrine therapy. A total of 13,642 women with BC were matched to 68,202 controls without BC. Over a 7-year average follow-up (range < 1-14 years), women who received anthracyclines and/or trastuzumab had high risk of heart failure/cardiomyopathy relative to controls, with the highest risk seen in women who received both anthracyclines and trastuzumab (HR, 3.68; 95% CI, 1.79 to 7.59). High risk of heart failure and/or cardiomyopathy was also observed in women with BC with a history of radiation therapy (HR, 1.38; 95% CI, 1.13 to 1.69) and aromatase inhibitor use (HR, 1.31; 95% CI, 1.07 to 1.60), relative to their controls. Elevated risks for stroke, arrhythmia, cardiac arrest, venous thromboembolic disease, CVD-related death, and death from any cause were also observed in women with BC on the basis of cancer treatment received. Women with BC had increased incidence of CVD events, CVD-related mortality, and all-cause mortality compared with women without BC, and risks varied according to the history of cancer treatment received. Studies are needed to determine how women who received BC treatment should be cared for to improve cardiovascular outcomes.
Authors: Greenlee, Heather; Rana, Jamal S; Cheng, Richard; Rillamas-Sun, Eileen; Neugebauer, Romain; Kwan, Marilyn L; Kwan, Marilyn L; et al.
J Clin Oncol. 2022 05 20;40(15):1647-1658. Epub 2022-04-06.
Risk of Cardiometabolic Risk Factors in Women With and Without a History of Breast Cancer: The Pathways Heart Study
The incidence of cardiometabolic risk factors in breast cancer (BC) survivors has not been well described. Thus, we compared risk of hypertension, diabetes, and dyslipidemia in women with and without BC. Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California (KPNC) were identified and matched 1:5 to noncancer controls on birth year, race, and ethnicity. Cumulative incidence rates of hypertension, diabetes, and dyslipidemia were estimated with competing risk of overall death. Subdistribution hazard ratios (sHRs) were estimated by Fine and Gray regression, adjusted for cardiovascular disease-related risk factors, and stratified by treatment and body mass index (BMI). A total of 14,942 BC cases and 74,702 matched controls were identified with mean age 61.2 years and 65% non-Hispanic White. Compared with controls, BC cases had higher cumulative incidence rates of hypertension (10.9% v 8.9%) and diabetes (2.1% v 1.7%) after 2 years, with higher diabetes incidence persisting after 10 years (9.3% v 8.8%). In multivariable models, cases had higher risk of diabetes (sHR, 1.16; 95% CI, 1.07 to 1.26) versus controls. Cases treated with chemotherapy (sHR, 1.23; 95% CI, 1.11 to 1.38), left-sided radiation (sHR, 1.29; 95% CI, 1.13 to 1.48), or endocrine therapy (sHR, 1.23; 95% CI, 1.12 to 1.34) continued to have higher diabetes risk. Hypertension risk was higher for cases receiving left-sided radiation (sHR, 1.11; 95% CI, 1.02 to 1.21) or endocrine therapy (sHR, 1.10; 95% CI, 1.03 to 1.16). Normal-weight (BMI < 24.9 kg/m2) cases had higher risks overall and within treatment subgroups versus controls. BC survivors at KPNC experienced elevated risks of diabetes and hypertension compared with women without BC depending on treatments received and BMI. Future studies should examine strategies for cardiometabolic risk factor prevention in BC survivors.
Authors: Kwan, Marilyn L; Iribarren, Carlos; Neugebauer, Romain; Rana, Jamal S; Nguyen-Huynh, Mai; Kushi, Lawrence H; Greenlee, Heather; et al.
J Clin Oncol. 2022 05 20;40(15):1635-1646. Epub 2022-01-13.
Reduced cardiovascular risks in women with endometriosis or polycystic ovary syndrome carrying a common functional IGF1R variant
Is the increased future cardiovascular risk seen in women with endometriosis or polycystic ovary syndrome (PCOS) mitigated by functional insulin-like growth factor-1 receptor (IGF1R) single-nucleotide polymorphism (SNP) rs2016347 as previously shown in women with hypertensive disorders of pregnancy? This cohort study found that women with endometriosis or PCOS who carry a T allele of IGF1R SNP rs2016347 had a reduced future risk of developing cardiovascular disease (CVD) and associated risk factors, with risk reduction dependent on cohort era. Women with endometriosis or PCOS have been shown to have an increased future risk of CVD and associated risk factors with limited predictive ability. This retrospective cohort study took place in the Nurses’ Health Study 2 (NHS2), which enrolled 116 430 participants in 1989 who were followed through 2015. The study population was analyzed in its entirety, and subdivided into entry (pre-1989) and after entry (post-1989) exposure cohorts. All NHS2 participants were eligible for inclusion in the study, 9599 (8.2%) were excluded for missing covariates. The NHS2 enrolled female registered nurses from 14 different states who ranged in age from 25 to 42 years at study entry. Data were collected from entry and biennial questionnaires, and analysis conducted from November 2020 to June 2021. Cox proportional hazard models were used to assess risk of CVD, hypertension (HTN), hypercholesterolemia (HC) and type 2 diabetes, both with and without genotyping for rs2016347. While women without endometriosis or PCOS, as a whole, demonstrated no impact of genotype on risk in either cohort, women with endometriosis carrying a T allele had a lower risk of CVD (hazard ratio (HR), 0.48; 95% CI, 0.27-0.86, P = 0.02) and HTN (HR, 0.80; 95% CI, 0.66-0.97, P = 0.03) in the pre-1989 cohort, while those in the post-1989 cohort had a decrease in risk for HC (HR, 0.76; 95% CI, 0.62-0.94, P = 0.01). Women with PCOS in the post-1989 cohort showed a significant protective impact of the T allele on HTN (HR, 0.44; 95% CI, 0.27-0.73, P = 0.002) and HC (HR, 0.62; 95% CI, 0.40-0.95, P = 0.03). Data on specific endometriosis lesion locations or disease stage, as well as on PCOS phenotypes were lacking. In addition, data on systemic medical treatments beyond the use of oral contraceptives were missing, and these treatments may have confounded the results. These findings implicate systemic dysregulation of the insulin-like growth factor-1 axis in the development of HTN, HC and clinical CVD in endometriosis and PCOS, suggesting a common underlying pathogenetic mechanism. The NHS2 infrastructure for questionnaire data collection was supported by National Institute of Health (NIH) grant U01CA176726. This work was also supported in part by NIH and National Cancer Institute grant U24CA210990; as well, research effort and publication costs were supported by the Elizabeth MA Stevens donor funds provided to the Buck Institute for Research on Aging. The authors declare they have no conflicts of interest. .
Authors: Powell, Mark J; Fuller, Sophia; Gunderson, Erica P; Benz, Christopher C
Hum Reprod. 2022 05 03;37(5):1083-1094.
Effect of Lifestyle Coaching or Enhanced Pharmacotherapy on Blood Pressure Control Among Black Adults With Persistent Uncontrolled Hypertension: A Cluster Randomized Clinical Trial
Greater difficulty in controlling blood pressure (BP) and adverse lifestyle practices such as higher salt intake or less physical activity may account for some of the differences between BP control rates in Black vs White adults, thereby exposing Black adults to a higher risk of vascular events. To determine whether a lifestyle coaching intervention or an enhanced pharmacotherapy protocol is more effective than usual care in improving BP control rates in Black adults treated within an integrated health care delivery system. Shake, Rattle & Roll, a cluster randomized clinical trial, was conducted from June 5, 2013, to June 11, 2018, in a large integrated health care delivery system. Enrollment was completed during a 12-month period and interventions were implemented for 12 months. Follow-up lasted 48 months after enrollment. Panels of Black adult members of the health care delivery system with BP of at least 140/90 mm Hg from 98 adult primary care physicians were randomly assigned at the primary care physician level to usual care (UC group [n = 1129]), enhanced pharmacotherapy monitoring (EP group [n = 346]) of current BP management protocol, or diet and lifestyle coaching consisting of photographs, stories, and recipes, for example, that are appropriate for Black adults (LC group [n = 286]) focused on the Dietary Approaches to Stop Hypertension (DASH) diet. Data were analyzed from June 1, 2016, to March 25, 2022. The UC group received care per customary protocol. The EP group was contacted by a research nurse and/or a clinical pharmacist to discuss barriers to hypertension control, and drug therapy emphasized the use of thiazide diuretic intensification and addition of spironolactone as needed. The LC group received as many as 16 telephone sessions with a lifestyle coach and an emphasis on implementing reduction of sodium intake and the DASH diet. Intention-to-treat analysis of BP control rates at end of the 12-month intervention. Among the 1761 participants, the mean (SD) age was 61 (13) years, and 1214 (68.9%) were women. At the end of the 12-month intervention period, there was no significant difference in BP control rate among study groups (UC, 61.8% [95% CI, 58.8%-64.9%]; EP, 64.5% [95% CI, 59.0%-69.4%]; LC, 67.8% [95% CI, 62.1%-73.2%]; LC vs EP, P = .07). However, greater BP control was present in the LC group vs UC at 24 months (UC, 61.2% [95% CI, 57.3%-64.7%]; EP, 67.6% [95% CI, 61.9%-72.8%]; LC, 72.4% [95% CI, 66.9%-78.1%]; LC vs UC, P = .001), and 48 months (UC, 64.5% [95% CI, 61.6%-67.2%]; EP, 66.5% [95% CI, 61.3%-71.3%]; LC, 73.1% [95% CI, 67.6%-77.9%]; LC vs UC, P = .006) after enrollment. The contribution of BP medication adherence to explain group differences was inconclusive. In this cluster randomized clinical trial including Black adults with persistent uncontrolled hypertension, a 12-month LC intervention was more effective at controlling BP than UC at 24 and 48 months after enrollment. Further research is needed to explore the potential implementation of this intervention into clinical practice. ClinicalTrials.gov Identifier: NCT01892592.
Authors: Nguyen-Huynh, Mai N; Young, Joseph D; Ovbiagele, Bruce; Alexander, Janet G; Alexeeff, Stacey; Lee, Catherine; Blick, Noelle; Caan, Bette J; Go, Alan S; Sidney, Stephen
JAMA Netw Open. 2022 May 02;5(5):e2212397. Epub 2022-05-02.
Perinatal Complications in Individuals in California With or Without SARS-CoV-2 Infection During Pregnancy
Additional research from population-based studies is needed to inform the treatment of SARS-CoV-2 infection during pregnancy and to provide health risk information to pregnant individuals. To assess the risk of perinatal complications associated with SARS-CoV-2 infection and to describe factors associated with hospitalizations. This population-based cohort study included 43 886 pregnant individuals with longitudinal electronic health record data from preconception to delivery who delivered at Kaiser Permanente Northern California between March 1, 2020, and March 16, 2021. Individuals with diagnostic codes for COVID-19 that did not have a confirmatory polymerase chain reaction test for SARS-CoV-2 were excluded. SARS-CoV-2 infection detected by polymerase chain reaction test (from 30 days before conception to 7 days after delivery) as a time varying exposure. Severe maternal morbidity including 21 conditions (eg, acute myocardial infarction, acute renal failure, acute respiratory distress syndrome, and sepsis) that occurred at any time during pregnancy or delivery; preterm birth; pregnancy hypertensive disorders; gestational diabetes; venous thromboembolism (VTE); stillbirth; cesarean delivery; and newborn birth weight and respiratory conditions. Standardized mean differences between individuals with and without SARS-CoV-2 were calculated. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for the association between SARS-CoV-2 infection and perinatal complications and hospitalization and to consider the timing of SARS-CoV-2 infection relative to outcomes. In this study of 43 886 pregnant individuals (mean [SD] age, 30.7 [5.2] years), individuals with a SARS-CoV-2 infection (1332 [3.0%]) were more likely to be younger, Hispanic, multiparous individuals with a higher neighborhood deprivation index and obesity or chronic hypertension. After adjusting for demographic characteristics, comorbidities, and smoking status, individuals with SARS-CoV-2 infection had higher risk for severe maternal morbidity (HR, 2.45; 95% CI, 1.91-3.13), preterm birth (<37 weeks; HR, 2.08; 95% CI, 1.75-2.47), and VTE (HR, 3.08; 95% CI, 1.09-8.74) than individuals without SARS-CoV-2. SARS-CoV-2 infection was also associated with increased risk of medically indicated preterm birth (HR, 2.56; 95% CI, 2.06-3.19); spontaneous preterm birth (HR, 1.61; 95% CI, 1.22-2.13); and early (HR, 2.52; 95% CI, 1.49-4.24), moderate (HR, 2.18; 95% CI, 1.25-3.80), and late (HR, 1.95; 95% CI, 1.61-2.37) preterm birth. Among individuals with SARS-CoV-2 infection, 76 (5.7%) had a hospitalization; pregestational diabetes (HR, 7.03; 95% CI, 2.22-22.2) and Asian or Pacific Islander (HR, 2.33; 95% CI, 1.06-5.11) and Black (HR, 3.14; 95% CI, 1.24-7.93) race and ethnicity were associated with an increased risk of hospitalization. In this cohort study, SARS-CoV-2 infection was associated with increased risk of severe maternal morbidity, preterm birth, and VTE. The study findings inform clinicians and patients about the risk of perinatal complications associated with SARS-CoV-2 infection in pregnancy and support vaccination of pregnant individuals and those planning conception.
Authors: Ferrara, Assiamira; Hedderson, Monique M; Zhu, Yeyi; Avalos, Lyndsay A; Kuzniewicz, Michael W; Myers, Laura C; Ngo, Amanda L; Gunderson, Erica P; Ritchie, Jenna L; Quesenberry, Charles P; Greenberg, Mara
JAMA Intern Med. 2022 05 01;182(5):503-512.
Genetic associations and architecture of asthma-chronic obstructive pulmonary disease overlap
Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.
Authors: John, Catherine; Iribarren, Carlos; Tesfaigzi, Yohannes; Tobin, Martin D; et al.
Chest. 2022 05;161(5):1155-1166. Epub 2022-01-31.
A Randomized Controlled Trial of Renin-Angiotensin-Aldosterone System Inhibitor Management in Patients Admitted in Hospital with COVID-19
Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle. Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients’ mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016). RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.
Authors: Sharma, Abhinav; Ambrosy, Andrew P; Ferreira, João Pedro; et al.
Am Heart J. 2022 05;247:76-89. Epub 2022-02-07.
Establishing a National Cardiovascular Disease Surveillance System in the United States Using Electronic Health Record Data: Key Strengths and Limitations
Cardiovascular disease surveillance involves quantifying the evolving population-level burden of cardiovascular outcomes and risk factors as a data-driven initial step followed by the implementation of interventional strategies designed to alleviate this burden in the target population. Despite widespread acknowledgement of its potential value, a national surveillance system dedicated specifically to cardiovascular disease does not currently exist in the United States. Routinely collected health care data such as from electronic health records (EHRs) are a possible means of achieving national surveillance. Accordingly, this article elaborates on some key strengths and limitations of using EHR data for establishing a national cardiovascular disease surveillance system. Key strengths discussed include the: (1) ubiquity of EHRs and consequent ability to create a more “national” surveillance system, (2) existence of a common data infrastructure underlying the health care enterprise with respect to data domains and the nomenclature by which these data are expressed, (3) longitudinal length and detail that define EHR data when individuals repeatedly patronize a health care organization, and (4) breadth of outcomes capable of being surveilled with EHRs. Key limitations discussed include the: (1) incomplete ascertainment of health information related to health care-seeking behavior and the disconnect of health care data generated at separate health care organizations, (2) suspect data quality resulting from the default information-gathering processes within the clinical enterprise, (3) questionable ability to surveil patients through EHRs in the absence of documented interactions, and (4) the challenge in interpreting temporal trends in health metrics, which can be obscured by changing clinical and administrative processes.
Authors: Williams, Brent A; Roger, Véronique L; Benziger, Catherine P; et al.
J Am Heart Assoc. 2022 Apr 19;11(8):e024409. Epub 2022-04-12.
Deoxycholic Acid and Coronary Artery Calcification in the Chronic Renal Insufficiency Cohort
Background Deoxycholic acid (DCA) is a secondary bile acid that may promote vascular calcification in experimental settings. Higher DCA levels were associated with prevalent coronary artery calcification (CAC) in a small group of individuals with advanced chronic kidney disease. Whether DCA levels are associated with CAC prevalence, incidence, and progression in a large and diverse population of individuals with chronic kidney disease stages 2 to 4 is unknown. Methods and Results In the CRIC (Chronic Renal Insufficiency Cohort) study, we evaluated cross-sectional (n=1057) and longitudinal (n=672) associations between fasting serum DCA levels and computed tomographic CAC using multivariable-adjusted regression models. The mean age was 57±12 years, 47% were women, and 41% were Black. At baseline, 64% had CAC (CAC score >0 Agatston units). In cross-sectional analyses, models adjusted for demographics and clinical factors showed no association between DCA levels and CAC >0 compared with no CAC (prevalence ratio per 1-SD higher log DCA, 1.08 [95% CI, 0.91-1.26). DCA was not associated with incident CAC (incidence per 1-SD greater log DCA, 1.08 [95% CI, 0.85-1.39]) or CAC progression (risk for increase in ≥100 and ≥200 Agatston units per year per 1-SD greater log DCA, 1.05 [95% CI, 0.84-1.31] and 1.26 [95% CI, 0.77-2.06], respectively). Conclusions Among CRIC study participants, DCA was not associated with prevalent, incident, or progression of CAC.
Authors: Jovanovich, Anna; Shafi, Tariq; CRIC Study Investigators [Link],; et al.
J Am Heart Assoc. 2022 04 05;11(7):e022891. Epub 2022-03-24.
Prediction of Incident Heart Failure in CKD: The CRIC Study
Heart failure (HF) is common in chronic kidney disease (CKD); identifying patients with CKD at high risk for HF may guide clinical care. We assessed the prognostic value of cardiac biomarkers and echocardiographic variables for 10-year HF prediction compared with a published clinical HF prediction equation in a cohort of participants with CKD. We studied 2147 Chronic Renal Insufficiency Cohort (CRIC) participants without prior HF with complete clinical, cardiac biomarker (N-terminal brain natriuretic peptide [NT-proBNP] and high sensitivity troponin-T [hsTnT]), and echocardiographic data (left ventricular mass [LVM] and left ventricular ejection fraction [LVEF] data). We compared the discrimination of the 11-variable Atherosclerosis Risk in Communities (ARIC) HF prediction equation with LVM, LVEF, hsTnT, and NT-proBNP to predict 10-year risk of hospitalization for HF using a Fine and Gray modeling approach. We separately evaluated prediction of HF with preserved and reduced LVEF (LVEF ≥50% and <50%, respectively). We assessed discrimination with internally valid C-indices using 10-fold cross-validation. Participants' mean (SD) age was 59 (11) years, 53% were men, 43% were Black, and mean (SD) estimated glomerular filtration rate (eGFR) was 44 (16) ml/min per 1.73 m2. A total of 324 incident HF hospitalizations occurred during median (interquartile range) 10.0 (5.7-10.0) years of follow-up. The ARIC HF model with clinical variables had a C-index of 0.68. Echocardiographic variables predicted HF (C-index 0.70) comparably to the published ARIC HF model, while NT-proBNP and hsTnT together (C-index 0.73) had significantly better discrimination (P = 0.004). A model including cardiac biomarkers, echocardiographic variables, and clinical variables had a C-index of 0.77. Discrimination of HF with preserved LVEF was lower than for HF with reduced LVEF for most models. The ARIC HF prediction model for 10-year HF risk had modest discrimination among adults with CKD. NT-proBNP and hsTnT discriminated better than the ARIC HF model and at least as well as a model with echocardiographic variables. HF clinical prediction models tailored to adults with CKD are needed. Until then, measurement of NT-proBNP and hsTnT may be a low-burden approach to predicting HF in this population, as they offer moderate discrimination.
Authors: Zelnick, Leila R; Go, Alan; CRIC Study Investigators,; et al.
Kidney Int Rep. 2022 Apr;7(4):708-719. Epub 2022-02-02.
Association of the 2020 US Presidential Election With Hospitalizations for Acute Cardiovascular Conditions
Prior studies found a higher risk of acute cardiovascular disease (CVD) around population-wide psychosocial or environmental stressors. Less is known about acute CVD risk in relation to political events. To examine acute CVD hospitalizations following the 2020 presidential election. This retrospective cohort study examined acute CVD hospitalizations following the 2020 presidential election. Participants were adult members aged 18 years or older at Kaiser Permanente Southern California and Kaiser Permanente Northern California, 2 large, integrated health care delivery systems. Statistical analysis was performed from March to July 2021. 2020 US presidential election. Hospitalizations for acute CVD around the 2020 presidential election were examined. CVD was defined as hospitalizations for acute myocardial infarction (AMI), heart failure (HF), or stroke. Rate ratios (RR) and 95% CIs were calculated comparing rates of CVD hospitalization in the 5 days following the 2020 election with the same 5-day period 2 weeks prior. Among 6 396 830 adults (3 970 077 [62.1%] aged 18 to 54 years; 3 422 479 [53.5%] female; 1 083 128 [16.9%] Asian/Pacific Islander, 2 101 367 [32.9%] Hispanic, and 2 641 897 [41.3%] White), rates of hospitalization for CVD following the election (666 hospitalizations; rate = 760.5 per 100 000 person-years [PY]) were 1.17 times higher (95% CI, 1.05-1.31) compared with the same 5-day period 2 weeks prior (569 hospitalizations; rate = 648.0 per 100 000 PY). Rates of AMI were significantly higher following the election (RR, 1.42; 95% CI, 1.13-1.79). No significant difference was found for stroke (RR, 1.02; 95% CI, 0.86-1.21) or HF (RR, 1.18; 95% CI, 0.98-1.42). Higher rates of acute CVD hospitalization were observed following the 2020 presidential election. Awareness of the heightened risk of CVD and strategies to mitigate risk during notable political events are needed.
Authors: Mefford, Matthew T; Rana, Jamal S; Sidney, Stephen; et al.
JAMA Netw Open. 2022 Apr 01;5(4):e228031. Epub 2022-04-01.
Prognostic Accuracy of Presepsis and Intrasepsis Characteristics for Prediction of Cardiovascular Events After a Sepsis Hospitalization
Sepsis survivors face increased risk for cardiovascular complications; however, the contribution of intrasepsis events to cardiovascular risk profiles is unclear. Kaiser Permanente Northern California (KPNC) and Intermountain Healthcare (IH) integrated healthcare delivery systems. Sepsis survivors (2011-2017 [KPNC] and 2018-2020 [IH]) greater than or equal to 40 years old without prior cardiovascular disease. Data across KPNC and IH were harmonized and grouped into presepsis (demographics, atherosclerotic cardiovascular disease scores, comorbidities) or intrasepsis factors (e.g., laboratory values, vital signs, organ support, infection source) with random split for training/internal validation datasets (75%/25%) within KPNC and IH. Models were bidirectionally, externally validated between healthcare systems. None. Changes to predictive accuracy (C-statistic) of cause-specific proportional hazards models predicting 1-year cardiovascular outcomes (atherosclerotic cardiovascular disease, heart failure, and atrial fibrillation events) were compared between models that did and did not contain intrasepsis factors. Among 39,590 KPNC and 16,388 IH sepsis survivors, 3,503 (8.8%) at Kaiser Permanente (KP) and 600 (3.7%) at IH experienced a cardiovascular event within 1-year after hospital discharge, including 996 (2.5%) at KP and 192 (1.2%) IH with an atherosclerotic event first, 564 (1.4%) at KP and 117 (0.7%) IH with a heart failure event, 2,310 (5.8%) at KP and 371 (2.3%) with an atrial fibrillation event. Death within 1 year after sepsis occurred for 7,948 (20%) KP and 2,085 (12.7%) IH patients. Combined models with presepsis and intrasepsis factors had better discrimination for cardiovascular events (KPNC C-statistic 0.783 [95% CI, 0.766-0.799]; IH 0.763 [0.726-0.801]) as compared with presepsis cardiovascular risk alone (KPNC: 0.666 [0.648-0.683], IH 0.660 [0.619-0.702]) during internal validation. External validation of models across healthcare systems showed similar performance (KPNC model within IH data C-statistic: 0.734 [0.725-0.744]; IH model within KPNC data: 0.787 [0.768-0.805]). Across two large healthcare systems, intrasepsis factors improved postsepsis cardiovascular risk prediction as compared with presepsis cardiovascular risk profiles. Further exploration of sepsis factors that contribute to postsepsis cardiovascular events is warranted for improved mechanistic and predictive models.
Authors: Walkey AJ; Myers LC; Go AS; Liu VX; et al.
Crit Care Explor. 2022 Apr;4(4):e0674. Epub 2022-04-08.
Trends and characteristics of hospitalizations for heart failure in the United States from 2004 to 2018
Hospitalization for heart failure (HF) constitutes a major healthcare and economic burden. Trends and characteristics of hospitalizations for HF for the recent years are not clear. We sought to determine the trends and characteristics of hospitalization for HF in the United States. A retrospective analysis of the National Inpatient Sample weighted data between 1 January 2004 and 31 December 2018, which included hospitalized adults ≥ 18 years with primary discharge diagnosis of HF using International Classification of Diseases-9/10 administrative codes. Main outcomes were trends in hospitalizations for HF (per 1000 person) and inpatient mortality (%) between 2004 and 2018. Hospitalizations for HF have been increasing across both sexes and age groups since 2013, whereas inpatient mortality has been decreasing over the study period. Blacks have the highest risk of hospitalization for HF, and Whites have the highest in-hospital mortality. There are significant racial and geographic disparities related to hospitalizations for HF.
Authors: Salah, Husam M; Minhas, Abdul Mannan Khan; Khan, Muhammad Shahzeb; Khan, Safi U; Ambrosy, Andrew P; Blumer, Vanessa; Vaduganathan, Muthiah; Greene, Stephen J; Pandey, Ambarish; Fudim, Marat
ESC Heart Fail. 2022 04;9(2):947-952. Epub 2022-01-30.
Gestational Diabetes and Hypertensive Disorders of Pregnancy by Maternal Birthplace
Gestational diabetes mellitus and hypertensive disorders of pregnancy increase the risk for future adverse health outcomes in the pregnant woman and baby, and disparities exist in the rates of gestational diabetes mellitus and hypertensive disorders of pregnancy by race/ethnicity. The objective of this study is to identify the differences in gestational diabetes mellitus and hypertensive disorders of pregnancy rates by maternal place of birth within race/ethnicity groups. In women aged 15-44 years at first live singleton birth in U.S. surveillance data between 2014 and 2019, age-standardized rates of gestational diabetes mellitus and hypertensive disorders of pregnancy and the rate ratios of gestational diabetes mellitus and hypertensive disorders of pregnancy in women born outside versus those born in the U.S. were evaluated, stratified by race/ethnicity. Analyses were conducted in 2021. Of 8,574,264 included women, 6,827,198 were born in the U.S. (mean age=26.2 [SD 5.7] years), and 1,747,066 were born outside the U.S. (mean age=28.2 [SD=5.8] years). Overall, the gestational diabetes mellitus rate was higher in women born outside than in those born in the U.S. (70.3, 95% CI=69.9, 70.7 vs 53.2, 95% CI=53.0, 53.4 per 1,000 live births; rate ratio=1.32, 95% CI=1.31, 1.33), a pattern observed in most race/ethnic groups. By contrast, the overall hypertensive disorders of pregnancy rate was lower in those born outside than in those born in the U.S. (52.5, 95% CI=52.2, 52.9 vs 90.1, 95% CI=89.9, 90.3 per 1,000 live births; rate ratio=0.58, 95% CI=0.58, 0.59), a pattern observed in most race/ethnic groups. In the U.S., gestational diabetes mellitus rates were higher and hypertensive disorders of pregnancy rates were lower in women born outside the U.S. than in those born in the U.S. in most race/ethnicity groups.
Authors: Shah, Nilay S; Wang, Michael C; Kandula, Namratha R; Carnethon, Mercedes R; Gunderson, Erica P; Grobman, William A; Khan, Sadiya S
Am J Prev Med. 2022 04;62(4):e223-e231. Epub 2021-12-08.
Long-term television viewing patterns and gray matter brain volume in midlife
The purpose of this study was to investigate whether long-term television viewing patterns, a common sedentary behavior, in early to mid-adulthood is associated with gray matter brain volume in midlife and if this is independent of physical activity. We evaluated 599 participants (51% female, 44% black, mean age 30.3 ± 3.5 at baseline and 50.2 ± 3.5 years at follow-up and MRI) from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. We assessed television patterns with repeated interviewer-administered questionnaire spanning 20 years. Structural MRI (3T) measures of frontal cortex, entorhinal cortex, hippocampal, and total gray matter volumes were assessed at midlife. Over the 20 years, participants reported viewing an average of 2.5 ± 1.7 h of television per day (range: 0-10 h). After multivariable adjustment, greater television viewing was negatively associated with gray matter volume in the frontal (β = - 0.77; p = 0.01) and entorhinal cortex (β = - 23.83; p = 0.05) as well as total gray matter (β = - 2.09; p = 0.003) but not hippocampus. These results remained unchanged after additional adjustment for physical activity. For each one standard deviation increase in television viewing, the difference in gray matter volume z-score was approximately 0.06 less for each of the three regions (p < 0.05). Among middle-aged adults, greater television viewing in early to mid-adulthood was associated with lower gray matter volume. Sedentariness or other facets of television viewing may be important for brain aging even in middle age.
Authors: Dougherty, Ryan J; Hoang, Tina D; Launer, Lenore J; Jacobs, David R; Sidney, Stephen; Yaffe, Kristine
Brain Imaging Behav. 2022 Apr;16(2):637-644. Epub 2021-09-06.
Early to Midlife Smoking Trajectories and Cognitive Function in Middle-Aged US Adults: the CARDIA Study
Smoking starts in early adulthood and persists throughout the life course, but the association between these trajectories and midlife cognition remains unclear. Determine the association between early to midlife smoking trajectories and midlife cognition. Prospective cohort study. Participants were 3364 adults (mean age = 50.1 ± 3.6, 56% female, 46% Black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study: 1638 ever smokers and 1726 never smokers. Smoking trajectories were identified in latent class analysis among 1638 ever smokers using smoking measures every 2-5 years from baseline (age 18-30 in 1985-1986) through year 25 (2010-2011). Poor cognition was based on cognitive domain scores ≥ 1 SD below the mean on tests of processing speed (Digit Symbol Substitution Test), executive function (Stroop), and memory (Rey Auditory Verbal Learning Test) at year 25. Five smoking trajectories emerged over 25 years: quitters (19%), and minimal stable (40%), moderate stable (20%), heavy stable (15%), and heavy declining smokers (5%). Heavy stable smokers showed poor cognition on all 3 domains compared to never smoking (processing speed AOR = 2.22 95% CI 1.53-3.22; executive function AOR = 1.58 95% CI 1.05-2.36; memory AOR = 1.48 95% CI 1.05-2.10). Compared to never smoking, both heavy declining (AOR = 1.95 95% CI 1.06-3.68) and moderate stable smokers (AOR = 1.56 95% CI 1.11-2.19) exhibited slower processing speed, and heavy declining smokers additionally had poor executive function. For minimal stable smokers (processing speed AOR = 1.12 95% CI 0.85-1.51; executive function AOR = 0.97 95% CI 0.71-1.31; memory AOR = 1.21 95% CI 0.94-1.55) and quitters (processing speed AOR = 0.96 95% CI 0.63-1.48; executive function AOR = 0.98 95% CI 0.63-1.52; memory AOR = 0.97 95% CI 0.67-1.39), no association was observed. The association between early to midlife smoking trajectories and midlife cognition was dose-dependent. Results underscore the cognitive health risk of moderate and heavy smoking and the potential benefits of quitting on cognition, even in midlife.
Authors: Bahorik, Amber L; Sidney, Stephen; Kramer-Feldman, Jonathan; Jacobs, David R; Mathew, Amanda R; Reis, Jared P; Yaffe, Kristine
J Gen Intern Med. 2022 04;37(5):1023-1030. Epub 2021-01-26.
Twenty-Five-Year Change in Cardiac Structure and Function and Midlife Cognition: The CARDIA Study
The goal of this work was to determine whether midlife cardiac structure and function and their 25-year change from early to middle adulthood are associated with lower midlife cognition. We studied 2,653 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study (57% women, 46% Black). Echocardiograms were obtained at year 5, 25, and 30 visits (participant mean age 30, 50, and 55 years) to assess left ventricular (LV) mass (LVM), LV systolic function with LV ejection fraction (LVEF), and LV diastolic function with left atrial volume (LAV) and early peak mitral velocity (E)/early peak mitral annular velocity (e’) ratio. LVM and LAV were indexed to body surface area (LVMi and LAVi). At year 30, 5 cognitive domains were measured: global cognition, processing speed, executive function, delayed verbal memory, and verbal fluency. We investigated the association between midlife (year 30) and 25-year change in cardiac structure and function on midlife cognition using linear regressions. Over 25 years, LVMi and LAVi increased with mean change (SD) per year of 0.27 (0.28) g/m2 and 0.42 (0.15) mL/m2, while LVEF decreased by 0.11% (0.02%). After adjustment for demographics and education, 25-year increase (≥1 SD) in LVMi was associated with lower cognition on most tests (p ≤ 0.02); 25-year increase in LAVi was associated with lower global cognition (p = 0.04), but 25-year decrease in LVEF was not associated with cognition. Further adjustment for cardiovascular risk factors led to similar results. In addition, unlike year 30 E/e’ ratio and LVEF, higher year 30 LVMi and LAVi were significantly associated with worse cognition on most cognitive tests. Midlife cardiac structure and its change from early to middle adulthood are associated with lower midlife cognition even after accounting for confounders. Unlike systolic function, midlife LV diastolic function and its 25-year change were also linked to cognition. Our results provide information linking early to midlife cardiac structure and function to cognition.
Authors: Rouch, Laure; Hoang, Tina; Xia, Feng; Sidney, Stephen; Lima, Joao A C; Yaffe, Kristine
Neurology. 2022 03 08;98(10):e1040-e1049. Epub 2022-01-26.
Breast Arterial Calcification: a Novel Cardiovascular Risk Enhancer Among Postmenopausal Women
Breast arterial calcification (BAC), a common incidental finding in mammography, has been shown to be associated with angiographic coronary artery disease and cardiovascular disease (CVD) outcomes. We aimed to (1) examine the association of BAC presence and quantity with hard atherosclerotic CVD (ASCVD) and global CVD; (2) ascertain model calibration, discrimination and reclassification of ASCVD risk; (3) assess the joint effect of BAC presence and 10-year pooled cohorts equations risk on ASCVD. A cohort study of 5059 women aged 60-79 years recruited after attending mammography screening between October 2012 and February 2015 was conducted in a large health plan in Northern California, United States. BAC status (presence versus absence) and quantity (calcium mass mg) was determined using digital mammograms. Prespecified end points were incident hard ASCVD and a composite of global CVD. Twenty-six percent of women had BAC >0 mg. After a mean (SD) follow-up of 6.5 (1.6) years, we ascertained 155 (3.0%) ASCVD events and 427 (8.4%) global CVD events. In Cox regression adjusted for traditional CVD risk factors, BAC presence was associated with a 1.51 (95% CI, 1.08-2.11; P=0.02) increased hazard of ASCVD and a 1.23 (95% CI, 1.002-1.52; P=0.04) increased hazard of global CVD. While there was no evidence of dose-response association with ASCVD, a threshold effect was found for global CVD at very high BAC burden (95th percentile when BAC present). BAC status provided additional risk stratification of the pooled cohorts equations risk. We noted improvements in model calibration and reclassification of ASCVD: the overall net reclassification improvement was 0.12 (95% CI, 0.03-0.14; P=0.01) and the bias-corrected clinical-net reclassification improvement was 0.11 (95% CI, 0.01-0.22; P=0.04) after adding BAC status. Our results indicate that BAC has potential utility for primary CVD prevention and, therefore, support the notion that BAC ought to be considered a risk-enhancing factor for ASCVD among postmenopausal women.
Authors: Iribarren, Carlos; Chandra, Malini; Lee, Catherine; Sanchez, Gabriela; Sam, Danny L; Azamian, Farima Faith; Cho, Hyo-Min; Ding, Huanjun; Wong, Nathan D; Molloi, Sabee
Circ Cardiovasc Imaging. 2022 03;15(3):e013526. Epub 2022-03-15.
Association of Early Adulthood 25-Year Blood Pressure Trajectories With Cerebral Lesions and Brain Structure in Midlife
Midlife elevated blood pressure (BP) is an important risk factor associated with brain structure and function. Little is known about trajectories of BP that modulate this risk. To identify BP trajectory patterns from young adulthood to midlife that are associated with brain structure in midlife. This cohort study used data of US adults from Coronary Artery Risk Development in Young Adults (CARDIA), a prospective longitudinal study of Black and White men and women (baseline age 18 to 30 years) examined up to 8 times over 30 years (1985-1986 to 2015-2016). There were 885 participants who underwent brain magnetic resonance imaging (MRI) in the 25th or 30th year examinations. Analyses were conducted November 2019 to December 2020. Using group-based trajectory modeling, 5 25-year BP trajectories for 3 BP traits were identified in the total CARDIA cohort of participants with 3 or more BP measures, which were then applied to analyses of the subset of 853 participants in the Brain MRI substudy. Mean arterial pressure (MAP) was examined as an integrative measure of systolic and diastolic BP. With linear regression, the associations of the BP trajectories with brain structures were examined, adjusting sequentially for demographics, cardiovascular risk factors, and antihypertensive medication use. Brain MRI outcomes include total brain, total gray matter, normal-looking and abnormal white matter volumes, gray matter cerebral blood flow, and white matter fractional anisotropy. Brain MRI analyses were conducted on 853 participants (mean [SD] age, 50.3 [3.6] years; 399 [46.8%] men; 354 [41.5%] Black and 499 [58.5%] White individuals). The MAP trajectory distribution was 187 individuals (21.1%) with low-stable, 385 (43.5%) with moderate-gradual, 71 (8.0%) with moderate-increasing, 204 (23.1%) with elevated-stable, and 38 (4.3%) with elevated-increasing. Compared with the MAP low-stable trajectory group, individuals in the moderate-increasing and elevated-increasing groups were more likely to have higher abnormal white matter volume (moderate: β, 0.52; 95% CI, 0.23 to 0.82; elevated: β, 0.57; 95% CI, 0.19 to 0.95). Those in the MAP elevated-increasing group had lower gray matter cerebral blood flow (β, -0.42; 95% CI, -0.79 to -0.05) after adjusting for sociodemographics and cardiovascular risk factors. After adjustment for antihypertensive medication use, the difference was consistent for abnormal white matter volume, but results were no longer significant for gray matter cerebral blood flow. Among young adults with moderate to high levels of BP, a gradual increase in BP to middle-age may increase the risk in diffuse small vessel disease and lower brain perfusion.
Authors: Hu, Yi-Han; Halstead, Michael R; Bryan, R Nick; Schreiner, Pamela J; Jacobs, David R; Sidney, Stephen; Lewis, Cora E; Launer, Lenore J
JAMA Netw Open. 2022 03 01;5(3):e221175. Epub 2022-03-01.
Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury
The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure. To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later. Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression. A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI.
Authors: Mansour, Sherry G; Ikizler, T Alp; ASSESS-AKI Consortium,; et al.
J Am Soc Nephrol. 2022 03;33(3):613-627. Epub 2022-01-11.
Global assessment improves risk stratification for major adverse cardiac events across a wide range of triglyceride levels: Insights from the KP REACH study
Patients with risk factors for or established atherosclerotic cardiovascular disease (ASCVD) remain at high risk for subsequent ischemic events despite statin therapy. Triglyceride (TG) levels may contribute to residual ASCVD risk, and the performance of global risk assessment calculators across a broad range of TG levels is unknown. We performed a retrospective cohort study of Kaiser Permanente Northern California members aged ≥45 years with ≥1 ASCVD risk factor (primary prevention cohort) or established ASCVD (secondary prevention cohort) between 2010 and 2017 who were receiving statin therapy and had a low-density lipoprotein cholesterol between 41-100 mg/dL. Global ASCVD risk assessment was performed using both the Kaiser Permanente ASCVD Risk Estimator (KPARE) and the ACC/AHA ASCVD Pooled Cohort Equation (PCE). Outcomes included major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, or peripheral artery disease, and expanded MACE (MACE + coronary revascularization + hospitalization for unstable angina). Among 373,389 patients in the primary prevention cohort, median TG was 122 mg/dL (IQR 88-172 mg/dL) and there were 0.2 MACE events and 0.3 expanded MACE events per 100-person years. Among 97,832 patients in the secondary prevention cohort, median TG level was 116 mg/dL (IQR 84-164 mg/dL) and there were 9.6 MACE events and 22.0 expanded MACE events per 100-person years. KPARE and the ACC/AHA PCE stratified patients for MACE and expanded MACE over the entire range of TGs. In a cohort receiving statin therapy for primary or secondary prevention, we found global assessment further improves risk stratification for initial and/or recurrent ASCVD events irrespective of baseline TG level.
Authors: Wagner, Jeffrey R; Fitzpatrick, Jesse K; Yang, Jingrong; Sung, Sue Hee; Allen, Amanda R; Philip, Sephy; Granowitz, Craig; Abrahamson, David; Ambrosy, Andrew P; Go, Alan S
Am J Prev Cardiol. 2022 Mar;9:100319. Epub 2022-01-29.
Human Immunodeficiency Virus Infection and Variation in Heart Failure Risk by Age, Sex, and Ethnicity: The HIV HEART Study
To evaluate the risk of heart failure (HF) linked to human immunodeficiency virus (HIV) infection, how risk varies by demographic characteristics, and whether it is explained by atherosclerotic disease or risk factor treatment. We performed a retrospective cohort study of persons with HIV (PWHs) from January 1, 2000, through December 31, 2016, frequency-matched 1:10 to persons without HIV on year of entry, age, sex, race/ethnicity, and treating facility. We evaluated the risk of incident HF associated with HIV infection, overall and by left ventricular systolic function, and whether HF risk varied by demographic characteristics. Among 38,868 PWHs and 386,586 matched persons without HIV, mean ± SD age was 41.4±10.8 years, with 12.3% female, 21.1% Black, 20.5% Hispanic, and 3.9% Asian/Pacific Islander. During median follow-up of 3.8 years (interquartile range, 1.4-9.0 years), the rate (per 100 person-years) of incident HF was 0.23 in PWHs vs 0.15 in those without HIV (P<.001). The PWHs had a higher adjusted HF rate (adjusted hazard ratio [aHR], 1.73; 95% confidence interval [CI], 1.57 to 1.91), which was only modestly attenuated after accounting for interim acute coronary syndrome events. Results were similar by systolic function category. The adjusted risk of HF in PWHs was more prominent for those 40 years and younger (aHR, 2.45; 95% CI, 1.92 to 3.03), women (aHR, 2.48; 95% CI, 1.90 to 3.26), and Asian/Pacific Islanders (aHR, 2.46; 95% CI, 1.27 to 4.74). HIV infection increases the risk of HF, which varied by demographic characteristics and was not primarily mediated through atherosclerotic disease pathways or differential use of cardiopreventive medications.
Authors: Go, Alan S; Lee, Keane K; Silverberg, Michael J; et al.
Mayo Clin Proc. 2022 03;97(3):465-479. Epub 2021-12-13.
Diagnostic Yield, Outcomes, and Resource Utilization With Different Ambulatory Electrocardiographic Monitoring Strategies
Accurate diagnosis of arrhythmias is improved with longer monitoring duration but can risk delayed diagnosis. We compared diagnostic yield, outcomes, and resource utilization by arrhythmia monitoring strategy in 330 matched adults (mean age 64 years, 40% women, and 30% non-White) without previously documented atrial fibrillation or atrial flutter (AF/AFL) who received ambulatory electrocardiographic monitoring by 14-day Zio XT (patch-based continuous monitor), 24-hour Holter, or 30-day event monitor (external loop recorder) between October 2011 and May 2014. Patients were matched by age, gender, site, likelihood of receiving Zio XT patch, and indication for monitoring, and subsequently followed for monitoring results, management changes, clinical outcomes, and resource utilization. AF/AFL ≥30 seconds was noted in 6% receiving Zio XT versus 0% by Holter (p = 0.04) and 3% by event monitor (p = 0.07). Nonsustained ventricular tachycardia was noted in 24% for Zio XT patch versus 8% (p <0.001) for Holter and 4% (p <0.001) for event monitor. No significant differences between monitoring strategies in outcomes or resource utilization were observed. Prolonged monitoring with 14-day Zio XT patch or 30-day event monitor was superior to 24-hour Holter in detecting new AF/AFL but not different from each other. Documented nonsustained ventricular tachycardia was more frequent with Zio XT than 24-hour Holter and 30-day event monitor without apparent increased risk of adverse outcomes or excess utilization. In conclusion, additional efforts are needed to further personalize electrocardiographic monitoring strategies that optimize clinical management and outcomes.
Authors: Gupta, Nigel; Yang, Jingrong; Reynolds, Kristi; Lenane, Judith; Garcia, Elisha; Sung, Sue Hee; Harrison, Teresa N; Solomon, Matthew D; Go, Alan S; KP-RHYTHM Study Group,
Am J Cardiol. 2022 03 01;166:38-44. Epub 2021-12-23.
Early Pregnancy Blood Pressure Patterns Identify Risk of Hypertensive Disorders of Pregnancy Among Racial and Ethnic Groups
Hypertensive disorders of pregnancy are a leading cause of severe maternal morbidity and mortality and confer 4-fold higher perinatal mortality in Black women. Early pregnancy blood pressure patterns may differentiate risk of hypertensive disorders of pregnancy. This study identified distinct blood pressure trajectories from 0 to 20 weeks’ gestation to evaluate subsequent pregnancy-related hypertension in a retrospective cohort of 174 925 women with no prior hypertension or history of preeclampsia, prenatal care entry ≤14 weeks, and a stillborn or live singleton birth delivered at Kaiser Permanente Northern California hospitals in 2009 to 2019. We used electronic health records to obtain clinical outcomes, covariables, and longitudinal outpatient blood pressure measurements ≤20 weeks’ gestation (mean 4.1 measurements). Latent class trajectory modeling identified 6 blood pressure groups: ultra-low-declining(referent), low-declining, moderate-fast-decline, low-increasing, moderate-stable, and elevated-stable. Multivariable logistic regression evaluated trajectory group-associations with the odds of preeclampsia/eclampsia and gestational hypertension’ and effect modification by race-ethnicity and prepregnancy body size. Compared with ultra-low-declining, adjusted odds ratios (95% confidence intervals [CIs]) for low-increasing, moderate-stable, and elevated-stable groups were 3.25 (2.7-3.9), 5.3 (4.5-6.3), and 9.2 (7.7-11.1) for preeclampsia/eclampsia’ and 6.4 (4.9-8.3), 13.6 (10.5-17.7), and 30.2 (23.2-39.4) for gestational hypertension. Race/ethnicity, and prepregnancy obesity modified the trajectory-group associations with preeclampsia/eclampsia (interaction P<0.01), with highest risks for Black, then Hispanic and Asian women for all blood pressure trajectories, and with increasing obesity class. Early pregnancy blood pressure patterns revealed racial and ethnic differences in associations with preeclampsia/eclampsia risk within equivalent levels and patterns. These blood pressure patterns may improve individual risk stratification permitting targeted surveillance and early mitigation strategies.
Authors: Gunderson, Erica P; Greenberg, Mara; Nguyen-Huynh, Mai N; Tierney, Cassidy; Roberts, James M; Go, Alan S; Tao, Wei; Alexeeff, Stacey E
Hypertension. 2022 03;79(3):599-613. Epub 2021-12-29.
Upper Reference Limits for High-Sensitivity Cardiac Troponin T and N-Terminal Fragment of the Prohormone Brain Natriuretic Peptide in Patients With CKD
The utility of conventional upper reference limits (URL) for N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population. Observational study. We studied participants of the Chronic Renal Insufficiency Cohort (CRIC) with CKD and no self-reported history of cardiovascular disease. Estimated glomerular filtration rate (eGFR). NT-proBNP and hsTnT at baseline. We described the proportion of participants above the conventional URL for NT-proBNP (125pg/mL) and hsTnT (14ng/L) overall and by eGFR. We then estimated 99th percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99th percentile, we modeled the association of eGFR with NT-proBNP and hsTnT. Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above the conventional URL, respectively. In those with eGFR <30mL/min/1.73m2, 71% and 68% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, respectively. Among all CKD participants, the 99th percentile for NT-proBNP was 3,592 (95% CI, 2,470-4,849) pg/mL and for hsTnT it was 126 (95% CI, 100-144) ng/L. Each 15mL/min/1.73m2 decrement in eGFR was associated with a ~40% higher threshold for the 99th percentile of NT-proBNP (1.43 [95% CI, 1.21-1.69]) and hsTnT (1.45 [95% CI, 1.31-1.60]). Study included ambulatory patients, and we could not test the accuracy of the URL of NT-proBNP and hsTnT in the acute care setting. In this ambulatory CKD population with no self-reported history of cardiovascular disease, a range of 40%-88% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, depending on eGFR strata. Developing eGFR-specific thresholds for these commonly used cardiac biomarkers in the setting of CKD may improve their utility for evaluation of suspected heart failure and myocardial infarction.
Authors: Bansal, Nisha; He, Jiang; CRIC Study Investigators,; et al.
Am J Kidney Dis. 2022 Mar;79(3):383-392. Epub 2021-07-19.
Mid-life epigenetic age, neuroimaging brain age, and cognitive function: coronary artery risk development in young adults (CARDIA) study
The proportion of aging populations affected by dementia is increasing. There is an urgent need to identify biological aging markers in mid-life before symptoms of age-related dementia present for early intervention to delay the cognitive decline and the onset of dementia. In this cohort study involving 1,676 healthy participants (mean age 40) with up to 15 years of follow up, we evaluated the associations between cognitive function and two classes of novel biological aging markers: blood-based epigenetic aging and neuroimaging-based brain aging. Both accelerated epigenetic aging and brain aging were prospectively associated with worse cognitive outcomes. Specifically, every year faster epigenetic or brain aging was on average associated with 0.19-0.28 higher (worse) Stroop score, 0.04-0.05 lower (worse) RAVLT score, and 0.23-0.45 lower (worse) DSST (all false-discovery-rate-adjusted p <0.05). While epigenetic aging is a more stable biomarker with strong long-term predictive performance for cognitive function, brain aging biomarker may change more dynamically in temporal association with cognitive decline. The combined model using epigenetic and brain aging markers achieved the highest accuracy (AUC: 0.68, p<0.001) in predicting global cognitive function status. Accelerated epigenetic age and brain age at midlife may aid timely identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal functioning across the lifespan.
Authors: Zheng, Yinan; Bryan, Nick; Hou, Lifang; et al.
Aging (Albany NY). 2022 02 27;14(4):1691-1712. Epub 2022-02-27.
Food security, diet quality, nutritional knowledge, and attitudes towards research in adults with heart failure during the COVID-19 pandemic
The impact of the novel coronavirus disease 2019 (COVID-19) pandemic on diet and nutrition among older adults with chronic medical conditions have not been well-described. We conducted a survey addressing (1) food access, (2) diet quality and composition, (3) nutritional understanding, and (4) attitudes towards research among adults with heart failure (HF) within an integrated health system. Adults (≥18 years) with diagnosed HF and at least one prior hospitalization for HF within the last 12 months were approached to complete the survey electronically or by mail. Outcomes included all-cause and HF-specific hospitalizations and all-cause death was ascertained via the electronic health record. Among 1212 survey respondents (32.5% of eligible patients) between May 18, 2020 and September 30, 2020, mean ± SD age was 77.9 ± 11.4 years, 50.1% were women, and median (25th-75th) left ventricular ejection fraction was 55% (40%-60%). Overall, 15.1% of respondents were food insecure, and only 65% of participants answered correctly more than half of the items assessing nutritional knowledge. Although most respondents were willing to participate in future research, that number largely declined for studies requiring blood draws (32.2%), study medication (14.4%), and/or behavior change (27.1%). Food security, diet quality, and nutritional knowledge were not independently associated with outcomes at 90 or 180 days. In a cohort of older adults with HF and multiple comorbidities, a significant proportion reported issues with food access, diet quality, and nutritional knowledge during the COVID-19 pandemic. Future research should evaluate interventions targeting these domains in at-risk individuals.
Authors: Ambrosy, Andrew P; Malik, Umar I; Leong, Thomas K; Allen, Amanda R; Sung, Sue Hee; Go, Alan S; Healthy Eating as a Means for Active Living in Heart Failure (HEAL-HF) Study,
Clin Cardiol. 2022 Feb;45(2):180-188. Epub 2022-02-02.
Pulmonary Function in Midlife as a Predictor of Later-Life Cognition: The Coronary Artery Risk Development in Adults (CARDIA) Study
Studies found associations between pulmonary function (PF) and cognition, but these are limited by mostly cross-sectional design and a single measure of PF (typically FEV1). Our objective was to prospectively analyze the association of repeatedly measured PF with cognition. We studied 3,499 participants in The Coronary Artery Risk Development in Young Adults cohort with cognition measured at year 25 (Y25) and Y30, and PF (FEV1 and FVC, reflecting better PF) measured up to six times from Y0-Y20. Cognition was measured via Stroop test, Rey-Auditory Verbal Learning Test [RAVLT], and Digit Symbol Substitution Test [DSST] which capture executive function, verbal learning and memory, and attention and psychomotor speed respectively; lower Stroop, and higher RAVLT and DSST scores indicate better cognition. We modeled linear, cross-sectional associations between cognition and PF at Y30 (mean age 55), and mixed models to examine associations between cognition at Y25-Y30 and longitudinal PF (both annual rate of change, and cumulative PF from Y0-Y20). At Y30 FEV1 and FVC were cross-sectionally associated with all three measures of cognition (β= 0.08-0.12, p<0.01-0.02). Annual change from peak FEV1/FVC ratio was associated with Stroop and DSST (β=18.06, 95% CI=7.71-28.40; β=10.30, 95% CI=0.26-20.34, respectively) but not RAVLT. Cumulative FEV1 and FVC were associated with Stroop and DSST (β= 0.07-0.12, p<0.01-0.02), but only cumulative FEV1 was associated with RAVLT (β=0.07, 95% CI=0.00-0.14). We identified prospective associations between measures of PF and cognition even at middle ages, adding evidence of a prospective association between reduced PF and cognitive decline.
Authors: Joyce, Brian T; Hou, Lifang; Hou, Lifang; et al.
J Gerontol A Biol Sci Med Sci. 2022 Feb 01.
Prepregnancy weight change associated with high gestational weight gain
Gestational weight gain (GWG) above recommendations is a risk factor for adverse maternal, perinatal, and long-term outcomes. This study hypothesized that prepregnancy weight gain may portend excess GWG. Among 1,126 women (51% of whom were of Black race) in the Coronary Artery Risk Development in Young Adults (CARDIA) study with post-baseline births, the prepregnancy annual rate of BMI change per woman was estimated (slope; 5 years before pregnancy) and was related to the risk of GWG above Institute of Medicine recommendations using mixed-effects models (binary) and GWG z score (continuous), adjusting for confounders, and stratified by prepregnancy overweight/obesity status. A total of 626 women (56%) had excess GWG. Each standard deviation increase in prepregnancy BMI (0.16 kg/m2 per year) was associated with an 18% increased risk of excess GWG (95% CI: 1.13-1.23), adjusted for covariates. Stratified results showed an association for women without overweight or obesity (adjusted relative risk = 1.71 [95% CI: 1.38-2.13]) but not among those with overweight or obesity (adjusted relative risk = 0.98 [95% CI: 0.91-1.05]). When evaluated as a z score, prepregnancy weight gain was associated with higher GWG among women with and without overweight or obesity (mean = 0.24 [0.10] and 0.28 [0.12] z score, respectively). Weight gain before pregnancy is associated with higher GWG during pregnancy. Assessment of prepregnancy weight changes may identify those at risk for high GWG.
Authors: Catov, Janet M; Sun, Baiyang; Lewis, Cora E; Bertolet, Marnie; Gunderson, Erica P
Obesity (Silver Spring). 2022 02;30(2):524-534. Epub 2022-01-26.
Management of Adults with Newly Diagnosed Atrial Fibrillation With and Without Chronic Kidney Disease
Atrial fibrillation (AF) is highly prevalent in CKD and is associated with worse cardiovascular and kidney outcomes. Limited data exist on use of AF pharmacotherapies and AF-related procedures by CKD status. We examined a large “real-world” contemporary population with incident AF to study the association of CKD with management of AF. We identified patients with newly diagnosed AF between 2010 and 2017 from two large, integrated health care delivery systems. eGFR (≥60, 45-59, 30-44, 15-29, <15 ml/min per 1.73 m2) was calculated from a minimum of two ambulatory serum creatinine measures separated by ≥90 days. AF medications and procedures were identified from electronic health records. We performed multivariable Fine-Gray subdistribution hazards regression to test the association of CKD severity with receipt of targeted AF therapies. Among 115,564 patients with incident AF, 34% had baseline CKD. In multivariable models, compared with those with eGFR >60 ml/min per 1.73 m2, patients with eGFR 30-44 (adjusted hazard ratio [aHR] 0.91; 95% CI, 0.99 to 0.93), 15-29 (aHR, 0.78; 95% CI, 0.75 to 0.82), and <15 ml/min per 1.73 m2 (aHR, 0.64; 95% CI, 0.58-0.70) had lower use of any AF therapy. Patients with eGFR 15-29 ml/min per 1.73 m2 had lower adjusted use of rate control agents (aHR, 0.61; 95% CI, 0.56 to 0.67), warfarin (aHR, 0.89; 95% CI, 0.84 to 0.94), and DOACs (aHR, 0.23; 95% CI, 0.19 to 0.27) compared with patients with eGFR >60 ml/min per 1.73 m2. These associations were even stronger for eGFR <15 ml/min per 1.73 m2. There was also a graded association between CKD severity and receipt of AF-related procedures (vs eGFR >60 ml/min per 1.73 m2): eGFR 30-44 ml/min per 1.73 (aHR, 0.78; 95% CI, 0.70 to 0.87), eGFR 15-29 ml/min per 1.73 m2 (aHR, 0.73; 95% CI, 0.61 to 0.88), and eGFR <15 ml/min per 1.73 m2 (aHR, 0.48; 95% CI, 0.31 to 0.74). In adults with newly diagnosed AF, CKD severity was associated with lower receipt of rate control agents, anticoagulation, and AF procedures. Additional data on efficacy and safety of AF therapies in CKD populations are needed to inform management strategies.
Authors: Bansal, Nisha; Zelnick, Leila; Reynolds, Kristi; Harrison, Teresa; Lee, Ming-Sum; Singer, Daniel; Sung, Sue Hee; Fan, Dongjie; Go, Alan
J Am Soc Nephrol. 2022 02;33(2):442-453. Epub 2021-12-17.
Differential Cardiometabolic Risk Factor Clustering Across U.S. Asian Ethnic Groups
Authors: Kizzee, Olivia P; Lo, Joan C; Ramalingam, Nirmala D; Rana, Jamal S; Gordon, Nancy P
Am J Prev Med. 2022 02;62(2):e129-e131. Epub 2021-10-07.
A Machine Learning Methodology for Identification and Triage of Heart Failure Exacerbations
Inadequate at-home management and self-awareness of heart failure (HF) exacerbations are known to be leading causes of the greater than 1 million estimated HF-related hospitalizations in the USA alone. Most current at-home HF management protocols include paper guidelines or exploratory health applications that lack rigor and validation at the level of the individual patient. We report on a novel triage methodology that uses machine learning predictions for real-time detection and assessment of exacerbations. Medical specialist opinions on statistically and clinically comprehensive, simulated patient cases were used to train and validate prediction algorithms. Model performance was assessed by comparison to physician panel consensus in a representative, out-of-sample validation set of 100 vignettes. Algorithm prediction accuracy and safety indicators surpassed all individual specialists in identifying consensus opinion on existence/severity of exacerbations and appropriate treatment response. The algorithms also scored the highest sensitivity, specificity, and PPV when assessing the need for emergency care. Here we develop a machine-learning approach for providing real-time decision support to adults diagnosed with congestive heart failure. The algorithm achieves higher exacerbation and triage classification performance than any individual physician when compared to physician consensus opinion.
Authors: Morrill, James; Qirko, Klajdi; Kelly, Jacob; Ambrosy, Andrew; Toro, Botros; Smith, Ted; Wysham, Nicholas; Fudim, Marat; Swaminathan, Sumanth
J Cardiovasc Transl Res. 2022 02;15(1):103-115. Epub 2021-08-28.
Loop and thiazide diuretic use and risk of chronic kidney disease progression: a multicentre observational cohort study
To evaluate the association between diuretic use by class with chronic kidney disease (CKD) progression and onset of end-stage renal disease (ESRD). Retrospective cohort study. Large integrated healthcare delivery system in Northern California. Adults with an estimated glomerular filtration rate (eGFR) 15-59 min/1.73 m2 by the CKD-Epidemiology Collaboration equation with no prior diuretic use. ESRD and a renal composite outcome including eGFR <15 mL/min/1.73 m2, 50% reduction in eGFR and/or ESRD. Among 47 666 eligible adults with eGFR 15-59 min/1.73 m2 and no previous receipt of loop or thiazide diuretics, mean age was 71 years, 49% were women and 26% were persons of colour. Overall, the rate (per 100 person-years) of the renal composite outcome was 1.35 (95% CI: 1.30 to 1.41) and 0.42 (95% CI: 0.39 to 0.45) for ESRD. Crude rates (per 100 person-years) of the composite renal outcome were higher in patients who initiated loop diuretics (12.85 (95% CI: 11.81 to 13.98) vs 1.06 (95% CI: 1.02 to 1.12)) and thiazide diuretics (2.68 (95% CI: 2.33 to 3.08) vs 1.29 (95% CI: 1.24 to 1.35)) compared with those who did not. Crude rates (per 100-person years) of ESRD where higher in patients who initiated loop diuretics (4.92 (95% CI: 4.34 to 5.59) vs 0.30 (95% CI: 0.28 to 0.33)), but not in those who initiated thiazide diuretics (0.30 (95% CI: 0.20 to 0.46) vs 0.43 (95% CI: 0.40 to 0.46)). However, neither initiation of diuretics or type of diuretic were significantly associated with CKD progression or ESRD after accounting for receipt of other medications and time-dependent confounders using causal inference methods. The use of thiazide and loop diuretics was not independently associated with an increased risk of CKD progression and/or ESRD in adults with stage 3/4 CKD.
Authors: Fitzpatrick, Jesse K; Yang, Jingrong; Ambrosy, Andrew P; Cabrera, Claudia; Stefansson, Bergur V; Greasley, Peter J; Patel, Jignesh; Tan, Thida C; Go, Alan S
BMJ Open. 2022 01 31;12(1):e048755. Epub 2022-01-31.
The anticoagulation length of therapy and risk of new adverse events in venous thromboembolism (ALTERNATIVE) study: Design and survey results
The Anticoagulation Length of Therapy and Risk of New Adverse Events In Venous Thromboembolism (ALTERNATIVE) study was designed to compare the benefits and harms of different treatment options for extended treatment of venous thromboembolism (VTE). In this paper, we describe the study cohort, survey data collection, and preliminary results. We identified 39,605 adult patients (age ≥ 18 years) from two large integrated health care delivery systems who were diagnosed with incident VTE and received initial anticoagulation therapy of 3 months or longer. A subset of the cohort (12,737) was invited to participate in a survey. Surveys were completed in English, Spanish or Mandarin via a mailed questionnaire, an online secure web link, or telephone. The survey domains included demographics, personal medical history, anticoagulant treatment history, anticoagulant treatment satisfaction, health-related quality of life and health literacy. A total of 5,017 patients participated in the survey for an overall response rate of 39.4%. The mean (SD) age of the survey respondents was 63.0 (14.5) years and self-reported race was 76.0% White/European, 11.1% Black/African American, and 3.8% Asian/Pacific Islander and 14.0% reported Hispanic ethnicity. Sixty percent of respondents completed the web survey, while 29.0% completed the mail-in paper survey, and 11.0% completed the survey via telephone. The ALTERNATIVE Study will address knowledge gaps by comparing several treatment alternatives for the extended management of VTE so that this information could be used by patients and clinicians to make more informed, patient-centered treatment choices.
Authors: Portugal, Cecilia; Fang, Margaret C; Go, Alan S; Zhou, Hui; Chang, John; Prasad, Priya; Fan, Dongjie; Garcia, Elisha A; Sung, Sue Hee; Reynolds, Kristi
PLoS One. 2022;17(12):e0277961. Epub 2022-12-08.
Higher literacy is associated with better white matter integrity and cognition in middle age
Literacy can be a better measure of quality of education. Its association with brain health in midlife has not been thoroughly investigated. We studied, cross-sectionally, 616 middle-aged adults (mean age of 55.1 ± 3.6 years, 53% female and 38% Black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study. We correlated literacy with cognitive tests, gray matter volumes, and fractional anisotropy (FA) values (indirect measures of white matter integrity) using linear regression. The higher-literacy group (n = 499) performed better than the low-literacy group (n = 117) on all cognitive tests. There was no association between literacy and gray matter volumes. The higher-literacy group had greater total-brain FA and higher temporal, parietal, and occipital FA values after multivariable adjustments. Higher literacy is associated with higher white matter integrity as well as with better cognitive performance in middle-aged adults. These results highlight the importance of focusing on midlife interventions to improve literacy skills.
Authors: de Resende, Elisa de Paula França; Xia, Feng; Sidney, Stephen; Launer, Lenore J; Schreiner, Pamela J; Erus, Guray; Bryan, Nick; Yaffe, Kristine
Alzheimers Dement (Amst). 2022;14(1):e12363. Epub 2022-12-09.
Society for Vascular Surgery clinical practice guidelines for management of extracranial cerebrovascular disease
Management of carotid bifurcation stenosis in stroke prevention has been the subject of extensive investigations, including multiple randomized controlled trials. The proper treatment of patients with carotid bifurcation disease is of major interest to vascular surgeons and other vascular specialists. In 2011, the Society for Vascular Surgery published guidelines for the treatment of carotid artery disease. At the time, several randomized trials, comparing carotid endarterectomy (CEA) and carotid artery stenting (CAS), were reported. Since the 2011 guidelines, several studies and a few systematic reviews comparing CEA and CAS have been reported, and the role of medical management has been reemphasized. In the present publication, we have updated and expanded on the 2011 guidelines with specific emphasis on five areas: (1) is CEA recommended over maximal medical therapy for low-risk patients; (2) is CEA recommended over transfemoral CAS for low surgical risk patients with symptomatic carotid artery stenosis of >50%; (3) the timing of carotid intervention for patients presenting with acute stroke; (4) screening for carotid artery stenosis in asymptomatic patients; and (5) the optimal sequence of intervention for patients with combined carotid and coronary artery disease. A separate implementation document will address other important clinical issues in extracranial cerebrovascular disease. Recommendations are made using the GRADE (grades of recommendation assessment, development, and evaluation) approach, as was used for other Society for Vascular Surgery guidelines. The committee recommends CEA as the first-line treatment for symptomatic low-risk surgical patients with stenosis of 50% to 99% and asymptomatic patients with stenosis of 70% to 99%. The perioperative risk of stroke and death in asymptomatic patients must be <3% to ensure benefit for the patient. In patients with recent stable stroke (modified Rankin scale score, 0-2), carotid revascularization is considered appropriate for symptomatic patients with >50% stenosis and should be performed as soon as the patient is neurologically stable after 48 hours but definitely <14 days after symptom onset. In the general population, screening for clinically asymptomatic carotid artery stenosis in patients without cerebrovascular symptoms or significant risk factors for carotid artery disease is not recommended. In selected asymptomatic patients with an increased risk of carotid stenosis, we suggest screening for clinically asymptomatic carotid artery stenosis as long as the patients would potentially be fit for and willing to consider carotid intervention if significant stenosis is discovered. For patients with symptomatic carotid stenosis of 50% to 99%, who require both CEA and coronary artery bypass grafting, we suggest CEA before, or concomitant with, coronary artery bypass grafting to potentially reduce the risk of stroke and stroke/death. The sequencing of the intervention depends on the clinical presentation and institutional experience.
Authors: AbuRahma, Ali F; Darling, R Clement; Zhou, Wei; et al.
J Vasc Surg. 2022 01;75(1S):4S-22S. Epub 2021-06-19.
The Society for Vascular Surgery implementation document for management of extracranial cerebrovascular disease
Authors: AbuRahma, Ali F; Avgerinos, Efthymios D; Chang, Robert W; Darling, R Clement; Duncan, Audra A; Forbes, Thomas L; Malas, Mahmoud B; Perler, Bruce Alan; Powell, Richard J; Rockman, Caron B; Zhou, Wei
J Vasc Surg. 2022 01;75(1S):26S-98S. Epub 2021-06-19.
The Metabolic Syndrome Is Associated With Lower Cognitive Performance and Reduced White Matter Integrity in Midlife: The CARDIA Study
Cardiovascular disease risk factors play a critical role in brain aging. The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, has been associated with poorer cognition in old age; however, it is unclear if it is connected to brain health earlier in life. We investigated the association of MetS (n = 534, 18.5%) vs. no MetS (n = 2,346, 81.5%) with cognition in midlife within the prospective study, Coronary Artery Risk Development in Young Adults (CARDIA). At midlife (mean age 50), MetS was defined using National Cholesterol Education Program guidelines. At the 5-year follow-up, a cognitive battery was administered including tests of processing speed (Digit Symbol Substitution Test, DSST), executive function (the Stroop Test), verbal memory (Rey Auditory Verbal Learning Test, RAVLT), verbal fluency (category and letter fluency), and global cognitive function (Montreal Cognitive Assessment, MoCA). A sub-sample (n = 453) underwent brain MRI. Participants with MetS had worse performance on tests of verbal fluency, processing speed, executive function, and verbal memory (p < 0.05), but not on global cognition. MetS was also associated with lower frontal, parietal, temporal, and total white matter integrity (p < 0.05), as assessed with fractional anisotropy. MetS is associated with lower cognition and microstructural brain alterations already at midlife, suggesting that MetS should be targeted earlier in life in order to prevent adverse brain and cognitive outcomes.
Authors: Dintica, Christina S; Hoang, Tina; Allen, Norrina; Sidney, Stephen; Yaffe, Kristine
Front Neurosci. 2022;16:942743. Epub 2022-07-18.
Blood Pressure and Later-Life Cognition in Hispanic and White Adults (BP-COG): A Pooled Cohort Analysis of ARIC, CARDIA, CHS, FOS, MESA, and NOMAS
Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. Pooled cohort study of individual participant data from six cohorts (1971-2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1-Q3, 5.2-20.1) years. We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.
Authors: Levine, Deborah A; Yaffe, Kristine; Galecki, Andrzej T; et al.
J Alzheimers Dis. 2022;89(3):1103-1117.
Undifferentiated Induced Pluripotent Stem Cells as a Genetic Model for Nonalcoholic Fatty Liver Disease
Authors: Muñoz, Antonio; Iribarren, Carlos; Medina, Marisa W; et al.
Cell Mol Gastroenterol Hepatol. 2022;14(5):1174-1176.e6. Epub 2022-07-19.
Deoxycholic Acid and Risks of Cardiovascular Events, ESKD, and Mortality in CKD: The CRIC Study
Elevated levels of deoxycholic acid (DCA) are associated with adverse outcomes and may contribute to vascular calcification in patients with chronic kidney disease (CKD). We tested the hypothesis that elevated levels of DCA were associated with increased risks of cardiovascular disease, CKD progression, and death in patients with CKD. Prospective observational cohort study. We included 3,147 Chronic Renal Insufficiency Cohort study participants who had fasting DCA levels. The average age was 59 ± 11 years, 45.3% were women, 40.6% were African American, and the mean estimated glomerular filtration rate was 42.5 ± 16.0 mL/min/1.73 m2. Fasting DCA levels in Chronic Renal Insufficiency Cohort study participants. Risks of atherosclerotic and heart failure events, end-stage kidney disease (ESKD), and all-cause mortality. We used Tobit regression to identify predictors of DCA levels. We used Cox regression to examine the association between fasting DCA levels and clinical outcomes. The strongest predictors of elevated DCA levels in adjusted models were increased age and nonuse of statins. The associations between log-transformed DCA levels and clinical outcomes were nonlinear. After adjustment, DCA levels above the median were independently associated with higher risks of ESKD (HR, 2.67; 95% CI, 1.51-4.74) and all-cause mortality (HR, 2.13; 95% CI, 1.25-3.64). DCA levels above the median were not associated with atherosclerotic and heart failure events, and DCA levels below the median were not associated with clinical outcomes. We were unable to measure DCA longitudinally or in urinary or fecal samples, and we were unable to measure other bile acids. We also could not measure many factors that affect DCA levels. In 3,147 participants with CKD stages 2-4, DCA levels above the median were independently associated with ESKD and all-cause mortality.
Authors: Frazier, Rebecca; Go, Alan S; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators,; et al.
Kidney Med. 2022 Jan;4(1):100387. Epub 2021-11-11.
Dialysis therapy and mortality in older adults with heart failure and advanced chronic kidney disease: A high-dimensional propensity-matched cohort study
Heart failure (HF) and chronic kidney disease (CKD) frequently coexist, and the combination is linked to poor outcomes, but limited data exist to guide optimal management. We evaluated the outcome of dialysis therapy in older patients with HF and advanced CKD. We examined adults aged ≥70 years with HF and eGFR ≤20 ml/min/1.73 m2 between 2008-2012 and no prior renal replacement therapy, cancer, cirrhosis or organ transplant. We identified patients who initiated chronic dialysis through 2013 and matched patients who did not initiate dialysis on age, gender, diabetes status, being alive on dialysis initiation date, and a high-dimensional propensity score for starting dialysis. Deaths were identified through 2013. We used Cox regression to evaluate the association of chronic dialysis and all-cause death. Among 348 adults with HF and advanced CKD who initiated dialysis and 947 matched patients who did not start dialysis, mean age was 80±5 years, 51% were women and 33% were Black. The crude rate of death was high overall but lower in those initiating vs. not initiating chronic dialysis (26.1 vs. 32.1 per 100 person-years, respectively, P = 0.02). In multivariable analysis, dialysis was associated with a 33% (95% Confidence Interval:17-46%) lower adjusted rate of death compared with not initiating dialysis. Among older adults with HF and advanced CKD, dialysis initiation was associated with lower mortality, but absolute rates of death were very high in both groups. Randomized trials should evaluate net outcomes of dialysis vs. conservative management on length and quality of life in this high-risk population.
Authors: Zheng, Sijie; Yang, Jingrong; Tan, Thida C; Belani, Sharina; Law, David; Pravoverov, Leonid V; Kim, Susan S; Go, Alan S
PLoS One. 2022;17(1):e0262706. Epub 2022-01-21.
Trends in Hospitalizations for Heart Failure, Acute Myocardial Infarction, and Stroke in the United States from 2004-2018
To determine the trends in hospitalizations for heart failure (HF), acute myocardial infarction (AMI), and stroke in the United States (US). A retrospective analysis of the National Inpatient Sample weighted data between January 1, 2004 and December 31, 2018 which included hospitalized adults ≥18 years with a primary discharge diagnosis of HF, AMI, or stroke using International Classification of Diseases-9/10 administrative codes. Main outcomes were hospitalization for HF, AMI, and stroke per 1000 United States adults, length of stay, and in-hospital mortality. There were 33.4 million hospitalizations for HF, AMI, and stroke, with most being for HF (48%). After the initial decline in HF hospitalizations (5.3 hospitalizations/1000 US adults in 2004 to 4 hospitalizations/1000 US adults in 2013, P < .001), there was a progressive increase in HF hospitalizations between 2013 and 2018 (4.0 hospitalizations/1000 US adults in 2013 to 4.9 hospitalizations/1000 US adults in 2018; P < .001). Hospitalization for AMI decreased (3.1 hospitalizations/1000 US adults in 2004 to 2.5 hospitalizations/1000 US adults in 2010, P < .001) and remained stable between 2010 and 2018. There was no significant change for hospitalization for stroke between 2004 and 2011 (2.3 hospitalizations/1000 US adults in 2004 vs 2.3 hospitalizations per 1000 US adults in 2011, P = .614); however, there was a small but significant increase in hospitalization for stroke after 2011 that reached 2.5 hospitalizations/1000 US adults in 2018. Adjusted length of stay and in-hospital mortality decreased for HF, AMI, and stroke hospitalizations. In contrast to the trend of AMI and stroke hospitalizations, a progressive increase in hospitalizations for HF has occurred since 2013. From 2004 to 2018, in-hospital mortality has decreased for HF, AMI, and stroke hospitalizations.
Authors: Salah, Husam M; Khan Minhas, Abdul Mannan; Khan, Muhammad Shahzeb; Khan, Safi U; Ambrosy, Andrew P; Blumer, Vanessa; Vaduganathan, Muthiah; Greene, Stephen J; Pandey, Ambarish; Fudim, Marat
Am Heart J. 2022 01;243:103-109. Epub 2021-09-25.
The Prevalence of Elevated Alanine Aminotransferase Levels Meeting Clinical Action Thresholds in Children with Obesity in Primary Care Practice
Using a clinically actionable threshold for alanine aminotransferase to define suspected nonalcoholic fatty liver disease in US children with obesity, the risk of suspected nonalcoholic fatty liver disease was highest for Asian and Hispanic race/ethnicity, male sex, and severe obesity.
Authors: Wu, Stephanie J; Darbinian, Jeanne A; Schwimmer, Jeffrey B; Yu, Elizabeth L; Ramalingam, Nirmala D; Greenspan, Louise C; Lo, Joan C
J Pediatr. 2022 01;240:280-283. Epub 2021-09-23.
Torsade de pointes: A nested case-control study in an integrated healthcare delivery system
TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real-world healthcare setting. Case-control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow-up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non-white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in-hospital and 1-year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.
Authors: Mantri, Neha; Lu, Meng; Zaroff, Jonathan G; Risch, Neil; Hoffmann, Thomas; Oni-Orisan, Akinyemi; Lee, Catherine; Iribarren, Carlos
Ann Noninvasive Electrocardiol. 2022 01;27(1):e12888. Epub 2021-09-21.
Time-Updated Changes in Estimated GFR and Proteinuria and Major Adverse Cardiac Events: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study
Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk. Prospective cohort study. Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC). Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows. Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death. A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes. Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19mL/min/1.73m2) and declining slope of eGFR (8mL/min/1.73m2 per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136mg/g) and increasing UPCR (240mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively). Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually. Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.
Authors: Cohen, Jordana B; Go, Alan S; CRIC Study Investigators,; et al.
Am J Kidney Dis. 2022 01;79(1):36-44.e1. Epub 2021-05-28.
Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma
Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.
Authors: Edris, Ahmed; de Roos, Emmely W; McGeachie, Michael J; Verhamme, Katia M C; Brusselle, Guy G; Tantisira, Kelan G; Iribarren, Carlos; Lu, Meng; Wu, Ann Chen; Stricker, Bruno H; Lahousse, Lies
Clin Exp Allergy. 2022 01;52(1):33-45. Epub 2021-01-25.
Remdesivir for Severe COVID-19 versus a Cohort Receiving Standard of Care
We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care. GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001). In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19. NCT04292899 and EUPAS34303.
Authors: Olender SA; Go AS; GS-US-540–5773 and GS-US-540–5807 Investigators; et al.
Clin Infect Dis. 2021 12 06;73(11):e4166-e4174.
Association of low-frequency and rare coding variants with information processing speed
Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10-6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
Authors: Bressler, Jan; Simino, Jeannette; Deary, Ian J; et al.
Transl Psychiatry. 2021 12 04;11(1):613. Epub 2021-12-04.
Change in ankle-brachial index and mortality among individuals with chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort Study
Patients with chronic kidney disease (CKD) have an increased risk of peripheral arterial disease (PAD). The ankle-brachial index (ABI), a noninvasive measure of PAD, is a predictor of adverse events among individuals with CKD. In general populations, changes in ABI have been associated with mortality, but this association is not well understood among patients with CKD. We conducted a prospective study of 2920 participants in the Chronic Renal Insufficiency Cohort Study without lower extremity revascularization or amputation at baseline and with at least one follow-up ABI measurement (taken at annual visits) during the first 4 years of follow-up. The ABI was obtained by the standard protocol. In Cox proportional hazard regression analyses, we found a U-shaped association of average annual change in ABI with all-cause mortality. After adjusting for baseline ABI and other covariates, compared with participants with an average annual change in ABI of 0-<0.02, individuals with an average annual change in ABI <-0.04 or ≥0.04 had multivariable-adjusted hazard ratios (HRs) of 1.81 [95% confidence interval (CI) 1.34-2.44) and 1.42 (95% CI 1.12-1.82) for all-cause mortality, respectively. Compared with the cumulative average ABI of 1.0-<1.4, multivariable-adjusted HRs for those with a cumulative average ABI of <0.9, 0.9-<1.0 and ≥1.4 were 1.93 (95% CI 1.42-2.61), 1.20 (0.90-1.62) and 1.31 (0.94-1.82), respectively. This study indicates both larger decreases and increases in average annual changes in ABI (>0.04/year) were associated with higher mortality risk. Monitoring changes in ABI over time may facilitate risk stratification for mortality among individuals with CKD.
Authors: Dorans, Kirsten S; Hamm, L Lee; CRIC Study Investigators,; et al.
Nephrol Dial Transplant. 2021 12 02;36(12):2224-2231.
Association of circulating cardiac biomarkers with electrocardiographic abnormalities in chronic kidney disease
Among patients with chronic kidney disease (CKD), the circulating cardiac biomarkers soluble ST2 (SST2), galectin-3, growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT) possibly reflect pathophysiologic processes and are associated with clinical cardiovascular disease. Whether these biomarkers are associated with electrocardiographic findings is not known. The aim of this study was to test the association between serum cardiac biomarkers and the presence of electrocardiographic changes potentially indicative of subclinical myocardial disease in patients with CKD. We performed a cross-sectional analysis using 3048 participants from the Chronic Renal Insufficiency Cohort (CRIC) without atrial fibrillation, atrioventricular block, bundle branch block or a pacemaker at the baseline visit. Using logistic regression, we tested the association of each of the five cardiac biomarkers with baseline electrocardiogram (ECG) findings: PR interval >200 ms, QRS interval >100 ms and a prolonged QTc interval. Models were adjusted for demographic variables, measures of kidney function, prevalent cardiovascular disease and cardiovascular risk factors. In adjusted models, hsTnT levels associated with prolonged PR {odds ratio [OR] 1.23 [95% confidence interval (CI) 1.08-1.40]}, QRS [OR 1.28 (95% CI 1.16-1.42)] and QTc [OR 1.94 (95% CI 1.50-2.51)] intervals. NT-proBNP levels were associated with prolonged QRS [OR 1.11 (95% CI 1.06-1.16)] and QTc [OR 1.82 (95% CI 1.58-2.10)] intervals. SST2, galectin-3 and GDF-15 were not significantly associated with any of the ECG parameters. hsTnT and NT-proBNP were associated with ECG measures indicative of subclinical myocardial dysfunction. These results may support future research investigating the significance of myocardial ischemia and volume overload in the pathogenesis of dysfunctional myocardial conduction in CKD.
Authors: Kula, Alexander J; Go, Alan; Bansal, Nisha; et al.
Nephrol Dial Transplant. 2021 12 02;36(12):2282-2289.
Euglycemic diabetic ketoacidosis following major vascular surgery is a new item on the differential for postoperative acidosis
New pharmacologic advances in the treatment of diabetes include SGLT-2 inhibitors, which have been demonstrated in randomized-controlled clinical trials to reduce overall and cardiac-specific mortality and slow progression of chronic kidney disease. Euglycemic diabetic ketoacidosis is a rare but life-threatening complication associated with the use of SGLT-2 inhibitors. Here we describe a case of severe euglycemic diabetic ketoacidosis after lower extremity bypass in a patient taking an SGLT-2 inhibitor. Awareness of this potential complication is essential as these novel agents are increasingly used in patients with cardiovascular disease.
Authors: Gomez-Sanchez, Clara M; Wu, Bian X; Gotts, Jeffrey E; Chang, Robert W
J Vasc Surg Cases Innov Tech. 2021 Dec;7(4):778-780. Epub 2021-10-22.
Adverse Pregnancy Outcomes and Incident Heart Failure in the Women’s Health Initiative
Some prior evidence suggests that adverse pregnancy outcomes (APOs) may be associated with heart failure (HF). Identifying unique factors associated with the risk of HF and studying HF subtypes are important next steps. To investigate the association of APOs with incident HF overall and stratified by HF subtype (preserved vs reduced ejection fraction) among postmenopausal women in the Women’s Health Initiative (WHI). In 2017, an APO history survey was administered in the WHI study, a large multiethnic cohort of postmenopausal women. The associations of 5 APOs (gestational diabetes, hypertensive disorders of pregnancy [HDP], low birth weight, high birth weight, and preterm delivery) with incident adjudicated HF were analyzed. In this cohort study, the association of each APO with HF was assessed using logistic regression models and with HF subtypes using multinomial regression, adjusting for age, sociodemographic characteristics, smoking, randomization status, reproductive history, and other APOs. Data analysis was performed from January 2020 to September 2021. APOs (gestational diabetes, HDP, low birth weight, high birth weight, and preterm delivery). All confirmed cases of women hospitalized with HF and HF subtype were adjudicated by trained physicians using standardized methods. Of 10 292 women (median [IQR] age, 60 [55-64] years), 3185 (31.0%) reported 1 or more APO and 336 (3.3%) had a diagnosis of HF. Women with a history of any APO had a higher prevalence of hypertension, diabetes, coronary heart disease, or smoking. Of the APOs studied, only HDP was significantly associated with HF with a fully adjusted odds ratio (OR) of 1.75 (95% CI, 1.22-2.50), and with HF with preserved ejection fraction in fully adjusted models (OR, 2.06; 95% CI, 1.29-3.27). In mediation analyses, hypertension explained 24% (95% CI, 12%-73%), coronary heart disease 23% (95% CI, 11%-68%), and body mass index 20% (95% CI, 10%-64%) of the association between HDP and HF. In this large cohort of postmenopausal women, HDP was independently associated with incident HF, particularly HF with preserved ejection fraction, and this association was mediated by subsequent hypertension, coronary heart disease, and obesity. These findings suggest that monitoring and modifying these factors early in women presenting with HDP may be associated with reduced long-term risk of HF.
Authors: Hansen, Aleksander L; Van Horn, Linda; Parikh, Nisha I; et al.
JAMA Netw Open. 2021 12 01;4(12):e2138071. Epub 2021-12-01.
Antithrombotic and anticoagulation therapies in cardiogenic shock: a critical review of the published literature
Cardiogenic shock (CS) is a complex multifactorial clinical syndrome, developing as a continuum, and progressing from the initial insult (underlying cause) to the subsequent occurrence of organ failure and death. There is a large phenotypic variability in CS, as a result of the diverse aetiologies, pathogenetic mechanisms, haemodynamics, and stages of severity. Although early revascularization remains the most important intervention for CS in settings of acute myocardial infarction, the administration of timely and effective antithrombotic therapy is critical to improving outcomes in these patients. In addition, other clinical settings or non-acute myocardial infarction aetiologies, associated with high thrombotic risk, may require specific regimens of short-term or long-term antithrombotic therapy. In CS, altered tissue perfusion, inflammation, and multi-organ dysfunction induce unpredictable alterations to antithrombotic drugs’ pharmacokinetics and pharmacodynamics. Other interventions used in the management of CS, such as mechanical circulatory support, renal replacement therapies, or targeted temperature management, influence both thrombotic and bleeding risks and may require specific antithrombotic strategies. In order to optimize safety and efficacy of these therapies in CS, antithrombotic management should be more adapted to CS clinical scenario or specific device, with individualized antithrombotic regimens in terms of type of treatment, dose, and duration. In addition, patients with CS require a close and appropriate monitoring of antithrombotic therapies to safely balance the increased risk of bleeding and thrombosis.
Authors: Radu, Razvan I; Ambrosy, Andrew P; Chioncel, Ovidiu; et al.
ESC Heart Fail. 2021 12;8(6):4717-4736. Epub 2021-10-19.
Physician adjudication of angioedema diagnosis codes in a population of patients with heart failure prescribed angiotensin-converting enzyme inhibitor therapy
Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.
Authors: Mansi, Elizabeth T; Go, Alan S; Smith, David H; et al.
Pharmacoepidemiol Drug Saf. 2021 12;30(12):1630-1634. Epub 2021-10-01.
Gestational Diabetes and Overweight/Obesity: Analysis of Nulliparous Women in the U.S., 2011-2019
The rates of gestational diabetes mellitus are increasing in parallel with the rates of overweight and obesity. This analysis examines nationwide trends in the population-attributable fraction for gestational diabetes mellitus associated with prepregnancy overweight and obesity. A serial, cross-sectional study was performed using U.S. population-based birth data files maintained by the National Center for Health Statistics between 2011 and 2019. Live singleton births to nulliparous women aged 15-44 years were included, and all analyses were stratified by race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, non-Hispanic Asian). Prevalences of prepregnancy overweight (25.0-29.9 kg/m2 and 23.0-27.4 kg/m2) and obesity (≥30.0 kg/m2 and ≥27.5 kg/m2) based on standard and Asian-specific BMI categories, respectively, were quantified. Logistic regression estimated the adjusted associations between prepregnancy overweight and obesity and gestational diabetes mellitus, with normal weight (18.0-24.9 kg/m2and 18.0-22.9 kg/m2) as the ref. Annual population-attributable fractions for gestational diabetes mellitus associated with prepregnancy overweight and obesity were calculated, which account for both the prevalence of the risk factor and the associated risk of gestational diabetes mellitus. Among 11,950,881 included women, the mean maternal age was 26.3 years. From 2011 to 2019, the population-attributable fractions for gestational diabetes mellitus associated with overweight were stable (Hispanic: 12.0%-11.3%, non-Hispanic Asian: 12.1%-11.6%, p≥0.20) or decreased (non-Hispanic White: 10.8%-9.4%, non-Hispanic Black: 12.3%-9.2%, p<0.002); the population-attributable fractions for gestational diabetes mellitus associated with obesity were stable (non-Hispanic Black: 36.3%-37.9%, p=0.11) or increased (non-Hispanic White: 30.9%-33.3%, Hispanic: 27.2%-33.3%, non-Hispanic Asian 12.2%-15.4%, p<0.001). The population-attributable fractions for gestational diabetes mellitus associated with obesity largely increased in the past decade, underscoring the importance of optimizing weight before pregnancy.
Authors: Wang, Michael C; Shah, Nilay S; Petito, Lucia C; Gunderson, Erica P; Grobman, William A; O'Brien, Matthew J; Khan, Sadiya S
Am J Prev Med. 2021 12;61(6):863-871. Epub 2021-08-24.
Establishing a Carotid Artery Stenosis Disease Cohort for Comparative Effectiveness Research Using Natural Language Processing
Investigation of asymptomatic carotid stenosis treatment is hindered by the lack of a contemporary population-based disease cohort. We describe the use of natural language processing (NLP) to identify stenosis in patients undergoing carotid imaging. Adult patients with carotid imaging between 2008 and 2012 in a large integrated health care system were identified and followed through 2017. An NLP process was developed to characterize carotid stenosis according to the Society of Radiologists in Ultrasound (for ultrasounds) and North American Symptomatic Carotid Endarterectomy Trial (NASCET) (for axial imaging) guidelines. The resulting algorithm assessed text descriptors to categorize normal/non-hemodynamically significant stenosis, moderate or severe stenosis as well as occlusion in both carotid ultrasound (US) and axial imaging (computed tomography and magnetic resonance angiography [CTA/MRA]). For US reports, internal carotid artery systolic and diastolic velocities and velocity ratios were assessed and matched for laterality to supplement accuracy. To validate the NLP algorithm, positive predictive value (PPV or precision) and sensitivity (recall) were calculated from simple random samples from the population of all imaging studies. Lastly, all non-normal studies were manually reviewed for confirmation for prevalence estimates and disease cohort assembly. A total of 95,896 qualifying index studies (76,276 US and 19,620 CTA/MRA) were identified among 94,822 patients including 1059 patients who underwent multiple studies on the same day. For studies of normal/non-hemodynamically significant stenosis arteries, the NLP algorithm showed excellent performance with a PPV of 99% for US and 96.5% for CTA/MRA. PPV/sensitivity to identify a non-normal artery with correct laterality in the CTA/MRA and US samples were 76.9% (95% confidence interval [CI], 74.1%-79.5%)/93.1% (95% CI, 91.1%-94.8%) and 74.7% (95% CI, 69.3%-79.5%)/94% (95% CI, 90.2%-96.7%), respectively. Regarding cohort assembly, 15,522 patients were identified with diseased carotid artery, including 2674 exhibiting equal bilateral disease. This resulted in a laterality-specific cohort with 12,828 moderate, 5283 severe, and 1895 occluded arteries and 326 diseased arteries with unknown stenosis. During follow-up, 30.1% of these patients underwent 61,107 additional studies. Use of NLP to detect carotid stenosis or occlusion can result in accurate exclusion of normal/non-hemodynamically significant stenosis disease states with more moderate precision with lesion identification, which can substantially reduce the need for manual review. The resulting cohort allows for efficient research and holds promise for similar reporting in other vascular diseases.
Authors: Chang, Robert W; Tucker, Lue-Yen; Rothenberg, Kara A; Lancaster, Elizabeth M; Avins, Andrew L; Kuang, Hui C; Faruqi, Rishad M; Nguyen-Huynh, Mai N
J Vasc Surg. 2021 12;74(6):1937-1947.e3. Epub 2021-06-25.
Race, Genetic Ancestry, and Estimating Kidney Function in CKD
The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
Authors: Hsu, Chi-Yuan; CRIC Study Investigators,; CRIC Study Investigators,; et al.
N Engl J Med. 2021 11 04;385(19):1750-1760. Epub 2021-09-23.
Human immunodeficiency virus infection and risks of morbidity and death in adults with incident heart failure
Human immunodeficiency virus (HIV) increases the risk of heart failure (HF), but whether it influences subsequent morbidity and mortality remains unclear. We investigated the risks of hospitalization for HF, HF-related emergency department (ED) visits, and all-cause death in an observational cohort of incident HF patients with and without HIV using data from three large US integrated healthcare delivery systems. We estimated incidence rates and adjusted hazard ratios (aHRs) by HIV status at the time of HF diagnosis for subsequent outcomes. We identified 448 persons living with HIV (PLWH) and 3429 without HIV who developed HF from a frequency-matched source cohort of 38 868 PLWH and 386 586 without HIV. Mean age was 59.5 ± 11.3 years with 9.8% women and 31.8% Black, 13.1% Hispanic, and 2.2% Asian/Pacific Islander. Compared with persons without HIV, PLWH had similar adjusted rates of HF hospitalization [aHR 1.01, 95% confidence interval (CI): 0.81-1.26] and of HF-related ED visits [aHR 1.22 (95% CI: 0.99-1.50)], but higher adjusted rates of all-cause death [aHR 1.31 (95% CI: 1.08-1.58)]. Adjusted rates of HF-related morbidity and all-cause death were directionally consistent across a wide range of CD4 counts but most pronounced in the subset with a baseline CD4 count <200 or 200-499 cells/μL. In a large, diverse cohort of adults with incident HF receiving care within integrated healthcare delivery systems, PLWH were at an independently higher risk of all-cause death but not HF hospitalizations or HF-related ED visits. Future studies investigating modifiable HIV-specific risk factors may facilitate more personalized care to optimize outcomes for PLWH and HF.
Authors: Avula, Harshith R; Ambrosy, Andrew P; Silverberg, Michael J; Lee, Keane K; Go, Alan S; et al.
Eur Heart J Open. 2021 Nov;1(3):oeab040. Epub 2021-12-01.
Description of Major Osteoporotic Fractures in Women with Invasive Breast Cancer Who Received Endocrine Therapy
Authors: Lo, Joan C; Laurent, Cecile A; Roh, Janise M; Lee, Jean; Chandra, Malini; Yao, Song; Kwan, Marilyn L
JAMA Netw Open. 2021 11 01;4(11):e2133861. Epub 2021-11-01.
A Natural Language Processing-Based Approach for Identifying Hospitalizations for Worsening Heart Failure Within an Integrated Health Care Delivery System
The current understanding of epidemiological mechanisms and temporal trends in hospitalizations for worsening heart failure (WHF) is based on claims and national reporting databases. However, these data sources are inherently limited by the accuracy and completeness of diagnostic coding and/or voluntary reporting. To assess the overall burden of and temporal trends in the rate of hospitalizations for WHF. This cohort study, performed from January 1, 2010, to December 31, 2019, used electronic health record (EHR) data from a large integrated health care delivery system. Calendar year trends. Hospitalizations for WHF (ie, excluding observation stays) were defined as 1 symptom or more, 2 objective findings or more including 1 sign or more, and 2 doses or more of intravenous loop diuretics and/or new hemodialysis or continuous kidney replacement therapy. Symptoms and signs were identified using natural language processing (NLP) algorithms applied to EHR data. The study population was composed of 118 002 eligible patients experiencing 287 992 unique hospitalizations (mean [SD] age, 75.6 [13.1] years; 147 203 [51.1%] male; 1655 [0.6%] American Indian or Alaska Native, 28 451 [9.9%] Asian or Pacific Islander, 34 903 [12.1%] Black, 23 452 [8.1%] multiracial, 175 840 [61.1%] White, and 23 691 [8.2%] unknown), including 65 357 with a principal discharge diagnosis and 222 635 with a secondary discharge diagnosis of HF. The study population included 59 868 patients (20.8%) with HF with a reduced ejection fraction (HFrEF) (<40%), 33 361 (11.6%) with HF with a midrange EF (HFmrEF) (40%-49%), 142 347 (49.4%) with HF with a preserved EF (HFpEF) (≥50%), and 52 416 (18.2%) with unknown EF. A total of 58 042 admissions (88.8%) with a primary discharge diagnosis of HF and 62 764 admissions (28.2%) with a secondary discharge diagnosis of HF met the prespecified diagnostic criteria for WHF. Overall, hospitalizations for WHF identified on NLP-based algorithms increased from 5.2 to 7.6 per 100 hospitalizations per year during the study period. Subgroup analyses found an increase in hospitalizations for WHF based on NLP from 1.5 to 1.9 per 100 hospitalizations for HFrEF, from 0.6 to 1.0 per 100 hospitalizations for HFmrEF, and from 2.6 to 3.9 per 100 hospitalizations for HFpEF. The findings of this cohort study suggest that the burden of hospitalizations for WHF may be more than double that previously estimated using only principal discharge diagnosis. There has been a gradual increase in the rate of hospitalizations for WHF with a more noticeable increase observed for HFpEF.
Authors: Ambrosy, Andrew P; Go, Alan S; et al.
JAMA Netw Open. 2021 11 01;4(11):e2135152. Epub 2021-11-01.
A Polygenic Risk Score for Asthma in a Large Racially Diverse Population
Polygenic risk scores (PRSs) will have important utility for asthma and other chronic diseases as a tool for predicting disease incidence and subphenotypes. We utilized findings from a large multiancestry GWAS of asthma to compute a PRS for asthma with relevance for racially diverse populations. We derived two PRSs for asthma using a standard approach (based on genome-wide significant variants) and a lasso sum regression approach (allowing all genetic variants to potentially contribute). We used data from the racially diverse Kaiser Permanente GERA cohort (68 638 non-Hispanic Whites, 5874 Hispanics, 6870 Asians and 2760 Blacks). Race was self-reported by questionnaire. For the standard PRS, non-Hispanic Whites showed the highest odds ratio for a standard deviation increase in PRS for asthma (OR = 1.16 (95% CI 1.14-1.18)). The standard PRS was also associated with asthma in Hispanic (OR = 1.12 (95% CI 1.05-1.19)) and Asian (OR = 1.10 (95% CI 1.04-1.17)) subjects, with a trend towards increased risk in Blacks (OR = 1.05 (95% CI 0.97-1.15)). We detected an interaction by sex, with men showing a higher risk of asthma with an increase in PRS as compared to women. The lasso sum regression-derived PRS showed stronger associations with asthma in non-Hispanic White subjects (OR = 1.20 (95% CI 1.18-1.23)), Hispanics (OR = 1.17 (95% 1.10-1.26)), Asians (OR = 1.18 (95% CI 1.10-1.27)) and Blacks (OR = 1.10 (95% CI 0.99-1.22)). Polygenic risk scores across multiple racial/ethnic groups were associated with increased asthma risk, suggesting that PRSs have potential as a tool for predicting disease development.
Authors: Sordillo, Joanne E; McGeachie, Michael; Wu, Ann Chen; et al.
Clin Exp Allergy. 2021 11;51(11):1410-1420. Epub 2021-09-05.
Anticoagulant treatment satisfaction with warfarin and direct oral anticoagulants for venous thromboembolism
Treatment options for patients with venous thromboembolism (VTE) include warfarin and direct oral anticoagulants (DOACs). Although DOACs are easier to administer than warfarin and do not require routine laboratory monitoring, few studies have directly assessed whether patients are more satisfied with DOACs. We surveyed adults from two large integrated health systems taking DOACs or warfarin for incident VTE occurring between January 1, 2015 and June 30, 2018. Treatment satisfaction was assessed using the validated Anti-Clot Treatment Scale (ACTS), divided into the ACTS Burdens and ACTS Benefits scores; higher scores indicate greater satisfaction. Mean treatment satisfaction was compared using multivariable linear regression, adjusting for patient demographic and clinical characteristics. The effect size of the difference in means was calculated using a Cohen’s d (0.20 is considered a small effect and ≥ 0.80 is considered large). We surveyed 2217 patients, 969 taking DOACs and 1248 taking warfarin at the time of survey. Thirty-one point five percent of the cohort was aged ≥ 75 years and 43.1% were women. DOAC users were on average more satisfied with anticoagulant treatment, with higher adjusted mean ACTS Burdens (50.18 v. 48.01, p < 0.0001) and ACTS Benefits scores (10.21 v. 9.84, p = 0.046) for DOACs vs. warfarin, respectively. The magnitude of the difference was small (Cohen's d of 0.29 for ACTS Burdens and 0.12 for ACTS Benefits). Patients taking DOACs for venous thromboembolism were on average more satisfied with anticoagulant treatment than were warfarin users, although the magnitude of the difference was small.
Authors: Fang, Margaret C; Go, Alan S; Prasad, Priya A; Hsu, Jin-Wen; Fan, Dongjie; Portugal, Cecilia; Sung, Sue Hee; Reynolds, Kristi
J Thromb Thrombolysis. 2021 Nov;52(4):1101-1109. Epub 2021-04-08.
Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure
Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
Authors: Wang, Heming; Shikany, James M; van Heemst, Diana; et al.
Mol Psychiatry. 2021 11;26(11):6293-6304. Epub 2021-04-15.
Long-Term Levels of LDL-C and Cognitive Function: The CARDIA Study
It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults. Lipids were measured at baseline (1985-1986; age: 18-30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes. There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C <100 mg/dL, 101-129 mg/dL, 130-159 mg/dL, and ≥160 mg/dL, respectively. Standardized differences in all cognitive function test scores ranged from 0.16 SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV. Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.
Authors: Mefford, Matthew T; Chen, Ligong; Lewis, Cora E; Muntner, Paul; Sidney, Stephen; Launer, Lenore J; Monda, Keri L; Ruzza, Andrea; Kassahun, Helina; Rosenson, Robert S; Carson, April P
J Int Neuropsychol Soc. 2021 11;27(10):1048-1057. Epub 2021-02-10.
Long-term cumulative blood pressure in young adults and incident heart failure, coronary heart disease, stroke, and cardiovascular disease: The CARDIA study
Cumulative blood pressure (BP) is a measure that incorporates the severity and duration of BP exposure. The prognostic significance of cumulative BP in young adults for cardiovascular diseases (CVDs) in comparison to BP severity alone is, however, unclear. We investigated 3667 Coronary Artery Risk Development in Young Adults participants who attended six visits over 15 years (year-0 (1985-1986), year-2, year-5, year-7, year-l0, and year-15 exams). Cumulative BP was calculated as the area under the curve (mmHg × years) from year 0 through year 15. Cox models assessed the association between cumulative BP (year 0 through year 15), current BP (year 15), and BP change (year 0 and year 15) and CVD outcomes. Mean (standard deviation) age at year 15 was 40.2 (3.6) years, 44.1% were men, and 44.1% were African-American. Over a median follow-up of 16 years, there were 47 heart failure (HF), 103 coronary heart disease (CHD), 71 stroke, and 191 CVD events. Cumulative systolic BP (SBP) was associated with HF (hazard ratio (HR) = 2.14 (1.58-2.90)), CHD (HR = 1.49 (1.19-1.87)), stroke (HR = 1.81 (1.38-2.37)), and CVD (HR = 1.73 (1.47-2.05)). For CVD, the C-statistic for SBP (year 15) was 0.69 (0.65-0.73) and change in C-statistic with the inclusion of SBP change and cumulative SBP was 0.60 (0.56-0.65) and 0.72 (0.69-0.76), respectively. For CVD, using year-15 SBP as a reference, the net reclassification index (NRI) for cumulative SBP was 0.40 (p < 0.0001) and the NRI for SBP change was 0.22 (p = 0.001). Cumulative BP in young adults was associated with the subsequent risk of HF, CHD, stroke, and CVD. Cumulative BP provided incremental prognostic value and improved risk reclassification for CVD, when compared to single BP assessments or changes in BP.
Authors: Nwabuo, Chike C; Muntner, Paul; Lima, João A C; et al.
Eur J Prev Cardiol. 2021 10 25;28(13):1445-1451.
Triglyceride Levels and Residual Risk of Atherosclerotic Cardiovascular Disease Events and Death in Adults Receiving Statin Therapy for Primary or Secondary Prevention: Insights From the KP REACH Study
Background Patients with risk factors or established atherosclerotic cardiovascular disease remain at high-risk for ischemic events. Triglyceride levels may play a causal role. Methods and Results We performed a retrospective study of adults aged ≥45 years receiving statin therapy, with a low-density lipoprotein cholesterol of 41 to 100 mg/dL, and ≥1 risk factor or established atherosclerotic cardiovascular disease between 2010 and 2017. Outcomes included death, all-cause hospitalization, and major adverse cardiovascular events (myocardial infarction, stroke, or peripheral artery disease). The study sample included 373 389 primary prevention patients and 97 832 secondary prevention patients. The primary prevention cohort had a mean age of 65±10 years, with 51% women and 44% people of color, whereas the secondary prevention cohort had a mean age of 71±11 years, with 37% women and 32% people of color. Median triglyceride levels for the primary and secondary prevention cohorts were 122 mg/dL (interquartile range, 88-172 mg/dL) and 116 mg/dL (interquartile range, 84-164 mg/dL), respectively. In multivariable analyses, primary prevention patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (hazard ratio [HR], 0.91; 95% CI, 0.89-0.94) and higher risk of major adverse cardiovascular events (HR, 1.14; 95% CI, 1.05-1.24). In the secondary prevention cohort, patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (HR, 0.95; 95% CI, 0.92-0.97) and higher risk of all-cause hospitalization (HR, 1.03; 95% CI, 1.01-1.05) and major adverse cardiovascular events (HR, 1.04; 95% CI, 1.05-1.24). Conclusions In a contemporary cohort receiving statin therapy, elevated triglyceride levels were associated with a greater risk of atherosclerotic cardiovascular disease events and lower risk of death.
Authors: Ambrosy, Andrew P; Yang, Jingrong; Sung, Sue Hee; Allen, Amanda R; Fitzpatrick, Jesse K; Rana, Jamal S; Wagner, Jeffrey; Philip, Sephy; Abrahamson, David; Granowitz, Craig; Go, Alan S
J Am Heart Assoc. 2021 10 19;10(20):e020377. Epub 2021-10-08.
Intensive lactation among women with recent gestational diabetes significantly alters the early postpartum circulating lipid profile: the SWIFT study
Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D). It is estimated that 20-50% of women with GDM history will progress to T2D within 10 years after delivery. Intensive lactation could be negatively associated with this risk, but the mechanisms behind a protective effect remain unknown. In this study, we utilized a prospective GDM cohort of 1010 women without T2D at 6-9 weeks postpartum (study baseline) and tested for T2D onset up to 8 years post-baseline (n=980). Targeted metabolic profiling was performed on fasting plasma samples collected at both baseline and follow-up (1-2 years post-baseline) during research exams in a subset of 350 women (216 intensive breastfeeding, IBF vs. 134 intensive formula feeding or mixed feeding, IFF/Mixed). The relationship between lactation intensity and circulating metabolites at both baseline and follow-up were evaluated to discover underlying metabolic responses of lactation and to explore the link between these metabolites and T2D risk. We observed that lactation intensity was strongly associated with decreased glycerolipids (TAGs/DAGs) and increased phospholipids/sphingolipids at baseline. This lipid profile suggested decreased lipogenesis caused by a shift away from the glycerolipid metabolism pathway towards the phospholipid/sphingolipid metabolism pathway as a component of the mechanism underlying the benefits of lactation. Longitudinal analysis demonstrated that this favorable lipid profile was transient and diminished at 1-2 years postpartum, coinciding with the cessation of lactation. Importantly, when stratifying these 350 women by future T2D status during the follow-up (171 future T2D vs. 179 no T2D), we discovered that lactation induced robust lipid changes only in women who did not develop incident T2D. Subsequently, we identified a cluster of metabolites that strongly associated with future T2D risk from which we developed a predictive metabolic signature with a discriminating power (AUC) of 0.78, superior to common clinical variables (i.e., fasting glucose, AUC 0.56 or 2-h glucose, AUC 0.62). In this study, we show that intensive lactation significantly alters the circulating lipid profile at early postpartum and that women who do not respond metabolically to lactation are more likely to develop T2D. We also discovered a 10-analyte metabolic signature capable of predicting future onset of T2D in IBF women. Our findings provide novel insight into how lactation affects maternal metabolism and its link to future diabetes onset. ClinicalTrials.gov NCT01967030 .
Authors: Zhang, Ziyi; Lai, Mi; Piro, Anthony L; Alexeeff, Stacey E; Allalou, Amina; Röst, Hannes L; Dai, Feihan F; Wheeler, Michael B; Gunderson, Erica P
BMC Med. 2021 10 08;19(1):241. Epub 2021-10-08.
QT Interval Dynamics and Cardiovascular Outcomes: A Cohort Study in an Integrated Health Care Delivery System
Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within-person QT change over time in relation to risk of incident CVD and all-cause mortality in a real-world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non-White) with 3 or more ECGs (baseline in 2005-2009; mean±SD follow-up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all-cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all-cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all-cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long-term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.
Authors: Mantri, Neha; Lu, Meng; Zaroff, Jonathan G; Risch, Neil; Hoffmann, Thomas; Oni-Orisan, Akinyemi; Lee, Catherine; Jorgenson, Eric; Iribarren, Carlos
J Am Heart Assoc. 2021 10 05;10(19):e018513. Epub 2021-09-28.
Contemporary Burden of Primary Versus Secondary Heart Failure Hospitalizations in the United States
Authors: Varshney, Anubodh S; Minhas, Abdul Mannan Khan; Bhatt, Ankeet S; Ambrosy, Andrew P; Fudim, Marat; Vaduganathan, Muthiah
Am J Cardiol. 2021 10 01;156:140-142. Epub 2021-07-24.
Epigenetic Age Acceleration Reflects Long-Term Cardiovascular Health
[Figure: see text].Authors: Joyce, Brian; Shikany, James M; Lloyd-Jones, Donald; et al.
Circ Res. 2021 10;129(8):770-781. Epub 2021-08-25.
Covid-19 and Risk of Venous Thromboembolism in Ethnically Diverse Populations
Limited existing data suggest that the novel COVID-19 may increase risk of VTE, but information from large, ethnically diverse populations with appropriate control participants is lacking. Does the rate of VTE among adults hospitalized with COVID-19 differ from matched hospitalized control participants without COVID-19? We conducted a retrospective study among hospitalized adults with laboratory-confirmed COVID-19 and hospitalized adults without evidence of COVID-19 matched for age, sex, race or ethnicity, acute illness severity, and month of hospitalization between January 2020 and August 2020 from two integrated health care delivery systems with 36 hospitals. Outcomes included VTE (DVT or pulmonary embolism ascertained using diagnosis codes combined with validated natural language processing algorithms applied to electronic health records) and death resulting from any cause at 30 days. Fine and Gray hazards regression was performed to evaluate the association of COVID-19 with VTE after accounting for competing risk of death and residual differences between groups, as well as to identify predictors of VTE in patients with COVID-19. We identified 6,319 adults with COVID-19 and 6,319 matched adults without COVID-19, with mean ± SD age of 60.0 ± 17.2 years, 46% women, 53.1% Hispanic, 14.6% Asian/Pacific Islander, and 10.3% Black. During 30-day follow-up, 313 validated cases of VTE (160 COVID-19, 153 control participants) and 1,172 deaths (817 in patients with COVID-19, 355 in control participants) occurred. Adults with COVID-19 showed a more than threefold adjusted risk of VTE (adjusted hazard ratio, 3.48; 95% CI, 2.03-5.98) compared with matched control participants. Predictors of VTE in patients with COVID-19 included age ≥ 55 years, Black race, prior VTE, diagnosed sepsis, prior moderate or severe liver disease, BMI ≥ 40 kg/m2, and platelet count > 217 k/μL. Among ethnically diverse hospitalized adults, COVID-19 infection increased the risk of VTE, and selected patient characteristics were associated with higher thromboembolic risk in the setting of COVID-19.
Authors: Go, Alan S; Reynolds, Kristi; Tabada, Grace H; Prasad, Priya A; Sung, Sue Hee; Garcia, Elisha; Portugal, Cecilia; Fan, Dongjie; Pai, Ashok P; Fang, Margaret C
Chest. 2021 10;160(4):1459-1470. Epub 2021-07-19.
Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy
Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.
Authors: Gu, K D; Ettinger, B; Grimsrud, C D; Lo, J C
Osteoporos Int. 2021 Oct;32(10):2119-2123. Epub 2021-04-29.
Cardiovascular Health Trajectories and Elevated C-Reactive Protein: The CARDIA Study
Background The relationship between long-term cardiovascular health (CVH) patterns and elevated CRP (C-reactive protein) in late middle age has yet to be investigated. We aimed to assess this relationship. Methods and Results Individual CVH components were measured in 4405 Black and White men and women (aged 18-30 years at baseline) in the CARDIA (Coronary Artery Risk Development in Young Adults) study at 8 examinations over 25 years. CRP was measured at 4 examinations (years 7, 15, 20, and 25). Latent class modeling was used to identify individuals with similar trajectories in CVH from young adulthood to middle age. Multivariable Poisson regression models were used to assess the association between race-specific CVH trajectories and prevalence of elevated CRP levels (>3.0 mg/L) after 25 years of follow-up. Five distinct CVH trajectories were identified for each race. Lower and decreasing trajectories had higher prevalence of elevated CRP relative to the highest trajectory. Prevalence ratios for elevated CRP in lowest trajectory groups at year 25 were 2.58 (95% CI, 1.89-3.51) and 7.20 (95% CI, 5.09-10.18) among Black and White people, respectively. Prevalence ratios for chronically elevated CRP (elevated CRP at 3 or more of the examinations) in the lowest trajectory groups were 8.37 (95% CI, 4.37-16.00) and 15.89 (95% CI, 9.01-28.02) among Black and White people, respectively. Conclusions Lower and decreasing CVH trajectories are associated with higher prevalence of elevated CRP during the transition from young adulthood to middle age.
Authors: Ruiz-Ramie, Jonathan J; Barber, Jacob L; Lloyd-Jones, Donald M; Gross, Myron D; Rana, Jamal S; Sidney, Stephen; Jacobs, David R; Lane-Cordova, Abbi D; Sarzynski, Mark A
J Am Heart Assoc. 2021 09 07;10(17):e019725. Epub 2021-08-21.
Timing of AKI after urgent percutaneous coronary intervention and clinical outcomes: a high-dimensional propensity score analysis
Acute kidney injury is a common complication of percutaneous coronary intervention and has been associated with an increased risk of death and progressive chronic kidney disease. However, whether the timing of acute kidney injury after urgent percutaneous coronary intervention could be used to improve patient risk stratification is not known. We conducted a retrospective cohort study in adults surviving an urgent percutaneous coronary intervention between 2008 and 2013 within Kaiser Permanente Northern California, a large integrated healthcare delivery system, to evaluate the impact of acute kidney injury during hospitalization at 12 (±6), 24 (±6) and 48 (±6) hours after urgent percutaneous coronary intervention and subsequent risks of adverse outcomes within the first year after discharge. We used multivariable Cox proportional hazards models with adjustment for a high-dimensional propensity score for developing acute kidney injury after percutaneous coronary intervention to examine the associations between acute kidney injury timing and all-cause death and worsening chronic kidney disease. Among 7250 eligible adults undergoing urgent percutaneous coronary intervention, 306 (4.2%) had acute kidney injury at one or more of the examined time periods after percutaneous coronary intervention. After adjustment, acute kidney injury at 12 (±6) hours was independently associated with higher risks of death (adjusted hazard ratio [aHR] 3.55, 95% confidence interval [CI] 2.19-5.75) and worsening kidney function (aHR 2.40, 95% CI:1.24-4.63). Similar results were observed for acute kidney injury at 24 (±6) hours and death (aHR 3.90, 95% CI:2.29-6.66) and worsening chronic kidney disease (aHR 4.77, 95% CI:2.46-9.23). Acute kidney injury at 48 (±6) hours was associated with excess mortality (aHR 1.97, 95% CI:1.19-3.26) but was not significantly associated with worsening kidney function (aHR 0.91, 95% CI:0.42-1.98). Timing of acute kidney injury after urgent percutaneous coronary intervention may be differentially associated with subsequent risk of worsening kidney function but not death.
Authors: Go, Alan S; Tan, Thida C; Parikh, Rishi V; Ambrosy, Andrew P; Pravoverov, Leonid V; Zheng, Sijie; Leong, Thomas K
BMC Nephrol. 2021 09 06;22(1):300. Epub 2021-09-06.
Steps per Day and All-Cause Mortality in Middle-aged Adults in the Coronary Artery Risk Development in Young Adults Study
Steps per day is a meaningful metric for physical activity promotion in clinical and population settings. To guide promotion strategies of step goals, it is important to understand the association of steps with clinical end points, including mortality. To estimate the association of steps per day with premature (age 41-65 years) all-cause mortality among Black and White men and women. This prospective cohort study was part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants were aged 38 to 50 years and wore an accelerometer from 2005 to 2006. Participants were followed for a mean (SD) of 10.8 (0.9) years. Data were analyzed in 2020 and 2021. Daily steps volume, classified as low (<7000 steps/d), moderate (7000-9999 steps/d), and high (≥10 000 steps/d) and stepping intensity, classified as peak 30-minute stepping rate and time spent at 100 steps/min or more. All-cause mortality. A total of 2110 participants from the CARDIA study were included, with a mean (SD) age of 45.2 (3.6) years, 1205 (57.1%) women, 888 (42.1%) Black participants, and a median (interquartile range [IQR]) of 9146 (7307-11 162) steps/d. During 22 845 person years of follow-up, 72 participants (3.4%) died. Using multivariable adjusted Cox proportional hazards models, compared with participants in the low step group, there was significantly lower risk of mortality in the moderate (hazard ratio [HR], 0.28 [95% CI, 0.15-0.54]; risk difference [RD], 53 [95% CI, 27-78] events per 1000 people) and high (HR, 0.45 [95% CI, 0.25-0.81]; RD, 41 [95% CI, 15-68] events per 1000 people) step groups. Compared with the low step group, moderate/high step rate was associated with reduced risk of mortality in Black participants (HR, 0.30 [95% CI, 0.14-0.63]) and in White participants (HR, 0.37 [95% CI, 0.17-0.81]). Similarly, compared with the low step group, moderate/high step rate was associated with reduce risk of mortality in women (HR, 0.28 [95% CI, 0.12-0.63]) and men (HR, 0.42 [95% CI, 0.20-0.88]). There was no significant association between peak 30-minute intensity (lowest vs highest tertile: HR, 0.98 [95% CI, 0.54-1.77]) or time at 100 steps/min or more (lowest vs highest tertile: HR, 1.38 [95% CI, 0.73-2.61]) with risk of mortality. This cohort study found that among Black and White men and women in middle adulthood, participants who took approximately 7000 steps/d or more experienced lower mortality rates compared with participants taking fewer than 7000 steps/d. There was no association of step intensity with mortality.
Authors: Paluch, Amanda E; Gabriel, Kelley Pettee; Fulton, Janet E; Lewis, Cora E; Schreiner, Pamela J; Sternfeld, Barbara; Sidney, Stephen; Siddique, Juned; Whitaker, Kara M; Carnethon, Mercedes R
JAMA Netw Open. 2021 09 01;4(9):e2124516. Epub 2021-09-01.
Implications of the Landmark ISCHEMIA Trial on the Initial Management of High-Risk Patients with Stable Ischemic Heart Disease
In the decades following the advent of percutaneous coronary intervention, the optimal treatment strategy for managing stable ischemic heart disease has remained a topic of debate. The purpose of this review is to discuss current literature that provides insight into preferred treatment strategies for managing stable coronary artery disease. The COURAGE trial (2007) compared patients with stable coronary artery disease treated with percutaneous coronary intervention plus optimal medical therapy versus optimal medical therapy alone and found no difference in death from any cause and non-fatal myocardial infarction at 4.6 years. The more recent ISCHEMIA trial (2020) compared an initial invasive revascularization strategy with optimal medical therapy to optimal medical therapy alone and similarly found no difference in death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest at 5 years. When applied to a broad population with stable coronary artery disease, evidence suggests there is no benefit to an initial invasive revascularization strategy relative to optimal medical therapy alone. Further investigation is warranted to determine whether there are subgroups of individuals that may benefit from earlier revascularization.
Authors: Vafaei, Paniz; Naderi, Sahar; Ambrosy, Andrew P; Slade, Justin J
Curr Atheroscler Rep. 2021 09 01;23(11):70. Epub 2021-09-01.
Primary Nephrotic Syndrome and Risks of ESKD, Cardiovascular Events, and Death: The Kaiser Permanente Nephrotic Syndrome Study
Little population-based data exist about adults with primary nephrotic syndrome. To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996 and 2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of ESKD, cardiovascular outcomes, and death through 2014, using multivariable Cox regression. We confirmed 907 patients with primary nephrotic syndrome (655 definite and 252 presumed patients with FSGS [40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR, 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR, 3.01; 95% CI, 2.16 to 4.19), ischemic stroke (aHR, 1.80; 95% CI, 1.06 to 3.05), venous thromboembolism (aHR, 2.56; 95% CI, 1.35 to 4.85), and death (aHR, 1.34; 95% CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death. Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in the risk for developing ESKD.
Authors: Go, Alan S; Chen, Kenneth K; Parikh, Rishi V; et al.
J Am Soc Nephrol. 2021 09;32(9):2303-2314. Epub 2021-06-18.
Longitudinal bidirectional associations of physical activity and depressive symptoms: The CARDIA study
Depression affects many aspects of health and may be attenuated through increases in physical activity. While bidirectional associations between physical activity (PA) and depressive symptoms have been examined, few studies have examined these associations using both self-reported and accelerometer-estimated measures. Using data from Years 20 (2005-06, age 38-50) and 30 of the Coronary Artery Risk Development in Young Adults (CARDIA) study (N = 2,871), the bidirectional associations between moderate to vigorous intensity physical activity (MVPA) and depressive symptoms were examined using a cross-lagged panel model. Differences in the observed associations by physical activity assessment method were also examined. An inverse bidirectional association between self-reported MVPA and depressive symptoms was found. In subsequent analyses stratified by intensity category, higher levels of vigorous intensity physical activity at baseline, but not moderate intensity physical activity were associated with lower levels of depressive symptoms at the 10-year follow-up (ϕ = -0.04, p < 0.01; ϕ = -0.03, p = 0.15, respectively). A 10-year increase in self-reported MVPA was associated with a 10-year decrease in depressive symptoms. No associations were observed between accelerometer MVPA estimates and depressive symptoms. These findings may support the notion that each assessment method captures related, but also unique, aspects of physical activity behavior. When possible, future studies should explore measures of association by each physical activity assessment method to gain a better understanding of the complex relationship between physical activity and health.
Authors: Zhang, Dong; Pettee Gabriel, Kelley; Sidney, Stephen; Sternfeld, Barbara; Jacobs, David; Whitaker, Kara M
Prev Med Rep. 2021 Sep;23:101489. Epub 2021-07-12.
Effect of SLCO1B1 T521C on Statin-related Myotoxicity with Use of Lovastatin and Atorvastatin
The association between the c.521T>C variant allele in SLCO1B1 (reference single nucleotide polymorphism (rs)4149056) and simvastatin-induced myotoxicity was discovered over a decade ago; however, whether this relationship represents a class effect is still not fully known. The aim of this study was to investigate the relationship between rs4149056 genotype and statin-induced myotoxicity in patients taking atorvastatin and lovastatin. Study participants were from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. A total of 233 statin-induced myopathy + rhabdomyolysis cases met the criteria for inclusion and were matched to 2,342 controls. To validate the drug response phenotype, we replicated the previously established association between rs4149056 genotype and simvastatin-induced myotoxicity. In particular, compared with homozygous T allele carriers, there was a significantly increased risk of simvastatin-induced myopathy + rhabdomyolysis in homozygous carriers of the C allele (CC vs. TT, odds ratio [OR] 4.62, 95% confidence interval [CI] 1.58-11.90, P = 0.003). For lovastatin users, homozygous carriers of the C allele were also at increased risk of statin-induced myopathy + rhabdomyolysis (CC vs. TT, OR 4.49, 95% CI 1.68-10.80, P = 0.001). In atorvastatin users, homozygous carriers of the C allele were twice as likely to experience statin-induced myopathy, though this association did not achieve statistical significance (CC vs. TT, OR 2.00, 95% CI 0.44-6.59, P = 0.30). In summary, our findings suggest that the association of rs4149056 with simvastatin-related myotoxicity may also extend to lovastatin. More data is needed to determine the extent of the association in atorvastatin users. Altogether, these data expand the evidence base for informing guidelines of pharmacogenetic-based statin prescribing practices.
Authors: Lu, Brian; Sun, Laura; Seraydarian, Manuel; Hoffmann, Thomas J; Medina, Marisa W; Risch, Neil; Iribarren, Carlos; Krauss, Ronald M; Oni-Orisan, Akinyemi
Clin Pharmacol Ther. 2021 09;110(3):733-740. Epub 2021-07-23.
Association Between Troponin I Levels During Sepsis and Post-Sepsis Cardiovascular Complications
Rationale: Sepsis commonly results in elevated serum troponin levels and increased risk for postsepsis cardiovascular complications; however, the association between troponin levels during sepsis and cardiovascular complications after sepsis is unclear.Objectives: To evaluate the association between serum troponin levels during sepsis and 1 year after sepsis cardiovascular events.Methods: We analyzed adults aged ⩾40 years without preexisting cardiovascular disease within 5 years, admitted with sepsis across 21 hospitals from 2011 to 2017. Peak serum troponin I levels during sepsis were grouped as normal (⩽0.04 ng/ml) or tertiles of abnormal (>0.04 to ⩽0.09 ng/ml, >0.09 to ⩽0.42 ng/ml, or >0.42 ng/ml). Multivariable adjusted cause-specific Cox proportional hazards models with death as a competing risk were used to assess associations between peak troponin I levels and a composite cardiovascular outcome (atherosclerotic cardiovascular disease, atrial fibrillation, and heart failure) in the year following sepsis. Models were adjusted for presepsis and intrasepsis factors considered potential confounders.Measurements and Main Results: Among 14,046 eligible adults with troponin I measured, 2,012 (14.3%) experienced the composite cardiovascular outcome, including 832 (10.9%) patients with normal troponin levels, as compared with 370 (17.3%), 376 (17.6%), and 434 (20.3%) patients within each sequential abnormal troponin tertile, respectively (P < 0.001). Patients within the elevated troponin tertiles had increased risks of adverse cardiovascular events (adjusted hazard ratio [aHR]troponin0.04-0.09 = 1.37; 95% confidence interval [CI], 1.20-1.55; aHRtroponin0.09-0.42 = 1.44; 95% CI, 1.27-1.63; and aHRtroponin>0.42 = 1.77; 95% CI, 1.56-2.00).Conclusions: Among patients without preexisting cardiovascular disease, troponin elevation during sepsis identified patients at increased risk for postsepsis cardiovascular complications. Strategies to mitigate cardiovascular complications among this high-risk subset of patients are warranted.
Authors: Garcia, Michael A; Go, Alan S; Liu, Vincent X; Walkey, Allan J; et al.
Am J Respir Crit Care Med. 2021 09 01;204(5):557-565.
Cardiovascular risk and functional burden at midlife: Prospective associations of isotemporal reallocations of accelerometer-measured physical activity and sedentary time in the CARDIA study
Cardiovascular risk and functional burden, or the accumulation of cardiovascular risk factors coupled with functional decline, may be an important risk state analogy to multimorbidity. We investigated prospective associations of sedentary time (ST), light intensity physical activity (LPA), and moderate to vigorous intensity physical activity (MVPA) with cardiovascular risk and functional burden at midlife. Participants were 1648 adults (mean ± SD age = 45 ± 4 years, 61% female, 39% Black) from Coronary Artery Risk Development in Young Adults (CARDIA) who wore accelerometers in 2005-2006 and 2015-2016. Cardiovascular risk and functional burden was defined as ≥2 cardiovascular risk factors (untreated/uncontrolled hypertension and hypercholesterolemia, type 2 diabetes, reduced kidney function) and/or functional decline conditions (reduced physical functioning and depressive symptoms). Prospective logistic regression models tested single activity, partition, and isotemporal substitution associations of accelerometer-measured ST, LPA, and MVPA with cardiovascular risk and functional burden 10 years later. In isotemporal models of baseline activity, reallocating 24 min of ST to MVPA was associated with 15% lower odds of cardiovascular risk and functional burden (OR: 0.85; CI: 0.75, 0.96). Reallocating 24 min of LPA to MVPA was associated with a 14% lower odds of cardiovascular risk and functional burden (OR: 0.86; CI: 0.75, 0.99). In longitudinal isotemporal models, similar beneficial associations were observed when 10-year increases in MVPA replaced time in ST or LPA. Findings suggest that maintaining an MVPA dose reflecting daily physical activity recommendations in early midlife is associated with lower odds of cardiovascular risk and functional burden later in midlife.
Authors: Full, Kelsie M; Whitaker, Kara M; Pettee Gabriel, Kelley; Lewis, Cora E; Sternfeld, Barbara; Sidney, Stephen; Reis, Jared P; Jacobs, David R; Gibbs, Bethany Barone; Schreiner, Pamela J
Prev Med. 2021 09;150:106626. Epub 2021-05-19.
Rates of Major Cardiovascular Events in Severe Asthma: US Real-World and Clinical Trial-Eligible Populations
Authors: Dayal, Parul; Iribarren, Carlos; Cheung, Dorothy; Rothenberg, Michael E; Spain, C Victor
Ann Am Thorac Soc. 2021 09;18(9):1580-1584.
A Randomized Trial of Icosapent Ethyl in Ambulatory Patients with COVID-19
The coronavirus disease 2019 (COVID-19) pandemic remains a source of considerable morbidity and mortality throughout the world. Therapeutic options to reduce symptoms, inflammatory response, or disease progression are limited. This randomized open-label trial enrolled 100 ambulatory patients with symptomatic COVID-19 in Toronto, Canada. Results indicate that icosapent ethyl (8g daily for 3 days followed by 4g daily for 11 days) significantly reduced high-sensitivity C-reactive protein (hs-CRP) and improved symptomatology compared with patients assigned to usual care. Specifically, the primary biomarker endpoint, change in hs-CRP, was significantly reduced by 25% among treated patients (-0.5mg/L, IQR[-6.9,0.4], within-group P=0.011). Conversely, a non-significant 5.6% reduction was observed among usual care patients (-0.1mg/L, IQR[-3.2,1.7], within-group P=0.51). An unadjusted between-group primary biomarker analysis was non-significant (P=0.082). Overall, this report provides evidence of an early anti-inflammatory effect of icosapent ethyl in a modest sample, including an initial well-tolerated loading dose, in symptomatic COVID-19 outpatients. ClinicalTrials.gov Identifier: NCT04412018.
Authors: Kosmopoulos, Andrew; Go, Alan S; Ambrosy, Andrew P; Mazer, C David; et al.
iScience. 2021 Aug 26:103040.
Trends in Gestational Diabetes at First Live Birth by Race and Ethnicity in the US, 2011-2019
Gestational diabetes is associated with adverse maternal and offspring outcomes. To determine whether rates of gestational diabetes among individuals at first live birth changed from 2011 to 2019 and how these rates differ by race and ethnicity in the US. Serial cross-sectional analysis using National Center for Health Statistics data for 12 610 235 individuals aged 15 to 44 years with singleton first live births from 2011 to 2019 in the US. Gestational diabetes data stratified by the following race and ethnicity groups: Hispanic/Latina (including Central and South American, Cuban, Mexican, and Puerto Rican); non-Hispanic Asian/Pacific Islander (including Asian Indian, Chinese, Filipina, Japanese, Korean, and Vietnamese); non-Hispanic Black; and non-Hispanic White. The primary outcomes were age-standardized rates of gestational diabetes (per 1000 live births) and respective mean annual percent change and rate ratios (RRs) of gestational diabetes in non-Hispanic Asian/Pacific Islander (overall and in subgroups), non-Hispanic Black, and Hispanic/Latina (overall and in subgroups) individuals relative to non-Hispanic White individuals (referent group). Among the 12 610 235 included individuals (mean [SD] age, 26.3 [5.8] years), the overall age-standardized gestational diabetes rate significantly increased from 47.6 (95% CI, 47.1-48.0) to 63.5 (95% CI, 63.1-64.0) per 1000 live births from 2011 to 2019, a mean annual percent change of 3.7% (95% CI, 2.8%-4.6%) per year. Of the 12 610 235 participants, 21% were Hispanic/Latina (2019 gestational diabetes rate, 66.6 [95% CI, 65.6-67.7]; RR, 1.15 [95% CI, 1.13-1.18]), 8% were non-Hispanic Asian/Pacific Islander (2019 gestational diabetes rate, 102.7 [95% CI, 100.7-104.7]; RR, 1.78 [95% CI, 1.74-1.82]), 14% were non-Hispanic Black (2019 gestational diabetes rate, 55.7 [95% CI, 54.5-57.0]; RR, 0.97 [95% CI, 0.94-0.99]), and 56% were non-Hispanic White (2019 gestational diabetes rate, 57.7 [95% CI, 57.2-58.3]; referent group). Gestational diabetes rates were highest in Asian Indian participants (2019 gestational diabetes rate, 129.1 [95% CI, 100.7-104.7]; RR, 2.24 [95% CI, 2.15-2.33]). Among Hispanic/Latina participants, gestational diabetes rates were highest among Puerto Rican individuals (2019 gestational diabetes rate, 75.8 [95% CI, 71.8-79.9]; RR, 1.31 [95% CI, 1.24-1.39]). Gestational diabetes rates increased among all race and ethnicity subgroups and across all age groups. Among individuals with a singleton first live birth in the US from 2011 to 2019, rates of gestational diabetes increased across all racial and ethnic subgroups. Differences in absolute gestational diabetes rates were observed across race and ethnicity subgroups.
Authors: Shah, Nilay S; Wang, Michael C; Freaney, Priya M; Perak, Amanda M; Carnethon, Mercedes R; Kandula, Namratha R; Gunderson, Erica P; Bullard, Kai McKeever; Grobman, William A; O'Brien, Matthew J; Khan, Sadiya S
JAMA. 2021 08 17;326(7):660-669.
Research Priorities in the Secondary Prevention of Atrial Fibrillation: A National Heart, Lung, and Blood Institute Virtual Workshop Report
There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF-related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced-based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF-related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team-based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.
Authors: Benjamin, Emelia J; Go, Alan S; et al.
J Am Heart Assoc. 2021 08 17;10(16):e021566. Epub 2021-08-05.
Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure
Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.
Authors: Ambrosy, Andrew P; von Haehling, Stephan; Kalra, Paul R; Court, Emma; Bhandari, Sunil; McDonagh, Theresa; Cleland, John G F
Am J Cardiol. 2021 08 01;152:138-145. Epub 2021-06-20.
Growth differentiation factor-15, treatment with liraglutide, and clinical outcomes among patients with heart failure
Associations between growth differentiation factor-15 (GDF-15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP-1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF-15 and change in GDF-15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF-15 value was 3221 pg/mL (interquartile range 1938-5511 pg/mL). Participants in the highest tertile of baseline GDF-15 were more likely to be male and have more co-morbidities. After adjustment, an increase in GDF-15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11-1.64]. In addition, higher baseline GDF-15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF-15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02-1.55 and odds ratio 1.37, 95% CI 1.12-1.69, respectively). GDF-15 levels remained stable among participants randomized to liraglutide. An increase in GDF-15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF-15 trajectory in informing risk of heart failure disease progression.
Authors: Sharma, Abhinav; Ambrosy, Andrew P; Felker, G Michael; et al.
ESC Heart Fail. 2021 08;8(4):2608-2616. Epub 2021-06-01.
Sex Differences in Cardiovascular Outcomes in CKD: Findings From the CRIC Study
Cardiovascular events are less common in women than men in general populations; however, studies in chronic kidney disease (CKD) are less conclusive. We evaluated sex-related differences in cardiovascular events and death in adults with CKD. Prospective cohort study. 1,778 women and 2,161 men enrolled in the Chronic Renal Insufficiency Cohort (CRIC). Sex (women vs men). Atherosclerotic composite outcome (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, cardiovascular death, and all-cause death. Cox proportional hazards regression. During a median follow-up period of 9.6 years, we observed 698 atherosclerotic events (women, 264; men, 434), 762 heart failure events (women, 331; men, 431), 435 cardiovascular deaths (women, 163; men, 274), and 1,158 deaths from any cause (women, 449; men, 709). In analyses adjusted for sociodemographic, clinical, and metabolic parameters, women had a lower risk of atherosclerotic events (HR, 0.71 [95% CI, 0.57-0.88]), heart failure (HR, 0.76 [95% CI, 0.62-0.93]), cardiovascular death (HR, 0.55 [95% CI, 0.42-0.72]), and death from any cause (HR, 0.58 [95% CI, 0.49-0.69]) compared with men. These associations remained statistically significant after adjusting for cardiac and inflammation biomarkers. Assessment of sex hormones, which may play a role in cardiovascular risk, was not included. In a large, diverse cohort of adults with CKD, compared with men, women had lower risks of cardiovascular events, cardiovascular mortality, and mortality from any cause. These differences were not explained by measured cardiovascular risk factors.
Authors: Toth-Manikowski, Stephanie M; Go, Alan S; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators,; et al.
Am J Kidney Dis. 2021 08;78(2):200-209.e1. Epub 2021-04-20.
Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study
The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain. A multicenter, prospective, cohort study. We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study. Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Incident heart failure, myocardial infarction, and stroke events. We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders. Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m2. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR. Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances. In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.
Authors: Chen, Yan; Go, Alan S; CRIC Study Investigators,; et al.
Am J Kidney Dis. 2021 08;78(2):226-235.e1. Epub 2021-01-07.
Changes in Mortality in Top 10 Causes of Death from 2011 to 2018
Authors: Rana JS; Khan SS; Lloyd-Jones DM; Sidney S
J Gen Intern Med. 2021 08;36(8):2517-2518. Epub 2020-07-23.
Achieved blood pressure post-acute kidney injury and risk of adverse outcomes after AKI: A prospective parallel cohort study
There has recently been considerable interest in better understanding how blood pressure should be managed after an episode of hospitalized AKI, but there are scant data regarding the associations between blood pressure measured after AKI and subsequent adverse outcomes. We hypothesized that among AKI survivors, higher blood pressure measured three months after hospital discharge would be associated with worse outcomes. We also hypothesized these associations between blood pressure and outcomes would be similar among those who survived non-AKI hospitalizations. We quantified how systolic blood pressure (SBP) observed three months after hospital discharge was associated with risks of subsequent hospitalized AKI, loss of kidney function, mortality, and heart failure events among 769 patients in the prospective ASSESS-AKI cohort study who had hospitalized AKI. We repeated this analysis among the 769 matched non-AKI ASSESS-AKI enrollees. We then formally tested for AKI interaction in the full cohort of 1538 patients to determine if these associations differed among those who did and did not experience AKI during the index hospitalization. Among 769 patients with AKI, 42 % had subsequent AKI, 13 % had loss of kidney function, 27 % died, and 18 % had heart failure events. SBP 3 months post-hospitalization did not have a stepwise association with the risk of subsequent AKI, loss of kidney function, mortality, or heart failure events. Among the 769 without AKI, there was also no stepwise association with these risks. In formal interaction testing using the full cohort of 1538 patients, hospitalized AKI did not modify the association between post-discharge SBP and subsequent risks of adverse clinical outcomes. Contrary to our first hypothesis, we did not observe that higher stepwise blood pressure measured three months after hospital discharge with AKI was associated with worse outcomes. Our data were consistent with our second hypothesis that the association between blood pressure measured three months after hospital discharge and outcomes among AKI survivors is similar to that observed among those who survived non-AKI hospitalizations.
Authors: McCoy, Ian; Hsu, Raymond K; Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) study investigators,; et al.
BMC Nephrol. 2021 07 29;22(1):270. Epub 2021-07-29.
Relative-Intensity Physical Activity and Its Association With Cardiometabolic Disease
Authors: Siddique, Juned; Welch, Whitney A; Aaby, David; Sternfeld, Barbara; Pettee Gabriel, Kelley; Carnethon, Mercedes R; Rana, Jamal S; Sidney, Stephen
J Am Heart Assoc. 2021 07 20;10(14):e019174. Epub 2021-07-14.
The Coronary Artery Risk Development In Young Adults (CARDIA) Study: JACC Focus Seminar 8/8
The CARDIA (Coronary Artery Risk Development in Young Adults) study began in 1985 to 1986 with enrollment of 5,115 Black or White men and women ages 18 to 30 years from 4 US communities. Over 35 years, CARDIA has contributed fundamentally to our understanding of the contemporary epidemiology and life course of cardiovascular health and disease, as well as pulmonary, renal, neurological, and other manifestations of aging. CARDIA has established associations between the neighborhood environment and the evolution of lifestyle behaviors with biological risk factors, subclinical disease, and early clinical events. CARDIA has also identified the nature and major determinants of Black-White differences in the development of cardiovascular risk. CARDIA will continue to be a unique resource for understanding determinants, mechanisms, and outcomes of cardiovascular health and disease across the life course, leveraging ongoing pan-omics work from genomics to metabolomics that will define mechanistic pathways involved in cardiometabolic aging.
Authors: Lloyd-Jones, Donald M; Lewis, Cora E; Schreiner, Pamela J; Shikany, James M; Sidney, Stephen; Reis, Jared P
J Am Coll Cardiol. 2021 07 20;78(3):260-277.
Changes in Patterns of Hospital Visits for Acute Myocardial Infarction or Ischemic Stroke During COVID-19 Surges
Authors: Solomon, Matthew D; Nguyen-Huynh, Mai; Leong, Thomas K; Alexander, Janet; Rana, Jamal S; Klingman, Jeffrey; Go, Alan S
JAMA. 2021 07 06;326(1):82-84.
Analysis of Estimated and Measured Glomerular Filtration Rates and the CKD-EPI Equation Race Coefficient in the Chronic Renal Insufficiency Cohort Study
Authors: Hsu, Chi-Yuan; Yang, Wei; Go, Alan S; Parikh, Rishi V; Feldman, Harold I
JAMA Netw Open. 2021 07 01;4(7):e2117080. Epub 2021-07-01.
Associations between menopause, cardiac remodeling, and diastolic function: the CARDIA study
Heart failure with preserved ejection fraction (HFpEF) affects more women than men. Menopause may influence HFpEF development in women. We assessed cross-sectional and longitudinal associations between menopause and echocardiographic measures of left ventricular (LV) function and cardiac remodeling. We studied 1,723 women with available echo data from at least two of: year 5 (Y5) (1990-1991), Y25 (2010-2011), or Y30 (2015-2016) in the Coronary Artery Risk Development in Young Adults study. Cardiac structure and function were measured using 2D and Doppler echocardiography. Cross-sectional associations between menopausal status and repeated echo measures at Y25 and Y30 were analyzed using linear mixed models. Two-segmented models were used to compare longitudinal changes in echocardiographic measures in the premenopausal period to changes in the postmenopausal period. Mean ± SD age (years) at enrollment was 27 ± 3 in those with menopause by Y25, 25 ± 3 in those with menopause between Y25 and Y30, and 21 ± 3 in those premenopausal at Y30. There were no significant differences in race, body mass index, systolic blood pressure, or diabetes between the groups. Postmenopausal women had higher early diastolic mitral inflow (E) to annular (e’) velocity ratio than premenopausal after adjusting for demographics and risk factors (P < 0.05). Menopause was associated with relative increases in the rates of change in LV mass and left atrial volume, even after adjustment. Change in E/e' ratio was similar before and after menopause. Menopause is associated cross-sectionally with worse diastolic function and longitudinally with adverse LV and left atrial remodeling. This may contribute to the increased HFpEF risk in postmenopausal women. Video Summary:https://links.lww.com/MENO/A787.
Authors: Ying, Wendy; Lima, Joao A C; Vaidya, Dhananjay; et al.
Menopause. 2021 06 14;28(10):1166-1175. Epub 2021-06-14.
Bidirectional associations of accelerometer-derived physical activity and stationary behavior with self-reported mental and physical health during midlife
Moderate-to-vigorous intensity physical activity (MVPA) is associated with favorable self-rated mental and physical health. Conversely, poor self-rated health in these domains could precede unfavorable shifts in activity. We evaluated bidirectional associations of accelerometer-estimated time spent in stationary behavior (SB), light intensity physical activity (LPA), and MVPA with self-rated health over 10 years in in the CARDIA longitudinal cohort study. Participants (n = 894, age: 45.1 ± 3.5; 63% female; 38% black) with valid accelerometry wear and self-rated health at baseline (2005-6) and 10-year follow-up (2015-6) were included. Accelerometry data were harmonized between exams and measured mean total activity and duration (min/day) in SB, LPA, and MVPA; duration (min/day) in long-bout and short-bout SB (≥30 min vs. < 30 min) and MVPA (≥10 min vs. < 10 min) were also quantified. The Short-Form 12 Questionnaire measured both a mental component score (MCS) and physical component score (PCS) of self-rated health (points). Multivariable linear regression associated baseline accelerometry variables with 10-year changes in MCS and PCS. Similar models associated baseline MCS and PCS with 10-year changes in accelerometry measures. Over 10-years, average (SD) MCS increased 1.05 (9.07) points, PCS decreased by 1.54 (7.30) points, and activity shifted toward greater SB and less mean total activity, LPA, and MVPA (all p < 0.001). Only baseline short-bout MVPA was associated with greater 10-year increases in MCS (+ 0.92 points, p = 0.021), while baseline mean total activity, MVPA, and long-bout MVPA were associated with greater 10-year changes in PCS (+ 0.53 to + 1.47 points, all p < 0.005). In the reverse direction, higher baseline MCS and PCS were associated with favorable 10-year changes in mean total activity (+ 9.75 cpm, p = 0.040, and + 15.66 cpm, p < 0.001, respectively) and other accelerometry measures; for example, higher baseline MCS was associated with - 13.57 min/day of long-bout SB (p < 0.001) and higher baseline PCS was associated with + 2.83 min/day of MVPA (p < 0.001) in fully adjusted models. The presence of bidirectional associations between SB and activity with self-rated health suggests that individuals with low overall activity levels and poor self-rated health are at high risk for further declines and supports intervention programming that aims to dually increase activity levels and improve self-rated health.
Authors: Barone Gibbs, Bethany; Sternfeld, Barbara; Whitaker, Kara M; Brach, Jennifer S; Hergenroeder, Andrea L; Jacobs, David R; Reis, Jared P; Sidney, Stephen; White, Daniel; Pettee Gabriel, Kelley
Int J Behav Nutr Phys Act. 2021 06 06;18(1):74. Epub 2021-06-06.
Pearls from a Clinician-Researcher in an Integrated Health care Delivery System
Authors: Ettinger, Kate Michi; Ettinger, Vivian M; Jaffe, Marc G; Schroeder, David A; Lo, Joan C
Perm J. 2021 06 02;25. Epub 2021-06-02.
Large-scale identification of aortic stenosis and its severity using natural language processing on electronic health records
Systematic case identification is critical to improving population health, but widely used diagnosis code-based approaches for conditions like valvular heart disease are inaccurate and lack specificity. To develop and validate natural language processing (NLP) algorithms to identify aortic stenosis (AS) cases and associated parameters from semi-structured echocardiogram reports and compare their accuracy to administrative diagnosis codes. Using 1003 physician-adjudicated echocardiogram reports from Kaiser Permanente Northern California, a large, integrated healthcare system (>4.5 million members), NLP algorithms were developed and validated to achieve positive and negative predictive values > 95% for identifying AS and associated echocardiographic parameters. Final NLP algorithms were applied to all adult echocardiography reports performed between 2008 and 2018 and compared to ICD-9/10 diagnosis code-based definitions for AS found from 14 days before to 6 months after the procedure date. A total of 927,884 eligible echocardiograms were identified during the study period among 519,967 patients. Application of the final NLP algorithm classified 104,090 (11.2%) echocardiograms with any AS (mean age 75.2 years, 52% women), with only 67,297 (64.6%) having a diagnosis code for AS between 14 days before and up to 6 months after the associated echocardiogram. Among those without associated diagnosis codes, 19% of patients had hemodynamically significant AS (ie, greater than mild disease). A validated NLP algorithm applied to a systemwide echocardiography database was substantially more accurate than diagnosis codes for identifying AS. Leveraging machine learning-based approaches on unstructured electronic health record data can facilitate more effective individual and population management than using administrative data alone.
Authors: Solomon, Matthew D; Tabada, Grace; Allen, Amanda; Sung, Sue Hee; Go, Alan S
Cardiovasc Digit Health J. 2021 Jun;2(3):156-163. Epub 2021-03-18.
Pregnancy-Associated Spontaneous Coronary Artery Dissection: Clinical Characteristics, Outcomes, and Risk During Subsequent Pregnancy
Spontaneous coronary artery dissection (SCAD) is a common cause of pregnancy-associated myocardial infarction. This study compares the clinical course and longitudinal follow-up of 22 cases of pregnancy-associated SCAD (P-SCAD) with 285 cases of non-pregnancy SCAD (NP-SCAD) from Kaiser Permanente Northern California between September 2002 through June 2017. Age in the P-SCAD group was significantly lower than in the NP-SCAD group (37.1 ± 5.7 years vs 50.9 ± 9.9 years, respectively; P<.001). Both cohorts were racially diverse, but the P-SCAD group had fewer whites (27.3% vs 50.7%; P=.03). The P-SCAD group had higher multigravidity (54.6% vs 31.4%; P=.03) and 68.2% were of advanced maternal age. The rates of ST-elevation myocardial infarction, ventricular tachycardia/fibrillation, and left main coronary dissection were similar. Proximal vessel dissection (31.8% vs 7.7%; P<.01), multiple vessel dissection (31.8% vs 9.5%; P<.01), and reduced ejection fraction at presentation (49.6 ± 10.5% vs 55.7 ± 10.4%; P=.01) were more common in the P-SCAD group vs the NP-SCAD group, respectively. More P-SCAD patients had cardiogenic shock and/or required intra-aortic balloon pump support (9.1% vs 1.1%; P=.04). Medical management was the principal coronary treatment strategy in both groups. P-SCAD patients experienced more major adverse cardiovascular events (50.0% vs 26.0%; P=.02), driven by persistent reduced ejection fraction ≤45% at follow-up (18.2% vs 5.3%; P=.04). Recurrent SCAD (18.2% vs 11.2%; P=.31) and cardiovascular death (0% vs 0.4%; P>.99) were similar in the P-SCAD group vs the NP-SCAD group, respectively. Seven patients had successful subsequent pregnancies without cardiac complications. P-SCAD has a higher-risk presentation, but similar long-term prognosis compared with NP-SCAD. In addition, subsequent pregnancy after SCAD may present acceptable risk.
Authors: Chen, Stephanie; Merchant, Maqdooda; Mahrer, Kenneth N; Ambrosy, Andrew P; Lundstrom, Robert J; Naderi, Sahar
J Invasive Cardiol. 2021 06;33(6):E457-E466. Epub 2021-05-14.
Potential accuracy of prehospital NIHSS-based triage for selection of candidates for acute endovascular stroke therapy
Whether patients with acute stroke and large vessel occlusion (LVO) benefit from prehospital identification and diversion by emergency medical services (EMS) to an endovascular stroke therapy (EST)-capable center is controversial. We sought to estimate the accuracy of field-based identification of potential EST candidates in a hypothetical best-of-all-worlds situation. In Kaiser Permanente Northern California, all acute stroke patients arriving at its 21 stroke centers between 7:00 am and midnight from January 2016 to December 2019 were evaluated by teleneurologists on arrival. Initial National Institutes of Health Stroke Scale (NIHSS) score, presence of LVO, and referral for EST were obtained from standardized teleneurology notes. Factors associated with LVO were evaluated using generalized estimating equations accounting for clustering by facility. Among 13,377 patients brought in by EMS with potential stroke, 7168 (53.6%) were not candidates for acute stroke interventions. Of the remaining 6089 cases, 2,573 (42.3%) had an NIHSS score >10, the cutoff with a higher association for LVO. Only 703 patients (27.3% with NIHSS score >10) were ultimately diagnosed with LVO and referred for EST. Across all NIHSS scores, only 884 (6.6%) suspected acute stroke patients had LVO and EST referral. Even if field-based tools were as accurate as NIHSS scoring and predictions by stroke neurologists, only about 1 in 4 acute stroke patients diverted to EST-capable centers would benefit by receiving EST. Depending on geography and stroke center performance on door-to-needle time, many systems may be better served by focusing on expediting evaluation, treatment with intravenous thrombolysis, and transfer to EST-capable centers.
Authors: Klingman, Jeffrey G; Alexander, Janet G; Vinson, David R; Klingman, Lauren E; Nguyen-Huynh, Mai N
J Am Coll Emerg Physicians Open. 2021 Jun;2(3):e12441. Epub 2021-05-01.
The Risks of Polycystic Ovary Syndrome and Diabetes Vary by Ethnic Subgroup Among Young Asian Women
Authors: Guo, Lynn; Gordon, Nancy P; Chandra, Malini; Dayo, Olumayowa; Lo, Joan C
Diabetes Care. 2021 06;44(6):e129-e130. Epub 2021-04-26.
Physical Activity and Hypertension From Young Adulthood to Middle Age
The optimum physical activity dose to achieve during young adulthood to prevent hypertension using the 2017 American College of Cardiology/American Heart Association guidelines remains undefined. This study aims to determine the association between level and change in physical activity through the adult life course and the onset of hypertension using these 2017 definitions. In 2020, prospective community-based cohort data of 5,115 Coronary Artery Risk Development in Young Adults study participants were analyzed. The cohort included Black and White men and women aged 18-30 years at baseline (1985-1986) at 4 urban sites, collected through 30 years of follow-up (2015-2016). Individualized physical activity trajectories were developed for each participant using linear mixed models. Black women reported the lowest physical activity levels from young adulthood through middle age. Lower physical activity score (per 100 units) at age 18 years was associated with 4% (95% CI=1%, 7%, p=0.002) higher odds of hypertension incidence. Each additional 1-unit reduction per year in physical activity score was associated with 2% (95% CI=1%, 3%, p=0.001) higher annual odds of hypertension incidence. Meeting approximately the current minimum physical activity guideline levels at age 18 years and through follow-up was not protective of hypertension incidence; however, meeting approximately twice the current minimum physical activity guideline level at age 18 years and through follow-up was protective of hypertension incidence. Moderate physical activity levels may need to exceed current minimum guidelines to prevent hypertension onset using 2017 American College of Cardiology/American Heart Association definitions.
Authors: Nagata, Jason M; Vittinghoff, Eric; Pettee Gabriel, Kelley; Garber, Andrea K; Moran, Andrew E; Sidney, Stephen; Rana, Jamal S; Reis, Jared P; Bibbins-Domingo, Kirsten
Am J Prev Med. 2021 06;60(6):757-765. Epub 2021-04-15.
DNA methylation GrimAge and Incident Diabetes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
DNA methylation (DNAm)-based biological age (epigenetic age) has been suggested as a useful biomarker of age-related conditions including type 2 diabetes (T2D), and its newest iterations (GrimAge measurements) have shown early promise. In this study, we explored the association between epigenetic age and incident T2D in the context of their relationships with obesity. A total of 1,057 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were included in the current analyses. We stratified the participants into three groups: normal weight, overweight, and obese. A 1-year increase of GrimAge was associated with higher 10-year (study years 15-25) incidence of T2D (odds ratio [OR] 1.06, 95% CI 1.01-1.11). GrimAge acceleration, which represents the deviation of GrimAge from chronological age, was derived from the residuals of a model of GrimAge and chronological age, and any GrimAge acceleration (positive GrimAA: having GrimAge older than chronological age) was associated with significantly higher odds of 10-year incidence of T2D in obese participants (OR 2.57, 95% CI 1.61-4.11). Cumulative obesity was estimated by years since obesity onset, and GrimAge partially mediated the statistical association between cumulative obesity and incident diabetes or prediabetes (proportion mediated = 8.0%). In conclusion, both older and accelerated GrimAge were associated with higher risk of T2D, particularly among obese participants. GrimAge also statistically mediated the associations between cumulative obesity and T2D. Our findings suggest that epigenetic age measurements with DNAm can potentially be used as a risk factor or biomarker associated with T2D development.
Authors: Kim, Kyeezu; Gunderson, Erica P; Hou, Lifang; et al.
Diabetes. 2021 06;70(6):1404-1413. Epub 2021-04-05.
Bidirectional associations of accelerometer measured sedentary behavior and physical activity with knee pain, stiffness, and physical function: The CARDIA study
The objective was to examine bidirectional associations of accelerometer estimated sedentary time and physical activity with reported knee symptoms. Participants were 2,034 adults (mean age 45.3 ± 3.6 years, 58.7% female) from CARDIA. Generalized estimating equations for logistic regression and linear mixed regression models examined associations of accelerometer estimated sedentary time, light-intensity physical activity (LPA), and moderate-to-vigorous intensity physical activity (MVPA) at baseline (2005-06) with knee discomfort, pain, stiffness, and physical function (yes/no and continuous scores from short-form WOMAC function scale) at the 5- and 10-year follow-up exams. Linear regression models examined associations between knee symptoms at the 5-year follow-up with accelerometer estimates at the 10-year follow-up. Models were adjusted for confounders; individuals with comorbidities were excluded in sensitivity analyses. A 30 min/day increment in sedentary time at baseline was associated with lower odds of knee symptoms at the 5- and 10-year follow-up (OR: 0.95, 95% CI range: 0.92-0.98), while LPA and MVPA were associated with greater odds of knee symptoms (LPA OR range: 1.04-1.05, 95% CI range: 1.01-1.09; MVPA OR range: 1.17-1.19, 95% CI range: 1.06-1.32). Report of knee symptoms at the 5-year follow-up was associated with 13.52-17.51 (95% CI range: -29.90, -0.56) fewer minutes/day of sedentary time and 14.58-17.51 (95% CI range: 2.48, 29.38) more minutes/day of LPA at the 10-year follow-up, compared to those reporting no symptoms. Many associations were no longer statistically significant when excluding individuals with comorbidities. Findings support a bidirectional association of accelerometer estimated sedentary time and physical activity with knee symptoms across midlife.
Authors: Whitaker, Kara M; Pettee Gabriel, Kelley; Laddu, Deepika; White, Daniel K; Sidney, Stephen; Sternfeld, Barbara; Lewis, Cora E; Jacobs, David R
Prev Med Rep. 2021 Jun;22:101348. Epub 2021-03-09.
COPD comorbidity profiles and two-year trajectory of acute and post-acute care utilization
Multiple morbidity is the norm in advanced COPD and contributes to high symptom burden and worse outcomes. Can distinct comorbidity profiles be identified and validated in a community-based sample of patients with COPD from a large integrated health care system using a standard, commonly used diagnostic code-based comorbidity index and downstream 2-year health care use data? In this retrospective cohort study, we used latent class analysis (LCA) to identify comorbidity profiles in a population-based sample of 91,453 patients with a COPD diagnosis between 2011 and 2015. We included specific comorbid conditions from the Charlson Comorbidity Index (CCI) and accounted for variation in underlying prevalence of different comorbidities across the three study sites. Sociodemographic, clinical, and health-care use data were obtained from electronic health records (EHRs). Multivariate logistic regression analysis was used to compare rates of acute and postacute care use by class. The mean age was 71 ± 11 years, 55% of patients were women, 23% of patients were people of color, and 80% of patients were former or current smokers. LCA identified four distinct comorbidity profiles with progressively higher CCI scores: low morbidity (61%; 1.9 ± 1.4), metabolic renal (21%; 4.7 ± 1.8), cardiovascular (12%; 4.6 ± 1.9), and multimorbidity (7%; 7.5 ± 1.7). In multivariate models, during 2 years of follow-up, a significant, nonoverlapping increase was found in the odds of having any all-cause acute (hospitalizations, observation stays, and ED visits) and postacute care use across the comorbidity profiles. Distinct comorbidity profiles can be identified in patients with COPD using standard EHR-based diagnostic codes, and these profiles are associated with subsequent acute and postacute care use. Population-based risk stratification schemes for end-to-end, comprehensive COPD management should consider integrating comorbidity profiles such as those found in this study.
Authors: Shen, Ernest; Lee, Janet S; Mularski, Richard A; Crawford, Phillip; Go, Alan S; Sung, Sue H; Tabada, Grace H; Gould, Michael K; Nguyen, Huong Q
Chest. 2021 06;159(6):2233-2243. Epub 2021-01-19.
Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study
Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD. Observational, case-cohort study design. Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study. Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile. The primary outcomes were incident HF and AF. Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker. The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232pg/mL over 2years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37ng/mL over 2years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤-3.78ng/mL over 2years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF. Observational study. In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.
Authors: Bansal, Nisha; Go, Alan S; CRIC Study Investigators,; et al.
Am J Kidney Dis. 2021 06;77(6):907-919. Epub 2020-12-09.
Breast Arterial Calcification Is Not Associated with Mild Cognitive Impairment or Incident All-Cause Dementia Among Postmenopausal Women: The MINERVA Study
Background: Since vascular risk factors are implicated in cognitive decline, and breast arterial calcification (BAC) is related to vascular risk, we postulated that BAC may be associated with cognitive impairment and dementia. Methods: We used a multiethnic cohort of 3,913 asymptomatic women 60-79 years of age recruited after mammography screening at a large health plan in 2012-2015. A BAC mass score (mg) was derived from digital mammograms. Cognitive function was measured at baseline using the Montreal Cognitive Assessment (MoCA) and incident all-cause dementia (n = 49 events; median follow-up = 5.6 years) were ascertained with validated ICD-9 and ICD-10 codes. We used cross-sectional linear regression of MoCA scores on BAC, then multinomial logistic regression predicting mild cognitive impairment not progressing to dementia and incident all-cause dementia and, finally, Cox regression of incident all-cause dementia. Results: No association by linear regression was found between MoCA scores and BAC presence in unadjusted or adjusted analysis. Women with severe (upper tertile) BAC had a MoCA score lower by 0.58 points (standard error [SE] = 0.18) relative to women with no BAC. However, this difference disappeared after multivariate adjustment. No significant associations were found in multinomial logistic regression for either BAC presence or gradation in unadjusted or adjusted analysis. No significant associations were found between BAC presence with incident all-cause dementia (fully adjusted hazard ratio = 0.74; 95% confidence interval: 0.39-1.39). Likewise, no significant association with incident all-cause dementia was noted for BAC gradation. Conclusions: Our results do not support the hypothesis that BAC presence or gradation may contribute to cognitive impairment or development of all-cause dementia.
Authors: Iribarren, Carlos; Chandra, Malini; Molloi, Sabee; Sanchez, Gabriela; Azamian-Bidgoli, Fatemeh; Cho, Hyo-Min; Ding, Huanjun; Yaffe, Kristine
J Womens Health (Larchmt). 2021 06;30(6):848-856. Epub 2020-12-07.
Mobile Health (mHealth) Technology: Assessment of Availability, Acceptability, and Use in CKD
Digital and mobile health (mHealth) technologies improve patient-provider communication and increase information accessibility. We assessed the use of technology, attitudes toward using mHealth technologies, and proficiency in using mHealth technologies among individuals with chronic kidney disease (CKD). Cross-sectional survey with open text responses. Chronic Renal Insufficiency Cohort (CRIC) Study participants who completed current use and interest in using mHealth technologies questionnaires and the eHealth literacy Survey (eHEALS). Participant characteristics. Use of technology (ie, internet, email, smartphone, and mHealth applications [apps]), interest in future mHealth use, and proficiency in using digital and mHealth technologies, or eHealth literacy, determined by eHEALS score. Poisson regression and a qualitative content analysis of open-ended responses. Study participants (n = 932) had a mean age of 68 years old and an estimated glomerular filtration rate (eGFR) of 54 mL/min/1.73 m2, and 59% were male. Approximately 70% reported current use of internet, email, and smartphones, and 35% used mHealth apps; only 27% had adequate eHealth literacy (eHEALS score ≥ 32). Participants <65 years of age (vs. ≥65), with more education, higher income, better cognition, and adequate health literacy reported more use of technology, and greater interest in using technologies. Participants of White (vs. non-White) race reported more use of internet and email but less interest in future use of mHealth. Younger age, higher annual income, and greater disease self-efficacy were associated with adequate eHealth literacy. Three themes regarding interest in using digital and mHealth technologies emerged: willingness, concerns, and barriers. Residual confounding, ascertainment bias. Many individuals with CKD currently use the internet and smartphones and are interested in using mHealth in the future, but few use mHealth apps or have adequate eHealth literacy. mHealth technologies present an opportunity to engage individuals with CKD, especially members of racial or ethnic minority groups because those groups reported greater interest in using mHealth technology than the nonminority population. Further research is needed to identify strategies to overcome inadequate eHealth literacy.
Authors: Schrauben, Sarah J; Go, Alan S; CRIC Study Investigators,; et al.
Am J Kidney Dis. 2021 06;77(6):941-950.e1. Epub 2020-12-09.
Cumulative Marijuana Use and Carotid Intima-Media Thickness at Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Long-term cardiovascular health effects of marijuana are understudied. Future cardiovascular disease is often indicated by subclinical atherosclerosis for which carotid intima-media thickness is an established parameter. Using the data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of 5115 Black and white women and men at Year 20 visit, we studied the association between carotid intima-media thickness in midlife and lifetime exposure to marijuana (1 marijuana year = 365 days of use) and tobacco smoking (1 pack-year = 20 cigarettes/day for 365 days). We measured carotid intima-media thickness by ultrasound and defined high carotid intima-media thickness at the threshold of the 75th percentile of all examined participants. We fit logistic regression models stratified by tobacco smoking exposure, adjusting for demographics, cardiovascular risk factors, and other drug exposures. Data was complete for 3257 participants; 2722 (84%) reported ever marijuana use; 374 (11%) were current users; 1539 (47%) reported ever tobacco smoking; 610 (19%) were current smokers. Multivariable adjusted models showed no association between cumulative marijuana exposure and high carotid intima-media thickness in never or ever tobacco smokers, odds ratio (OR) 0.87 (95% confidence interval [CI]: 0.63-1.21) at 1 marijuana-year among never smokers and OR 1.11 (95% CI: 0.85-1.45) among ever tobacco smokers. Cumulative exposure to tobacco was strongly associated with high carotid intima-media thickness, OR 1.88 (95%CI: 1.20-2.94) for 20 pack-years of exposure. This study adds to the growing body of evidence that there might be no association between the average population level of marijuana use and subclinical atherosclerosis.
Authors: Jakob, Julian; von Wyl, Roman; Stalder, Odile; Pletcher, Mark J; Vittinghoff, Eric; Tal, Kali; Rana, Jamal S; Sidney, Stephen; Reis, Jared P; Auer, Reto
Am J Med. 2021 06;134(6):777-787.e9. Epub 2020-12-24.
Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Authors: de Las Fuentes L; Sims M; Fornage M; et al.
Mol Psychiatry. 2021 06;26(6):2111-2125. Epub 2020-05-05.
Body mass index and chronic kidney disease outcomes after acute kidney injury: a prospective matched cohort study
Acute kidney injury (AKI) and obesity are independent risk factors for chronic kidney disease (CKD). This study aimed to determine if obesity modifies risk for CKD outcomes after AKI. This prospective multisite cohort study followed adult survivors after hospitalization, with or without AKI. The primary outcome was a combined CKD event of incident CKD, progression of CKD and kidney failure, examined using time-to-event Cox proportional hazards models, adjusted for diabetes status, age, pre-existing CKD, cardiovascular disease status and intensive care unit admission, and stratified by study center. Body mass index (BMI) was added as an interaction term to examine effect modification by body size. The cohort included 769 participants with AKI and 769 matched controls. After median follow-up of 4.3 years, among AKI survivors, the rate of the combined CKD outcome was 84.7 per1000-person-years with BMI ≥30 kg/m2, 56.4 per 1000-person-years with BMI 25-29.9 kg/m2, and 72.6 per 1000-person-years with BMI 20-24.9 kg/m2. AKI was associated with a higher risk of combined CKD outcomes; adjusted-HR 2.43 (95%CI 1.87-3.16), with no evidence that this was modified by BMI (p for interaction = 0.3). After adjustment for competing risk of death, AKI remained associated with a higher risk of the combined CKD outcome (subdistribution-HR 2.27, 95%CI 1.76-2.92) and similarly, there was no detectable effect of BMI modifying this risk. In this post-hospitalization cohort, we found no evidence for obesity modifying the association between AKI and development or progression of CKD.
Authors: MacLaughlin, Helen L; Go, Alan S; ASSESS-AKI Study Investigators,; et al.
BMC Nephrol. 2021 05 28;22(1):200. Epub 2021-05-28.
Temporal trends in heart failure mortality in an integrated healthcare delivery system, California, and the US, 2001-2017
In recent years, decreases in mortality rates attributable to cardiovascular diseases have slowed but mortality attributable to heart failure (HF) has increased. Between 2001-2017, trends in age-adjusted mortality with HF as an underlying cause for Kaiser Permanente Southern California (KPSC) members were derived through linkage with state death files and compared with trends among California residents and the US. Average annual percent change (AAPC) and 95% confidence intervals (CI) were calculated using Joinpoint regression. Analyses were repeated examining HF as a contributing cause of death. In KPSC, the age-adjusted HF mortality rates were comparable to California but lower than the US, increasing from 23.9 per 100,000 person-years (PY) in 2001 to 44.7 per 100,000 PY in 2017, representing an AAPC of 1.3% (95% CI 0.0%, 2.6%). HF mortality also increased in California from 33.9 to 46.5 per 100,000 PY (AAPC 1.5%, 95% CI 0.3%, 2.7%), while remaining unchanged in the US at 57.9 per 100,000 PY in 2001 and 2017 (AAPC 0.0%, 95% CI - 0.5%, 0.5%). Trends among KPSC members ≥ 65 years old were similar to the overall population, while trends among members 45-64 years old were flat between 2001-2017. Small changes in mortality with HF as a contributing cause were observed in KPSC members between 2001 and 2017, which differed from California and the US. Lower rates of HF mortality were observed in KPSC compared to the US. Given the aging of the US population and increasing prevalence of HF, it will be important to examine individual and care-related factors driving susceptibility to HF mortality.
Authors: Mefford, Matthew T; Zhuang, Zimin; Liang, Zhi; Chen, Wansu; Koyama, Sandra Y; Taitano, Maria T; Watson, Heather L; Lee, Ming-Sum; Sidney, Stephen; Reynolds, Kristi
BMC Cardiovasc Disord. 2021 05 26;21(1):261. Epub 2021-05-26.
Making The Case For Sacubitril/Valsartan In Patients With Heart Failure With A Preserved Ejection Fraction
Authors: Tai, Andrew; Ambrosy, Andrew P; Fudim, Marat
Eur Heart J Cardiovasc Pharmacother. 2021 05 23;7(3):e5-e6.
The Association of Lactation Duration with Visceral and Pericardial Fat Volumes in Parous Women: the CARDIA Study
Lactation is associated with lower risks for cardiovascular disease in women. Organ-related adiposity, which plays significant roles in the development of cardiometabolic diseases, could help explain this observation. We evaluated the association of lactation duration with visceral (VAT) and pericardial (PAT) fat volumes in women. Data were obtained from 910 women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study (1985-1986) without diabetes prior to pregnancy who had ≥1 birth during 25 years of follow-up and had VAT and PAT measured from computed tomographic scans in 2010-2011. Cumulative lactation duration across all births since baseline was calculated from self-reports collected at periodic exams. At baseline, the average age of women (48% black, 52% white) was 24 ± 3.7 years. After controlling for baseline age, race, smoking status, body mass index, fasting glucose, family history of diabetes, fat intake, total cholesterol, physical activity, and follow-up covariates (parity, gestational diabetes), the mean fat volumes across categories of lactation [none (n = 221), 1-5 months (n = 306), 6-11 months (n = 210), and ≥12 months (n = 173)] were 122.0, 113.7 105.0, and 110.1 cm3 for VAT and 52.2, 46.7, 44.5, and 43.4 cm3 for PAT, respectively. Changes in body weight from the first post-baseline birth to the end of follow-up mediated 21% and 18% of the associations of lactation with VAT and PAT, respectively. In this prospective study, longer cumulative lactation duration was associated with lower VAT and PAT volumes, with weight gain partially mediating these associations.
Authors: Appiah, Duke; Lewis, Cora E; Jacobs, David R; Shikany, James M; Quesenberry, Charles P; Gross, Myron; Carr, Jeff; Sidney, Stephen; Gunderson, Erica P
J Clin Endocrinol Metab. 2021 05 13;106(6):1821-1831.
Blood Pressure Levels in Young Adulthood and Midlife Stroke Incidence in a Diverse Cohort
[Figure: see text].Authors: Gerber, Yariv; Rana, Jamal S; Nguyen-Huynh, Mai N; Sidney, Stephen; et al.
Hypertension. 2021 05 05;77(5):1683-1693. Epub 2021-03-29.
Adverse Pregnancy Outcomes and Cardiovascular Disease Risk: Unique Opportunities for Cardiovascular Disease Prevention in Women: A Scientific Statement From the American Heart Association
This statement summarizes evidence that adverse pregnancy outcomes (APOs) such as hypertensive disorders of pregnancy, preterm delivery, gestational diabetes, small-for-gestational-age delivery, placental abruption, and pregnancy loss increase a woman’s risk of developing cardiovascular disease (CVD) risk factors and of developing subsequent CVD (including fatal and nonfatal coronary heart disease, stroke, peripheral vascular disease, and heart failure). This statement highlights the importance of recognizing APOs when CVD risk is evaluated in women, although their value in reclassifying risk may not be established. A history of APOs is a prompt for more vigorous primordial prevention of CVD risk factors and primary prevention of CVD. Adopting a heart-healthy diet and increasing physical activity among women with APOs, starting in the postpartum setting and continuing across the life span, are important lifestyle interventions to decrease CVD risk. Lactation and breastfeeding may lower a woman’s later cardiometabolic risk. Black and Asian women experience a higher proportion APOs, with more severe clinical presentation and worse outcomes, than White women. More studies on APOs and CVD in non-White women are needed to better understand and address these health disparities. Future studies of aspirin, statins, and metformin may better inform our recommendations for pharmacotherapy in primary CVD prevention among women who have had an APO. Several opportunities exist for health care systems to improve transitions of care for women with APOs and to implement strategies to reduce their long-term CVD risk. One proposed strategy includes incorporation of the concept of a fourth trimester into clinical recommendations and health care policy.
Authors: Parikh, Nisha I; Gonzalez, Juan M; Anderson, Cheryl A M; Judd, Suzanne E; Rexrode, Kathryn M; Hlatky, Mark A; Gunderson, Erica P; Stuart, Jennifer J; Vaidya, Dhananjay; American Heart Association Council on Epidemiology and Prevention; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; and the Stroke Council,
Circulation. 2021 05 04;143(18):e902-e916. Epub 2021-03-29.
Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design
Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited. The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance. The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.
Authors: Mentz, Robert J; Ambrosy, Andrew P; HEART-FID Trial Investigators,; et al.
Circ Heart Fail. 2021 05;14(5):e008100. Epub 2021-05-18.
Ten-year Thyroid Cancer Incidence in an Integrated Healthcare Delivery System
The incidence of papillary thyroid cancer (PTC) has increased in recent decades, but data from community-based settings are limited. This study characterizes PTC trends in a large, integrated healthcare system over 10 years. The annual incidence of PTC (2006-2015) was examined among Kaiser Permanente Northern California adults aged 21 to 84 years using Cancer Registry data, including tumor size and stage. Incidence estimates were age-adjusted using the 2010 US Census. Of 2990 individuals newly diagnosed with PTC (76.8% female, 52.7% non-Hispanic White), 38.5% and 61.5% were aged < 45 and < 55 years, respectively. At diagnosis, 60.9% had PTC tumors ≤ 2 cm, 9.2% had tumors > 4 cm, and 66.1% had Stage I disease. The annual age-adjusted incidence of PTC increased from 9.4 (95% confidence interval [CI] = 8.1-10.7) to 14.5 (95% CI = 13.1-16.0) per 100,000 person-years and was higher for female patients than for male patients. Incidence tended to be higher in Asian/Pacific Islanders and lower in Black individuals. Increasing incidence was notable for Stage I disease (especially 2006-2012) and evident across a range of tumor sizes (3.0-4.6 for ≤ 1 cm, 2.5-3.5 for 1-2 cm, and 2.4-4.7 for 2-4 cm) but was modest for large tumors (0.9-1.5 for > 4 cm) per 100,000 person-years. Increasing PTC incidence over 10 years was most evident for tumors ≤ 4 cm and Stage I disease. Although these findings may be attributable to greater PTC detection, the increase across a range of tumor sizes suggests that PTC burden might also have increased.
Authors: Kim, Stephanie J; Durr, Megan L; Darbinian, Jeanne A; Sakoda, Lori C; Meltzer, Charles J; Arzumanyan, Hasmik; Wang, Kevin H; Lin, Jonathan K; Gurushanthaiah, Deepak; Lo, Joan C
Perm J. 2021 05;25.
Magnesium intake was inversely associated with hostility among American young adults
Hostility is a complex personality trait associated with many cardiovascular risk factor phenotypes. Although magnesium intake has been related to mood and cardio-metabolic disease, its relation with hostility remains unclear. We hypothesize that high total magnesium intake is associated with lower levels of hostility because of its putative antidepressant mechanisms. To test the hypothesis, we prospectively analyzed data in 4,716 young adults aged 18-30 years at baseline (1985-1986) from four U.S. cities over five years of follow-up using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Magnesium intake was estimated from a dietary history questionnaire plus supplements at baseline. Levels of hostility were assessed using the Cook-Medley scale at baseline and year 5 (1990-1991). Generalized estimating equations were applied to estimate the association of magnesium intake with hostility as repeated measures at the two time-points (baseline and year 5). General linear model was used to determine the association between magnesium intake and change in hostility over 5 years. After adjustment for socio-demographic and major lifestyle factors, a significant inverse association was observed between magnesium intake and hostility level over 5 years of follow-up. Beta coefficients (95% CI) across higher quintiles of magnesium intake were 0 (reference), -1.28 (-1.92, -0.65), -1.45 (-2.09, -0.81), -1.41 (-2.08, -0.75) and -2.16 (-2.85, -1.47), respectively (Plinear-trend<.01). The inverse association was independent of socio-demographic and major lifestyle factors, supplement use, and depression status at year 5. This prospective study provides evidence that in young adults, high magnesium intake was inversely associated with hostility level independent of socio-demographic and major lifestyle factors.
Authors: Lyu, Chen; Tsinovoi, Cari L; Xun, Pengcheng; Song, Yiqing; Pu, Yongjia; Rosanoff, Andrea; Iribarren, Carlos; Schreiner, Pamela J; Shikany, James M; Jacobs, David R; Kahe, Ka
Nutr Res. 2021 05;89:35-44. Epub 2021-04-21.
Timing of Dialysis Initiation and End-Stage Kidney Disease Incidence-Reply
Authors: Hsu, Chi-Yuan; Go, Alan S
JAMA Intern Med. 2021 05 01;181(5):725-726.
Association of infant diet with subsequent obesity at 2-5 years among children exposed to gestational diabetes: the SWIFT study
This longitudinal analysis evaluated the independent and joint associations of any breastfeeding (BF) or exclusive BF (EBF) and intake of sugar-sweetened beverages (SSBs) and 100% fruit juice from birth to 1 year with subsequent overweight and obesity among young children exposed to gestational diabetes (GDM). The analysis utilised prospectively collected data from participants enrolled in the Study of Women, Infant Feeding and Type 2 Diabetes after GDM (SWIFT); 1035 pregnant women (20-45 years) diagnosed with GDM, of whom 75% were of Black, Hispanic or Asian race and ethnicity. Mother-infant dyad characteristics and infant dietary intake were assessed via research protocols at in-person examinations, telephone interviews and monthly mailed surveys from birth to 1 year. Child weight, length and height were obtained from electronic health records at birth (2008-2011) and ages 2-5 years (2010-2016) to classify BMI percentile groups (n = 835). Adequate BF (≥6 months), adequate EBF duration (≥6 months), and SSB and 100% fruit juice intake in the first year were independently associated with child obesity at ages 2-5 years (all p < 0.05). Compared with children with adequate EBF and no intake of SSB or 100% fruit juice, those with adequate EBF and intake of 100% fruit juice and/or SSBs had a four- to fivefold higher odds of obesity (aOR 4.2, 95% CI:1.6, 11.2 for 100% fruit juice; aOR 4.5, 95% CI:1.4, 8.5 for fruit juice or SSBs; and aOR 4.7, 95% CI:1.4, 15 for SSBs; all p < 0.01), while those with inadequate EBF (<6 months) and intake of 100% fruit juice and/or SSBs had a six- to 12-fold higher odds of obesity (aOR 6.4, 95% CI:2.4, 17.2 for fruit juice; aOR 6.6, 95% CI:2.7, 14.8 for fruit juice or SSBs; and aOR 12.2, 95% CI:4.3, 25 for SSBs; all p < 0.001). Compared with children with adequate BF and no intake of SSB or 100% fruit juice, those with adequate BF and intake of 100% fruit juice and/or SSBs had a threefold higher odds of obesity (aOR 3.1, 95% CI:1.1, 7.3 for fruit juice; aOR 3.3, 95% CI:1.3, 8.3 for fruit juice or SSBs; and aOR 3.4, 95% CI:1.3, 8.5 for SSBs; all p < 0.05), while those with inadequate BF (<6 months) and intake of 100% fruit juice and/or SSB were associated with five- to tenfold higher odds of obesity (aOR 4.8, 95% CI:2.3, 12.2 for fruit juice; aOR 6.0, 95% CI:2.5, 12.8 for fruit juice or SSBs; aOR 9.5, 95% CI:3.7, 15.1 for SSBs; all p < 0.05). This is the first study to prospectively evaluate the relation of BF or EBF duration and intake of SSB and 100% fruit juice during the first year of life with subsequent obesity in children exposed to GDM. Adequate BF or EBF combined with avoidance of SSB and 100% fruit juice during early infancy may ameliorate future child obesity in this high-risk population.
Authors: Vandyousefi, Sarvenaz; Davis, Jaimie N; Gunderson, Erica P
Diabetologia. 2021 05;64(5):1121-1132. Epub 2021-01-26.
Rationale and Design of the Pragmatic Randomized Trial of Icosapent Ethyl for High Cardiovascular Risk Adults (MITIGATE)
The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD). IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs. MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California – a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time. The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.
Authors: Ambrosy, Andrew P; Solomon, Matthew D; Skarbinski, Jacek; Go, Alan S; et al.
Am Heart J. 2021 05;235:54-64. Epub 2021-01-28.
Improving adherence to guideline-directed medical therapies and outcomes in the developing world: A call to end global inequities in heart failure
Authors: Chioncel, Ovidiu; Ambrosy, Andrew P
Int J Cardiol. 2021 04 15;329:74-76. Epub 2020-12-02.
Longitudinal Associations of Fitness and Obesity in Young Adulthood With Right Ventricular Function and Pulmonary Artery Systolic Pressure in Middle Age: The CARDIA Study
Background Low cardiorespiratory fitness (CRF) and obesity are risk factors for heart failure but their associations with right ventricular (RV) systolic function and pulmonary artery systolic pressure (PASP) are not well understood. Methods and Results Participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who underwent maximal treadmill testing at baseline and had a follow-up echocardiographic examination at year 25 were included. A subset of participants had repeat CRF and body mass index (BMI) assessment at year 20. The associations of baseline and changes in CRF and BMI on follow-up (baseline to year 20) with RV systolic function parameters (tricuspid annular plane systolic excursion, RV Doppler systolic velocity of the lateral tricuspid annulus), and PASP were assessed using multivariable-adjusted linear regression models. The study included 3433 participants. In adjusted analysis, higher baseline BMI but not CRF was significantly associated with higher PASP. Among RV systolic function parameters, higher baseline CRF and BMI were significantly associated with higher tricuspid annular plane systolic excursion and RV systolic velocity of the lateral tricuspid annulus. In the subgroup of participants with follow-up assessment of CRF or BMI at year 20, less decline in CRF was associated with higher RV systolic velocity of the lateral tricuspid annulus and lower PASP, while greater increase in BMI was significantly associated with higher PASP in middle age. Conclusions Higher CRF in young adulthood and less decline in CRF over time are each significantly associated with better RV systolic function. Higher baseline BMI and greater age-related increases in BMI are each significantly associated with higher PASP in middle age. These findings provide insights into possible mechanisms through which low fitness and obesity may contribute toward risk of heart failure.
Authors: Patel, Kershaw V; Goff, David C; Pandey, Ambarish; et al.
J Am Heart Assoc. 2021 04 06;10(7):e016968. Epub 2021-03-28.
Maternal weight change from prepregnancy to 18 months postpartum and subsequent risk of hypertension and cardiovascular disease in Danish women: A cohort study
One-fourth of women experience substantially higher weight years after childbirth. We examined weight change from prepregnancy to 18 months postpartum according to subsequent maternal risk of hypertension and cardiovascular disease (CVD). We conducted a cohort study of 47,966 women with a live-born singleton within the Danish National Birth Cohort (DNBC; 1997-2002). Interviews during pregnancy and 6 and 18 months postpartum provided information on height, gestational weight gain (GWG), postpartum weights, and maternal characteristics. Information on pregnancy complications, incident hypertension, and CVD was obtained from the National Patient Register. Using Cox regression, we estimated adjusted hazard ratios (HRs; 95% confidence interval [CI]) for hypertension and CVD through 16 years of follow-up. During this period, 2,011 women were diagnosed at the hospital with hypertension and 1,321 with CVD. The women were on average 32.3 years old (range 18.0-49.2) at start of follow-up, 73% had a prepregnancy BMI <25, and 27% a prepregnancy BMI ≥25. Compared with a stable weight (±1 BMI unit), weight gains from prepregnancy to 18 months postpartum of >1-2 and >2 BMI units were associated with 25% (10%-42%), P = 0.001 and 31% (14%-52%), P < 0.001 higher risks of hypertension, respectively. These risks were similar whether weight gain presented postpartum weight retention or a new gain from 6 months to 18 months postpartum and whether GWG was below, within, or above the recommendations. For CVD, findings differed according to prepregnancy BMI. In women with normal-/underweight, weight gain >2 BMI units and weight loss >1 BMI unit were associated with 48% (17%-87%), P = 0.001 and 28% (6%-55%), P = 0.01 higher risks of CVD, respectively. Further, weight loss >1 BMI unit combined with a GWG below recommended was associated with a 70% (24%-135%), P = 0.001 higher risk of CVD. No such increased risks were observed among women with overweight/obesity (interaction by prepregnancy BMI, P = 0.01, 0.03, and 0.03, respectively). The limitations of this observational study include potential confounding by prepregnancy metabolic health and self-reported maternal weights, which may lead to some misclassification. Postpartum weight retention/new gain in all mothers and postpartum weight loss in mothers with normal-/underweight may be associated with later adverse cardiovascular health.
Authors: Kirkegaard, Helene; Bliddal, Mette; Støvring, Henrik; Rasmussen, Kathleen M; Gunderson, Erica P; Køber, Lars; Sørensen, Thorkild I A; Nøhr, Ellen A
PLoS Med. 2021 04;18(4):e1003486. Epub 2021-04-02.
Age-Related Development of Cardiac Remodeling and Dysfunction in Young Black and White Adults: the Coronary Artery Risk Development in Young Adults Study
Little is known about the timing of preclinical heart failure (HF) development, particularly among blacks. The primary aims of this study were to delineate age-related left ventricular (LV) structure and function evolution in a biracial cohort and to test the hypothesis that young-adult LV parameters within normative ranges would be associated with incident stage B-defining LV abnormalities over 25 years, independent of cumulative risk factor burden. Data from the Coronary Artery Risk Development in Young Adults study were analyzed. Participants (n = 2,833) had a mean baseline age of 30.1 years; 45% were black, and 56% were women. Generalized estimating equation logistic regression was used to estimate age-related probabilities of stage B LV abnormalities (remodeling, hypertrophy, or dysfunction) and logistic regression to examine risk factor-adjusted associations between baseline LV parameters and incident abnormalities. Cox regression was used to assess whether baseline LV parameters associated with incident stage B LV abnormalities were also associated with incident clinical (stage C/D) HF events over >25 years’ follow-up. Probabilities of stage B LV abnormalities at ages 25 and 60 years were 10.5% (95% CI, 9.4%-11.8%) and 45.0% (95% CI, 42.0%-48.1%), with significant race-sex disparities (e.g., at age 60, black men 52.7% [95% CI, 44.9%-60.3%], black women 59.4% [95% CI, 53.6%-65.0%], white men 39.1% [95% CI, 33.4%-45.0%], and white women 39.1% [95% CI, 33.9%-44.6%]). Over 25 years, baseline LV end-systolic dimension indexed to height was associated with incident systolic dysfunction (adjusted odds ratio per 1 SD higher, 2.56; 95% CI, 1.87-3.52), eccentric hypertrophy (1.34; 95% CI, 1.02-1.75), concentric hypertrophy (0.69; 95% CI, 0.51-0.91), and concentric remodeling (0.68; 95% CI, 0.58-0.79); baseline LV mass indexed to height2.7 was associated with incident eccentric hypertrophy (1.70; 95% CI, 1.25-2.32]), concentric hypertrophy (1.63; 95% CI, 1.19-2.24), and diastolic dysfunction (1.24; 95% CI, 1.01-1.52). Among the entire cohort with baseline echocardiographic data available (n = 4,097; 72 HF events), LV end-systolic dimension indexed to height and LV mass indexed to height2.7 were significantly associated with incident clinical HF (adjusted hazard ratios per 1 SD higher, 1.56 [95% CI, 1.26-1.93] and 1.42 [95% CI, 1.14-1.75], respectively). Stage B LV abnormalities and related racial disparities were present in young adulthood, increased with age, and were associated with baseline variation in indexed LV end-systolic dimension and mass. Baseline indexed LV end-systolic dimension and mass were also associated with incident clinical HF. Efforts to prevent the LV abnormalities underlying clinical HF should start from a young age.
Authors: Perak, Amanda M; Khan, Sadiya S; Colangelo, Laura A; Gidding, Samuel S; Armstrong, Anderson C; Lewis, Cora E; Reis, Jared P; Schreiner, Pamela J; Sidney, Stephen; Lima, Joao A C; Lloyd-Jones, Donald M
J Am Soc Echocardiogr. 2021 04;34(4):388-400. Epub 2020-11-17.
Gestational Diabetes History and Glucose Tolerance After Pregnancy Associated With Coronary Artery Calcium in Women During Midlife: The CARDIA Study
Gestational diabetes (GD) leads to earlier onset and heightened risk of type 2 diabetes, a strong risk factor for cardiovascular disease (CVD). However, it is unclear whether attaining normoglycemia can ameliorate the excess CVD risk associated with GD history. This study sought to evaluate GD history and glucose tolerance after pregnancy associated with coronary artery calcification (CAC) in women, a manifestation of atherosclerotic CVD and a predictor of CVD clinical events. Data were obtained from the CARDIA study (Coronary Artery Risk Development in Young Adults), a US multicenter, community-based prospective cohort of young Black (50%) and White adults aged 18 to 30 years at baseline (1985-1986). The sample included 1133 women without diabetes at baseline, who had ≥1 singleton births (n=2066) during follow-up, glucose tolerance testing at baseline and up to 5 times during 25 years (1986-2011), GD status, and CAC measurements obtained from 1 or more follow up examinations at years 15, 20, and 25 (2001-2011). CAC was measured by noncontrast cardiac computed tomography; dichotomized as Any CAC (score>0) or No CAC (score=0). Complementary log-log models for interval-censored data estimated adjusted hazard ratios of CAC and 95% confidence intervals for GD history and subsequent glucose tolerance groups (normoglycemia, prediabetes, or incident diabetes) on average 14.7 years after the last birth adjusted for prepregnancy and follow-up covariates. Of 1133 women, 139 (12.3%) reported GD and were 47.6 years of age (4.8 SD) at follow-up. CAC was present in 25% (34/139) of women with GD and 15% (149/994) of women with no GD. In comparison with no GD/normoglycemia, adjusted hazard ratios (95% CIs) were 1.54 (1.06-2.24) for no GD/prediabetes and 2.17 (1.30-3.62) for no GD/incident diabetes, and 2.34 (1.34-4.09), 2.13 (1.09-4.17), and 2.02 (0.98-4.19) for GD/normoglycemia, GD/prediabetes, and GD/incident diabetes, respectively (overall P=0.003). Women without previous GD showed a graded increase in the risk of CAC associated with worsening glucose tolerance. Women with a history of GD had a 2-fold higher risk of CAC across all subsequent levels of glucose tolerance. Midlife atherosclerotic CVD risk among women with previous GD is not diminished by attaining normoglycemia.
Authors: Gunderson, Erica P; Sun, Baiyang; Catov, Janet M; Carnethon, Mercedes; Lewis, Cora E; Allen, Norrina B; Sidney, Stephen; Wellons, Melissa; Rana, Jamal S; Hou, Lifang; Carr, John Jeffrey
Circulation. 2021 03 09;143(10):974-987. Epub 2021-02-01.
Non-alcoholic fatty liver disease and cognitive function in middle-aged adults: the CARDIA study
Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease (CVD) risk factors that have been linked to cognitive decline. Whether NAFLD is associated with cognitive performance in midlife remains uncertain. Coronary Artery Risk Development in Young Adults study participants with CT examination and cognitive assessment at Y25 (2010-2011; n = 2809) were included. Cognitive function was reassessed at Y30. NAFLD was defined according to liver attenuation and treated both continuously and categorically (using ≤ 40 and ≤ 51 Hounsfield units to define severity) after exclusion for other causes of liver fat. Cognitive tests including the Digit Symbol Substitution (processing speed), Rey Auditory Verbal Learning (verbal memory), and Stroop (executive function) were analyzed with standardized z-scores. Linear models were constructed to (a) examine the cross-sectional associations of NAFLD with cognitive scores and (b) evaluate its predictive role in 5-year change in cognitive performance. Participants’ mean age (Y25) was 50.1 (SD 3.6) years (57% female; 48% black), with 392 (14%) having mild NAFLD and 281 (10%) having severe NAFLD. NAFLD was positively associated with CVD risk factors and inversely associated with cognitive scores. However, after adjustment for CVD risk factors, no associations were shown between NAFLD and cognitive scores (all βs ≈ 0). Similarly, no associations were observed with 5-year cognitive decline. CVD history, hypertension, smoking, diabetes and hypertriglyceridemia showed stronger associations with baseline cognitive scores and were predictive of subsequent cognitive decline (all P ≤ .05). Among middle-aged adults, inverse associations between NAFLD and cognitive scores were attenuated after adjustment for CVD risk factors, with the latter predictive of poorer cognitive performance both at baseline and follow-up.
Authors: Gerber, Yariv; VanWagner, Lisa B; Yaffe, Kristine; Terry, James G; Rana, Jamal S; Reis, Jared P; Sidney, Stephen
BMC Gastroenterol. 2021 Mar 02;21(1):96. Epub 2021-03-02.
Mid-term outcomes for 605 patients receiving Endologix AFX or AFX2 Endovascular AAA Systems in an integrated healthcare system
Endologix issued important safety updates for the AFX Endovascular AAA System in 2016 and 2018 owing to the risk of type III endoleaks. Outcomes with these devices are limited to small case series with short-term follow-up. We describe the midterm outcomes for a large cohort of patients who received an Endologix AFX or AFX2 device. Data from an integrated healthcare system’s implant registry, which prospectively monitors all patients after endovascular aortic repair, was used for this descriptive study. Patients undergoing endovascular aortic repair with three AFX System variations (Strata [AFX-S], Duraply [AFX-D], and AFX2 with Duraply [AFX2]) were identified (2011-2017). Crude cumulative event probabilities for endoleak (types I and III), major reintervention, conversion to open, rupture, and mortality (aneurysm related and all cause) were estimated. Among 605 patients, 375 received AFX-S, 197 received AFX-D, and 33 received AFX2. Median follow-up for the cohort was 3.9 (interquartile range, 2.5-5.1) years. The crude 2-year incidence of overall endoleak, any subsequent reintervention or conversion, and mortality was 8.8% (95% confidence interval [CI], 6.3-12.3), 12.0% (95% CI, 9.1-15.9), and 8.8% (95% CI, 6.3-12.2) for AFX-S. Respective estimates for AFX-D were 7.9% (95% CI, 4.8-13.0), 10.6% (95% CI, 6.9-16.1), and 9.7% (95% CI, 6.3-14.7); for AFX2, they were 14.1% (95% CI, 4.7-38.2), 16.2% (95% CI, 6.4-37.7), and 21.2% (95% CI, 10.7-39.4). The midterm outcomes of a large U.S. patient cohort with an Endologix AFX or AFX2 System demonstrate a concerning rate of adverse postoperative events. Patients with these devices should receive close clinical surveillance to prevent device-related adverse events.
Authors: Chang RW; Rothenberg KA; Harris JE; Gologorsky RC; Hsu JH; Rehring TF; Hajarizadeh H; Nelken NA; Paxton EW; Prentice HA
J Vasc Surg. 2021 03;73(3):856-866. Epub 2020-07-03.
Atrial Fibrillation and Longitudinal Change in Cognitive Function in CKD
Studies in the general population suggest that atrial fibrillation (AF) is an independent risk factor for decline in cognitive function, but this relationship has not been examined in adults with chronic kidney disease (CKD). We investigated the association between incident AF and changes in cognitive function over time in this population. We studied a subgroup of 3254 adults participating in the Chronic Renal Insufficiency Cohort Study. Incident AF was ascertained by 12-lead electrocardiogram (ECG) obtained at a study visit and/or identification of a hospitalization with AF during follow-up. Cognitive function was assessed biennially using the Modified Mini-Mental State Exam. Linear mixed effects regression was used to evaluate the association between incident AF and longitudinal change in cognitive function. Compared with individuals without incident AF (n = 3158), those with incident AF (n = 96) were older, had a higher prevalence of cardiovascular disease and hypertension, and lower estimated glomerular filtration rate. After median follow-up of 6.8 years, we observed no significant multivariable association between incident AF and change in cognitive function test score. In this cohort of adults with CKD, incident AF was not associated with a decline in cognitive function.
Authors: McCauley, Mark D; Go, Alan S; CRIC Study Investigators,; et al.
Kidney Int Rep. 2021 Mar;6(3):669-674. Epub 2021-01-05.
Variation in fracture risk estimation among East Asian women
Bone mineral density (BMD) testing and fracture risk calculation help clinicians assess fracture risk and counsel patients. However, predicted fracture risks and outcomes for US East Asian individuals remain understudied. Retrospective cohort study. Using standardized clinical profiles for East Asian women aged 70 years, fracture probabilities were estimated using the US Fracture Risk Assessment Tool (FRAX) version 4.1 and corresponding FRAX tools for East Asian countries. Next, clinical and BMD data from 3785 US Asian women aged 65 to 74 years were used to estimate 10-year hip fracture risk (US-Asian FRAX-v3.1) in comparison with actual observed 10-year hip fracture risk (Kaplan-Meier product limit estimate). For the same patient profile entered in the US-Asian FRAX and country-specific FRAX, the calculated 10-year hip fracture probability varied. Compared with the US-Asian FRAX calculator, the estimate was 2-fold higher using the Taiwan FRAX and Hong Kong FRAX, somewhat higher using the South Korea FRAX and Japan FRAX, and similar using the China FRAX. Among 3785 US Asian women (mean [SD] age, 69 [3] years), 23 experienced a hip fracture during a median follow-up of 6.8 years. Their observed 10-year hip fracture risk was 1.5% (95% CI, 0.8%-2.7%), and their median (interquartile range) predicted fracture probability (US-Asian FRAX-v3.1) was 1.1% (0.6%-2.0%). Country-specific FRAX estimates varied between the United States and East Asian countries. For US Asian women, the US FRAX-predicted hip fracture probabilities were in the lower range of observed risk. Although these findings support the use of the US-Asian FRAX for hip fracture risk assessment in US East Asian women, further studies are needed, including the examination of Asian subgroups.
Authors: Lo, Joan C; Nath, Shefali; Patel, Minal; Chandra, Malini; Yang, Betsy; Weintraub, Miranda Ritterman; Ettinger, Bruce
Am J Manag Care. 2021 03 01;27(3):e97-e100. Epub 2021-03-01.
Temporal trends in the outcomes of acute heart failure: between consolatory evidences and real progress
Authors: Chioncel, Ovidiu; Ambrosy, Andrew P; Maggioni, Aldo P
Eur J Heart Fail. 2021 03;23(3):432-435. Epub 2021-02-26.
Adverse Childhood Experiences and Early and Continued Breastfeeding: Findings from an Integrated Health Care Delivery System
Purpose: To examine whether adverse childhood experiences (ACEs) are associated with breastfeeding behaviors. Methods: Women in three Kaiser Permanente Northern California medical centers were screened for ACEs during standard prenatal care (N = 926). Multivariable binary and multinomial logistic regression was used to test whether ACEs (count and type) were associated with early breastfeeding at the 2-week newborn pediatric visit and continued breastfeeding at the 2-month pediatric visit, adjusting for covariates. Results: Overall, 58.2% of women reported 0 ACEs, 19.2% reported 1 ACE, and 22.6% reported 2+ ACEs. Two weeks postpartum, 92.2% reported any breastfeeding (62.9% exclusive, 29.4% mixed breastfeeding/formula). Compared with women with 0 ACEs, those with 2+ ACEs had increased odds of any breastfeeding (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.3-5.6) and exclusive breastfeeding 2 weeks postpartum (OR = 3.0, 95% CI = 1.4-6.3). Among those who breastfed 2 weeks postpartum, 86.4% reported continued breastfeeding (57.5% exclusive, 28.9% mixed breastfeeding/formula) 2 months postpartum. ACE count was not associated with continued breastfeeding 2 months postpartum. Individual ACEs were not related to breastfeeding outcomes, with the exception that living with someone who went to jail or prison was associated with lower odds of continued breastfeeding 2 months postpartum. Conclusions: ACE count was associated with greater early breastfeeding, but not continued breastfeeding, among women screened for ACEs as part of standard prenatal care. Results reiterate the need to educate and assist all women to meet their breastfeeding goals, regardless of ACE score.
Authors: Watson, Carey; Wei, Julia; Varnado, Nicole; Rios, Normelena; Flanagan, Tracy; Alabaster, Amy; Staunton, Mary; Sterling, Stacy A; Gunderson, Erica P; Young-Wolff, Kelly C
J Womens Health (Larchmt). 2021 03;30(3):367-376. Epub 2021-02-04.
Long-term Stroke Risk with Carotid Endarterectomy in Patients with Severe Carotid Stenosis
Informed debate regarding the optimal use of carotid endarterectomy (CEA) for stroke risk reduction requires contemporary assessment of both long-term risk and periprocedural risk. In this study, we report long-term stroke and death risk after CEA in a large integrated health care system. All patients with documented severe (70%-99%) stenosis from 2008 to 2012 who underwent CEA were identified and stratified by asymptomatic or symptomatic indication. Those with prior ipsilateral interventions were excluded. Patients were followed up through 2017 for the primary outcomes of any stroke/death within 30 days of intervention and long-term ipsilateral ischemic stroke; secondary outcomes were any stroke and overall survival. Overall, 1949 patients (63.2% male; mean age, 71.3 ± 8.9 years) underwent 2078 primary CEAs, 1196 (58%) for asymptomatic stenosis and 882 (42%) for symptomatic stenosis. Mean follow-up was 5.5 ± 2.7 years. Median time to surgery was 72.0 (interquartile range, 38.5-198.0) days for asymptomatic patients and 21.0 (interquartile range, 5.0-55.0) days for symptomatic patients (P < .001). Most of the patients' demographics and characteristics were similar in both groups. Controlled blood pressure rates were similar at the time of CEA. Baseline statin use was seen in 60.5% of the asymptomatic group compared with 39.9% in the symptomatic group (P < .001), and statin adherence by 80% medication possession ratio was 19.3% asymptomatic vs 12.4% symptomatic (P < .001). The crude overall 30-day any stroke/death rates were 0.9% and 1.5% for the asymptomatic group and the symptomatic group, respectively. The 5-year risk of ipsilateral stroke and a combined end point of any stroke/death by Kaplan-Meier survival analysis were 2.5% and 28.7% for the asymptomatic group and 4.0% and 31.4% for the symptomatic group, respectively. Unadjusted cumulative all-cause survival was 74.2% for the asymptomatic group and 71.8% for the symptomatic group at 5 years. In a contemporary review of CEA, outcomes for either operative indication show low adverse events perioperatively and low long-term stroke risk up to 5 years. These results are well within consensus guidelines and published trial outcomes and should help inform the discussion around optimal CEA use for severe carotid stenosis.
Authors: Rothenberg KA; Tucker LY; Gologorsky RC; Avins AL; Kuang HC; Faruqi RM; Flint AC; Nguyen-Huynh MN; Chang RW
J Vasc Surg. 2021 03;73(3):983-991. Epub 2020-07-21.
Association between marijuana use and electrocardiographic abnormalities by middle age The Coronary Artery Risk Development in Young Adults (CARDIA) Study
To evaluate the prevalence of electrocardiogram (ECG) abnormalities in marijuana users as an indirect measure of subclinical cardiovascular disease (CVD). Longitudinal and cross-sectional secondary data analysis from the CARDIA (Coronary Artery Risk Development in Young Adults) study. Four communities in the United States. A total of 2585 participants from the 5115 black and white men and women recruited at age 18-30 years in 1985 to 1986 in CARDIA. ECG abnormalities coded as minor and major abnormalities with the Minnesota code of electrocardiographic findings at year 20. Self-reported current (past 30 days) and computed cumulative life-time marijuana use (one ‘marijuana-year’ corresponds to 365 days of use) through assessments every 2-5 years. We fitted logistic regression models adjusting for sex, race, center, education, age, tobacco smoking, physical activity, alcohol use and body mass index. Among the 2585 participants with an ECG at year 20, mean age was 46, 57% were women, 45% were black; 83% had past exposure to marijuana and 11% were using marijuana currently. One hundred and seventy-three participants (7%) had major abnormalities and 944 (37%) had minor abnormalities. Comparing current with never use in multivariable-adjusted models, the odds ratio (OR) for major ECG abnormalities was 0.60 [95% confidence interval (CI) = 0.32-1.15] and for minor ECG abnormalities 1.21 (95% CI = 0.87-1.68). Results did not change after stratifying by sex and race. Cumulative marijuana use was not associated with ECG abnormalities. In a middle-aged US population, life-time cumulative and occasional current marijuana use were not associated with increases in electrocardiogram abnormalities. This adds to the growing body of evidence that occasional marijuana use and cardiovascular disease events and markers of subclinical atherosclerosis are not associated.
Authors: Jakob J; Stalder O; Syrogiannouli L; Pletcher MJ; Vittinghoff E; Ning H; Tal K; Rana JS; Sidney S; Lloyd-Jones DM; Auer R
Addiction. 2021 03;116(3):583-595. Epub 2020-08-09.
Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40 and Beyond
More than 40 years after the 1978 Bethesda Conference on the Declining Mortality from Coronary Heart Disease provided the scientific community with a blueprint for systematic analysis to understand declining rates of coronary heart disease, there are indications the decline has ended or even reversed despite advances in our knowledge about the condition and treatment. Recent data show a more complex situation, with mortality rates for overall cardiovascular disease, including coronary heart disease and stroke, decelerating, whereas those for heart failure are increasing. To mark the 40th anniversary of the Bethesda Conference, the National Heart, Lung, and Blood Institute and the American Heart Association cosponsored the “Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40” symposium. The objective was to examine the immediate and long-term outcomes of the 1978 conference and understand the current environment. Symposium themes included trends and future projections in cardiovascular disease (in the United States and internationally), the evolving obesity and diabetes epidemics, and harnessing emerging and innovative opportunities to preserve and promote cardiovascular health and prevent cardiovascular disease. In addition, participant-led discussion explored the challenges and barriers in promoting cardiovascular health across the lifespan and established a potential framework for observational research and interventions that would begin in early childhood (or ideally in utero). This report summarizes the relevant research, policy, and practice opportunities discussed at the symposium.
Authors: Goff, David Calvin; Wei, Gina S; Wright, Janet S; et al.
Circulation. 2021 02 23;143(8):837-851. Epub 2021-02-22.
Management of Renin-Angiotensin-Aldosterone System blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): A structured summary of a study protocol for a randomized controlled trial
The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials. This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy. Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis. All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7. PRIMARY ENDPOINT: In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay > 4 days, development of acute kidney injury ( > 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to > 30% in 48 hours and lymphocyte count drop> 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts. Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm. This is an open label study with no blinding. The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations. Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1st 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1st 2021. Trial registration: ClincalTrials.gov : NCT04508985 , date of registration: August 11th , 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Authors: Aflaki, Mona; Ambrosy, Andrew P; Sharma, Abhinav; et al.
Trials. 2021 Feb 05;22(1):115. Epub 2021-02-05.
Contemporary Reevaluation of Race and Ethnicity With Outcomes in Heart Failure
Background Variation in outcomes by race/ethnicity in adults with heart failure (HF) has been previously observed. Identifying factors contributing to these variations could help target interventions. We evaluated the association of race/ethnicity with HF outcomes and potentially contributing factors within a contemporary HF cohort. Methods and Results We identified members of Kaiser Permanente Northern California, a large integrated healthcare delivery system, who were diagnosed with HF between 2012 and 2016 and had at least 1 year of prior continuous membership and left ventricular ejection fraction data. We used Cox regression with time-dependent covariates to evaluate the association of self-identified race/ethnicity with HF or all-cause hospitalization and all-cause death, with backward selection for potential explanatory variables. Among 34 621 patients with HF, compared with White patients, Black patients had a higher rate of HF hospitalization (adjusted hazard ratio [HR], 1.28; 95% CI, 1.18-1.38) but a lower rate of death (adjusted HR, 0.78; 95% CI, 0.72-0.85). In contrast, Asian/Pacific Islander patients had similar rates of HF hospitalization, but lower rates of all-cause hospitalization (adjusted HR, 0.89; 95% CI, 0.85-0.93) and death (adjusted HR, 0.75; 95% CI, 0.69-0.80). Hispanic patients also had a lower rate of death (adjusted HR, 0.85; 95% CI, 0.80-0.91). Sensitivity analyses showed that effect sizes for Black patients were larger among patients with reduced ejection fraction. Conclusions In a contemporary and diverse population with HF, Black patients experienced a higher rate of HF hospitalization and a lower rate of death compared with White patients. In contrast, selected outcomes for Asian/Pacific Islander and Hispanic patients were more favorable compared with White patients. The observed differences were not explained by measured potentially modifiable factors, including pharmacological treatment. Future research is needed to identify explanatory mechanisms underlying ongoing racial/ethnic variation to target potential interventions.
Authors: Savitz, Samuel T; Leong, Thomas; Sung, Sue Hee; Lee, Keane; Rana, Jamal S; Tabada, Grace; Go, Alan S
J Am Heart Assoc. 2021 02 02;10(3):e016601. Epub 2021-01-21.
Longitudinal Associations of Midlife Accelerometer Determined Sedentary Behavior and Physical Activity With Cognitive Function: The CARDIA Study
Background To determine if accelerometer measured sedentary behavior (SED), light-intensity physical activity (LPA), and moderate-to-vigorous-intensity physical activity (MVPA) in midlife is prospectively associated with cognitive function. Methods and Results Participants were 1970 adults enrolled in the CARDIA (Coronary Artery Risk Development in Young Adults) study who wore an accelerometer in 2005 to 2006 (ages 38-50 years) and had cognitive function assessments completed 5 and/or 10 years later. SED, LPA, and MVPA were measured by an ActiGraph 7164 accelerometer. Cognitive function tests included the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop Test. Compositional isotemporal substitution analysis examined associations of SED, LPA, and MVPA with repeated measures of the cognitive function standardized scores. In men, statistical reallocation of 30 minutes of LPA with 30 minutes of MVPA resulted in an estimated difference of SD 0.07 (95% CI, 0.01-0.14), SD 0.09 (95% CI, 0.02-0.17), and SD -0.11 (95% CI, -0.19 to -0.04) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating better performance. Associations were similar when reallocating time in SED with MVPA, but results were less robust. Reallocation of time in SED with LPA resulted in an estimated difference of SD -0.05 (95% CI, -0.06 to -0.03), SD -0.03 (95% CI, -0.05 to -0.01), and SD 0.05 (95% CI, 0.03- 0.07) in the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop scores, respectively, indicating worse performance. Associations were largely nonsignificant among women. Conclusions Our findings support the idea that for men, higher-intensity activities (MVPA) may be necessary in midlife to observe beneficial associations with cognition.
Authors: Whitaker, Kara M; Zhang, Dong; Pettee Gabriel, Kelley; Ahrens, Monica; Sternfeld, Barbara; Sidney, Stephen; Jacobs, David R; Palta, Priya; Yaffe, Kristine
J Am Heart Assoc. 2021 02 02;10(3):e018350. Epub 2021-01-20.
Loop Diuretic Use and Outcomes in Chronic Stable Heart Failure With Preserved Ejection Fraction-Reply
Authors: Rao, Vishal N; Pandey, Ambarish; Zhong, Lin; Ambrosy, Andrew P; Fudim, Marat
Mayo Clin Proc. 2021 02;96(2):503-506.
Sex Differences in Cognitive Decline Among US Adults
Sex differences in dementia risk are unclear, but some studies have found greater risk for women. To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk. This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020. Sex. The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61). The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.
Authors: Levine, Deborah A; Sacco, Ralph L; Galecki, Andrzej T; et al.
JAMA Netw Open. 2021 02 01;4(2):e210169. Epub 2021-02-01.
Biomarkers of inflammation and repair in kidney disease progression
INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.
Authors: Puthumana, Jeremy; Go, Alan S; Parikh, Chirag R; et al.
J Clin Invest. 2021 02 01;131(3).
Implications of peripheral oedema in heart failure with preserved ejection fraction: a heart failure network analysis
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS-HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter-quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P < 0.001), greater burden of co-morbidities, higher intravascular pressures estimated on physical examination (elevated jugular venous pressure: 50% vs. 24.7%, P < 0.001), poorer renal function (creatinine: 1.2 mg/dL [IQR 0.9, 1.5] vs. 1 mg/dL [IQR 0.8, 1.3], P = 0.003), and lower peak VO2 (adjusted mean difference -1.04 mL/kg/min, 95% confidence interval [-1.71, -0.37], P < 0.003). Among hospitalized patients, despite greater in-hospital fluid/weight loss in the ≥moderate oedema group, there was no difference in the improvement in dyspnoea by the visual analogue scale or well-being visual analogue scale from baseline to 3-4 days and no statistically significant difference in the rate of 60 day rehospitalization/death (adjusted hazard ratio 1.44, 95% confidence interval [0.87, 2.39], P = 0.156). Patients with HFpEF and oedema display higher body mass, greater burden of co-morbidities, and more severe exercise intolerance, but clinical responses to treatment appear similar. Further research is required to better understand the nature of volume distribution in different HFpEF phenotypes.
Authors: Fudim, Marat; Ambrosy, Andrew P; Mentz, Robert J; et al.
ESC Heart Fail. 2021 02;8(1):662-669. Epub 2020-12-09.
A prospective cohort study that examined acute kidney injury and kidney outcomes, cardiovascular events and death informs on long-term clinical outcomes
Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes.
Authors: Ikizler TA; Go AS; ASSESS-AKI Study Investigators; et al.
Kidney Int. 2021 02;99(2):456-465. Epub 2020-07-22.
Progression of retinopathy and incidence of cardiovascular disease: findings from the Chronic Renal Insufficiency Cohort Study
Chronic kidney disease (CKD) patients often develop cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess the association between progression of retinopathy and concurrent incidence of CVD events in participants with CKD. We assessed 1051 out of 1936 participants in the Chronic Renal Insufficiency Cohort Study that were invited to have fundus photographs obtained at two timepoints separated by 3.5 years, on average. Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive or other) and vessel diameter calibre were assessed at a retinal image reading centre by trained graders masked to study participants’ information. Participants with a self-reported history of CVD were excluded. Incident CVD events were physician adjudicated using medical records and standardised criteria. Kidney function and proteinuria measurements along with CVD risk factors were obtained at study visits. Worsening of retinopathy by two or more steps in the EDTRS retinopathy grading scale was observed in 9.8% of participants, and was associated with increased risk of incidence of any CVD in analysis adjusting for other CVD and CKD risk factors (OR 2.56, 95% CI 1.25 to 5.22, p<0.01). After imputation of missing data, these values were OR=1.66 (0.87 to 3.16), p=0.12. Progression of retinopathy is associated with higher incidence of CVD events, and retinal-vascular pathology may be indicative of macrovascular disease even after adjustment for kidney diseases and CVD risk factors. Assessment of retinal morphology may provide important information when assessing CVD in patients with CKD.
Authors: Grunwald JE; Go AS; CRIC Study investigators; et al.
Br J Ophthalmol. 2021 02;105(2):246-252. Epub 2020-06-05.
Research Priorities in Atrial Fibrillation Screening: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop
Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute’s virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.
Authors: Benjamin, Emelia J; Go, Alan S; Al-Khatib, Sana M; et al.
Circulation. 2021 01 26;143(4):372-388. Epub 2021-01-25.
The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change
In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.
Authors: Oni-Orisan A; Haldar T; Ranatunga DK; Medina MW; Schaefer C; Krauss RM; Iribarren C; Risch N; Hoffmann TJ
NPJ Genom Med. 2020 Jan 16;5(1):1. Epub 2020-01-16.
Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits
Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
Authors: Sun, Daokun; Sims, Mario; Fornage, Myriam; et al.
HGG Adv. 2021 Jan 14;2(1). Epub 2020-10-31.
Hyponatremia, Inflammation at Admission, and Mortality in Hospitalized COVID-19 Patients: A Prospective Cohort Study
Background: Systemic inflammation has been associated with severe coronavirus disease 2019 (COVID-19) disease and mortality. Hyponatremia can result from inflammation due to non-osmotic stimuli for vasopressin production. Methods: We prospectively studied 799 patients hospitalized with COVID-19 between March 7 and November 7, 2020, at Hospital Posadas in Buenos Aires, Argentina in order to evaluate the association between hyponatremia, inflammation, and its impact on clinical outcomes. Admission biochemistries, high-sensitivity C-reactive protein (hsCRP), ferritin, patient demographics, and outcome data were recorded. Outcomes (within 30 days after symptoms) evaluated included ICU admission, mechanical ventilation, dialysis-requiring acute kidney injury (AKI), and in-hospital mortality. Length of hospital stay (in days) were evaluated using comprehensive data from the EHR. Results: Hyponatremia (median Na = 133 mmol/L) was present on admission in 366 (45.8%). Hyponatremic patients had higher hsCRP (median 10.3 [IR 4.8-18.4] mg/dl vs. 6.6 [IR 1.6-14.0] mg/dl, p < 0.01) and ferritin levels (median 649 [IQR 492-1,168] ng/dl vs. 393 [IQR 156-1,440] ng/dl, p = 0.02) than normonatremic patients. Hyponatremia was associated with higher odds of an abnormal hsCRP (unadjusted OR 5.03, 95%CI: 2.52-10.03), and remained significant after adjustment for potential confounders (adjusted OR 4.70 [95%CI: 2.33-9.49], p < 0.01). Hyponatremic patients had increased mortality on unadjusted (HR 3.05, 95%CI: 2.14-4.34) and adjusted (HR 2.76, 95%CI:1.88-4.06) in Cox proportional hazard models. Crude 30-day survival was lower for patients with hyponatremia at admission (mean [SD] survival 22.1 [0.70] days) compared with patients who were normonatremic (mean [SD] survival 27.2 [0.40] days, p < 0.01). Conclusion: Mild hyponatremia on admission is common, is associated with systemic inflammation and is an independent risk factor for hospital mortality. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT04493268.
Authors: Ayus, Juan Carlos; Negri, Armando Luis; Moritz, Michael L; Lee, Kyung Min; Caputo, Daniel; Borda, Maria Elena; Go, Alan S; Eghi, Carlos
Front Med (Lausanne). 2021;8:748364. Epub 2021-12-02.
Population-based identification and temporal trend of children with primary nephrotic syndrome: The Kaiser Permanente nephrotic syndrome study
Limited population-based data exist about children with primary nephrotic syndrome (NS). We identified a cohort of children with primary NS receiving care in Kaiser Permanente Northern California, an integrated healthcare delivery system caring for >750,000 children. We identified all children <18 years between 1996 and 2012 who had nephrotic range proteinuria (urine ACR>3500 mg/g, urine PCR>3.5 mg/mg, 24-hour urine protein>3500 mg or urine dipstick>300 mg/dL) in laboratory databases or a diagnosis of NS in electronic health records. Nephrologists reviewed health records for clinical presentation and laboratory and biopsy results to confirm primary NS. Among 365 cases of confirmed NS, 179 had confirmed primary NS attributed to presumed minimal change disease (MCD) (72%), focal segmental glomerulosclerosis (FSGS) (23%) or membranous nephropathy (MN) (5%). The overall incidence of primary NS was 1.47 (95% Confidence Interval:1.27-1.70) per 100,000 person-years. Biopsy data were available in 40% of cases. Median age for patients with primary NS was 6.9 (interquartile range:3.7 to 12.9) years, 43% were female and 26% were white, 13% black, 17% Asian/Pacific Islander, and 32% Hispanic. This population-based identification of children with primary NS leveraging electronic health records can provide a unique approach and platform for describing the natural history of NS and identifying determinants of outcomes in children with primary NS.
Authors: Parikh, Rishi V; Zheng, Sijie; Go, Alan S; et al.
PLoS One. 2021;16(10):e0257674. Epub 2021-10-14.
Pre-Statistical Considerations for Harmonization of Cognitive Instruments: Harmonization of ARIC, CARDIA, CHS, FHS, MESA, and NOMAS
Meta-analyses of individuals’ cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear. To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study. We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item’s administration and scoring procedures, and score distributions. We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences. Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies.
Authors: Brice�o, Emily M; Hingtgen, Stephanie; Levine, Deborah A; et al.
J Alzheimers Dis. 2021;83(4):1803-1813.
The presence of emphysema on chest imaging and mid-life cognition
Airflow obstruction is associated with cognitive dysfunction but studies have not assessed how emphysema, a structural phenotype of lung disease, might be associated with cognitive function independent from pulmonary function measured by spirometry. We aimed to determine the relationship between the presence of visually detectable emphysema on chest computed tomography (CT) imaging and cognitive function. We examined 2491 participants, mean age of 50 years, from the Coronary Artery Risk Development in Young Adults study who were assessed for the presence of emphysema on chest CT imaging and had cognitive function measured 5 years later with a battery of six cognitive tests. Of those assessed, 172 (7%) had emphysema. After adjusting for age, sex, height, study centre, race, body mass index, education and smoking, visual emphysema was significantly associated with worse performance on most cognitive tests. Compared to those without emphysema, participants with emphysema performed worse on cognitive testing: 0.39 sd units lower (95% CI -0.53- -0.25) on the Montreal Cognitive Assessment, 0.27 sd units lower (95% CI -0.42- -0.12) on the Rey Auditory Verbal Learning Test, 0.29 sd units lower (95% CI -0.43- -0.14) on the Digit Symbol Substitution Test and 0.25 sd units lower (95% CI -0.42- -0.09) on letter fluency. Further adjustment for forced expiratory volume in 1 s (FEV1), peak FEV1 and annualised FEV1 decline did not attenuate these associations. The presence of emphysema on chest CT is associated with worse cognitive function, independent of airflow obstruction. These data suggest that emphysema may be a novel risk factor for cognitive impairment.
Authors: Henkle, Benjamin E; Thyagarajan, Bharat; Kunisaki, Ken M; et al.
ERJ Open Res. 2021 Jan;7(1). Epub 2021-03-15.
Understanding the Uptake of Digital Technologies for Health-Related Purposes in Frail Older Adults
Authors: Lee, David R; Lo, Joan C; Ramalingam, Nirmala; Gordon, Nancy P
J Am Geriatr Soc. 2021 01;69(1):269-272. Epub 2020-10-03.
The Degree of the Predischarge Pulmonary Congestion in Patients Hospitalized for Worsening Heart Failure Predicts Readmission and Mortality
Prediction of readmission and death after hospitalization for heart failure (HF) is an unmet need. We evaluated the ability of clinical parameters, NT-proBNP level and noninvasive lung impedance (LI), to predict time to readmission (TTR) and time to death (TTD). The present study is a post hoc analysis of the IMPEDANCE-HF extended trial comprising 290 patients with LVEF ≤45% and New York Heart Association functional class II-IV, randomized 1:1 to LI-guided or conventional therapy. Of all patients, 206 were admitted 766 times for HF during a follow-up of 57 ± 39 months. The normal LI (NLI), representing the “dry” lung status, was calculated for each patient at study entry. The current degree of pulmonary congestion (PC) compared with its dry status was represented by ΔLIR = ([measured LI/NLI] – 1) × 100%. Twenty-six parameters recorded during HF admission were used to predict TTR and TTD. To determine the parameter which mainly impacted TTR and TTD, variables were standardized, and effect size (ES) was calculated. Multivariate analysis by the Andersen-Gill model demonstrated that ΔLIRadmission (ES = 0.72), ΔLIRdischarge (ES = -3.14), group assignment (ES = 0.2), maximal troponin during HF admission (ES = 0.19), LVEF related to admission (ES = -0.22) and arterial hypertension (ES = 0.12) are independent predictors of TTR (p < 0.01, χ2 = 1,206). Analysis of ES showed that residual PC assessed by ∆LIRdischarge was the most prominent predictor of TTR. One percent improvement in predischarge PC, assessed by ∆LIRdischarge, was associated with a likelihood of TTR increase by 14% (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.13-1.15, p < 0.01) and TTD increase by 8% (HR 1.08, 95% CI 1.07-1.09, p < 0.01). The degree of predischarge PC assessed by ∆LIR is the most dominant predictor of TTR and TTD.
Authors: Kleiner-Shochat, Michael; Kapustin, Daniel; Fudim, Marat; Ambrosy, Andrew P; Glantz, Juliya; Kazatsker, Mark; Kleiner, Ilia; Weinstein, Jean Marc; Panjrath, Gurusher; Roguin, Ariel; Meisel, Simcha R
Cardiology. 2021;146(1):49-59. Epub 2020-10-28.
Relationships of Inflammation Trajectories with White Matter Volume and Integrity in Midlife
Elevated inflammation is associated with worse late-life cognitive functioning and brain health. Our goal was to examine the relationship between inflammation trajectories and white matter integrity in midlife. Participants were 508 adults from the Coronary Artery Risk Development in Young Adults Study (CARDIA; 51% female). Latent class analysis was used to identify inflammation trajectories based on repeated measures of the inflammatory marker C-reactive protein (CRP) over the 18 years before brain magnetic resonance imaging (MRI). Outcomes were brain MRI measures of total and region-specific white matter volume and integrity at a mean age of 50.6 ± 3.4 years. Linear regression was used to examine if inflammation trajectories were associated with brain MRI outcomes, adjusting for potential confounds in all models and for disease and health behaviors in follow-up models. Lower-stable (38%), moderate-increasing (7%), and consistently-higher (54%), trajectories emerged. Compared to the lower-stable group, the moderate-increasing group showed lower white matter volume (β = -0.18, 95% CI -0.29, -0.06) and worse white matter integrity as indexed by lower fractional anisotropy (FA; β = -0.37, 95% CI -0.70, -0.04) and higher mean diffusivity (β = 0.44, 95% CI 0.11, 0.78) in the whole brain. The consistently-higher group showed lower whole-brain FA (β = -0.20, -0.38, -0.03). In exploratory analyses, the moderate-increasing group showed lower white matter volume, lower FA and higher MD in the frontal, temporal, and parietal lobes compared to the lower-stable group. The consistently-higher group showed lower white matter volume in the parietal lobe and lower FA in the frontal, temporal, and parietal lobes, but similar MD, compared to the lower-stable group. Findings for the moderate-increasing, but not the consistently-higher, group were robust to adjustment for disease and lifestyle factors. Increasing or high inflammation trajectories from early to mid adulthood are associated with worse brain health, as indexed by lower white matter volume and/or worse white matter integrity.
Authors: O'Donovan, Aoife; Bahorik, Amber; Sidney, Stephen; Launer, Lenore J; Yaffe, Kristine
Brain Behav Immun. 2021 01;91:81-88. Epub 2020-09-20.
Impact of idiopathic pulmonary fibrosis on longitudinal healthcare utilization in a community-based cohort of patients
Idiopathic pulmonary fibrosis (IPF) is a rare, chronic lung disease associated with substantial symptom burden, morbidity, and cost. Delivery of high-quality effective care in IPF requires understanding health-care resource utilization (HRU) patterns; however, longitudinal data from real-world populations are limited. This study aimed to define HRU attributable to IPF by evaluating a longitudinal cohort of community patients with IPF compared with matched control subjects. Incident IPF cases were identified in the Kaiser Permanente Northern California electronic health records (2000-2015) using case-validated code-based algorithms. IPF cases were compared with matched control subjects by age, sex, and length of enrollment. Annual rates of HRU measures were assessed during the 5 years pre- and postdiagnosis. Poisson generalized estimating equations were used to estimate adjusted case-control differences in HRU. IPF treatment trends were assessed before and after the availability of IPF-specific medications. A total of 691 IPF cases were identified and matched with 3,452 control subjects. Adjusted rates of all diagnostic procedures were significantly increased (P < .001) for IPF cases compared with control subjects in both the pre- and postindex periods, including chest CT scans (pre-relative risk [RR], 80.35; post-RR, 32.79), 6-min walk tests (pre-RR, 20.81; post-RR, 34.49), and pulmonary function tests (pre-RR, 9.50; post-RR, 13.24). All-cause hospitalizations (pre-RR, 1.42; post-RR, 2.33) and outpatient visits (pre-RR, 1.22; post-RR, 1.80) were significantly higher among cases compared with control subjects during both the preindex (P < .05) and postindex (P < .001) periods. We observed use of immunosuppressive and IPF-specific therapies prior to diagnosis, and high rates of corticosteroid use before and after diagnosis. This study defines a marked increase in HRU in patients with IPF compared with control subjects, with accelerated use beginning at least 1 year prediagnosis and elevated use sustained over the following 5 years. To our knowledge, this is the first study to evaluate longitudinal medication trends in IPF. Collectively, this information is foundational to advancing IPF care delivery models and supporting clinical decision-making.
Authors: Farrand E; Iribarren C; Vittinghoff E; Levine-Hall T; Ley B; Minowada G; Collard HR
Chest. 2021 01;159(1):219-227. Epub 2020-07-24.
Prospective Cohort Study of Renin-Angiotensin System Blocker Usage after Hospitalized Acute Kidney Injury
The risk-benefit ratio of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy after AKI may be altered due to concerns regarding recurrent AKI. We evaluated, in a prospective cohort, the association between use (versus nonuse) of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the subsequent risk of AKI and other adverse outcomes after hospitalizations with and without AKI. We studied 1538 patients recently discharged from the hospital who enrolled in the multicenter, prospective ASSESS-AKI study, with approximately half of patients experiencing AKI during the index hospitalization. All participants were seen at a baseline visit 3 months after their index hospitalization and were categorized at that time on whether they were using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or not. We used multivariable Cox regression, adjusting for demographics, comorbidities, eGFR, urine protein-creatinine ratio, and use of other medications, to examine the association between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and subsequent risks of AKI, death, kidney disease progression, and adjudicated heart-failure events. The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 50% (386/769) among those with AKI during the index hospitalization and 47% (362/769) among those without. Among those with AKI during the index hospitalization, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was not associated with a higher risk of recurrent hospitalized AKI (adjusted hazard ratio, 0.88; 95% confidence interval, 0.69 to 1.13). Associations between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and death, kidney disease progression, and adjudicated heart-failure events appeared similar in study participants who did and did not experience AKI during the index hospitalization (all interaction P values >0.05). The risk-benefit ratio of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy after hospital discharge appears to be similar regardless of whether AKI occurred during the hospitalization.
Authors: Brar, Sandeep; Go, Alan S; ASSESS-AKI Investigators,; et al.
Clin J Am Soc Nephrol. 2020 12 31;16(1):26-36. Epub 2020-12-03.
Response by Flint et al to Letter Regarding Article, “Risk of Distal Embolization From tPA (Tissue-Type Plasminogen Activator) Administration Prior to Endovascular Stroke Treatment”
Authors: Flint AC; Avins AL; Nguyen-Huynh MN
Stroke. 2021 Jan;52(1):e39-e40. Epub 2020-12-28.
Cerebral small vessel disease genomics and its implications across the lifespan
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
Authors: Sargurupremraj, Muralidharan; Turner, Stephen T; Debette, Stéphanie; et al.
Nat Commun. 2020 12 08;11(1):6285. Epub 2020-12-08.
Guidance to Reduce the Cardiovascular Burden of Ambient Air Pollutants: A Policy Statement From the American Heart Association
In 2010, the American Heart Association published a statement concluding that the existing scientific evidence was consistent with a causal relationship between exposure to fine particulate matter and cardiovascular morbidity and mortality, and that fine particulate matter exposure is a modifiable cardiovascular risk factor. Since the publication of that statement, evidence linking air pollution exposure to cardiovascular health has continued to accumulate and the biological processes underlying these effects have become better understood. This increasingly persuasive evidence necessitates policies to reduce harmful exposures and the need to act even as the scientific evidence base continues to evolve. Policy options to mitigate the adverse health impacts of air pollutants must include the reduction of emissions through action on air quality, vehicle emissions, and renewable portfolio standards, taking into account racial, ethnic, and economic inequality in air pollutant exposure. Policy interventions to improve air quality can also be in alignment with policies that benefit community and transportation infrastructure, sustainable food systems, reduction in climate forcing agents, and reduction in wildfires. The health care sector has a leadership role in adopting policies to contribute to improved environmental air quality as well. There is also potentially significant private sector leadership and industry innovation occurring in the absence of and in addition to public policy action, demonstrating the important role of public-private partnerships. In addition to supporting education and research in this area, the American Heart Association has an important leadership role to encourage and support public policies, private sector innovation, and public-private partnerships to reduce the adverse impact of air pollution on current and future cardiovascular health in the United States.
Authors: Kaufman, Joel D; Burroughs Peña, Melissa S; American Heart Association Advocacy Coordinating Committee,; et al.
Circulation. 2020 12 08;142(23):e432-e447. Epub 2020-11-05.
Risk of complete atypical femur fracture with Oral bisphosphonate exposure beyond three years
Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). However, the threshold of treatment duration leading to increased AFF risk is unclear. In a retrospective cohort of older women initiating BP, we compared the AFF risk associated with treatment for at least three years to the risk associated with treatment less than three years. We used observational data from a large population of female members of an integrated healthcare system who initiated oral BP during 2002-2014. Women were retrospectively followed for incident AFF confirmed by radiologic adjudication. Demographic data, pharmacologic exposures, comorbidity, bone density, and fracture history were ascertained from electronic health records. Inverse probability weighting was used to estimate risk differences comparing the cumulative incidence (risk) of AFF if women discontinued BP within three years to the cumulative incidence of AFF if women continued BP for three or more years, adjusting for potential time-dependent confounding by the aforementioned factors. Among 87,820 women age 45-84 years who initiated BP (mean age 68.6, median T-score - 2.6, 14% with prior major osteoporotic fracture), 16,180 continued BP for three or more years. Forty-six confirmed AFFs occurred during follow-up in the two groups. AFF-free survival was greater for BP treatment < 3 years compared to treatment ≥3 years (p = 0.004 comparing areas under survival curves). At five years, the risk of AFF was 27 per 100,000 (95% confidence interval, CI: 8-46) if women received BP treatment < 3 years and 120 per 100,000 (95% CI: 56-183) if women received BP treatment ≥3 years (risk difference 93 per 100,000, 95% CI: 30-160). By ten years, the risks were 27 (95% CI: 8-46) and 363 (95% CI: 132-593) per 100,000 for BP treatment < 3 and ≥ 3 years, respectively (risk difference 336 per 100,000, 95% CI: 110-570). Bisphosphonate treatment for 3 or more years was associated with greater risk of AFF than treatment for less than 3 years. Although AFFs are uncommon among BP-treated women, this increased risk should be considered when counseling women about long-term BP use. Future studies should further characterize the dose-response relationship between BP duration and incident AFF and identify patients at highest risk.
Authors: Lo, Joan C; Neugebauer, Romain S; Ettinger, Bruce; Chandra, Malini; Hui, Rita L; Ott, Susan M; Grimsrud, Christopher D; Izano, Monika A
BMC Musculoskelet Disord. 2020 Dec 03;21(1):801. Epub 2020-12-03.
Validation Study of Kaiser Permanente Bedside Dysphagia Screening Tool in Acute Stroke Patients
Dysphagia occurs in up to 50% of patients with acute stroke symptoms, resulting in increased aspiration pneumonia rates and mortality. The purpose of this study was to validate a health system’s dysphagia (swallow) screening tool used since 2007 on all patients with suspected stroke symptoms. Annual rates of aspiration pneumonia for ischemic stroke patients have ranged from 2% to 3% since 2007. From August 17, 2015 through September 30, 2015, a bedside dysphagia screening was prospectively performed by 2 nurses who were blinded to all patients age 18 years or older admitted through the emergency department with suspected stroke symptoms at 21 Joint Commission accredited primary stroke centers in an integrated health system. The tool consists of 3 parts: pertinent history, focused physical examination, and progressive testing from ice chips to 90 mL of water. A speech language pathologist blinded to the nurse’s screening results performed a formal swallow evaluation on the same patient. The end study population was 379 patients. Interrater reliability between 2 nurses of the dysphagia screening was excellent at 93.7% agreement (Ƙ = 0.83). When the dysphagia screenings were compared with the gold standard speech language pathologist professional swallow evaluation, the tool demonstrated both high sensitivity (86.4%; 95% confidence interval = 73.3-93.6) and high negative predictive value (93.8%; 95% confidence interval = 87.2-97.1). This tool is highly reliable and valid. The dysphagia screening tool requires minimal training and is easily administered in a timely manner.
Authors: Finnegan, Barbara Schumacher; Meighan, Melissa M; Warren, Noelani C; Hatfield, Meghan K; Alexeeff, Stacey; Lipiz, Jorge; Nguyen-Huynh, Mai
Perm J. 2020 12;24:1.
Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women
Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], -2.2 per 1000 individuals; 95% CI, -20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, -7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, -9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.
Authors: Izano, Monika A; Lo, Joan C; Adams, Annette L; Ettinger, Bruce; Ott, Susan M; Chandra, Malini; Hui, Rita L; Niu, Fang; Li, Bonnie H; Neugebauer, Romain S
JAMA Netw Open. 2020 12 01;3(12):e2025190. Epub 2020-12-01.
Cancer and Cardiovascular Risk in Women With Hypertensive Disorders of Pregnancy Carrying a Common IGF1R Variant
To evaluate the impact of insulin-like growth factor 1 receptor variant rs2016347 on the risk for breast and nonbreast cancers and cardiovascular disease in women with a history of hypertensive disorders of pregnancy (HDP). This retrospective cohort study included all parous women in the UK Biobank with prior rs2016347 genotyping (N=204,155), with enrollment taking place from March 2006 to July 2010. History of HDP was self-reported, and outcomes included breast and all nonbreast cancers, hospital diagnoses of hypertension and cardiovascular disease, and direct blood pressure measurements. Women with previous HDP had a higher risk for future hypertension and cardiovascular diagnoses, increased blood pressures, and lower risk for breast cancer compared with women without HDP, consistent with prior studies. Hazard ratios for all nonbreast cancers were unchanged. However, when taking genotype into account, HDP-positive women carrying at least 1 thymine (T) allele of rs2016347 had a lower risk for nonbreast cancer (hazard ratio, 0.59; 95% CI, 0.37 to 0.92; P=.02) and lower systolic blood pressure (-2.08±0.98 mm Hg; P=.03) compared with women with the guanine/guanine (GG) genotype with positive evidence of interaction (HDP:T allele) for both outcomes; P=.04 and P=.03, respectively. Women who experience HDP and carry a T allele of rs2016347 have 41% lower risk for developing nonbreast cancer and a lower systolic blood pressure of 2.08 mm Hg when compared with those with the GG genotype, suggesting a possible role of the insulin-like growth factor 1 axis for both cardiovascular and cancer risk in women with HDP.
Authors: Powell, Mark J; Dufault, Suzanne M; Gunderson, Erica P; Benz, Christopher C
Mayo Clin Proc. 2020 12;95(12):2684-2696. Epub 2020-11-06.
Implication of Trends in Timing of Dialysis Initiation for Incidence of End-stage Kidney Disease
In the last 2 decades, there have been notable changes in the level of estimated glomerular filtration rate (eGFR) at which patients initiate long-term dialysis in the US and around the world. How changes over time in the likelihood of dialysis initiation at any given eGFR level in at-risk patients are associated with the population burden of end-stage kidney disease (ESKD) has not been not well defined. To examine temporal trends in long-term dialysis initiation by level of eGFR and to quantify how these patterns are associated with the number of patients with ESKD. Retrospective cohort study analyzing data obtained from a large, integrated health care delivery system in Northern California from 2001 to 2018 in successive 3-year intervals. Included individuals, ranging in number from as few as 983 122 (2001-2003) to as many as 1 844 317 (2016-2018), were adult members with 1 or more outpatient serum creatinine levels determined in the prior year. One-year risk of initiating long-term dialysis stratified by eGFR levels. Multivariable logistic regression was performed to assess temporal trends in each 3-year cohort with adjustment for age, sex, race, and diabetes status. The potential change in dialysis initiation in the final cohort (2016-2018) was estimated using the relative difference between the standardized risks in the initial cohort (2001-2003) and the final cohort. In the initial 3-year cohort, the mean (SD) age was 55.4 (16.3) years, 55.0% were women, and the prevalence of diabetes was 14.9%. These characteristics, as well as the distribution of index eGFR, were stable across the study period. The likelihood of receiving dialysis at eGFR levels of 10 to 24 mL/min/1.73 m2 generally increased over time. For example, the 1-year odds of initiating dialysis increased for every 3-year interval by 5.2% (adjusted odds ratio, 1.052; 95% CI, 1.004-1.102) among adults with an index eGFR of 20 to 24 mL/min/1.73 m2, by 6.6% (adjusted odds ratio, 1.066; 95% CI, 1.007-1.130) among adults with an eGFR of 16 to 17 mL/min/1.73 m2, and by 5.3% (adjusted odds ratio, 1.053; 95% CI, 1.008-1.100) among adults with an eGFR of 10 to 13 mL/min/1.73 m2, adjusting for age, sex, race, and diabetes. The incidence of new cases of ESKD was estimated to have potentially been 16% (95% CI, 13%-18%) lower if there were no changes in system-level practice patterns or other factors besides timing of initiating long-term dialysis from the initial 3-year interval (2001-2003) to the final interval (2016-2018) assessed in this study. The present results underscore the importance the timing of initiating long-term dialysis has on the size of the population of individuals with ESKD.
Authors: Hsu, Chi-Yuan; Parikh, Rishi V; Pravoverov, Leonid N; Zheng, Sijie; Glidden, David V; Tan, Thida C; Go, Alan S
JAMA Intern Med. 2020 12 01;180(12):1647-1654.
Hospitalizations for Heart Failure and Mortality Risk During the Evolving Coronavirus Disease 2019 Pandemic – The Wave May Break but A Dangerous Undertow Persists
Authors: Wagner, Jeffrey R; Ambrosy, Andrew P
Eur J Heart Fail. 2020 12;22(12):2225-2227. Epub 2020-11-16.
Association of negative financial shocks during the Great Recession with depressive symptoms and substance use in the USA: the CARDIA study
The Great Recession of 2008 was marked by large increases in unemployment and decreases in the household wealth of many Americans. In the 21st century, there have also been increases in depressive symptoms, alcohol use and drug use among some groups in the USA. The objective of this analysis is to evaluate the influence of negative financial shocks incurred during the Great Recession on depressive symptoms, alcohol and drug use. We employed a quasi-experimental fixed-effects design, using data from adults enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Our financial shock predictors were within-person change in employment status, income and debt to asset ratio between 2005 and 2010. Our outcomes were within-person change in depressive symptoms score, alcohol use and past 30-day drug use. In adjusted models, we found that becoming unemployed and experiencing a drop in income and were associated with an increase in depressive symptoms. Incurring more debts than assets was also associated with an increase in depressive symptoms and a slight decrease in daily alcohol consumption (mL). Our findings suggest that multiple types of financial shocks incurred during an economic recession negatively influence depressive symptoms among black and white adults in the USA, and highlight the need for future research on how economic recessions are associated with health.
Authors: Swift, Samuel Longworth; Elfassy, Tali; Bailey, Zinzi; Florez, Hermes; Feaster, Daniel J; Calonico, Sebastian; Sidney, Steve; Kiefe, Catarina I; Zeki Al Hazzouri, Adina
J Epidemiol Community Health. 2020 12;74(12):995-1001. Epub 2020-08-11.
Incident frailty and cognitive impairment by heart failure status in older patients with atrial fibrillation: the SAGE-AF study
Atrial fibrillation (AF) and heart failure (HF) frequently co-occur in older individuals. Among patients with AF, HF increases risks for stroke and death, but the associations between HF and incident cognition and physical impairment remain unknown. We aimed to examine the cross-sectional and prospective associations between HF, cognition, and frailty among older patients with AF. The SAGE-AF (Systematic Assessment of Geriatric Elements in AF) study enrolled 1244 patients with AF (mean age 76 years, 48% women) from five practices in Massachusetts and Georgia. HF at baseline was identified from electronic health records using ICD-9/10 codes. At baseline and 1-year, frailty was assessed by Cardiovascular Health Survey score and cognition was assessed by the Montreal Cognitive Assessment. Patients with prevalent HF (n = 463, 37.2%) were older, less likely to be non-Hispanic white, had less education, and had greater cardiovascular comorbidity burden and higher CHA2DS2VASC and HAS-BLED scores than patients without HF (all P’s < 0.01). In multivariable adjusted regression models, HF (present vs. absent) was associated with both prevalent frailty (adjusted odds ratio [aOR]: 2.38, 95% confidence interval [CI]: 1.64-3.46) and incident frailty at 1 year (aOR: 2.48, 95% CI: 1.37-4.51). HF was also independently associated with baseline cognitive impairment (aOR: 1.60, 95% CI: 1.22-2.11), but not with developing cognitive impairment at 1 year (aOR 1.04, 95%CI: 0.64-1.70). Among ambulatory older patients with AF, the co-existence of HF identifies individuals with physical and cognitive impairments who are at higher short-term risk for becoming frail. Preventive strategies to this vulnerable subgroup merit consideration.
Authors: Wang, Wei-Jia; Lessard, Darleen; Saczynski, Jane; Goldberg, Robert J; Go, Alan S; Paul, Tenes; Gracia, Ely; McManus, David D
J Geriatr Cardiol. 2020 Nov 28;17(11):653-658.
Association of tubular solute clearances with the glomerular filtration rate and complications of chronic kidney disease: the Chronic Renal Insufficiency Cohort study
The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. The degree to which secretory solute clearance corresponds with the glomerular filtration rate (GFR) and potential metabolic implications of net secretory clearance are largely unknown. We evaluated 1240 participants with chronic kidney disease (CKD) from the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used targeted mass-spectrometry to quantify candidate secretory solutes in paired 24-h urine and plasma samples. CRIC study personnel measured GFR using 125I-iothalamate clearance (iGFR). We used correlation and linear regression to determine cross-sectional associations of secretory clearances with iGFR and common metabolic complications of CKD. Correlations between iGFR and secretory solute clearances ranged from ρ = +0.30 for hippurate to ρ = +0.58 for kynurenic acid. Lower net clearances of most secretory solutes were associated with higher serum concentrations of parathyroid hormone (PTH), triglycerides and uric acid. Each 50% lower kynurenic acid clearance was associated with a 21% higher serum PTH concentration [95% confidence interval (CI) 15-26%] and a 10% higher serum triglyceride concentration (95% CI 5-16%) after adjustment for iGFR, albuminuria and other potential confounders. Secretory solute clearances were not associated with statistically or clinically meaningful differences in serum calcium, phosphate, hemoglobin or bicarbonate concentrations. Tubular secretory clearances are modestly correlated with measured GFR among adult patients with CKD. Lower net secretory clearances are associated with selected metabolic complications independent of GFR and albuminuria, suggesting potential clinical and biological relevance.
Authors: Chen, Yan; Go, Alan S; CRIC Study Investigators,; et al.
Nephrol Dial Transplant. 2020 Nov 17.
Cardiac Biomarkers and Risk of Mortality in CKD (the CRIC Study)
Cardiovascular disease (CVD) is the leading cause of mortality among individuals with chronic kidney disease (CKD). Cardiac biomarkers of myocardial distention, injury, and inflammation may signal unique pathways underlying CVD in CKD. In this analysis, we studied the association of baseline levels and changes in 4 traditional and novel cardiac biomarkers with risk of all-cause, CV, and non-CV mortality in a large cohort of patients with CKD. Among 3664 adults with CKD enrolled in the Chronic Renal Insufficiency Cohort Study, we conducted a cohort study to examine the associations of baseline levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac high-sensitivity troponin T (hsTnT), growth differentiation factor-15 (GDF-15), and soluble ST-2 (sST-2) with risks of all-cause and cardiovascular (CV) mortality. Among a subcohort of 842 participants, we further examined the associations between change in biomarker levels over 2 years with risk of all-cause mortality. We used Cox proportional hazards regression models and adjusted for demographics, kidney function measures, cardiovascular risk factors, and medication use. After adjustment, elevated baseline levels of each cardiac biomarker were associated with increased risk of all-cause mortality: NT-proBNP (hazard ratio [HR] = 1.92, 95% confidence interval [CI] = 1.73-2.12); hsTnT (HR = 1.62, 95% CI = 1.48, 1.78]); GDF-15 (HR = 1.61, 95% CI = 1.46-1.78]); and sST-2 (HR = 1.26, CI = 1.16-1.37). Higher baseline levels of all 4 cardiac biomarkers were also associated with increased risk of CV. Declines in NT-proBNP (adjusted HR = 0.55, 95% CI = 0.36-0.86) and sST2 (HR = 0.55, 95% CI = 0.36-0.86]) over 2 years were associated with lower risk of all-cause mortality. In a large cohort of CKD participants, elevations of NT-proBNP, hsTnT, GDF-15, and sST-2 were independently associated with greater risks of all-cause and CV mortality.
Authors: Wang, Ke; Go, Alan; CRIC Study Investigators,; et al.
Kidney Int Rep. 2020 Nov;5(11):2002-2012. Epub 2020-09-10.
Interventions Targeting Racial/Ethnic Disparities in Stroke Prevention and Treatment
Systemic racism is a public health crisis. Systemic racism and racial/ethnic injustice produce racial/ethnic disparities in health care and health. Substantial racial/ethnic disparities in stroke care and health exist and result predominantly from unequal treatment. This special report aims to summarize selected interventions to reduce racial/ethnic disparities in stroke prevention and treatment. It reviews the social determinants of health and the determinants of racial/ethnic disparities in care. It provides a focused summary of selected interventions aimed at reducing stroke risk factors, increasing awareness of stroke symptoms, and improving access to care for stroke because these interventions hold the promise of reducing racial/ethnic disparities in stroke death rates. It also discusses knowledge gaps and future directions.
Authors: Levine, Deborah A; Duncan, Pamela W; Nguyen-Huynh, Mai N; Ogedegbe, Olugbenga G
Stroke. 2020 11;51(11):3425-3432. Epub 2020-10-26.
Bone Mineral Density in Older U.S. Filipino, Chinese, Japanese, and White Women
Bone mineral density (BMD) reference data exist for U.S. White, Black, and Hispanic (Mexican American) populations but not for U.S. Asians. Few studies have compared BMD findings among different U.S. Asian ethnicities. Retrospective observational study. Large northern California healthcare system. Asian and White women aged 50 to 79 years with BMD testing from 1998 to 2017 excluding those with estrogen or osteoporosis treatment, recent fracture, or select disorders affecting skeletal health. Femoral neck (FN)-BMD and height data. Differences in FN-BMD were examined by ethnicity and age, comparing Filipino, Chinese, and Japanese women and non-Hispanic White women. Differences in BMD were also examined after adjustment for height. There were 37,224 Asian women (including 11,147 Filipino, 10,648 Chinese, and 2,519 Japanese) and 115,318 non-Hispanic White women. Mean height was similar among the Asian subgroups and about 6 to 8 cm lower than Whites. Mean FN-BMDs differed by less than 3% for Filipino, Chinese, and Japanese and all were lower than Whites, with smaller Asian-White differences among younger women (<3%; ages 50-59) and larger differences among older women (6-8%; ages 65-79). Adjusting FN-BMD for height reduced White-Asian differences by about 30% to 40%. Mean FN-BMD and height for Filipino, Chinese, and Japanese women were similar but consistently lower than White women, especially among older women. Although Asian-White BMD differences were substantially attenuated after height adjustment; some differences persisted for older women. Future studies should investigate potential age-cohort effects and the extent to which these BMD differences influence fracture risk and clinical care.
Authors: Lo, Joan C; Chandra, Malini; Lee, Catherine; Darbinian, Jeanne A; Ramaswamy, Mohan; Ettinger, Bruce
J Am Geriatr Soc. 2020 11;68(11):2656-2661. Epub 2020-10-12.
Sociopolitical stress and acute cardiovascular disease hospitalizations around the 2016 presidential election
Previous research suggests that stressors may trigger the onset of acute cardiovascular disease (CVD) events within hours to days, but there has been limited research around sociopolitical events such as presidential elections. Among adults ≥18 y of age in Kaiser Permanente Southern California, hospitalization rates for acute CVD were compared in the time period immediately prior to and following the 2016 presidential election date. Hospitalization for CVD was defined as an inpatient or emergency department discharge diagnosis of acute myocardial infarction (AMI) or stroke using International Classification of Diseases, 10th revision codes. Rate ratios (RR) and 95% confidence intervals (CIs) were calculated comparing CVD rates in the 2 d following the 2016 election to rates in the same 2 d of the prior week. In a secondary analysis, AMI and stroke were analyzed separately. The rate of CVD events in the 2 d after the 2016 presidential election (573.14 per 100,000 person-years [PY]) compared to the rate in the window prior to the 2016 election (353.75 per 100,000 PY) was 1.62 times higher (95% CI 1.17, 2.25). Results were similar across sex, age, and race/ethnicity groups. The RRs were similar for AMI (RR 1.67, 95% CI 1.00, 2.76) and stroke (RR 1.59, 95% CI 1.03, 2.44) separately. Transiently heightened cardiovascular risk around the 2016 election may be attributable to sociopolitical stress. Further research is needed to understand the intersection between major sociopolitical events, perceived stress, and acute CVD events.
Authors: Mefford, Matthew T; Sloan, Richard P; Williams, David R; et al.
Proc Natl Acad Sci U S A. 2020 10 27;117(43):27054-27058. Epub 2020-10-12.
Decline in kidney function over the course of adulthood and cognitive function in midlife
To test the hypothesis that end-stage renal disease (ESRD) risk exposure during young adulthood is related to worse cognitive performance in midlife. We included 2,604 participants from the population-based Coronary Artery Risk Development in Young Adults (CARDIA) Study (mean age 35 years, 54% women, 45% Black). Estimated glomerular filtration rate and albumin-to-creatinine ratio were measured every 5 years at year (Y) 10 through Y30. At each visit, moderate/high risk of ESRD according to the Kidney Disease: Improving Global Outcomes guidelines (estimated glomerular filtration rate <60 mL/min/1.73 m2 or albumin-to-creatinine ratio >30 mg/g) was defined, totaled over examinations, and categorized into 0 episodes, 1 episode, and >1 episodes of ESRD risk. At Y30, participants underwent global and multidomain cognitive assessment. We used analysis of covariance to assess the association of ESRD risk categories with cognitive function, controlling for cardiovascular risk factors. Over the course of 20 years, 427 participants (16% of the study population) had ≥1 episodes of ESRD risk exposure. Individuals with more risk episodes had lower composite cognitive function (p < 0.001), psychomotor speed (p < 0.001), and executive function (p = 0.007). All these associations were independent of sociodemographic status and cardiovascular risk factors. In this population-based longitudinal study, we show that episodes of decline in kidney function over the young-adulthood course are associated with worse cognitive performance at midlife. Preserving kidney function in young age needs to be investigated as a potential strategy to preserve cognitive function in midlife.
Authors: Sedaghat, Sanaz; Sorond, Farzaneh; Yaffe, Kristine; Sidney, Stephen; Kramer, Holly J; Jacobs, David R; Launer, Lenore J; Carnethon, Mercedes R
Neurology. 2020 10 27;95(17):e2389-e2397. Epub 2020-09-02.
Baseline Functional Capacity and Transcatheter Mitral Valve Repair in Heart Failure With Secondary Mitral Regurgitation
The aim of this study was to determine the prognostic utility of baseline functional status and its impact on the outcomes of transcatheter mitral valve repair (TMVr) in patients with heart failure (HF) with secondary mitral regurgitation (SMR). The COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial demonstrated that TMVr with the MitraClip in patients with HF with moderate to severe or severe SMR improved health-related quality of life. The clinical utility of a baseline assessment of functional status for evaluating prognosis and identifying candidates likely to derive a robust benefit from TMVr has not been previously studied in patients with HF with SMR. The COAPT study was a multicenter, randomized, controlled, parallel-group, open-label trial of TMVr with the MitraClip plus guideline-directed medical therapy (GDMT) versus GDMT alone in patients with HF, left ventricular ejection fraction 20% to 50%, and moderate to severe or severe SMR. Baseline functional status was assessed by 6-min walk distance (6MWD). Patients with 6MWD less than the median (240 m) were older, were more likely to be female, and had more comorbidities. After multivariate modeling, age (p = 0.005), baseline hemoglobin (p = 0.007), and New York Heart Association functional class III/IV symptoms (p < 0.0001) were independent clinical predictors of 6MWD. Patients with 6MWD <240 m versus ≥240 m had a higher unadjusted and adjusted rate of the 2-year composite of all-cause death or HF hospitalization (64.4% vs. 48.6%; adjusted hazard ratio: 1.53; 95% confidence interval: 1.19 to 1.98; p = 0.001). However, there was no interaction between baseline 6MWD and the relative effectiveness of TMVr plus GDMT versus GDMT alone with respect to the composite endpoint (p = 0.633). Baseline assessment of functional capacity by 6MWD was a powerful discriminator of prognosis in patients with HF with SMR. TMVr with the MitraClip provided substantial improvements in clinical outcomes for this population irrespective of baseline functional capacity.
Authors: Malik, Umar I; Ambrosy, Andrew P; Stone, Gregg W; et al.
JACC Cardiovasc Interv. 2020 10 26;13(20):2331-2341.
Acute Kidney Injury and Risk of CKD and Hypertension after Pediatric Cardiac Surgery
The association of AKI after pediatric cardiac surgery with long-term CKD and hypertension development is unclear. The study objectives were to determine whether AKI after pediatric cardiac surgery is associated with incident CKD and hypertension. This was a prospective cohort study of children of 1 month to 18 years old who were undergoing cardiac surgery at two tertiary care centers (Canada, United States). Participants were recruited before cardiac surgery and were followed during hospitalization and at 3, 12, 24, 36, and 48 months after discharge. Exposures were postoperative AKI, based on the Kidney Disease Improving Global Outcomes (KDIGO) definition, and age <2 years old at surgery. Outcomes and measures were CKD (low eGFR or albuminuria for age) and hypertension (per the 2017 American Academy of Pediatrics guidelines) at follow-up, with the composite outcome of CKD or hypertension. Among 124 participants, 57 (46%) developed AKI. AKI versus non-AKI participants had a median (interquartile range) age of 8 (4.8-40.8) versus 46 (6.0-158.4) months, respectively, and higher preoperative eGFR. From the 3- to 48-month follow-up, the cohort prevalence of CKD was high (17%-20%); hypertension prevalence was also high (22%-30%). AKI was not significantly associated with the development of CKD throughout follow-up. AKI was associated with hypertension development at 12 months after discharge (adjusted relative risk, 2.16; 95% confidence interval, 1.18 to 3.95), but not at subsequent visits. Children aged <2 years old at surgery had a significantly higher prevalence of hypertension during follow-up than older children (40% versus 21% at 3-month follow-up; 32% versus 13% at 48-month follow-up). CKD and hypertension burden in the 4 years after pediatric cardiac surgery is high. Young age at surgery, but not AKI, is associated with their development.
Authors: Zappitelli, Michael; Go, Alan S; ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Investigators,; et al.
Clin J Am Soc Nephrol. 2020 10 07;15(10):1403-1412. Epub 2020-09-18.
Occupation versus environmental factors in hypersensitivity pneumonitis: population attributable fraction
Despite well-documented case series of hypersensitivity pneumonitis (HP), epidemiological data delineating relative contributions of risk factors are sparse. To address this, we estimated HP risk in a case-referent study of occupational and nonoccupational exposures. We recruited cases of HP by ICD-9 codes from an integrated healthcare delivery system (IHCDS) and a tertiary medical care centre. We drew referents, matched for age and sex, from the IHCDS. Participants underwent comprehensive, structured telephone interviews eliciting details of occupational and home environmental exposures. We employed a hierarchical analytic approach for data reduction based on the false discovery rate method within clusters of exposures. We measured lung function and selected biomarkers in a subset of participants. We used multivariate logistic regression to estimate exposure-associated odds ratios (ORs) and population attributable fractions (PAFs) for HP. We analysed data for 192 HP cases (148 IHCDS; 44 tertiary care) and 229 referents. Occupational exposures combined more than doubled the odds of developing HP (OR 2.67; 95% CI 1.73-4.14) with a PAF of 34% (95% CI 21-46%); nonoccupational bird exposure also doubled the HP odds (OR 2.02; 95% CI 1.13-3.60), with a PAF of 12% (3-21%). Lung function and selected biomarkers did not substantively modify the risk estimates on the basis of questionnaire data alone. In a case-referent approach evaluating HP risk, identifiable exposures accounted, on an epidemiological basis, for approximately two in three cases of disease; conversely, for one in three, the risk factors for disease remained elusive.
Authors: Barnes, Hayley; Olin, Anna-Carin; Torén, Kjell; McSharry, Charles; Donnelly, Iona; Lärstad, Mona; Iribarren, Carlos; Quinlan, Patricia; Blanc, Paul D
ERJ Open Res. 2020 Oct;6(4). Epub 2020-10-05.
The Heart Failure Readmission Intervention by Variable Early Follow-up (THRIVE) Study: A Pragmatic Randomized Trial
In-person clinic follow-up within 7 days after discharge from a heart failure hospitalization is associated with lower 30-day readmission. However, health systems and patients may find it difficult to complete an early postdischarge clinic visit, especially during the current pandemic. We evaluated the effect on 30-day readmission and death of follow-up within 7 days postdischarge guided by an initial structured nonphysician telephone visit compared with follow-up guided by an initial clinic visit with a physician. We conducted a pragmatic randomized trial in a large integrated healthcare delivery system. Adults being discharged home after hospitalization for heart failure were randomly assigned to either an initial telephone visit with a nurse or pharmacist to guide follow-up or an initial in-person clinic appointment with primary care physicians providing usual care within the first 7 days postdischarge. Telephone appointments included a structured protocol enabling medication titration, laboratory ordering, and booking urgent clinic visits as needed under physician supervision. Outcomes included 30-day readmissions and death and frequency and type of completed follow-up within 7 days of discharge. Among 2091 participants (mean age 78 years, 44% women), there were no significant differences in 30-day heart failure readmission (8.6% telephone, 10.6% clinic, P=0.11), all-cause readmission (18.8% telephone, 20.6% clinic, P=0.30), and all-cause death (4.0% telephone, 4.6% clinic, P=0.49). Completed 7-day follow-up was higher in 1027 patients randomized to telephone follow-up (92%) compared with 1064 patients assigned to physician clinic follow-up (79%, P<0.001). Overall frequency of clinic visits during the first 7 days postdischarge was lower in participants assigned to nonphysician telephone guided follow-up (48%) compared with physician clinic-guided follow-up (77%, P<0.001). Early, structured telephone follow-up after hospitalization for heart failure can increase 7-day follow-up and reduce in-person visits with comparable 30-day clinical outcomes within an integrated care delivery framework. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03524534.
Authors: Lee, Keane K; Thomas, Rachel C; Tan, Thida C; Leong, Thomas K; Steimle, Anthony; Go, Alan S
Circ Cardiovasc Qual Outcomes. 2020 10;13(10):e006553. Epub 2020-09-24.
Angiotensin-Neprilysin Inhibition in Black Americans: Data From the PIONEER-HF Trial
This study compared the efficacy and safety of sacubitril/valsartan to enalapril in Black and non-Black Americans with acute decompensated heart failure (ADHF). Black patients have a different response to treatment with angiotensin-converting enzyme inhibitors compared with other racial and ethnic groups. How Black patients with ADHF respond to sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is unclear. PIONEER-HF was a double-blind randomized clinical trial of sacubitril/valsartan versus enalapril in hospitalized patients with ADHF following hemodynamic stabilization. In a pre-specified subgroup analysis, we examined changes in N-terminal pro-B-type natriuretic peptide, clinical outcomes, and safety according to race. The study population, all enrolled in the United States, included 316 (36%) Black participants, 515 (58%) White participants, and 50 (5.7%) participants of other racial groups. The reduction in N-terminal pro-B-type natriuretic peptide concentration at weeks 4 and 8 was significantly greater with sacubitril/valsartan than enalapril in both Black (ratio of change with sacubitril/valsartan vs. enalapril: 0.71; 95% confidence interval [CI]: 0.58 to 0.88) and non-Black patients (ratio of change: 0.71; 95% CI: 0.61 to 0.83; interaction p = 1.00). Compared with enalapril, sacubitril/valsartan also reduced the pre-specified exploratory composite of cardiovascular death or HF rehospitalization in both Black (hazard ratio: 0.47; 95% CI: 0.24 to 0.93) and non-Black patients (hazard ratio: 0.65; 95% CI: 0.40 to 1.06; interaction p = 0.44). Among Black patients admitted with ADHF in the United States, the in-hospital initiation of sacubitril/valsartan was more effective than enalapril in reducing natriuretic peptide levels and the composite of cardiovascular death or HF rehospitalization. The effect of sacubitril/valsartan did not differ by race. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).
Authors: Berardi, Cecilia; Braunwald, Eugene; Morrow, David A; Mulder, Hillary S; Duffy, Carol I; O'Brien, Terrence X; Ambrosy, Andrew P; Chakraborty, Hrishikesh; Velazquez, Eric J; DeVore, Adam D; PIONEER-HF Investigators,
JACC Heart Fail. 2020 10;8(10):859-866. Epub 2020-09-09.
Hospitalizations for heart failure during the COVID-19 pandemic: making sense of the known knowns, known unknowns, and unknown unknowns
Authors: Ambrosy, Andrew P; Fitzpatrick, Jesse K; Fudim, Marat
Eur J Heart Fail. 2020 10;22(10):1752-1754. Epub 2020-08-04.
Acute Stroke Presentation, Care, and Outcomes in Community Hospitals in Northern California During the COVID-19 Pandemic
Shelter-in-place (SIP) orders implemented to mitigate severe acute respiratory syndrome coronavirus 2 spread may inadvertently discourage patient care-seeking behavior for critical conditions like acute ischemic stroke. We aimed to compare temporal trends in volume of acute stroke alerts, patient characteristics, telestroke care, and short-term outcomes pre- and post-SIP orders. We conducted a cohort study in 21 stroke centers of an integrated healthcare system serving 4.4+ million members across Northern California. We included adult patients who presented with suspected acute stroke and were evaluated by telestroke between January 1, 2019, and May 9, 2020. SIP orders announced the week of March 15, 2020, created pre (January 1, 2019, to March 14, 2020) and post (March 15, 2020, to May 9, 2020) cohort for comparison. Main outcomes were stroke alert volumes and inpatient mortality for stroke. Stroke alert weekly volume post-SIP (mean, 98 [95% CI, 92-104]) decreased significantly compared with pre-SIP (mean, 132 [95% CI, 130-136]; P<0.001). Stroke discharges also dropped, in concordance with acute stroke alerts decrease. In total, 9120 patients were included: 8337 in pre- and 783 in post-SIP cohorts. There were no differences in patient demographics. Compared with pre-SIP, post-SIP patients had higher National Institutes of Health Stroke Scale scores (P=0.003), lower comorbidity score (P<0.001), and arrived more often by ambulance (P<0.001). Post-SIP, more patients had large vessel occlusions (P=0.03), and there were fewer stroke mimics (P=0.001). Discharge outcomes were similar for post-SIP and pre-SIP cohorts. In this cohort study, regional stroke alert and ischemic stroke discharge volumes decreased significantly in the early COVID-19 pandemic. Compared with pre-SIP, the post-SIP population showed no significant demographic differences but had lower comorbidity scores, more severe strokes, and more large vessel occlusions. The inpatient mortality was similar in both cohorts. Further studies are needed to understand the causes and implications of care avoidance to patients and healthcare systems.
Authors: Nguyen-Huynh, Mai N; Tang, Xian Nan; Vinson, David R; Flint, Alexander C; Alexander, Janet G; Meighan, Melissa; Burnett, Molly; Sidney, Stephen; Klingman, Jeffrey G
Stroke. 2020 10;51(10):2918-2924. Epub 2020-08-07.
Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial
The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).
Authors: Mann DL; Ambrosy AP; LIFE Investigators; et al.
JACC Heart Fail. 2020 10;8(10):789-799. Epub 2020-06-10.
Shared Decision Making in Atrial Fibrillation: Patient-Reported Involvement in Treatment Decisions
To determine the extent of shared decision-making (SDM), during selection of oral anticoagulant (OAC) and rhythm control treatments, in patients with newly diagnosed atrial fibrillation (AF). We evaluated survey data from 1006 patients with new-onset AF enrolled at 56 US sites participating in the SATELLITE substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II). Patients completed surveys at enrolment and at 6-month follow-up. Patients were asked about who made their AF treatment decisions. Shared decision-making was classified as one that the patient felt was an autonomous decision or a shared decision with their healthcare provider (HCP). Approximately half of patients reported that their OAC treatment decisions were made entirely by their HCP. Compared with those reporting no SDM, patients reporting SDM for OAC were more often female (47.2% vs. 38.4%), while patients reporting SDM for rhythm control were more often male (62.2% vs. 57.6%). The most important factors cited by patients during decision-making for OAC were reducing stroke and bleeding risk, and their HCP’s recommendations. After adjustment, patients with self-reported understanding of OAC, and rhythm control options, had higher odds of having participated in SDM [odds ratio (OR) 2.54, confidence interval (CI): 1.75-3.68 and OR 2.36, CI: 1.50-3.71, both P ≤ 0.001, respectively]. Shared decision-making is not widely implemented in contemporary AF practice. Patient understanding about available therapeutic options is associated with a more than a two-fold higher likelihood of SDM, and may be a potential target for future interventions.
Authors: Ali-Ahmed F; Gersh BJ; O'Brien EC; et al.
Eur Heart J Qual Care Clin Outcomes. 2020 10 01;6(4):263-272.
Non-cardiac-related morbidity, mobility limitation, and outcomes in older adults with heart failure
To examine the individual and combined associations of noncardiac-related conditions and mobility limitation with morbidity and mortality in adults with heart failure (HF). We conducted a retrospective cohort study in a large, diverse group of adults with HF from five U.S. integrated healthcare delivery systems. We characterized patients with respect to the presence of noncardiac conditions (<3 vs ≥3) and/or mobility impairment (defined by the use/nonuse of a wheelchair, cane, or walker), categorizing them into four subgroups. Outcomes included all-cause death and hospitalizations for HF or any cause. Among 114,553 adults diagnosed with HF (mean age: 73 years old, 46% women), compared with <3 noncardiac conditions/no mobility limitation, adjusted hazard ratios (HR) for all-cause death among those with <3 noncardiac conditions/mobility limitation, ≥3 noncardiac conditions/no mobility limitation, ≥3 noncardiac conditions/mobility limitation (vs) were 1.40 (95% CI, 1.31-1.51), 1.72 (95% CI, 1.69-1.75), and 1.93 (95% CI, 1.85-2.01), respectively. We did not observe an increased risk of any-cause or HF-related hospitalization related to the presence of mobility limitation among those with a greater burden of noncardiac multimorbidity. Consistent findings regarding mortality were observed within groups defined according to age, gender, and HF type (preserved, reduced, mid-range ejection fraction), with the most prominent impact of mobility limitation in those <65 years of age. There is an additive association of mobility limitation, beyond the burden of noncardiac multimorbidity, on mortality for patients with HF, and especially prominent in younger patients.
Authors: Tisminetzky M; Gurwitz JH; Fan D; Reynolds K; Smith DH; Fouayzi H; Sung SH; Goldberg R; Go AS
J Gerontol A Biol Sci Med Sci. 2020 09 25;75(10):1981-1988.
Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction
Gestational diabetes mellitus (GDM) is the top risk factor for future type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-control design was applied to a prospective cohort with GDM history. Women who were non-diabetic 6-9 weeks postpartum (baseline) were monitored for the development of T2D. Metabolomics were performed on baseline plasma to identify metabolic pathways associated with T2D risk. Notably, diminished sphingolipid metabolism was highly associated with future T2D. Defects in sphingolipid metabolism were further implicated by integrating metabolomics and genome-wide association data, which identified two significantly enriched T2D-linked genes, CERS2 and CERS4. Follow-up experiments in mice and cells demonstrated that inhibiting sphingolipid metabolism impaired pancreatic β cell function. These data suggest early postpartum alterations in sphingolipid biosynthesis contribute to β cell dysfunction and T2D risk.
Authors: Khan SR; Manialawy Y; Obersterescu A; Cox BJ; Gunderson EP; Wheeler MB
iScience. 2020 Oct 23;23(10):101566. Epub 2020-09-15.
How much can we trust electronic health record data?
Trust in EHR data is becoming increasingly important as a greater share of clinical and health services research use EHR data. We discuss reasons for distrust and acknowledge limitations. Researchers continue to use EHR data because of strengths including greater clinical detail than sources like administrative billing claims. Further, many limitations are addressable with existing methods including data quality checks and common data frameworks. We discuss how to build greater trust in the use of EHR data for research, including additional transparency and research priority areas that will both enhance existing strengths of the EHR and mitigate its limitations.
Authors: Savitz, Samuel T; Savitz, Lucy A; Fleming, Neil S; Shah, Nilay D; Go, Alan S
Healthc (Amst). 2020 Sep;8(3):100444. Epub 2020-07-08.
Establishing a Graduate Medical Education Task Force for the American Medical Women’s Association
Authors: Lo, Joan C
Perm J. 2020 09;24:1-2.
Bruce Ettinger, MD
Authors: Marcus R; Cummings S; Lo J; Genant H
J Bone Miner Res. 2020 Sep;35(9):1621-1622. Epub 2020-09-08.
Kidney Function and Potassium Monitoring After Initiation of Renin-Angiotensin-Aldosterone System Blockade Therapy and Outcomes in 2 North American Populations
Clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating ACE (angiotensin-converting enzyme) inhibitor or angiotensin II receptor blocker therapy. However, evidence is lacking about whether follow-up testing reduces therapy-related adverse outcomes. We conducted 2 population-based retrospective cohort studies in Kaiser Permanente Northern California and Ontario, Canada. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACE inhibitor or angiotensin II receptor blocker therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression. We also developed and externally validated a risk score to identify patients at risk of having abnormally high serum creatinine and potassium values in follow-up. We identified 75 251 matched pairs initiating ACE inhibitor or angiotensin II receptor blocker therapy between January 1, 2007, and December 31, 2017, in Kaiser Permanente Northern California. Follow-up testing was not significantly associated with 30-day all-cause mortality in Kaiser Permanente Northern California (hazard ratio, 0.75 [95% CI, 0.54-1.06]) and was associated with higher mortality in 84 905 matched pairs in Ontario (hazard ratio, 1.32 [95% CI, 1.07-1.62]). In Kaiser Permanente Northern California, follow-up testing was significantly associated with higher rates of hospitalization with acute kidney injury (hazard ratio, 1.66 [95% CI, 1.10-2.22]) and hyperkalemia (hazard ratio, 3.36 [95% CI, 1.08-10.41]), as was observed in Ontario. The risk score for abnormal potassium provided good discrimination (area under the curve [AUC], 0.75) and excellent calibration of predicted risks, while the risk score for abnormal serum creatinine provided moderate discrimination (AUC, 0.62) but excellent calibration. Routine laboratory monitoring after ACE inhibitor or angiotensin II receptor blocker initiation was not associated with a lower risk of 30-day mortality. We identified patient subgroups in which targeted testing may be effective in identifying therapy-related changes in serum potassium or kidney function.
Authors: Parikh, Rishi V; Pravoverov, Leonid; Go, Alan S; et al.
Circ Cardiovasc Qual Outcomes. 2020 09;13(9):e006415. Epub 2020-09-02.
Community-Based Epidemiology of Hospitalized Acute Kidney Injury
Acute kidney injury (AKI) may lead to short- and long-term consequences in children, but its epidemiology has not been well described at a population level and outside of ICU settings. In a large, diverse pediatric population receiving care within an integrated health care delivery system between 2008 and 2016, we calculated age- and sex-adjusted incidences of hospitalized AKI using consensus serum creatinine (SCr)-based diagnostic criteria. We also investigated the proportion of AKI detected in non-ICU settings and the rates of follow-up outpatient SCr testing after AKI hospitalization. Among 1 500 546 children, the mean age was 9.8 years, 49.0% were female, and 33.1% were minorities. Age- and sex-adjusted incidence of hospitalized AKI among the entire pediatric population did not change significantly across the study period, averaging 0.70 (95% confidence interval: 0.68-0.73) cases per 1000 person-years. Among the subset of hospitalized children, the adjusted incidence of AKI increased from 6.0% of hospitalizations in 2008 to 8.8% in 2016. Approximately 66.7% of AKI episodes were not associated with an ICU stay, and 54.3% of confirmed, unresolved Stage 2 or 3 AKI episodes did not have outpatient follow-up SCr testing within 30 days postdischarge. Community-based pediatric AKI incidence was ∼1 per 1000 per year, with two-thirds of cases not associated with an ICU stay and more than one-half not receiving early outpatient follow-up kidney function testing. Further efforts are needed to increase the systematic recognition of AKI in all inpatient settings with appropriate, targeted postdischarge kidney function monitoring and associated management.
Authors: Parikh, Rishi V; Tan, Thida C; Salyer, Anne S; Auron, Ari; Kim, Peter S; Ku, Elaine; Go, Alan S
Pediatrics. 2020 09;146(3). Epub 2020-08-11.
Risk of Distal Embolization From tPA (Tissue-Type Plasminogen Activator) Administration Prior to Endovascular Stroke Treatment
In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion. We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes. Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; P<0.001). Distal embolization was associated with an inability to attempt EST: after distal embolization, 26/63 (41.3%) could not have attempted EST because of the new clot location, while in cases without distal embolization, only 8/249 (3.2%) were unable to have attempted EST (P<0.001). Among patients who received IV tPA, 13/242 (5.4%) had sufficient symptom improvement that a catheter angiogram was not performed; 6/342 (2.5%) had improvement to within 2 points of their baseline NIHSS. At catheter angiogram, 2/229 (0.9%) of patients who had received tPA had complete recanalization without distal embolization. Both IV tPA and EST recanalization were associated with improved long-term outcome. IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.
Authors: Flint, Alexander C; Avins, Andrew L; Nguyen-Huynh, Mai N; et al.
Stroke. 2020 09;51(9):2697-2704. Epub 2020-08-06.
Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists
The PIONEER-HF (comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode) trial demonstrated the efficacy and safety of sacubitril/valsartan (S/V) in stabilized patients with acute decompensated heart failure (HF) and reduced ejection fraction. The study sought to determine whether and how prior HF history and treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) affected the results. The PIONEER-HF trial was a prospective, multicenter, double-blind, randomized clinical trial enrolling 881 patients with an ejection fraction ≤40%. Patients were randomly assigned 1:1 to in-hospital initiation of S/V (n = 440) versus enalapril (n = 441). Pre-specified subgroup analyses were performed based on prior HF history (i.e., de novo HF vs. worsening chronic HF) and treatment with an ACE inhibitor or ARB (i.e., ACE inhibitor or ARB-yes vs. ACE inhibitor or ARB-no) at admission. At enrollment, 303 (34%) patients presented with de novo HF and 576 (66%) patients with worsening chronic HF. A total of 421 (48%) patients had been treated with an ACE inhibitor or ARB, while 458 (52%) had not been treated with an ACE inhibitor or ARB. N-terminal pro-B-type natriuretic peptide declined significantly in all 4 subgroups (p < 0.001), with greater decreases in the S/V versus the enalapril arm (p < 0.001). There was no interaction between prior HF history (p = 0.350) or ACE inhibitor or ARB treatment (p = 0.880) and the effect of S/V versus enalapril on cardiovascular death or rehospitalization for HF. The incidences of adverse events were comparable between S/V and enalapril across all 4 subgroups. Among patients admitted for acute decompensated HF, S/V was safe and well tolerated, led to a significantly greater reduction in N-terminal pro-B-type natriuretic peptide, and improved clinical outcomes compared with enalapril irrespective of previous HF history or ACE inhibitor or ARB treatment. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).
Authors: Ambrosy, Andrew P; Braunwald, Eugene; Morrow, David A; DeVore, Adam D; McCague, Kevin; Meng, Xiangyi; Duffy, Carol I; Rocha, Ricardo; Velazquez, Eric J; PIONEER-HF Investigators,
J Am Coll Cardiol. 2020 09 01;76(9):1034-1048.
Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes
The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising in young adults, with potential implications for reproductive-aged women. Whether NAFLD during pregnancy confers more serious risks for maternal or perinatal health is unclear. Using weighted discharge data from the US national inpatient sample, we evaluated temporal trends of NAFLD in pregnancies after 20 weeks gestation, and compared outcomes to pregnancies with other chronic liver diseases (CLDs) or no CLD. Study outcomes included preterm birth, postpartum hemorrhage, hypertensive complications (pre-eclampsia, eclampsia, and/or hemolysis, elevated liver enzymes, and low platelets syndrome), and maternal or fetal death. NAFLD prevalence was estimated by calendar year and temporal trends tested by linear regression. Outcomes were analyzed by logistic regression adjusted for age, race, multiple gestation, and pre-pregnancy diabetes, obesity, dyslipidemia and hypertension. Among 18,574,225 pregnancies, 5,640 had NAFLD and 115,210 had other, non-NAFLD CLD. Pregnancies with NAFLD nearly tripled from 10.5/100,000 pregnancies in 2007 to 28.9/100,000 in 2015 (p <0.001). Compared to the other groups, patients with NAFLD during pregnancy more frequently experienced gestational diabetes (7-8% vs. 23%), hypertensive complications (4% vs. 16%), postpartum hemorrhage (3-5% vs. 6%), and preterm birth (5-7% vs. 9%), all p values ≤0.01. On adjusted analysis, compared to no CLD, NAFLD was associated with hypertensive complications, preterm birth, postpartum hemorrhage and possibly maternal (but not fetal) death. The prevalence of NAFLD in pregnancy has nearly tripled in the last decade and is independently associated with hypertensive complications, postpartum hemorrhage and preterm birth. NAFLD should be considered a high-risk obstetric condition, with clinical implications for pre-conception counseling and pregnancy care. The prevalence of non-alcoholic fatty liver disease (NAFLD) in pregnancy has almost tripled over the past 10 years. Having NAFLD during pregnancy increases risks for both the mother and the baby, including hypertensive complications of pregnancy, bleeding after delivery, and preterm birth. Thus, pre-conception counseling is warranted with consideration of high-risk obstetric management among women with NAFLD in pregnancy.
Authors: Sarkar M; Grab J; Dodge JL; Gunderson EP; Rubin J; Irani RA; Cedars M; Terrault N
J Hepatol. 2020 09;73(3):516-522. Epub 2020-06-09.
Improving Physical Activity and Exercise Capacity in Heart Failure Taking the First Step is Always the Hardest
Authors: Ambrosy AP; Chioncel O
Eur J Heart Fail. 2020 09;22(9):1734-1736. Epub 2020-07-15.
Association of blood pressure with cognitive function at midlife: a Mendelian randomization study
Whether high blood pressure has a causal effect on cognitive function as early as middle age is unclear. We investigated whether high blood pressure (BP) causally impairs cognitive function at midlife using Mendelian Randomization (MR). We applied a two-sample MR approach to investigate the causal relationship between BP and midlife cognitive performance measured by the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and Stroop Interference test. We used a total of 109 genetic polymorphisms with established associations with BP as instrumental variables and estimated gene-cognitive function association in 1369 middle-aged adults (Mean age (SD): 50.8 (3.3), 54.0% women) from the CARDIA study. A 10 mmHg increment in genetically-predicted systolic, diastolic, or pulse pressure was associated with a 4.9 to 7.7-point lower DSST score (P = 0.002, SBP; P = 0.005, DBP and P = 0.008, PP), while a 10 mmHg increment in genetically-predicted SBP was associated with a 0.7 point lower RAVLT and a 2.3 point higher Stroop (P = 0.046 and 0.011, respectively). This MR analysis shows that high BP, especially SBP, is causally associated with poorer processing speed, verbal memory, and executive function during midlife. These findings emphasize the need for further investigation of the role and mechanisms of BP dysregulation on cognitive health in middle age and perhaps, more broadly, across the lifespan.
Authors: Sun, Daokun; Thomas, Emy A; Launer, Lenore J; Sidney, Stephen; Yaffe, Kristine; Fornage, Myriam
BMC Med Genomics. 2020 08 26;13(1):121. Epub 2020-08-26.
Cardiovascular Risk Factors and Accelerated Cognitive Decline in Midlife: the CARDIA Study
Increasing evidence supports an association between midlife cardiovascular risk factors (CVRFs) and risk of dementia, but less is known about whether CVRFs influence cognition in midlife. We examined the relationship between CVRFs and midlife cognitive decline. In 2,675 black and white middle-aged adults (mean age 50.2 ± 3.6 years, 57% female, 45% black), we measured CVRFs at baseline: hypertension (31%), diabetes mellitus (11%), obesity (43%), high cholesterol (9%), and current cigarette smoking (15%). We administered cognitive tests of memory, executive function, and processing speed at baseline and 5 years later. Using logistic regression, we estimated the association of CVRFs with accelerated cognitive decline (race-specific decline ≥1.5 SD from the mean change) on a composite cognitive score. Five percent (n = 143) of participants had accelerated cognitive decline over 5 years. Smoking, hypertension, and diabetes mellitus were associated with an increased likelihood of accelerated decline after multivariable adjustment (adjusted odds ratio [AOR] 1.65, 95% confidence interval [CI] 1.00-2.71; AOR 1.87, 95% CI 1.26-2.75; AOR 2.45, 95% CI 1.54-3.88, respectively), while obesity and high cholesterol were not associated with risk of decline. These results were similar when stratified by race. The likelihood of accelerated decline also increased with greater number of CVRFs (1-2 CVRFs: AOR 1.77, 95% CI 1.02-3.05; ≥3 CVRFs: AOR 2.94, 95% CI 1.64-5.28) and with Framingham Coronary Heart Disease Risk Score ≥10 (AOR 2.29, 95% CI 1.21-4.34). Midlife CVRFs, especially hypertension, diabetes mellitus, and smoking, are common and associated with accelerated cognitive decline at midlife. These results identify potential modifiable targets to prevent midlife cognitive decline and highlight the need for a life course approach to cognitive function and aging.
Authors: Yaffe K; Bahorik AL; Hoang TD; Forrester S; Jacobs DR; Lewis CE; Lloyd-Jones DM; Sidney S; Reis JP
Neurology. 2020 08 18;95(7):e839-e846. Epub 2020-07-15.
Heterogeneous trends in burden of heart disease mortality by subtypes in the United States, 1999-2018: observational analysis of vital statistics
To describe trends in the burden of mortality due to subtypes of heart disease from 1999 to 2018 to inform targeted prevention strategies and reduce disparities. Serial cross sectional analysis of cause specific heart disease mortality rates using national death certificate data in the overall population as well as stratified by race-sex, age, and geography. United States, 1999-2018. 12.9 million decedents from total heart disease (49% women, 12% black, and 19% <65 years old). Age adjusted mortality rates (AAMR) and years of potential life lost (YPLL) for each heart disease subtype, and respective mean annual percentage change. Deaths from total heart disease fell from 752 192 to 596 577 between 1999 and 2011, and then increased to 655 381 in 2018. From 1999 to 2018, the proportion of total deaths from heart disease attributed to ischemic heart disease decreased from 73% to 56%, while the proportion attributed to heart failure increased from 8% to 13% and the proportion attributed to hypertensive heart disease increased from 4% to 9%. Among heart disease subtypes, AAMR was consistently highest for ischemic heart disease in all subgroups (race-sex, age, and region). After 2011, AAMR for heart failure and hypertensive heart disease increased at a faster rate than for other subtypes. The fastest increases in heart failure mortality were in black men (mean annual percentage change 4.9%, 95% confidence interval 4.0% to 5.8%), whereas the fastest increases in hypertensive heart disease occurred in white men (6.3%, 4.9% to 9.4%). The burden of years of potential life lost was greatest from ischemic heart disease, but black-white disparities were driven by heart failure and hypertensive heart disease. Deaths from heart disease in 2018 resulted in approximately 3.8 million potential years of life lost. Trends in AAMR and years of potential life lost for ischemic heart disease have decelerated since 2011. For almost all other subtypes of heart disease, AAMR and years of potential life lost became stagnant or increased. Heart failure and hypertensive heart disease account for the greatest increases in premature deaths and the largest black-white disparities and have offset declines in ischemic heart disease. Early and targeted primary and secondary prevention and control of risk factors for heart disease, with a focus on groups at high risk, are needed to avoid these suboptimal trends beginning earlier in life.
Authors: Shah, Nilay S; Molsberry, Rebecca; Rana, Jamal S; Sidney, Stephen; Capewell, Simon; O'Flaherty, Martin; Carnethon, Mercedes; Lloyd-Jones, Donald M; Khan, Sadiya S
BMJ. 2020 08 13;370:m2688. Epub 2020-08-13.
The Covid-19 Pandemic and the Incidence of Acute Myocardial Infarction
Authors: Solomon MD; McNulty EJ; Rana JS; Leong TK; Lee C; Sung SH; Ambrosy AP; Sidney S; Go AS
N Engl J Med. 2020 08 13;383(7):691-693. Epub 2020-05-19.
Underlying dyslipidemia postpartum in women with a recent GDM pregnancy who develop type 2 diabetes
Approximately, 35% of women with Gestational Diabetes (GDM) progress to Type 2 Diabetes (T2D) within 10 years. However, links between GDM and T2D are not well understood. We used a well-characterised GDM prospective cohort of 1035 women following up to 8 years postpartum. Lipidomics profiling covering >1000 lipids was performed on fasting plasma samples from participants 6-9 week postpartum (171 incident T2D vs. 179 controls). We discovered 311 lipids positively and 70 lipids negatively associated with T2D risk. The upregulation of glycerolipid metabolism involving triacylglycerol and diacylglycerol biosynthesis suggested activated lipid storage before diabetes onset. In contrast, decreased sphingomyelines, hexosylceramide and lactosylceramide indicated impaired sphingolipid metabolism. Additionally, a lipid signature was identified to effectively predict future diabetes risk. These findings demonstrate an underlying dyslipidemia during the early postpartum in those GDM women who progress to T2D and suggest endogenous lipogenesis may be a driving force for future diabetes onset.
Authors: Lai, Mi; Al Rijjal, Dana; Röst, Hannes L; Dai, Feihan F; Gunderson, Erica P; Wheeler, Michael B
Elife. 2020 08 04;9. Epub 2020-08-04.
Life Course Changes in Cardiometabolic Risk Factors Associated With Preterm Delivery: The 30-Year CARDIA Study
Background Women who deliver preterm infants (<37 weeks) have excess cardiovascular risk; however, it is unclear whether the unfavorable changes in the cardiometabolic profile associated with preterm delivery initiate before, during, or after childbearing. Methods and Results We identified 1306 women (51% Black) with births between baseline (1985-1986) and year 30 in the CARDIA (Coronary Artery Risk Development in Young Adults) study. We compared life course changes in blood pressure, body mass index, waist circumference, and lipids in women with preterm deliveries (n=318) with those with all term deliveries (n=988), using piecewise linear mixed-effects models. Specifically, we evaluated group differences in rates of change before and after the childbearing period and change in level across the childbearing period. After adjusting for the covariates, women with preterm deliveries had a higher change in diastolic blood pressure across the childbearing period than those with all term deliveries (1.59 versus -0.73 mm Hg, P<0.01); the rates of change did not differ by group, both prechildbearing and postchildbearing. Women with preterm deliveries had a larger body mass index increase across the childbearing period (1.66 versus 1.22 kg/m2, P=0.03) compared with those with all term deliveries, followed by a steeper increase after the childbearing period (0.22 versus 0.17 kg/m2 per year, P=0.02). Conclusions Preterm delivery was associated with unfavorable patterns of change in diastolic blood pressure and adiposity that originate during the childbearing years and persist or exacerbate later in life. These adverse changes may contribute to the elevated cardiovascular risk among women with preterm delivery.
Authors: Sun B; Bertolet M; Brooks MM; Hubel CA; Lewis CE; Gunderson EP; Catov JM
J Am Heart Assoc. 2020 08 04;9(15):e015900. Epub 2020-07-22.
Meta-analysis of 26,638 Individuals Identifies Two Genetic Loci Associated with Left Ventricular Ejection Fraction
Left ventricular ejection fraction (EF) is an indicator of cardiac function, usually assessed in individuals with heart failure and other cardiac conditions. Although family studies indicate that EF has an important genetic component with heritability estimates up to 0.61, to date only 6 EF-associated loci have been reported. Here, we conducted a genome-wide association study (GWAS) of EF in 26 638 adults from the Genetic Epidemiology Research on Adult Health and Aging and the UK Biobank cohorts. A meta-analysis combining results from Genetic Epidemiology Research on Adult Health and Aging and UK Biobank identified a novel locus: TMEM40 on chromosome 3p25 (rs11719526; β=0.47 and P=3.10×10-8) that replicated in Biobank Japan and confirmed recent findings implicating the BAG3 locus on chromosome 10q26 in EF variation, with the strongest association observed for rs17617337 (β=-0.83 and P=8.24×10-17). Although the minor allele frequencies of TMEM40 rs11719526 were generally common (between 0.13 and 0.44) in different ethnic groups, BAG3 rs17617337 was rare (minor allele frequencies<0.05) in Asian and African ancestry populations. These associations were slightly attenuated, after considering antecedent cardiac conditions (ie, heart failure/cardiomyopathy, hypertension, myocardial infarction, atrial fibrillation, valvular disease, and revascularization procedures). This suggests that the effects of the lead variants at TMEM40 or BAG3 on EF are largely independent of these conditions. In this large and multiethnic study, we identified 2 loci, TMEM40 and BAG3, associated with EF at a genome-wide significance level. Identifying and understanding the genetic determinants of EF is important to better understand the pathophysiology of this strong correlate of cardiac outcomes and to help target the development of future therapies.
Authors: Choquet H; Thai KK; Jiang C; Ranatunga DK; Hoffmann TJ; Go AS; Lindsay AC; Ehm MG; Waterworth DM; Risch N; Schaefer C
Circ Genom Precis Med. 2020 08;13(4):e002804. Epub 2020-06-30.
Changes in Cardiometabolic Risk Factors Before and After Gestational Diabetes: A Prospective Life-Course Analysis in CARDIA Women
This study hypothesized that both preconception and postchildbearing patterns of cardiometabolic risk factors may be different for women with gestational diabetes mellitus (GDM) compared with women without GDM. Among 1,302 (51% black) women in the Coronary Artery Risk Development in Young Adults (CARDIA) study with births and followed for 30 years, this study evaluated changes in cardiometabolic factors (BMI, waist circumference [WC], lipids, blood pressure) during prechildbearing (prior to the first postbaseline birth) and postchildbearing periods (after the last birth) by GDM status using piecewise linear mixed models adjusted for sociodemographics, parity, and time-varying covariates. Compared with women who did not develop GDM, weight and WC increases in women who developed GDM (n = 152, 12%) were faster (BMI difference: +0.12 kg/m2 /y, P = 0.04; WC difference: +0.28 cm/y, P = 0.04) during the prechildbearing period, accounting for covariates. This translated to an average of 1.3 kg of excess weight gain across 4 years among women with subsequent GDM versus non-GDM births. In contrast, slopes after childbearing did not differ by GDM status, nor were there other cardiometabolic differences. Women with GDM exhibited an increasing prepregnancy pattern of weight gain and central adiposity. Absolute postchildbearing weight was also higher in GDM-affected women, but the slope of gain after GDM was not.
Authors: Catov JM; Sun B; Bertolet M; Snyder GG; Lewis CE; Allen NB; Shikany JM; Ingram KH; Appiah D; Gunderson EP
Obesity (Silver Spring). 2020 08;28(8):1397-1404. Epub 2020-07-06.
Discontinuation rates of warfarin versus direct acting oral anticoagulants in US clinical practice: Results from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II)
While oral anticoagulation is a cornerstone of stroke prevention therapy in atrial fibrillation (AF), few studies have evaluated comparative discontinuation rates in clinical practice. The objective of this study is to evaluate discontinuation rates among patients on warfarin and direct oral anticoagulants (DOACs) in clinical practice. The ORBIT-AF II Registry enrolled 10,005 total AF patients with a CHA2DS2VASc score of ≥2 on warfarin or DOACs from 235 clinical practices across the US from February 13, 2013 and July 12, 2017. Descriptive statistics and multivariable Cox regression modeling were used to describe baseline characteristics and predictors of discontinuation. Unadjusted and adjusted discontinuation rates and 95% confidence intervals (CI) were calculated using Cox proportional hazards models and propensity score adjustment, respectively. At baseline, 16.4% (N = 1642/10,005) were treated with warfarin, 83.6% (N = 8363/10,005) with DOACs and 1498/10,005 patients (15.0%) discontinued therapy [warfarin = 236/1642 (14.4%) vs DOACs = 1262/8363 (15.1%)]. At 6 and 12 months respectively, among 7049 patients with a new diagnosis of AF within 6 months, adjusted discontinuation rates for warfarin versus DOACs were as follows: [6 months: 7.9%, 95%CI (6.8%-9.0%) vs 9.6% (8.4%-10.7%), P = .16]; [12 months: 12.7% (11.0%-14.3%) vs 15.3% (13.6%-16.9%), P = .02)]. Patients who discontinued therapy with warfarin or DOACs had higher risk of adverse clinical outcomes including: all-cause mortality and cardiovascular death (CV) than those who continued treatment. In a community based AF cohort, adjusted rates of discontinuation at 12-months were higher in DOAC-treated versus VKA-treated patients. Discontinuation of oral anticoagulation was associated with increased absolute risk of all-cause mortality and CV death. URL:https://clinicaltrials.gov. Unique Identifier: NCT01701817.
Authors: Jackson LR; Go AS; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II; et al.
Am Heart J. 2020 08;226:85-93. Epub 2020-04-28.
Association of Racial Residential Segregation Throughout Young Adulthood and Cognitive Performance in Middle-aged Participants in the CARDIA Study
Neighborhood-level residential segregation is implicated as a determinant for poor health outcomes in black individuals, but it is unclear whether this association extends to cognitive aging, especially in midlife. To examine the association between cumulative exposure to residential segregation during 25 years of young adulthood among black individuals and cognitive performance in midlife. The ongoing prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) Study recruited 5115 black and white participants aged 18 to 30 years from 4 field centers at the University of Alabama, Birmingham; University of Minnesota, Minneapolis; Northwestern University, Chicago, Illinois; and Kaiser Permanente, Oakland, California. Data were acquired from February 1985 to May 2011. Among the surviving CARDIA cohort, 3671 (71.8%) attended examination year 25 of the study in 2010, when cognition was measured, and 3008 (81.9%) of those completed the cognitive assessments. To account for time-varying confounding and differential censoring, marginal structural models using inverse probability weighting were applied. Data were analyzed from April 16 to July 20, 2019. Racial residential segregation was measured using the Getis-Ord Gi* statistic, and the mean cumulative exposure to segregation was calculated across 6 follow-up visits from baseline to year 25 of the study, then categorized into high, medium, and low segregation. Cognitive function was measured at year 25 of the study, using the Digit Symbol Substitution Test (DSST), Stroop color test (reverse coded), and Rey Auditory Verbal Learning Test. To facilitate comparison of estimates, z scores were calculated for all cognitive tests. A total of 1568 black participants with available cognition data were included in the analysis. At baseline, participants had a mean (SD) age of 25 (4) years and consisted of 936 women (59.7%). Greater cumulative exposure to segregated neighborhoods was associated with a worse DSST z score (for high segregation, β = -0.37 [95% CI, -0.61 to -0.13]; for medium segregation, β = -0.25 [95% CI, -0.51 to 0.0002]) relative to exposure to low segregation. In this cohort study, exposure to residential segregation throughout young adulthood was associated with worse processing speed among black participants as early as in midlife. This association may potentially explain black-white disparities in dementia risk at older age.
Authors: Caunca MR; Odden MC; Glymour MM; Elfassy T; Kershaw KN; Sidney S; Yaffe K; Launer L; Zeki Al Hazzouri A
JAMA Neurol. 2020 08 01;77(8):1000-1007.
Coffee and tea consumption in the early adult lifespan and left ventricular function in middle age: the CARDIA study
The long-term impact of coffee or tea consumption on subclinical left ventricular (LV) systolic or diastolic function has not been previously studied. We examined the association between coffee or tea consumption beginning in early adulthood and cardiac function in midlife. We investigated 2735 Coronary Artery Risk Development in Young Adults (CARDIA) study participants with long-term total caffeine intake, coffee, and tea consumption data from three visits over a 20 year interval and available echocardiography indices at the CARDIA Year-25 exam (2010-2011). Linear regression models were used to assess the association between caffeine intake, tea, and coffee consumption (independent variables) and echocardiography outcomes [LV mass, left atrial volume, and global longitudinal strain (GLS), LV ejection fraction (LVEF), and transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e´)]. Models were adjusted for standard cardiovascular risk factors, socioeconomic status, physical activity, alcohol use, and dietary factors (calorie intake, whole and refined grain intake, and fruit and vegetable consumption). Mean (standard deviation) age was 25.2 (3.5) years at the CARDIA Year-0 exam (1985-1986), 57.4% were women, and 41.9% were African-American. In adjusted multivariable linear regression models assessing the relationship between coffee consumption and GLS, beta coefficients when comparing coffee drinkers of <1, 1-2, 3-4, and >4 cups/day with non-coffee drinkers were β = -0.30%, P < 0.05; β = -0.35%, P < 0.05; β = -0.32%, P < 0.05; β = -0.40%, P > 0.05; respectively (more negative values implies better systolic function). In adjusted multivariable linear regression models assessing the relationship between coffee consumption and E/e´, beta coefficients when comparing coffee drinkers of <1, 1-2, 3-4, and >4 cups/day with non-coffee drinkers were β = -0.29, P < 0.05; β = -0.38, P < 0.01; β = -0.20, P > .05; and β = -0.37, P > 0.05, respectively (more negative values implies better diastolic function). High daily coffee consumption (>4 cups/day) was associated with worse LVEF (β = -1.69, P < 0.05). There were no associations between either tea drinking or total caffeine intake and cardiac function (P > 0.05 for all). Low-to-moderate daily coffee consumption from early adulthood to middle age was associated with better LV systolic and diastolic function in midlife. High daily coffee consumption (>4cups/day) was associated with worse LV function. There was no association between caffeine or tea intake and cardiac function.
Authors: Nwabuo CC; Ambale-Venkatesh B; Lima JAC; et al.
ESC Heart Fail. 2020 08;7(4):1510-1519. Epub 2020-05-25.
Analysis of putative cis-regulatory elements regulating blood pressure variation
Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of ‘expressed’ genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.
Authors: Nandakumar P; Kwok PY; Risch N; Chakravarti A; Chakravarti A; et al.
Hum Mol Genet. 2020 07 21;29(11):1922-1932.
Neighborhood socioeconomic status and risk of hospitalization in patients with chronic kidney disease: A chronic renal insufficiency cohort study
Patients with chronic kidney disease (CKD) experience significantly greater morbidity than the general population. The hospitalization rate for patients with CKD is significantly higher than the general population. The extent to which neighborhood-level socioeconomic status (SES) is associated with hospitalization has been less explored, both in the general population and among those with CKD.We evaluated the relationship between neighborhood SES and hospitalizations for adults with CKD participating in the Chronic Renal Insufficiency Cohort Study. Neighborhood SES quartiles were created utilizing a validated neighborhood-level SES summary measure expressed as z-scores for 6 census-derived variables. The relationship between neighborhood SES and hospitalizations was examined using Poisson regression models after adjusting for demographic characteristics, individual SES, lifestyle, and clinical factors while taking into account clustering within clinical centers and census block groups.Among 3291 participants with neighborhood SES data, mean age was 58 years, 55% were male, 41% non-Hispanic white, 49% had diabetes, and mean estimated glomerular filtration rate (eGFR) was 44 ml/min/1.73 m. In the fully adjusted model, compared to individuals in the highest SES neighborhood quartile, individuals in the lowest SES neighborhood quartile had higher risk for all-cause hospitalization (rate ratio [RR], 1.28, 95% CI, 1.09-1.51) and non-cardiovascular hospitalization (RR 1.30, 95% CI, 1.10-1.55). The association with cardiovascular hospitalization was in the same direction but not statistically significant (RR 1.21, 95% CI, 0.97-1.52).Neighborhood SES is associated with risk for hospitalization in individuals with CKD even after adjusting for individual SES, lifestyle, and clinical factors.
Authors: Saunders MR; Go AS; CRIC Study Investigators; et al.
Medicine (Baltimore). 2020 Jul 10;99(28):e21028.
Association of Cardiac Biomarkers With the Kansas City Cardiomyopathy Questionnaire in Patients With Chronic Kidney Disease Without Heart Failure
Background The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a measure of heart failure (HF) health status. Worse KCCQ scores are common in patients with chronic kidney disease (CKD), even without diagnosed heart failure (HF). Elevations in the cardiac biomarkers GDF-15 (growth differentiation factor-15), galectin-3, sST2 (soluble suppression of tumorigenesis-2), hsTnT (high-sensitivity troponin T), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) likely reflect subclinical HF in CKD. Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score <75 at year 1 and (2) incident decline in KCCQ score to <75. We used multivariable logistic regression and Cox regression models to evaluate the associations between baseline cardiac biomarkers and cross-sectional and longitudinal KCCQ scores. Among 2873 participants, GDF-15 (adjusted odds ratio 1.42 per SD; 99% CI, 1.19-1.68) and galectin-3 (1.28; 1.12-1.48) were significantly associated with KCCQ scores <75, whereas sST2, hsTnT, and NT-proBNP were not significantly associated with KCCQ scores <75 after multivariable adjustment. Of the 2132 participants with KCCQ ≥75 at year 1, GDF-15 (adjusted hazard ratio, 1.36 per SD; 99% CI, 1.12-1.65), hsTnT (1.20; 1.01-1.44), and NT-proBNP (1.30; 1.08-1.56) were associated with incident decline in KCCQ to <75 after multivariable adjustment, whereas galectin-3 and sST2 did not have significant associations with KCCQ decline. Conclusions Among participants with CKD without clinical HF, GDF-15, galectin-3, NT-proBNP, and hsTnT were associated with low KCCQ either at baseline or during follow-up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.
Authors: Tummalapalli SL; Go AS; CRIC Study Investigators †; et al.
J Am Heart Assoc. 2020 07 07;9(13):e014385. Epub 2020-06-24.
Associations Between Cardiac Biomarkers and Cardiac Structure and Function in CKD
Subclinical changes to cardiac structure and function detected with echocardiography precede the development of clinical heart failure (HF) in persons with chronic kidney disease (CKD). Circulating cardiac biomarkers may reflect these pathophysiological changes. This study investigated associations between established biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and high-sensitivity troponin T [hsTnT]) and novel biomarkers (growth differentiation factor 15 [GDF-15], galectin-3 [Gal-3], and soluble ST-2 [sST-2]), using echocardiographic measurements in persons with CKD. In cross-sectional analyses among 2101 participants with mild to moderate CKD in the Chronic Renal Insufficiency Cohort (CRIC), biomarker levels measured at baseline were evaluated with echocardiographic measurements 1 year later. These included left ventricular mass index (LVMI), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), and left atrial diameter (LAD). Multivariable linear regression analyses tested associations of each biomarker with echocardiographic measurements, adjusting for covariates. GDF-15 was significantly associated with higher LVMI (1.0 g/m2.7; 95% CI, 0.4-1.7), LVESV (0.4 ml/m2.7; 95% CI, 0.0-0.7), and LVEDV (0.6 ml/m2.7; 95% CI, 0.1-1.1), but not with LVEF or LAD. These findings were not significant when adjusting for NT-proBNP and hsTnT. Gal-3 and sST-2 had no significant associations. Higher levels of NT-proBNP and hsTnT were associated with all echocardiographic measurements. In patients with CKD, the novel biomarker GDF-15, a marker of inflammation and tissue injury, and clinical biomarkers NT-proBNP and hsTnT, were associated with echocardiographic measurements of subclinical cardiovascular disease. Collectively, these biomarkers may highlight biological pathways that contribute to the development of clinical HF.
Authors: Stein NR; Go AS; CRIC Study Investigators; et al.
Kidney Int Rep. 2020 Jul;5(7):1052-1060. Epub 2020-05-07.
How Should We Counsel Asian Americans about Fracture Risk?
Authors: Lo JC; Ettinger B
J Am Geriatr Soc. 2020 07;68(7):1613-1614. Epub 2020-05-06.
Association between systolic ejection time and outcomes in heart failure by ejection fraction
Worsening heart failure (HF) is associated with shorter left ventricular systolic ejection time (SET), but there are limited data describing the relationship between SET and clinical outcomes. Thus, the objective was to describe the association between SET and clinical outcomes in an ambulatory HF population irrespective of ejection fraction (EF). We identified ambulatory patients with HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) who had an outpatient transthoracic echocardiogram performed between August 2008 and July 2010 at a tertiary referral centre. Multivariable logistic regression was used to evaluate the association between SET and 1-year outcomes. A total of 545 HF patients (171 HFrEF, 374 HFpEF) met eligibility criteria. Compared with HFpEF, HFrEF patients were younger [median age 60 years (25th-75th percentiles 50-69) vs. 64 years (25th-75th percentiles 53-74], with fewer females (30% vs. 56%) and a similar percentage of African Americans (36% vs. 35%). Median (25th-75th percentiles) EF with HFrEF was 30% (25-35%) and with HFpEF was 54% (48-58%). Median SET was shorter (280 ms vs. 315 ms, P < 0.001), median pre-ejection period was longer (114 ms vs. 89 ms, P < 0.001), and median relaxation time was shorter (78.7 ms vs. 93.3 ms, P < 0.001) among patients with HFrEF vs. HFpEF. Death or HF hospitalization occurred in 26.9% (n = 46) HFrEF and 11.8% (n = 44) HFpEF patients. After adjustment, longer SET was associated with lower odds of the composite of death or HF hospitalization at 1 year among HFrEF but not HFpEF patients. Longer SET is independently associated with improved outcomes among HFrEF patients but not HFpEF patients, supporting a potential role for normalizing SET as a therapeutic strategy with systolic dysfunction.
Authors: Patel PA; Ambrosy AP; Phelan M; Alenezi F; Chiswell K; Van Dyke MK; Tomfohr J; Honarpour N; Velazquez EJ
Eur J Heart Fail. 2020 07;22(7):1174-1182. Epub 2019-12-21.
A reduced transferrin saturation is independently associated with excess morbidity and mortality in older adults with heart failure and incident anemia
Low transferrin saturation (TSAT) or reduced serum ferritin level are suggestive of iron deficiency but the relationship between iron parameters and outcomes has not been systematically evaluated in older adults with heart failure (HF) and anemia. We identified a multicenter cohort of adults age ≥ 65 years with HF and incident anemia (hemoglobin <13 g/dL [men] or < 12 g/dL [women]) between 2005 and 2012. Patients were included if ferritin (ng/mL) and TSAT (%) were evaluated within 90 days of incident anemia. HF hospitalizations and all-cause death were ascertained from electronic health records. Among 4103 older adults with HF and incident anemia, 47% had TSAT <20% and the median (IQR) ferritin was 126 (53, 256) ng/mL. In multivariable analyses, compared with TSAT ≥20%, patients with TSAT <20% were at increased risk of HF hospitalization for serum ferritin <100 ng/mL (adjusted HR [aHR] 1.40, 95% CI:1.16-1.70) and 100-300 ng/mL (aHR 1.24, 95% CI:1.01-1.52) but not for a ferritin >300 ng/mL (aHR 0.89, 95% CI 0.65-1.23). In addition, TSAT <20% was independently associated with an increased risk of all-cause death regardless of serum ferritin level (<100 ng/mL: aHR 1.42, 95% CI:1.20-1.68; 100-300 ng/mL: aHR 1.18, 95% CI:1.00-1.38; >300 ng/mL: aHR 1.33, 95% CI:1.06-1.69). Among older adults with HF and incident anemia who had iron studies tested, nearly half had a TSAT <20%, which was independently associated with higher rates of morbidity and death.
Authors: Ambrosy AP; Go AS; RBC HEART Investigators/PACTTE Consortium; et al.
Int J Cardiol. 2020 06 15;309:95-99. Epub 2020-03-12.
Advancing Research on the Complex Interrelations Between Atrial Fibrillation and Heart Failure: A Report From a US National Heart, Lung, and Blood Institute Virtual Workshop
The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.
Authors: Al-Khatib SM; Go AS; et al.
Circulation. 2020 06 09;141(23):1915-1926. Epub 2020-06-08.
The burden of non-cardiac comorbidities and association with clinical outcomes in an acute heart failure trial – insights from ASCEND-HF
Non-cardiac comorbidities are highly prevalent in patients with heart failure (HF). Our objective was to define the association between non-cardiac comorbidity burden and clinical outcomes, costs of care, and length of stay within a large randomized trial of acute HF patients. Patients with complete medical history for the following comorbidities were included: diabetes mellitus, chronic obstructive pulmonary disease, chronic liver disease, history of cancer within the last 5 years, chronic renal disease (baseline serum creatinine >3.0 mg/mL), current smoking, alcohol abuse, depression, anaemia, peripheral arterial disease, and cerebrovascular disease. Patients were classified by overall burden of non-cardiac comorbidities (0, 1, 2, 3, and 4+). Hierarchical generalized linear models were used to assess associations between comorbidity burden and 30-day all-cause death or HF hospitalization and 180-day all-cause death in addition to costs of care and length of stay. A total of 6945 patients were included in the final analysis. Mean comorbidity number was 2.2 (± 1.34). Patients with 4+ comorbidities had higher rates of 30-day all-cause death/HF hospitalization as compared with patients with no comorbidities [odds ratio (OR) 3.32, 95% confidence interval (CI) 1.61-6.84; P < 0.01]. Similar results were seen with respect to 180-day death (OR 2.13, 95% CI 1.33-3.43; P < 0.01). Higher comorbidity burden was associated with higher 180-day costs of care and length of stay. Higher comorbidity burden is associated with poor clinical outcomes, higher costs of care, and extended length of stay. Further studies are needed to define the impact of comorbidity management programmes on outcomes for HF patients.
Authors: Bhatt AS; Ambrosy AP; Mentz RJ; et al.
Eur J Heart Fail. 2020 06;22(6):1022-1031. Epub 2020-03-25.
Periprocedural Risk and Survival Associated With Implantable Cardioverter-Defibrillator Placement in Older Patients With Advanced Heart Failure
Little is known about the utilization rates and outcomes of implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy defibrillator (CRT-D) placement among patients with advanced heart failure (HF). To examine utilization rates, patient characteristics, and outcomes of ICD and CRT-D placements among patients with advanced HF. This cohort study was a post hoc analysis of 81 492 Medicare fee-for-service beneficiaries enrolled in the National Cardiovascular Data Registry ICD Registry between January 2010 and December 2014. Inclusion criteria were patients who had received an HF diagnosis, had a left ventricular ejection fraction of 35% or lower, and showed evidence of advanced HF, which was defined as New York Heart Association (NYHA) class IV symptoms, inotrope use within the last 60 days, left ventricular assist device in situ, or orthotopic heart transplant listing. The comparator group included patients with NYHA class II and no HF hospitalization within the last 12 months, no left ventricular assist device, no orthotopic heart transplant listing, and no current or recent inotrope use. All eligible patients underwent first-time ICD or CRT-D placement for primary prevention of sudden cardiac death. Data were analyzed from January 2010 to December 2014. All-cause mortality and periprocedural complications. Of 81 492 Medicare patients, 3343 had advanced HF (4.1%) and 19 424 were in the comparator group (23.8%). Among the advanced HF population, the mean (SD) age of patients was 74 (9) years, and patients were predominantly white individuals (81.5%) and men (71.1%). The all-cause mortality rate at 30 days was 3.1% (95% CI, 2.6%-3.8%) in the advanced HF group vs 0.5% (0.4%-0.6%) in the comparator group (P < .001). In the advanced HF population, the aggregate in-hospital periprocedural complication rate was 3.74% (95% CI, 3.12%-4.44%) vs 1.10% (95% CI, 0.95%-1.25%) in the comparator group (P < .001). Most adverse events in this group were in-hospital fatality (1.82%; 95% CI, 1.40%-2.34%) and resuscitated cardiac arrest (1.05%; 95% CI, 0.73%-1.45%). Patients with NYHA class IV (hazard ratio, 1.40; 95% CI, 1.02-1.93; P = .04), ischemic heart disease (hazard ratio, 1.24; 95% CI, 1.04-1.48; P = .02), or diabetes (hazard ratio, 1.17; 95% CI, 1.04-1.33; P = .01) had a higher risk of death. Among patients undergoing ICD or CRT-D placement for primary prevention of sudden cardiac death, only a small proportion had advanced HF. These patients experienced clinically important periprocedural complication rates associated with in-hospital death and cardiac arrest relative to patients with nonadvanced HF.
Authors: Fudim M; Ali-Ahmed F; Parzynski CS; Ambrosy AP; Friedman DJ; Pokorney SD; Curtis JP; Fonarow GC; Masoudi FA; Hernandez AF; Al-Khatib SM
JAMA Cardiol. 2020 06 01;5(6):643-651.
Life-Course Reproductive History and Cardiovascular Risk Profile in Late Mid-Life: The CARDIA Study
Background Reproductive events, that is, a preterm birth (PTB), small-for-gestational-age infant (SGA), and vasomotor symptoms of menopause, are associated with subclinical atherosclerotic cardiovascular disease (ASCVD). We evaluated whether women with a past PTB and/or SGA (henceforth PTB/SGA) were more likely to have severe vasomotor symptoms of menopause and whether the estimated 10-year ASCVD risk was higher in women with PTB/SGA and vasomotor exposures. Methods and Results We assigned 1866 women (mean age=55±1 years) in the CARDIA (Coronary Artery Risk Development in Young Adults) study to the following categories of reproductive exposures: none, PTB/SGA only, vasomotor symptoms only, or both PTB/SGA and vasomotor symptoms. We used Kruskal-Wallis tests to evaluate the differences in pooled cohort equation ASCVD risk scores by category and linear regression to evaluate the associations of categories with ASCVD risk scores adjusted for study center, body mass index, education, current hormone replacement therapy use, parity, and hysterectomy. Women with PTB/SGA were more likely to have severe vasomotor symptoms, 36% versus 30%, P<0.02. ASCVD risk score was higher in women with both PTB/SGA and vasomotor symptoms (4.6%; 95% CI, 4.1%-5.1%) versus women with no exposures (3.3%; 95% CI, 2.9%-3.7%) or vasomotor symptoms only (3.8%; 95% CI, 3.5%-4.0%). ASCVD risk score was higher in women PTB/SGA (4.8%; 95% CI, 3.6%-5.9%) versus no exposures. PTB/SGA and vasomotor symptoms was associated with ASCVD risk score in white women versus no exposures (β=0.40; 95% CI, 0.02-0.78). Conclusions Women with prior PTB/SGA were more likely to have severe vasomotor symptoms of menopause. Reproductive exposures were associated with an estimated 10-year ASCVD risk in white women.
Authors: Lane-Cordova AD; Gunderson EP; Greenland P; Catov JM; Lewis CE; Pettee Gabriel K; Wellons MF; Carnethon MR
J Am Heart Assoc. 2020 05 18;9(10):e014859. Epub 2020-05-05.
The Relationship of Diagnosed Acne and Weight Status in Adolescent Girls
Authors: Mundluru SN; Darbinian JA; Ramalingam ND; Lo JC; McCleskey PE
J Am Acad Dermatol. 2020 May 12.
Association of Childhood Psychosocial Environment With 30-Year Cardiovascular Disease Incidence and Mortality in Middle Age
Background Childhood adversity and trauma have been shown to be associated with poorer cardiovascular disease (CVD) outcomes in adulthood. However, longitudinal studies of this association are rare. Methods and Results Our study used the CARDIA (Coronary Artery Risk Development in Young Adults) Study, a longitudinal cohort that has followed participants from recruitment in 1985-1986 through 2018, to determine how childhood psychosocial environment relates to CVD incidence and all-cause mortality in middle age. Participants (n=3646) completed the Childhood Family Environment (CFE) questionnaire at the year 15 (2000-2001) CARDIA examination and were grouped by high, moderate, or low relative CFE adversity scores. We used sequential multivariable regression models to estimate hazard ratios of incident (CVD) and all-cause mortality. Participants were 25.1±3.6 years old, 47% black, and 56% female at baseline and 198 participants developed CVD (17.9 per 10 000 person-years) during follow-up. CVD incidence was >50% higher for those in the high CFE adversity group compared with those in the low CFE adversity group. In fully adjusted models, CVD hazard ratios (95% CI) for participants who reported high and moderate CFE adversity versus those reporting low CFE adversity were 1.40 (0.98-2.11) and 1.25 (0.89-1.75), respectively. The adjusted hazard ratios for all-cause mortality was 1.68 (1.17-2.41) for those with high CFE adversity scores and 1.55 (1.11-2.17) for those with moderate CFE adversity scores. Conclusions Adverse CFE was associated with CVD incidence and all-cause mortality later in life, even after controlling for CVD risk factors in young adulthood.
Authors: Pierce JB; Kershaw KN; Kiefe CI; Jacobs DR; Sidney S; Merkin SS; Feinglass J
J Am Heart Assoc. 2020 05 05;9(9):e015326. Epub 2020-04-28.
Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: A metabolic profiling study
Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) during midlife and an elevated risk of developing hypertension and cardiovascular disease. Glucose tolerance reclassification after delivery is recommended, but fewer than 40% of women with GDM are tested. Thus, improved risk stratification methods are needed, as is a deeper understanding of the pathology underlying the transition from GDM to T2D. We hypothesize that metabolites during the early postpartum period accurately distinguish risk of progression from GDM to T2D and that metabolite changes signify underlying pathophysiology for future disease development. The study utilized fasting plasma samples collected from a well-characterized prospective research study of 1,035 women diagnosed with GDM. The cohort included racially/ethnically diverse pregnant women (aged 20-45 years-33% primiparous, 37% biparous, 30% multiparous) who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. Participants attended in-person research visits including 2-hour 75-g oral glucose tolerance tests (OGTTs) at study baseline (6-9 weeks postpartum) and annually thereafter for 2 years, and we retrieved diabetes diagnoses from electronic medical records for 8 years. In a nested case-control study design, we collected fasting plasma samples among women without diabetes at baseline (n = 1,010) to measure metabolites among those who later progressed to incident T2D or did not develop T2D (non-T2D). We studied 173 incident T2D cases and 485 controls (pair-matched on BMI, age, and race/ethnicity) to discover metabolites associated with new onset of T2D. Up to 2 years post-baseline, we analyzed samples from 98 T2D cases with 239 controls to reveal T2D-associated metabolic changes. The longitudinal analysis tracked metabolic changes within individuals from baseline to 2 years of follow-up as the trajectory of T2D progression. By building prediction models, we discovered a distinct metabolic signature in the early postpartum period that predicted future T2D with a median discriminating power area under the receiver operating characteristic curve of 0.883 (95% CI 0.820-0.945, p < 0.001). At baseline, the most striking finding was an overall increase in amino acids (AAs) as well as diacyl-glycerophospholipids and a decrease in sphingolipids and acyl-alkyl-glycerophospholipids among women with incident T2D. Pathway analysis revealed up-regulated AA metabolism, arginine/proline metabolism, and branched-chain AA (BCAA) metabolism at baseline. At follow-up after the onset of T2D, up-regulation of AAs and down-regulation of sphingolipids and acyl-alkyl-glycerophospholipids were sustained or strengthened. Notably, longitudinal analyses revealed only 10 metabolites associated with progression to T2D, implicating AA and phospholipid metabolism. A study limitation is that all of the analyses were performed with the same cohort. It would be ideal to validate our findings in an independent longitudinal cohort of women with GDM who had glucose tolerance tested during the early postpartum period. In this study, we discovered a metabolic signature predicting the transition from GDM to T2D in the early postpartum period that was superior to clinical parameters (fasting plasma glucose, 2-hour plasma glucose). The findings suggest that metabolic dysregulation, particularly AA dysmetabolism, is present years prior to diabetes onset, and is revealed during the early postpartum period, preceding progression to T2D, among women with GDM. ClinicalTrials.gov Identifier: NCT01967030.
Authors: Lai M; Liu Y; Ronnett GV; Wu A; Cox BJ; Dai FF; Röst HL; Gunderson EP; Wheeler MB
PLoS Med. 2020 05;17(5):e1003112. Epub 2020-05-20.
Effects of Liraglutide on Worsening Renal Function Among Patients With Heart Failure With Reduced Ejection Fraction: Insights From the FIGHT Trial
The FIGHT (Functional Impact of GLP-1 [glucagon-like peptide-1] for Heart Failure Treatment) trial randomized 300 patients with heart failure with reduced ejection fraction (HFrEF) and a recent hospitalization for heart failure to liraglutide versus placebo. While there was no difference in the primary outcome (rank score of time to death, time to rehospitalization for heart failure, and change in NT-proBNP [N-terminal pro-B-type natriuretic peptide]), there was a significant increase in cystatin C among patients randomized to liraglutide raising concern of adverse renal outcomes. We performed a post hoc analysis of FIGHT to investigate whether liraglutide was associated with worsening renal function (WRF). The relationship between randomization to liraglutide and WRF was evaluated using logistic regression models. Two hundred seventy-four patients (91%) had complete data to assess for WRF defined as: increase in SCr ≥0.3 mg/dL, or ≥25% decrease in estimated glomerular filtration rate, or an increase in cystatin C ≥0.3 mg/L from baseline to 180-days. Patients with WRF (n=113, 41%), compared with those without, were older, had more comorbidities, and lower utilization of guideline-directed medical treatment. Logistic regression models showed that age and baseline cystatin C levels were associated with WRF. In adjusted models, liraglutide was not associated with excess risk of WRF compared with placebo (odds ratio, 1.02 [95% CI, 0.62-1.67]). There was also no difference in the rank score when WRF was added as a fourth-tier outcome. Liraglutide was not associated with WRF among patients with HFrEF and a recent hospitalization for heart failure. These data support the relative renal safety profile of liraglutide among patients with HFrEF. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01800968.
Authors: Redouane B; Ambrosy AP; Sharma A; et al.
Circ Heart Fail. 2020 05;13(5):e006758. Epub 2020-05-04.
Administrative codes inaccurately identify recurrent venous thromboembolism: The CVRN VTE study
Studies using administrative data commonly rely on diagnosis codes to identify venous thromboembolism (VTE) events. Our objective was to assess the validity of using International Classification of Disease, 9th Revision (ICD-9) codes in identifying recurrent VTE. Among 5497 adults with confirmed incident VTE from four healthcare delivery systems in the Cardiovascular Research Network (CVRN), we identified all subsequent inpatient, emergency department (ED), and ambulatory clinical encounters associated with an ICD-9 code for VTE (combined with relevant radiology procedure codes for inpatient/ED VTE codes in the secondary discharge position or outpatient codes) during the follow-up period. Medical records were reviewed using standardized diagnostic criteria to assess for the presence of new, recurrent VTE. The positive predictive value (PPV) of codes was calculated as the number of valid events divided by total encounters. We identified 2397 encounters that were considered potential recurrent VTE by ICD-9 codes. However, only 31.1% (95%CI: 29.3-33.0%) of encounters were verified by reviewers as true recurrent VTE. Hospital or ED encounters with VTE codes in the primary position were more likely to represent valid recurrent VTE (PPV 61.3%, 95%CI: 56.7-66.3%) than codes in secondary positions (PPV 35.4%, 95%CI: 31.9-39.3%), or outpatient codes (PPV 20.3%, 95%CI: 18.3-22.5%). PPV was low for all VTE types (29.9% for pulmonary embolism, 38.3% for lower and 37.7% for upper extremity deep venous thrombosis, and 14.1% for other VTE). ICD-9 codes do not accurately identify new VTE events in patients with a prior history of VTE.
Authors: Baumgartner C; Go AS; Fan D; Sung SH; Witt DM; Schmelzer JR; Williams MS; Yale SH; VanWormer JJ; Fang MC
Thromb Res. 2020 05;189:112-118. Epub 2020-03-05.
One-year mortality after implantable cardioverter-defibrillator placement within the Veterans Affairs Health System
Implantable cardioverter-defibrillator (ICD) therapy reduces mortality in patients with heart failure and current guidelines advise implantation of ICDs in patients with a life expectancy of >1 year. We examined trends in all-cause mortality in patients who underwent primary or secondary prevention ICD placement in the Veterans Affairs (VA) Health System. US veterans receiving a new ICD placement for primary or secondary prevention of sudden cardiac death between January 2007 and January 2015, who had heart failure with reduced ejection fraction (HFrEF) were included in the analysis. We assessed all-cause mortality 1 year post-ICD implantation. ICD implantation and HFrEF diagnosis were established with associated ICD-9 codes. The VA death registry was utilized to identify mortality rates following ICD placement. Results were subsequently age-stratified. There were 17 901 veterans with HFrEF with ICD placement nationwide. There was no statistically significant difference in 1-year mortality from 2007 (13.1%) to 2014 (13.4%, P > 0.05). There was a significant increase in 1-year mortality in patients in the oldest age quartile (81.6 years, 32.3% mortality) compared to the youngest quartile (55.5 years, 7% mortality). The finding of diverging clinical outcomes extended to the 30-day but also 8-year mark. Our data suggest there is a high 1-year mortality in aging HFrEF patients undergoing primary and secondary prevention ICD placement. This highlights the importance of developing better predictive models for mortality in our ICD eligible patient population.
Authors: Fudim M; Carlisle MA; Devaraj S; Ajam T; Ambrosy AP; Pokorney SD; Al-Khatib SM; Kamalesh M
Eur J Heart Fail. 2020 05;22(5):859-867. Epub 2020-02-28.
Association Between Blood Pressure and Later-Life Cognition Among Black and White Individuals
Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain. To determine whether cumulative BP levels explain racial differences in cognitive decline. Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018. The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function. Race (black vs white). Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (-0.03 points per year faster [95% CI, -0.05 to -0.01]; P = .004) and memory (-0.08 points per year faster [95% CI, -0.11 to -0.06]; P
Authors: Levine DA; Sidney S; Galecki AT; et al.
JAMA Neurol. 2020 Apr 13.
Long-term cumulative blood pressure in young adults and incident heart failure, coronary heart disease, stroke, and cardiovascular disease: The CARDIA study
Authors: Nwabuo CC; Muntner P; Lima JA; et al.
Eur J Prev Cardiol. 2020 Apr 10:2047487320915342.
Author response: Dietary patterns during adulthood and cognitive performance in midlife: The CARDIA study
Authors: McEvoy CT; Hoang T; Sidney S; Steffen LM; Jacobs DR; Shikany JM; Wilkins JT; Yaffe K
Neurology. 2020 Apr 07;94(14):636.
Association Between Early Recovery of Kidney Function After Acute Kidney Injury and Long-term Clinical Outcomes
The severity of acute kidney injury (AKI) is usually determined based on the maximum serum creatinine concentration. However, the trajectory of kidney function recovery could be an additional important dimension of AKI severity. To assess whether the trajectory of kidney function recovery within 72 hours after AKI is associated with long-term risk of clinical outcomes. This prospective, multicenter cohort study enrolled 1538 adults with or without AKI 3 months after hospital discharge between December 1, 2009, and February 28, 2015. Statistical analyses were completed November 1, 2018. Participants with or without AKI were matched based on demographic characteristics, site, comorbidities, and prehospitalization estimated glomerular filtration rate. Participants with AKI were classified as having resolving or nonresolving AKI based on previously published definitions. Resolving AKI was defined as a decrease in serum creatinine concentration of 0.3 mg/dL or more or 25% or more from maximum in the first 72 hours after AKI diagnosis. Nonresolving AKI was defined as AKI not meeting the definition for resolving AKI. The primary outcome was a composite of major adverse kidney events (MAKE), defined as incident or progressive chronic kidney disease, long-term dialysis, or all-cause death during study follow-up. Among 1538 participants (964 men; mean [SD] age, 64.6 [12.7] years), 769 (50%) had no AKI, 475 (31%) had a resolving AKI pattern, and 294 (19%) had a nonresolving AKI pattern. After a median follow-up of 4.7 years, the outcome of MAKE occurred in 550 (36%) of all participants. The adjusted hazard ratio for MAKE was higher for patients with resolving AKI (adjusted hazard ratio, 1.52; 95% CI, 1.01-2.29; P = .04) and those with nonresolving AKI (adjusted hazard ratio 2.30; 95% CI, 1.52-3.48; P
Authors: Bhatraju PK; Go AS; Wurfel MM; et al.
JAMA Netw Open. 2020 Apr 01;3(4):e202682. Epub 2020-04-01.
Association of Blood Pressure Patterns in Young Adulthood With Cardiovascular Disease and Mortality in Middle Age
Determining blood pressure (BP) patterns in young adulthood that are associated with cardiovascular disease (CVD) events in later life may help to identify young adults who have an increased risk for CVD. To determine whether the long-term variability of BP across clinical visits and the rate of change in BP from young adulthood to midlife are associated with CVD and all-cause mortality by middle age, independently of mean BP during young adulthood and a single BP in midlife. This prospective cohort study included a community-based sample of 3394 African American and white participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, enrolled from March 1985 through June 1986. Patterns of systolic BP (SBP) were evaluated with measurements at year 0 (baseline) and 2, 5, 7, and 10 years after baseline. Visit-to-visit SBP variability was estimated as BP variability independent of the mean (VIM). Data were collected from March 1985 through August 2015 and analyzed from June through October 2019. Cardiovascular disease and all-cause mortality experienced through August 2015 were adjudicated. The associations of each SBP pattern with CVD events and all-cause mortality were determined using Cox proportional hazards regression models. At year 10, the mean (SD) age of the 3394 participants was 35.1 (3.6) years; 1557 (45.9%) were African American; 1892 (55.7%) were women; and 103 (3.0%) were taking antihypertensive medication. During a median follow-up of 20.0 (interquartile range, 19.4-20.2) years, 162 CVD events and 181 deaths occurred. When all BP pattern measurements were entered into the same model including a single SBP measurement at the year 10 examination, the hazard ratios for CVD events for each 1-SD increase in SBP measures were 1.25 (95% CI, 0.90-1.74) for mean SBP, 1.23 (95% CI, 1.07-1.43) for VIM SBP, and 0.99 (95% CI, 0.81-1.26) for annual change of SBP. The VIM for SBP was the only BP pattern associated with all-cause mortality (hazard ratio, 1.24; 95% CI, 1.09-1.41). The results of this study suggest that the assessment of visit-to-visit SBP variability may help identify young adults at increased risk for CVD and all-cause mortality later in life.
Authors: Yano Y; Pletcher MJ; Lloyd-Jones DM; et al.
JAMA Cardiol. 2020 04 01;5(4):382-389.
The effect of frequent hemodialysis on matrix metalloproteinases, their tissue inhibitors, and FGF23: Implications for blood pressure and left ventricular mass modification in the Frequent Hemodialysis Network trials
Frequent hemodialysis modifies serum phosphorus, blood pressure, and left ventricular mass (LVM). We ascertained whether frequent hemodialysis is associated with specific changes in biomarker profile among patients enrolled in the frequent hemodialysis network (FHN) trials. This was a post hoc analysis of biomarkers among patients enrolled to the FHN trials. In particular, we hypothesized that frequent hemodialysis is associated with changes in a specific set of biomarkers which are linked with changes in blood pressure or LVM. Among 332 randomized patients, 243 had biomarker data available. Of these, 124 patients were assigned to 3-times-a-week hemodialysis (94 [Daily Trial] and 30 [Nocturnal Trial]) and 119 patients were assigned to 6-times-a-week hemodialysis (87 [Daily Trial] and 32 [Nocturnal Trial]). Frequent hemodialysis lowered phosphate, blood pressures, LVM, log fibroblast growth factor (FGF)23, and tissue inhibitors of metalloproteinase (TIMP)-2 levels. The fall in phosphate was associated with changes in FGF23 (r = 0.48, P < 0.001) [Daily Trial] and (r = 0.55, P < 0.001) [Nocturnal Trial]) and tended to be associated with changes in systolic blood pressure (r = 0.18, P = 0.057) [Daily Trial] and (r = 0.31, P = 0.04) [Nocturnal Trial]. Within the Daily Trial, changes in MMP2 (r = 0.20, P = 0.034) were associated with changes in LVM. In the Nocturnal Trial, changes in TIMP-1 (r = 0.37, P = 0.029) and MMP 9 (r = -0.38, P = 0.01) were associated with LVM changes. MMP2 changes were associated with changes in systolic blood pressure. Reduction of serum phosphate by frequent hemodialysis may modulate FGF23 levels and systolic blood pressure. Markers of matrix turnover are associated with LVM changes. Frequent hemodialysis may affect pathological mediators of chronic kidney disease-mineral bone-metabolism disorder.
Authors: Chan CT; Kaysen GA; Beck GJ; Li M; Lo JC; Rocco MV; Kliger AS; FHN Trials
Hemodial Int. 2020 04;24(2):162-174. Epub 2019-12-11.
Real-Life Patterns of Exacerbations While on Inhaled Corticosteroids and Long-Acting Beta Agonists for Asthma over 15 Years
Asthma affects more than 300 million people in the world, costs over $80 billion annually in the United States, and is efficaciously treated with inhaled corticosteroids (ICS). To our knowledge, no studies have examined the real-world effectiveness of ICS, including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), and patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. Data included longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS-LABA combination. Asthma exacerbations were defined as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We used an expected-value approach to determine ICS and ICS-LABA coverage over exacerbation events. We compared rates of exacerbation of subjects on ICS or ICS-LABAs to their own rates of exacerbation when off controller medications. We found ICS-LABA therapy had significant effects, reducing all types of exacerbations per day by a factor of 1.76 (95% CI (1.06, 2.93), p = 0.03) and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53), p = 0.037). In conclusion, ICS-LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years.
Authors: McGeachie MJ; Wang AL; Lutz SM; Sordillo JE; Weiss ST; Tantisira KG; Iribarren C; Lu MX; Wu AC
J Clin Med. 2020 Mar 18;9(3). Epub 2020-03-18.
Cumulative Adherence to Secondary Prevention Guidelines and Mortality After Acute Myocardial Infarction
Background The survival benefit associated with cumulative adherence to multiple clinical and lifestyle-related guideline recommendations for secondary prevention after acute myocardial infarction (AMI) is not well established. Methods and Results We examined adults with AMI (mean age 68 years; 64% men) surviving at least 30 (N=25 778) or 90 (N=24 200) days after discharge in a large integrated healthcare system in Northern California from 2008 to 2014. The association between all-cause death and adherence to 6 or 7 secondary prevention guideline recommendations including medical treatment (prescriptions for β-blockers, renin-angiotensin-aldosterone system inhibitors, lipid medications, and antiplatelet medications), risk factor control (blood pressure <140/90 mm Hg and low-density lipoprotein cholesterol <100 mg/dL), and lifestyle approaches (not smoking) at 30 or 90 days after AMI was evaluated with Cox proportional hazard models. To allow patients time to achieve low-density lipoprotein cholesterol <100 mg/dL, this metric was examined only among those alive 90 days after AMI. Overall guideline adherence was high (35% and 34% met 5 or 6 guidelines at 30 days; and 31% and 23% met 6 or 7 at 90 days, respectively). Greater guideline adherence was independently associated with lower mortality (hazard ratio, 0.57 [95% CI, 0.49-0.66] for those meeting 7 and hazard ratio, 0.69 [95% CI, 0.61-0.78] for those meeting 6 guidelines versus 0 to 3 guidelines in 90-day models, with similar results in the 30-day models), with significantly lower mortality per each additional guideline recommendation achieved. Conclusions In a large community-based population, cumulative adherence to guideline-recommended medical therapy, risk factor control, and lifestyle changes after AMI was associated with improved long-term survival. Full adherence was associated with the greatest survival benefit.
Authors: Solomon MD; Leong TK; Levin E; Rana JS; Jaffe MG; Sidney S; Sung SH; Lee C; DeMaria A; Go AS
J Am Heart Assoc. 2020 03 17;9(6):e014415. Epub 2020-03-05.
Recommendations for Cardiovascular Health and Disease Surveillance for 2030 and Beyond: A Policy Statement From the American Heart Association
The release of the American Heart Association’s 2030 Impact Goal and associated metrics for success underscores the importance of cardiovascular health and cardiovascular disease surveillance systems for the acquisition of information sufficient to support implementation and evaluation. The aim of this policy statement is to review and comment on existing recommendations for and current approaches to cardiovascular surveillance, identify gaps, and formulate policy implications and pragmatic recommendations for transforming surveillance of cardiovascular disease and cardiovascular health in the United States. The development of community platforms coupled with widespread use of digital technologies, electronic health records, and mobile health has created new opportunities that could greatly modernize surveillance if coordinated in a pragmatic matter. However, technology and public health and scientific mandates must be merged into action. We describe the action and components necessary to create the cardiovascular health and cardiovascular disease surveillance system of the future, steps in development, and challenges that federal, state, and local governments will need to address. Development of robust policies and commitment to collaboration among professional organizations, community partners, and policy makers are critical to ultimately reduce the burden of cardiovascular disease and improve cardiovascular health and to evaluate whether national health goals are achieved.
Authors: Roger VL; Sidney S; Fairchild AL; Howard VJ; Labarthe DR; Shay CM; Tiner AC; Whitsel LP; Rosamond WD; American Heart Association Advocacy Coordinating Committee
Circulation. 2020 03 03;141(9):e104-e119. Epub 2020-01-29.
Long-term freedom from aneurysm-related mortality remains favorable after endovascular abdominal aortic aneurysm repair in a 15-year multicenter registry
Endovascular aneurysm repair (EVAR) has become the preferred approach to abdominal aortic aneurysm (AAA) because of lower early morbidity and mortality than open repair. However, the ability of EVAR to prevent long-term aneurysm-related mortality (ARM) has been questioned in light of recent trial data. We have updated our long-term EVAR experience in a large multicenter registry to further examine this issue. Between 2000 and 2010, 1736 patients with AAA underwent EVAR in a large integrated regional healthcare system. We extended follow-up in this previously reported cohort through 2015 and identified predictors associated with ARM and need for major reintervention. The primary outcome was ARM. Secondary outcomes were all-cause mortality, delayed aneurysm rupture, major adverse event, major reintervention, sac growth of more than 5 mm, and type I or III endoleak. End points were analyzed for the whole cohort and compared for patients who underwent EVAR during the earlier (2000-2005) and latter (2006-2010) halves of the enrollment period to assess for changes in outcomes over time of repair. The overall follow-up rate was 96.3%, and median follow-up was 5.5 years (interquartile range, 2.8-7.7 years). During the study period, 958 patients died, of whom 63 experienced ARM (6.6%). Overall crude rate of freedom from ARM was 96.4%. Delayed aneurysm rupture was seen in 1.3% (n = 23), with a median time to event of 4.1 years (interquartile range, 1.7-7.2 years). Major adverse events occurred in 12.4% of patients, and major reintervention was performed in 10.3%. Overall freedom from major adverse event or major reintervention was seen in 84.0%. Significant predictors of ARM included female sex, age 80 to 89 years, urgent EVAR, and any major reintervention. The unadjusted cumulative probability of all-cause survival was significantly higher in the late group than the early group at 5 years (66.8% vs 59.8%; P = .01, log-rank test); however, freedom from ARM at 5 years was not significantly different (96.5% and 97.1%, respectively; P = .67, log-rank test). Our results demonstrate favorable long-term freedom from major adverse event or major reintervention after EVAR and extremely low rates of ARM and delayed rupture. Our findings support EVAR as a safe, long-term solution for managing patients with AAA and provide insight into clinical parameters that can be used to stratify patients’ post-EVAR surveillance and need for reintervention.
Authors: Rich N; Tucker LY; Okuhn S; Hua H; Hill B; Goodney P; Chang R
J Vasc Surg. 2020 03;71(3):790-798. Epub 2019-09-05.
The Epidemiology of Metatarsal Fractures Among Older Females With Bisphosphonate Exposure
Bisphosphonates (BP) are used to treat osteoporosis, although rare atypical femur fractures have occurred with long-term exposure, especially among Asians. Metatarsal fractures have also been reported with atypical femur fracture. We examined the epidemiology of metatarsal fractures among 48,390 females aged ≥50 years who initiated oral BP and were followed for a median 7.7 years, including 68 females who experienced an atypical femur fracture. Incident metatarsal fractures after BP initiation were identified by clinical diagnoses and validated by record review. The association of BP, clinical risk factors, race/ethnicity, and metatarsal fracture was examined by using Cox proportional hazard analyses. Among 1123 females with incident metatarsal fracture, 61.0% had an isolated fifth metatarsal fracture. The incidence of metatarsal fracture was 312 per 100,000 person-years of follow-up and was substantially lower for Asians. The adjusted relative rate for metatarsal fractures was 0.5 (95% confidence interval 0.4 to 0.6) for Asians compared with whites. Younger age, prior fracture, other risk factors, and current BP were associated with an increased relative rate of metatarsal fracture, but BP duration was not. Females with atypical femur fracture were not more likely to experience metatarsal fracture (2.9% versus 2.3%, p = .7), but only 68 females had an atypical fracture and stress fracture of the metatarsals was not examined. Except for age, the demographic profile for metatarsal fracture after initiating BP was similar to that for osteoporotic fracture, with Asians at a much lower risk. Although metatarsal fractures were not associated with BP duration or atypical femur fracture, the subset of metatarsal stress fractures was not specifically examined.
Authors: West TA; Pollard JD; Chandra M; Hui RL; Weintraub MR; King CM; Grimsrud CD; Lo JC
J Foot Ankle Surg. 2020 Mar - Apr;59(2):269-273.
Post-Acute Kidney Injury Proteinuria and Subsequent Kidney Disease Progression: The Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Study
Among patients who had acute kidney injury (AKI) during hospitalization, there is a need to improve risk prediction such that those at highest risk for subsequent loss of kidney function are identified for appropriate follow-up. To evaluate the association of post-AKI proteinuria with increased risk of future loss of renal function. The Assessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Study was a multicenter prospective cohort study including 4 clinical centers in North America included 1538 patients enrolled 3 months after hospital discharge between December 2009 and February 2015. Urine albumin-to-creatinine ratio (ACR) quantified 3 months after hospital discharge. Kidney disease progression defined as halving of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Of the 1538 participants, 769 (50%) had AKI durring hospitalization. The baseline study visit took place at a mean (SD) 91 (23) days after discharge. The mean (SD) age was 65 (13) years; the median eGFR was 68 mL/min/1.73 m2; and the median urine ACR was 15 mg/g. Overall, 547 (37%) study participants were women and 195 (13%) were black. After a median follow-up of 4.7 years, 138 (9%) participants had kidney disease progression. Higher post-AKI urine ACR level was associated with increased risk of kidney disease progression (hazard ratio [HR], 1.53 for each doubling; 95% CI, 1.45-1.62), and urine ACR measurement was a strong discriminator for future kidney disease progression (C statistic, 0.82). The performance of urine ACR was stronger in patients who had had AKI than in those who had not (C statistic, 0.70). A comprehensive model of clinical risk factors (eGFR, blood pressure, and demographics) including ACR provided better discrimination for predicting kidney disease progression after hospital discharge among those who had had AKI (C statistic, 0.85) vs those who had not (C statistic, 0.76). In the entire matched cohort, after taking into account urine ACR, eGFR, demographics, and traditional chronic kidney risk factors determined 3 months after discharge, AKI (HR, 1.46; 95% CI, 0.51-4.13 for AKI vs non-AKI) or severity of AKI (HR, 1.54; 95% CI, 0.50-4.72 for AKI stage 1 vs non-AKI; HR, 0.56; 95% CI, 0.07-4.84 for AKI stage 2 vs non-AKI; HR, 2.24; 95% CI, 0.33-15.29 for AKI stage 3 vs non-AKI) was not independently associated with more rapid kidney disease progression. Proteinuria level is a valuable risk-stratification tool in the post-AKI period. These results suggest there should be more widespread and routine quantification of proteinuria after hospitalized AKI.
Authors: Hsu CY; Go AS; ASSESS-AKI Investigators; et al.
JAMA Intern Med. 2020 03 01;180(3):402-410.
Polygenic Risk, Fitness, and Obesity in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Obesity is a major determinant of disease burden worldwide. Polygenic risk scores (PRSs) have been posited as key predictors of obesity. How a PRS can be translated to the clinical encounter (especially in the context of fitness, activity, and parental history of overweight) remains unclear. To quantify the relative importance of a PRS, fitness, activity, parental history of overweight, and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) in young adulthood on BMI trends over 25 years. This population-based prospective cohort study at 4 US centers included white individuals and black individuals with assessments of polygenic risk of obesity, fitness, activity, and BMI in young adulthood (in their 20s) and up to 25 years of follow-up. Data collected between March 1985 and August 2011 were analyzed from April 25, 2019, to September 29, 2019. Body mass index at the initial visit and 25 years later. This study evaluated an obesity PRS from a recently reported study of 1608 white individuals (848 women [52.7%]) and 909 black individuals (548 women [60.3%]) across the United States. At baseline (year 0), mean (SD) overall BMI was 24.2 (4.5), which increased to 29.6 (6.9) at year 25. Among white individuals, the PRS (combined with age, sex, self-reported parental history of overweight, and principal components of ancestry) explained 11.9% (at year 0) and 13.6% (at year 25) of variation in BMI. Although the addition of fitness increased the explanatory capability of the model (24.0% variance at baseline and up to 18.1% variance in BMI at year 25), baseline BMI in young adulthood was the strongest factor, explaining 52.3% of BMI in midlife in combination with age, sex, and self-reported parental history of overweight. Accordingly, models that included baseline BMI (especially BMI surveillance over time) were better in predicting BMI at year 25 compared with the PRS. In fully adjusted models, the effect sizes for fitness and the PRS on BMI were comparable in opposing directions. The added explanatory capacity of the PRS among black individuals was lower than among white individuals. Among white individuals, addition of baseline BMI and surveillance of BMI over time was associated with improved precision of predicted BMI at year 25 (mean error in predicted BMI 0 kg/m2 [95% CI, -11.4 to 11.4] to 0 kg/m2 [95% CI, -8.5 to 8.5] for baseline BMI and mean error 0 kg/m2 [95% CI, -5.3 to 5.3] for BMI surveillance). Cardiorespiratory fitness in young adulthood and a PRS are modestly associated with midlife BMI, although future BMI is associated with BMI in young adulthood. Fitness has a comparable association with future BMI as does the PRS. Caution should be exercised in the widespread use of polygenic risk for obesity prevention in adults, and close clinical surveillance and fitness may have prime roles in limiting the adverse consequences of elevated BMI on health.
Authors: Murthy VL; Bouchard C; Shah RV; et al.
JAMA Cardiol. 2020 03 01;5(3):40-48.
Sedentary Time and Physical Activity Across Occupational Classifications
To examine differences in activity patterns across employment and occupational classifications. Cross-sectional. A 2005-2006 Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants with valid accelerometry data (n = 2068). Uniaxial accelerometry data (ActiGraph 7164), accumulated during waking hours, were summarized as mean activity counts (counts/min) and time spent (min/d) in long-bout sedentary (≥30 minutes, SED≥30), short-bout sedentary (<30 minutes, SED<30), light physical activity (LPA), short-bout moderate-to-vigorous physical activity (<10 minutes, MVPA<10), and long-bout MVPA (≥10 minutes, MVPA≥10) using Freedson cut-points. Employment status was self-reported as full time, part time, unemployed, keeping house, or raising children. Self-reported job duties were categorized into 23 major groups using the 2010 Standard Occupational Classification. Omnibus differences were analyzed using adjusted analysis of covariance and repeated after stratification by race (black/white) and sex (female/male). SED≥30, SED<30, LPA, and MVPA<10 differed significantly by employment and occupational categories (P ≤ .05), while MVPA≥10 did not (P ≥ .50). SED≥30, SED<30, and LPA differed by occupational classification in men, women, blacks, and whites (P < .05). Mean activity counts, MVPA<10, and MVPA≥10 were significantly different across occupational classifications in whites (P ≤ .05), but not in blacks (P > .05). Significant differences in mean activity counts and MVPA<10 across occupational classifications were found in males (P ≤ .001), but not in females (P > .05). Time within activity intensity categories differs across employment and occupational classifications and by race and sex.
Authors: Quinn TD; Pettee Gabriel K; Siddique J; Aaby D; Whitaker KM; Lane-Cordova A; Sidney S; Sternfield B; Barone Gibbs B
Am J Health Promot. 2020 03;34(3):247-256. Epub 2019-11-14.
Race and Mortality in CKD and Dialysis: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study
Few studies have investigated racial disparities in survival among dialysis patients in a manner that considers risk factors and mortality during the phase of kidney disease before maintenance dialysis. Our objective was to explore racial variations in survival among dialysis patients and relate them to racial differences in comorbid conditions and rates of death in the setting of kidney disease not yet requiring dialysis therapy. Retrospective cohort study. 3,288 black and white participants in the Chronic Renal Insufficiency Cohort (CRIC), none of whom were receiving dialysis at enrollment. Race. Mortality. Cox proportional hazards regression was used to examine the association between race and mortality starting at: (1) time of dialysis initiation and (2) entry into the CRIC. During 7.1 years of median follow-up, 678 CRIC participants started dialysis. Starting from the time of dialysis initiation, blacks had lower risk for death (unadjusted HR, 0.67; 95% CI, 0.51-0.87) compared with whites. Starting from baseline CRIC enrollment, the strength of the association between some risk factors and dialysis was notably stronger for whites than blacks. For example, the HR for dialysis onset in the presence (vs absence) of heart failure at CRIC enrollment was 1.30 (95% CI, 1.01-1.68) for blacks versus 2.78 (95% CI, 1.90-4.50) for whites, suggesting differential severity of these risk factors by race. When we included deaths occurring both before and after dialysis, risk for death was higher among blacks (vs whites) starting from CRIC enrollment (HR, 1.41; 95% CI, 1.22-1.64), but this finding was attenuated in adjusted models (HR, 1.08; 95% CI, 0.91-1.28). Residual confounding. The apparent survival advantage among blacks over whites treated with dialysis may be attributed to selected transition of a subset of whites with more severe comorbid conditions onto dialysis.
Authors: Ku E; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2020 03;75(3):394-403. Epub 2019-11-12.
Spontaneous Coronary Artery Dissection and Incident Ventricular Arrhythmias: Frequency, Clinical Characteristics, and Outcomes
Authors: Chen S; Ambrosy AP; Mahrer KN; Lundstrom RJ; Naderi S
JACC Cardiovasc Interv. 2020 02 24;13(4):539-541.
Cardiac valvular abnormalities associated with use and cumulative exposure of cabergoline for hyperprolactinemia: the CATCH study
Whether lower dose cabergoline therapy for hyperprolactinemia increases risk of valvular dysfunction remains controversial. We examined valvular abnormalities among asymptomatic adults with hyperprolactinemia treated with dopamine agonists. This cross-sectional study was conducted among adults receiving cabergoline or bromocriptine for > 12 months for hyperprolactinemia and had no cardiac-related symptoms. Cardiac valve morphology and function were assessed from transthoracic echocardiograms at the study visit (except for two participants) with evaluation performed blinded to type and duration of dopamine agonist received. Among 174 participants (mean age 49 ± 13 years, 63% women) without known structural heart disease before starting therapy, 62 received only cabergoline, 63 received only bromocriptine, and 49 received both. Median cabergoline use was 2.8 years in cabergoline only users and 3.2 years for those exposed to both cabergoline and bromocriptine; median bromocriptine use was 5.5 years in bromocriptine only users and 1.1 years for those exposed to both cabergoline and bromocriptine. Compared with bromocriptine only users (17.5%), regurgitation of ≥1 valve was more common for cabergoline only (37.1%, P = 0.02) but not for combined exposure (26.5%, P = 0.26). Compared with bromocriptine only exposure (1.6%), regurgitation of ≥2 valves was more common for cabergoline only (11.3%, P = 0.03) and combined exposure (12.2%, P = 0.04). Cabergoline only users had higher age-sex-adjusted odds for ≥1 valve with grade 2+ regurgitation compared to bromocriptine only users (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI]:1.3-7.5, P = 0.008), but the association for combined exposure to cabergoline and bromocriptine was not significant (aOR 1.7, 95%CI:0.7-4.3, P = 0.26). Compared to bromocriptine only, age-sex-adjusted odds of ≥2 valves with grade 2+ regurgitation were higher for both cabergoline only (aOR 8.4, 95% CI:1.0-72.2, P = 0.05) and combined exposure (aOR 8.8, 95% CI:1.0-75.8, P = 0.05). Cumulative cabergoline exposure > 115 mg was associated with a higher age-sex adjusted odds of ≥2 valves with grade 2+ regurgitation (aOR 9.6, 95%CI:1.1-81.3, P = 0.04) compared to bromocriptine only. Among community-based adults treated for hyperprolactinemia, cabergoline use and greater cumulative cabergoline exposure were associated with a higher prevalence of primarily mild valvular regurgitation compared with bromocriptine. Research is needed to clarify which patients treated with dopamine agonists may benefit from echocardiographic screening and surveillance.
Authors: Budayr A; Tan TC; Lo JC; Zaroff JG; Tabada GH; Yang J; Go AS
BMC Endocr Disord. 2020 Feb 19;20(1):25. Epub 2020-02-19.
Comparison of Long-Term Adverse Outcomes in Patients With Atrial Fibrillation Having Ablation Versus Antiarrhythmic Medications
The impact of atrial fibrillation (AF) catheter ablation versus chronic antiarrhythmic therapy alone on clinical outcomes such as death and stroke remains unclear. We compared adverse outcomes for AF ablation versus chronic antiarrhythmic therapy in 1,070 adults with AF treated between 2010 and 2014 in the Kaiser Permanente Northern California and Southern California healthcare delivery systems. Patients who underwent AF catheter ablation were matched to patients treated with only antiarrhythmic medications, based on age, gender, history of heart failure, history of coronary heart disease, history of hypertension, history of diabetes, and high-dimensional propensity score. We compared crude and adjusted rates of death, ischemic stroke or transient ischemic attack, intracranial hemorrhage, and hospitalization. The matched cohort of 535 patients treated with AF ablation and 535 treated with antiarrhythmic therapy had a median follow-up of 2.0 (interquartile range 1.1 to 3.5) years. There was no significant difference in adjusted rates of death (adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.03 to 1.95), intracranial hemorrhage (adjusted HR 0.17, CI 0.02 to 1.71), ischemic stroke or transient ischemic attack (adjusted HR 0.53, CI 0.18 to 1.60), and heart failure hospitalization (adjusted HR 0.85, CI 0.34 to 2.12), although there was a trend toward improvement in these outcomes with ablation. However, there was a significantly increased risk of all-cause hospitalization following ablation (adjusted HR 1.60, CI 1.25 to 2.05). In a contemporary, multicenter, propensity-matched observational cohort, AF ablation was not significantly associated with death, intracranial hemorrhage, ischemic stroke or transient ischemic attack, or heart failure hospitalization, but was associated with a higher rate of all cause-hospitalization.
Authors: Freeman JV; Tabada GH; Reynolds K; Sung SH; Singer DE; Wang PJ; Liu TI; Gupta N; Hlatky MA; Go AS
Am J Cardiol. 2020 02 15;125(4):553-561. Epub 2019-11-19.
Statin Therapy and Risk of Incident Diabetes Mellitus in Adults With Cardiovascular Risk Factors
The association between statins and diabetes mellitus (DM) remains controversial. The Kaiser Permanente CHAMP Study identified adults without DM who had cardiovascular (CV) risk factors and no previous lipid lowering therapy (LLT) between 2008 and 2010. The CV risk factors included known atherosclerotic CV disease (ASCVD), elevated low-density lipoprotein cholesterol ≥190 mg/dl, or a low-density lipoprotein cholesterol between 70 and 189 mg/dl and an estimated 10-year ASCVD risk ≥7.5%. Incident DM was defined as ≥2 abnormal tests (i.e., A1C ≥6.5% or a fasting blood glucose ≥126 mg/dl) or ≥1 abnormal test result plus a new diagnostic code or medication for DM. Among 213,289 eligible adults, 28,149 patients initiating statins were carefully matched to an equal number of patients who remained off LLT during follow-up. Compared with matched patients not receiving statins, those initiating statin therapy had the same mean age (67.9 ± 9.4 years) and gender (42.8% women). The crude rate (per 100 person-years) of incident DM was low (0.55, 95% confidence interval [CI] 0.52 to 0.59) but was marginally higher in patients who were treated with a statin (0.69, 95% CI 0.64 to 0.74) versus no LLT (0.42, 95% CI 0.38 to 0.46). After additional adjustment, statin therapy was associated with a modestly increased risk of incident DM (adjusted hazard ratio 1.17, 95% CI 1.02 to 1.34). In conclusion, in adults without DM at increased ASCVD risk, initiation of statin therapy was independently associated with a modestly higher risk of incident DM.
Authors: Go AS; Ambrosy AP; Kheder K; Fan D; Sung SH; Inveiss AI; Romo-LeTourneau V; Thomas SM; Koren A; Lo JC; Kaiser Permanente Cholesterol-Lowering Therapy in High-Risk Adults: Management and Patient Risks (KP CHAMP) Study
Am J Cardiol. 2020 02 15;125(4):534-541. Epub 2019-11-19.
Risk of atherosclerotic cardiovascular disease by cardiovascular health metric categories in approximately 1 million patients
Authors: Rana JS; Liu JY; Moffet HH; Karter AJ; Nasir K; Solomon MD; Jaffe MG; Ambrosy AP; Go AS; Sidney S
Eur J Prev Cardiol. 2020 Feb 10:2047487320905025.
Risk of atherosclerotic cardiovascular disease by cardiovascular health metric categories in approximately 1 million patients
Authors: Rana, Jamal S; Liu, Jennifer Y; Moffet, Howard H; Karter, Andrew J; Nasir, Khurram; Solomon, Matthew D; Jaffe, Marc G; Ambrosy, Andrew P; Go, Alan S; Sidney, Stephen
Eur J Prev Cardiol. 2020 Feb 07.
No Association Between Bone Mineral Density and Breast Arterial Calcification Among Postmenopausal Women
The association between bone mineral density (BMD) and breast arterial calcification (BAC) remains poorly understood and controversial. The objective of this article is to examine the association between BMD and BAC in a large cohort of postmenopausal women undergoing routine mammography. A cross-sectional analysis of baseline data from a multiethnic cohort was performed. The setting for this analysis is an integrated health care delivery system in Northern California in the United States. A total of 1273 women age 60 to 79 years (mean age, 67 years) were recruited within 12 months of screening mammography. A BAC score (mg) was obtained from digital mammograms using a novel densitometry method. BAC presence was defined as a BAC score greater than 0 mg, and severe BAC as a BAC score greater than 20 mg. Overall, 53% of women had osteopenia and 21% had osteoporosis. The prevalence of BAC greater than 0 mg was 29%, 30%, and 29% among women with normal BMD, osteopenia, and osteoporosis, respectively (P = 0.98). The prevalence of BAC greater than 20 mg was 5%, 3%, and 5% among women with normal BMD, osteopenia and osteoporosis, respectively (P = .65). The odds ratios (ORs) of BAC greater than 0 mg vs BAC = 0 mg after multivariable adjustment were 1.09 (95% CI, 0.81-1.48; P = .54) for osteopenia and 0.99 (95% CI, 0.69-1.48; P = .98) for osteoporosis. The adjusted ORs for BAC greater than 20 mg vs BAC 20 mg or less were 1.03 (95% CI, 0.52-2.01; P = .93) for osteopenia and 1.89 (95 CI, 0.81-4.47; P = .14) for osteoporosis. Our findings do not support an association of either osteopenia or osteoporosis with BAC presence or severity among postmenopausal women.
Authors: Iribarren C; Chandra M; Molloi S; Sam D; Sanchez G; Bidgoli FA; Cho HM; Ding H; Lo JC
J Endocr Soc. 2020 Feb 01;4(2):bvz026. Epub 2019-11-27.
Determinants of Oral Bisphosphonate Use Beyond 5 Years
Few studies have examined factors that determine bisphosphonate (BP) continuation beyond 5 years in clinical practice. To investigate factors associated with BP continuation among women who completed 5 years of BP therapy. Women who received 5 consecutive years of oral BP treatment entered the cohort during 2002-2014 and were followed up to 5 additional years. Multivariable logistic regression was used to evaluate the association of demographic and clinical factors with adherent treatment continuation. The cohort included 19,091 women with a median age of 72 years. Baseline and time-varying factors associated with increased odds of BP continuation after 5 years were (a) most recent bone mineral density (BMD) T-score -2 to -2.4 (OR = 1.31, 95% CI = 1.25-1.38), T-score -2.5 to -2.9 (OR = 1.48, 95% CI = 1.39-1.57), and T-score ≤ -3.0 (OR = 1.57, 95% CI = 1.47-1.68) versus T-scores above -2.0; (b) index date before 2008 (OR =1.35, 95% CI = 1.29-1.41); and (c) diabetes mellitus (OR = 1.08, 95% CI = 1.01-1.16). In contrast, factors associated with decreased odds of BP continuation were (a) recent hip (OR = 0.61, 95% CI = 0.52-0.71) or humerus (OR = 0.79, 95% CI = 0.66-0.94) fracture or fracture other than hip, wrist, spine, or humerus (OR = 0.90, 95% CI = 0.84-0.97); (b) Charlson Comorbidity Index score > 2 (OR = 0.91, 95% CI = 0.84-0.98); (c) history of rheumatoid arthritis (OR = 0.89, 95% CI = 0.80-0.99); (d) Hispanic (OR = 0.89, 95% CI=0.85-0.94) or Asian (OR = 0.90, 95% CI = 0.85-0.94) race/ethnicity; and (e) use of proton pump inhibitors (OR = 0.65, 95% CI = 0.59-0.71). Patient age and fracture before BP initiation were not associated with treatment continuation. Clinical factors predicting continued BP treatment beyond 5 years include low BMD T-score, absence of recent fracture, and earlier era of treatment. Use of proton pump inhibitors was associated with lower likelihood of BP continuation. Other clinical and demographic factors were also noted to have variable effects on BP treatment continuation. This study was supported by a grant from the National Institute on Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH; R01AG047230, S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Kaiser Permanente. Lo has received previous research funding from Amgen and Sanofi, unrelated to the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, unrelated to the current study. Ettinger has served as an expert witness for Teva Pharmaceuticals, unrelated to the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. The other authors have nothing to disclose. These data were presented at the 2018 Annual Meeting of the American Society of Bone and Mineral Research (ASBMR), September 28-October 1, 2018, Montreal, Quebec, Canada.
Authors: Izano MA; Lo JC; Ettinger B; Ott SM; Li BH; Niu F; Hui RL; Neugebauer R; Adams AL
J Manag Care Spec Pharm. 2020 Feb;26(2):197-202.
Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial
In PIONEER-HF, among stabilized patients with acute decompensated heart failure (ADHF), the in-hospital initiation of sacubitril/valsartan was well tolerated and led to improved outcomes compared with enalapril. However, there are limited data comparing the strategies of in-hospital vs postdischarge initiation of sacubitril/valsartan. To describe changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients recently hospitalized for ADHF and switching from taking enalapril to taking sacubitril/valsartan after discharge and compare clinical outcomes for patients randomized to receive in-hospital initiation of sacubitril/valsartan vs in-hospital initiation of enalapril who later switched to taking sacubitril/valsartan during an open-label extension phase. Sacubitril/valsartan titrated to 97/103 mg twice daily. The PIONEER-HF trial was a multicenter, randomized, double-blind, active-controlled trial conducted at 129 US sites between May 2016 and May 2018 that compared the in-hospital initiation of sacubitril/valsartan vs enalapril (titrated to target dose, 10 mg twice daily) for 8 weeks among patients admitted for ADHF with reduced ejection fraction and hemodynamic stability. All patients were to continue in a 4-week, open-label study of sacubitril/valsartan; of 881 patients enrolled in PIONEER-HF, 832 (94%) continued in the open-label study. Changes in NT-proBNP levels from week 8 to 12 as well as the exploratory composite of heart failure rehospitalization or cardiovascular death from randomization through week 12. Of 881 participants, 226 (27.7%) were women, 487 (58.5%) were white, 297 (35.7%) were black, 15 (1.8%) were Asian, and 73 (8.8%) were of Hispanic ethnicity; the mean (SD) age was 61 (14) years. For patients who continued to take sacubitril/valsartan, NT-proBNP levels declined -17.2% (95% CI, -3.2 to -29.1) from week 8 to 12. The NT-proBNP levels declined to a greater extent for those switching from taking enalapril to sacubitril/valsartan after the week 8 visit (-37.4%; 95% CI, -28.1 to -45.6; P < .001; comparing changes in 2 groups). Over the entire 12 weeks of follow-up, patients that began taking sacubitril/valsartan in the hospital had a lower hazard for the composite outcome compared with patients that initiated enalapril in the hospital and then had a delayed initiation of sacubitril/valsartan 8 weeks later (hazard ratio, 0.69; 95% CI 0.49-0.97). Switching patients' treatment from enalapril to sacubitril/valsartan at 8 weeks after randomization led to a further 37% reduction in NT-proBNP levels in patients with heart failure with reduced ejection fraction and a recent hospitalization for ADHF. ClinicalTrials.gov identifier: NCT02554890.
Authors: DeVore AD; Braunwald E; Morrow DA; Duffy CI; Ambrosy AP; Chakraborty H; McCague K; Rocha R; Velazquez EJ; PIONEER-HF Investigators
JAMA Cardiol. 2020 02 01;5(2):202-207.
Are existing and emerging biomarkers associated with cardiorespiratory fitness in patients with chronic heart failure?
Cardiorespiratory fitness (CRF) is closely linked to health status and clinical outcomes in heart failure (HF) patients. We aimed to test whether biomarkers can reflect CRF and its change over time. This post hoc analysis used data from ambulatory cohorts of heart failure with reduced ejection fraction (HFrEF) (IRONOUT) and heart failure with preserved ejection fraction (HFpEF) (RELAX). Cardiopulmonary exercise testing, 6-minute walk distance (6MWD), and serum biomarkers were measured at baseline and 16- or 24-week follow-up (for IRONOUT and RELAX respectively). Biomarkers included N-terminal pro-B-type natriuretic peptide (NT-proBNP), soluble ST2, growth differentiation factor-15, and Galectin-3. Analysis included 225 patients with HFrEF and 216 with HFpEF. Baseline peak VO2, VE/VCO2 slope, and 6MWD showed a mild correlation with the doubling of all 4 tested biomarkers in HFrEF and HFpEF. Following multivariable adjustment (including all biomarkers), the only significant association between change in biomarker and functional parameter in HFrEF was change in NT-proBNP and change in VE/VCO2 slope (3.596% increase per doubling, 95% CI 0.779-6.492, P = .012). In HFpEF, a decrease in peak VO2 was associated with an increase in NT-proBNP (-0.726 mL/min/kg per doubling, 95% CI -1.100 to -0.353, P < .001), and a decrease in 6MWD was associated with an increase in growth differentiation factor-15 (-31.606 m per doubling, 95% CI -61.404 to -1.809, P = .038). In these ambulatory trial cohorts, NT-proBNP was associated with baseline and change in CRF in HFrEF and HFpEF. In contrast, novel biomarkers do not appear suitable as a reliable surrogate for serial assessment of exercise capacity in HF patients given lack of consistent independent association with CRF beyond traditional risk factors and NT-proBNP.
Authors: Fudim M; Ambrosy AP; Felker GM; et al.
Am Heart J. 2020 02;220:97-107. Epub 2019-11-16.
Hyperglycemia and outcomes in acute heart failure – A bittersweet relationship
Authors: Chioncel O; Ambrosy AP
Int J Cardiol. 2020 02 01;300:196-197. Epub 2019-11-18.
Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study
The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. Retrospective analysis nested in a cohort study. Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). Years before ESKD. Serial FGF-23, PTH, serum phosphate, and serum calcium levels. To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used “ESKD-anchored longitudinal analyses” to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.
Authors: Isakova T; Lo J; CRIC Study Investigators; et al.
Am J Kidney Dis. 2020 02;75(2):235-244. Epub 2019-10-23.
Individualized Relative Intensity Physical Activity Accelerometer Cut-points
Physical activity (PA) intensity is expressed as either absolute or relative intensity. Absolute intensity refers to the energy required to perform an activity. Relative intensity refers to a level of effort that takes into account how hard an individual is working relative to their maximum capacity. We sought to develop methods for obtaining individualized relative-intensity accelerometer cut points using data from a maximal graded exercise treadmill test (GXT) so that each individual has their own cut point. A total of 2363 men and women 38 to 50 yr old from the CARDIA fitness study wore ActiGraph 7164 accelerometers during a maximal GXT and for seven consecutive days in 2005-2006. Using mixed-effects regression models, we regressed accelerometer counts on heart rate as a percentage of maximum (%HRmax) and on RPE. Based on these two models, we obtained a moderate-intensity (%HRmax = 64% or RPE = 12) count cut point that is specific to each participant. We applied these subject-specific cut points to the available CARDIA accelerometer data. Using RPE, the mean moderate-intensity accelerometer cut point was 4004 (SD = 1120) counts per minute. On average, cut points were higher for men (4189 counts per minute) versus women (3865 counts per minute) and were higher for Whites (4088 counts per minute) versus African Americans (3896 counts per minute). Cut points were correlated with body mass index (rho = -0.11) and GXT duration (rho = 0.33). Mean daily minutes of absolute- and relative-intensity moderate to vigorous PA were 34.1 (SD = 31.1) min·d and 9.1 (SD = 18.2) min·d, respectively. RPE cut points were higher than those based on %HRmax. This is likely due to some participants ending the GXT before achieving their HRmax. Accelerometer-based relative-intensity PA may be a useful measure of intensity relative to maximal capacity.
Authors: Siddique J; Sternfeld B; Freedson P; et al.
Med Sci Sports Exerc. 2020 02;52(2):398-407.
Adult Life-Course Trajectories of Lung Function and the Development of Emphysema: The CARDIA Lung Study
Peak lung function and rate of decline predict future airflow obstruction and nonrespiratory comorbid conditions. Associations between lung function trajectories and emphysema have not been explored. Using data from the population-based CARDIA Study, we sought to describe the prevalence of visually ascertained emphysema at multiple time points and contextualize its development based upon participant’s adult life course measures of lung function. There were 3171 men and women enrolled at a mean age of 25 years, who underwent serial spirometric examinations through a mean age of 55 years. Trajectories for the change in percent-predicted forced expiratory volume in one second (FEV1) were determined by fitting a mixture model via maximum likelihood. Emphysema was visually identified on computed tomographic scans and its prevalence reported at mean ages of 40, 45, and 50 years. We identified 5 trajectories describing peak and change in FEV1: “Preserved Ideal,” “Preserved Good,” “Preserved Impaired,” “Worsening,” and “Persistently Poor.” Ever smokers comprised part of all 5 trajectories. The prevalence of emphysema was 1.7% (n = 46; mean age of 40 years), 2.5% (n = 67; mean age of 45 years), and 7.1% (n = 189; mean age of 50 years). Of those with emphysema at a mean age of 50 years, 18.0% were never smokers. Worsening and poor lung health trajectories were associated with increased odds of future emphysema independent of chronic tobacco smoke exposure (odds ratio 5.06; confidence interval, 1.84-13.96; odds ratio 4.85; confidence interval, 1.43-16.44). Lower peak and accelerated decline in FEV1 are risk factors for future emphysema independent of smoking status.
Authors: Washko GR; Iribarren C; Kalhan R; et al.
Am J Med. 2020 02;133(2):222-230.e11. Epub 2019-07-29.
Serum bone markers and risk of osteoporosis and fragility fractures in women who received endocrine therapy for breast cancer: a prospective study
Osteoporosis and fragility fracture are major bone toxicities of aromatase inhibitors (AIs) for postmenopausal hormone receptor-positive breast cancer. Except for a few small studies on bone turnover markers and reduced bone mineral density after AI treatment, data on the associations of bone markers and risk of osteoporosis or fracture from prospective studies are lacking. In a prospective study of 1709 women on AIs, two bone turnover markers, BALP and TRACP, and two bone regulatory markers, RANKL and OPG, were measured and examined in relation to risk of osteoporosis and fragility fractures during a median follow-up time of 6.1 years. Higher levels of BALP and TRACP were both associated with increased risk of osteoporosis and higher BALP/TRACP ratios were associated with lower risk of osteoporosis, but no associations were observed for fracture risk. Higher levels of OPG were associated with increased risk of fracture, whereas higher levels of RANKL were associated with lower risk. As a result, OPG/RANKL ratios were positively associated with fracture risk [hazard ratio (HR) = 2.49, 95% confidence interval (CI) 1.34-4.61]. After controlling for age and fracture history, the associations became non-significant but a suggestive trend remained (HR = 1.80, 95% CI 0.96-3.37). Our study provides suggestive evidence for the potential utility of OPG/RANKL ratios in predicting risk of fracture in women treated with AIs for breast cancer. Further validation may be warranted.
Authors: Yao S; Laurent CA; Roh JM; Lo J; Tang L; Hahn T; Ambrosone CB; Kushi LH; Kwan ML
Breast Cancer Res Treat. 2020 Jan 07.
Renin-Angiotensin System Blockade after Acute Kidney Injury (AKI) and Risk of Recurrent AKI
How to best medically manage patients who survived hospitalized AKI is unclear. Use of renin-angiotensin system blockers in this setting may increase risk of recurrent AKI. This is a cohort study of 10,242 members of an integrated health care delivery system in Northern California who experienced AKI and survived a hospitalization between January 1, 2006 and December 31, 2013. All study participants did not have prior heart failure or use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) up to 5 years prior. New receipt and time-updated exposure of ACE-Is/ARBs was identified on the basis of dispensed prescriptions found in outpatient health plan pharmacy databases. The main outcome of interest was subsequent episode of hospitalized AKI after discharge from an initial index hospitalization complicated by AKI. Recurrent AKI episode was defined using acute changes in serum creatinine concentrations. Marginal structural models were used to adjust for baseline and potential time-dependent confounders. Forty-seven percent of the study population had a documented eGFR<60 ml/min per 1.73 m2 or documented proteinuria before hospitalization. With a median of 3 (interquartile range, 1-5) years of follow-up, 1853 (18%) patients initiated use of ACE-Is/ARBs and 2124 (21%) patients experienced recurrent AKI. Crude rate of recurrent AKI was 6.1 (95% confidence interval [95% CI], 5.9 to 6.4) per 100 person-years off ACE-Is/ARBs and 5.7 (95% CI, 4.9 to 6.5) per 100 person-years on ACE-Is/ARBs. In marginal structural causal inference models that adjusted for baseline and potential time-dependent confounders, exposure to ACE-I/ARB use was not associated with higher incidence of recurrent AKI (adjusted odds ratio, 0.71; 95% CI, 0.45 to 1.12). In this study of AKI survivors without heart failure, new use of ACE-I/ARB therapy was not independently associated with increased risk of recurrent hospitalized AKI.
Authors: Hsu CY; Liu KD; Yang J; Glidden DV; Tan TC; Pravoverov L; Zheng S; Go AS
Clin J Am Soc Nephrol. 2020 01 07;15(1):26-34. Epub 2019-12-16.
The impact of adjusting for baseline in pharmacogenomic genome-wide association studies of quantitative change
In pharmacogenomic studies of quantitative change, any association between genetic variants and the pretreatment (baseline) measurement can bias the estimate of effect between those variants and drug response. A putative solution is to adjust for baseline. We conducted a series of genome-wide association studies (GWASs) for low-density lipoprotein cholesterol (LDL-C) response to statin therapy in 34,874 participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort as a case study to investigate the impact of baseline adjustment on results generated from pharmacogenomic studies of quantitative change. Across phenotypes of statin-induced LDL-C change, baseline adjustment identified variants from six loci meeting genome-wide significance (SORT/CELSR2/PSRC1, LPA, SLCO1B1, APOE, APOB, and SMARCA4/LDLR). In contrast, baseline-unadjusted analyses yielded variants from three loci meeting the criteria for genome-wide significance (LPA, APOE, and SLCO1B1). A genome-wide heterogeneity test of baseline versus statin on-treatment LDL-C levels was performed as the definitive test for the true effect of genetic variants on statin-induced LDL-C change. These findings were generally consistent with the models not adjusting for baseline signifying that genome-wide significant hits generated only from baseline-adjusted analyses (SORT/CELSR2/PSRC1, APOB, SMARCA4/LDLR) were likely biased. We then comprehensively reviewed published GWASs of drug-induced quantitative change and discovered that more than half (59%) inappropriately adjusted for baseline. Altogether, we demonstrate that (1) baseline adjustment introduces bias in pharmacogenomic studies of quantitative change and (2) this erroneous methodology is highly prevalent. We conclude that it is critical to avoid this common statistical approach in future pharmacogenomic studies of quantitative change.
Authors: Oni-Orisan A; Haldar T; Ranatunga DK; Medina MW; Schaefer C; Krauss RM; Iribarren C; Risch N; Hoffmann TJ
NPJ Genom Med. 2020;5:1. Epub 2020-01-16.
Smoking mediates the relationship between SES and brain volume: The CARDIA study
Investigate whether socioeconomic status (SES) was related to brain volume in aging related regions, and if so, determine whether this relationship was mediated by lifestyle factors that are known to associate with risk of dementia in a population-based sample of community dwelling middle-aged adults. We studied 645 (41% black) participants (mean age 55.3±3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent brain magnetic resonance imaging. SES was operationalized as a composite measure of annual income and years of education. Gray matter volume was estimated within the insular cortex, thalamus, cingulate, frontal, inferior parietal, and lateral temporal cortex. These regions are vulnerable to age-related atrophy captured by the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) index. Lifestyle factors of interest included physical activity, cognitive activity (e.g. book/newspaper reading), smoking status, alcohol consumption, and diet. Multivariable linear regressions tested the association between SES and brain volume. Sobel mediation analyses determined if this association was mediated by lifestyle factors. All models were age, sex, and race adjusted. Higher SES was positively associated with brain volume (β = .109 SE = .039; p < .01) and smoking status significantly mediated this relationship (z = 2.57). With respect to brain volume, smoking accounted for 27% of the variance (β = -.179 SE = .065; p < .01) that was previously attributed to SES. Targeting smoking cessation could be an efficacious means to reduce the health disparity of low SES on brain volume and may decrease vulnerability for dementia.
Authors: Dougherty, Ryan J; Moonen, Justine; Yaffe, Kristine; Sidney, Stephen; Davatzikos, Christos; Habes, Mohamad; Launer, Lenore J
PLoS One. 2020;15(9):e0239548. Epub 2020-09-21.
Chronicity of Uncorrected Hyponatremia and Clinical Outcomes in Older Patients Undergoing Hip Fracture Repair
Background: Chronic hyponatremia is a risk factor for hip fracture but remains uncorrected in most patients. This study evaluated if preoperative chronicity of uncorrected hyponatremia influences outcomes after hip fracture repair. Materials and Methods: Evaluated were older patients hospitalized for hip fracture repair between 2007 and 2012 with plasma sodium measured at admission and ≥1 preadmission outpatient measurement. Patients were classified as being normonatremic (NN; plasma sodium 135-145 mmol/L), chronic prolonged hyponatremia (CPH; ≥2 consecutive plasma sodium values <135 mmol/L over >90 days), or recent hyponatremia (one plasma sodium <135 mmol/L within 30 days before admission with previously normal plasma sodium). Length of hospital stay, in-hospital death, post-operative complications, 30-day readmission, and long-term mortality were the evaluated outcomes. Multivariable Cox regression was used to evaluate the association of hyponatremia status with outcomes. Results: Among 1,571 eligible patients, 76.7% were NN, 14% had CPH, and 9.1% had RH. Compared with NN patients, CHN patients were older and had more prior heart failure, alcoholism, and anticonvulsant drug use. In multivariable analyses, neither CPH or RH was associated with hospital length of stay, in-hospital or 30-day death, or 30-day readmission, while RH was associated with post-operative sepsis [adjusted odds ratio (aOR) 1.84, 95% CI: 1.01-3.35). Only CPH was independently associated with long-term all-cause death (OR 1.53, 95% CI: 1.12-2.09). Conclusions: Hyponatremia affects nearly 25% of patients undergoing hip fracture repair. Preoperative chronic untreated hyponatremia is associated with increased post-operative mortality following surgical repair of a hip fracture in older patients. Future studies should evaluate if correction of hyponatremia could decrease long-term mortality after hip fracture repair.
Authors: Ayus JC; Fuentes N; Go AS; Achinger SG; Moritz ML; Nigwekar SU; Waikar SS; Negri AL
Front Med (Lausanne). 2020;7:263. Epub 2020-06-30.
Association of smoking and right ventricular function in middle age: CARDIA study
To evaluate the association of cigarette smoking and right ventricular (RV) systolic and diastolic functions in a population-based cohort of individuals at middle age. This cross-sectional study included participants who answered the smoking questionnaire and underwent echocardiography at the Coronary Artery Risk Development in Young Adulthood year 25 examination. RV systolic function was assessed by echocardiographic-derived tricuspid annular plane systolic excursion (TAPSE) and by right ventricular peak systolic velocity (RVS’), while RV diastolic function was evaluated by early right ventricular tissue velocity (RVE’). Multivariable linear regression models assessed the relationship of smoking with RV function, adjusting for age, sex, race, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes mellitus, alcohol consumption, pulmonary function, left ventricular systolic and diastolic function and coronary artery calcium score. A total of 3424 participants were included. The mean age was 50±4 years; 57% were female; and 53% were black. There were 2106 (61%) never smokers, 750 (22%) former smokers and 589 (17%) current smokers. In the multivariable analysis, current smokers had significantly lower TAPSE (β=-0.082, SE=0.031, p=0.008), RVS’ (β=-0.343, SE=0.156, p=0.028) and RVE’ (β=-0.715, SE=0.195, p<0.001) compared with never smokers. Former smokers had a significantly lower RVE' compared with never smokers (β=-0.414, SE=0.162, p=0.011), whereas no significant difference in RV systolic function was found between former smokers and never smokers. In a large multicenter community-based biracial cohort of middle-aged individuals, smoking was independently related to both worse RV systolic and diastolic functions.
Authors: Moreira HT; Ogunyankin KO; Lima JAC; et al.
Open Heart. 2020;7(1):e001270. Epub 2020-03-08.
A longitudinal study of pre-pregnancy antioxidant levels and subsequent perinatal outcomes in black and white women: The CARDIA Study
Although protective associations between dietary antioxidants and pregnancy outcomes have been reported, randomized controlled trials of supplementation have been almost uniformly negative. A possible explanation is that supplementation during pregnancy may be too late to have a beneficial effect. Therefore, we examined the relationship between antioxidant levels prior to pregnancy and birth outcomes. Serum carotenoids and tocopherols were assayed in fasting specimens at 1985-86 (baseline) and 1992-1993 (year 7) from 1,215 participants in Coronary Artery Risk Development in Young Adults (CARDIA) study. An interviewer-administered quantitative food-frequency questionnaire assessed dietary intake of antioxidants. Pregnancy outcome was self-reported at exams every 2 to 5 years. Linear and logistic regression modeling was used to assess relationships of low birthweight (LBW; <2,500 g), continuous infant birthweight, preterm birth (PTB; <37 weeks) and length of gestation with antioxidant levels adjusted for confounders, as well as interactions with age and race. In adjusted models, lycopene was associated with higher odds of LBW (adjusted odds ratio for top quartile, 2.15, 95% confidence interval 1.14, 3.92) and shorter gestational age (adjusted beta coefficient -0.50 weeks). Dietary intake of antioxidants was associated with lower birthweight, while supplement use of vitamin C was associated with higher gestational age (0.41 weeks, 0.01, 0.81). Higher preconception antioxidant levels are not associated with better birth outcomes.
Authors: Harville EW; Lewis CE; Catov JM; Jacobs DR; Gross MD; Gunderson EP
PLoS One. 2020;15(2):e0229002. Epub 2020-02-14.
Don’t Fall for That: A Residency Curricular Innovation about Fall Prevention
Amid a growing geriatric population and rise in frailty-related morbidity, fall prevention represents an opportunity to improve patient outcomes and reduce health care costs. Traditional lectures on geriatric content have had limited impact on physician behaviors; however, use of multimodal teaching can be more effective in building knowledge and skills. To develop a novel, engaging fall prevention program to empower internal medicine residents to identify and manage patients at risk of falls and fall-related injuries. Two 20-minute multimodal workshops were created: 1) a classroom session with a video depicting a fall scenario, a team exercise (“Where’s the Fall Risk?”) and review of the American Geriatrics Society Beers Criteria; and 2) a small-group session reviewing a screening algorithm, case study, physical examination maneuvers, and patient resources. The first workshop included a 5-minute Kaiser Permanente video depicting an older couple whose travel plans are upended by a fall and how they modify their home and lifestyle, a competitive game in which trainees identify fall hazards, an overview of Beers Criteria, and Medical Knowledge Self-Assessment Program questions to apply knowledge to practice. The second workshop, held in small groups before clinic, included a discussion of the Centers for Disease Control and Prevention’s fall prevention screening algorithm, review of a case, and education on how to properly perform the Timed Up and Go test. Fall prevention remains an important yet undertaught topic for trainees and practicing physicians. These brief multicomponent workshops can be easily implemented and adapted for all clinical learners.
Authors: Lee DR; Lo JC; Tran HN
Perm J. 2020;24. Epub 2019-12-06.
Outcomes and Anticoagulation Use After Catheter Ablation for Atrial Fibrillation
Studies evaluating the effects of atrial fibrillation (AF) catheter ablation versus antiarrhythmic therapy on outcomes have shown mixed results. In addition, guidelines recommend continuing oral anticoagulation (OAC) after ablation for those at risk of stroke, but real-world data are lacking. We evaluated outcomes including death, myocardial infarction, stroke or systemic embolism, intracranial bleeding, major bleeding, and hospitalization in patients undergoing AF ablation compared with a propensity score matched cohort of patients treated with anti-arrhythmic medications only in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation registries. Cox proportional hazards regression was performed to evaluate the association between AF ablation and outcomes. We then evaluated patterns of treatment with OAC among AF ablation patients. Among 21 595 patients, 1190 (6%) underwent de novo AF ablation. Our propensity score-matched cohort included 1087 patients who underwent AF ablation matched 1:1 with 1087 patients treated with antiarrhythmic medications only. There were no significant differences in the risk of all-cause and cardiovascular death, and most other major adverse cardiovascular and neurological events. AF catheter ablation was associated with an increased risk of all-cause hospitalization during follow-up (hazard ratio, 1.24 [95% CI, 1.05-1.46]), particularly in the first 3 months (the standard blanking period) after the procedure. Among those who underwent AF ablation with a CHA2DS2 VASc score ≥2 for men and ≥3 for women, 23% had OAC discontinued after ablation. Among those who discontinued OAC, the median time to discontinuation was 6.2 months. In this large US national registry, we found no difference in adjusted rates of cardiovascular or all-cause death between patients treated with AF catheter ablation and antiarrhythmic medications only. Notably, discontinuation of OAC after ablation remains relatively common despite guideline recommendations for continued stroke prevention therapy in patients at risk of stroke.
Authors: Freeman JV; Go AS; Piccini JP; et al.
Circ Arrhythm Electrophysiol. 2019 12;12(12):e007612. Epub 2019-12-13.
Association Between Aging of the US Population and Heart Disease Mortality From 2011 to 2017
A deceleration in the rate of decrease of heart disease (HD) mortality between 2011 and 2014 has been reported. In the context of the rapid increase in the population of adults aged 65 years and older, extending the examination of HD mortality through 2017 has potentially important implications for public health and medical care. To examine changes in the age-adjusted mortality rate and the number of deaths within subcategories of HD from 2011 to 2017 in conjunction with the change in the size of the US population during the same period. In this quality improvement study, the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) data set was used to identify national changes in the US population aged 65 years and older and in the age-adjusted mortality rates and number of deaths that were listed with an underlying cause of HD, coronary heart disease (CHD), heart failure, and other HDs from January 1, 2011, to December 31, 2017. Changes from 2011 to 2017 in the US population and in age-adjusted mortality rates and number of deaths that were listed with an underlying cause of HD, CHD, heart failure (both as an underlying and a contributing cause), and other HDs overall, by sex and race/ethnicity. The total size of this population of US adults aged 65 years and older increased 22.9% from 41.4 million to 50.9 million between January 1, 2011, and December 31, 2017, while the population of adults younger than 65 years increased by only 1.7%. During this period, the age-adjusted mortality rate decreased 5.0% for HD and 14.9% for CHD while increasing 20.7% for heart failure and 8.4% for other HDs. The number of deaths increased 8.5% for HD, 38.0% for heart failure, and 23.4% for other HDs while decreasing 2.5% for CHD. A total of 80% of HD deaths occurred in the group of adults aged 65 years and older. The substantial increase in the growth rate of the group of adults aged 65 years and older who have the highest risk of HD was associated with an increase in the number of HD deaths in this group despite a slowly declining HD mortality rate in the general population. With the number of adults aged 65 years and older projected to increase an additional 44% from 2017 to 2030, innovative and effective approaches to prevent and treat HD, particularly the substantially increasing rates of heart failure, are needed.
Authors: Sidney S; Go AS; Jaffe MG; Solomon MD; Ambrosy AP; Rana JS
JAMA Cardiol. 2019 12 01;4(12):1280-1286.
Atypical femur fracture incidence in women increases with duration of bisphosphonate exposure
In a northern California population of older women who were treated with oral bisphosphonate drugs, the incidence of atypical femur fracture, a rare complication of treatment, increased with longer duration of bisphosphonate exposure. These findings align with those previously reported in an independent southern California population. The age-adjusted incidence of atypical femur fracture (AFF) reported in southern California increased with bisphosphonate (BP) exposure, ranging up to 113 per 100,000 person-years for 8-10-year exposure. This study examines the incidence of AFF in a northern California population. Women age 45-89 years who initiated oral BP during 2002-2014 in Kaiser Permanente Northern California were followed for AFF outcome, defined by a primarily transverse diaphyseal femur fracture through both cortices, with focal periosteal/endosteal hypertrophy, minimal trauma, and minimal/no comminution. Total BP exposure was determined from dispensed prescriptions. The incidence of AFF, calculated for 2-year BP categories ranging from < 2 to > 10 years, was age-adjusted using the 2000 US Census. Among 94,542 women, 107 experienced an AFF during or < 1 year after BP cessation (mean exposure 6.6 ± 3.0 years and total days' supply 5.7 ± 2.8 years at AFF). A strong relationship between AFF incidence and increasing BP exposure was seen, more than doubling for each 2-year category until 8-10 years. Among women with 2- to < 4-year BP, the crude and age-adjusted incidence was 18 and 9 per 100,000 person-years but increased over 2- and 5-fold for women with 4- to < 6- and 6- to < 8-year BP, respectively. For those receiving ≥ 8-year BP, the crude and age-adjusted incidence peaked at 196 and 112 per 100,000 person-years exposure. Incidence of AFF increases markedly after 4-6 years of BP. These trends align with southern California and confirm a strong BP duration-related risk of this rare but serious event.
Authors: Lo JC; Grimsrud CD; Ott SM; Chandra M; Hui RL; Ettinger B
Osteoporos Int. 2019 Dec;30(12):2515-2520. Epub 2019-09-25.
Single Measurements of Carboxy-Terminal Fibroblast Growth Factor 23 and Clinical Risk Prediction of Adverse Outcomes in CKD
An elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals. Prospective cohort study. Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789). Baseline carboxy-terminal FGF-23 (cFGF-23) level. All-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years. We assessed changes in model performance by change in area under the receiver operating characteristic curve (?AUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort. Addition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (?AUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (?AUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome. Power to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds. Among individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.
Authors: Edmonston D; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2019 12;74(6):771-781. Epub 2019-08-21.
Treatment and Outcomes of Acute Pulmonary Embolism and Deep Venous Thrombosis: The Cardiovascular Research Network Venous Thromboembolism (CVRN VTE) Study
Few studies describe both inpatient and outpatient treatment and outcomes of patients with acute venous thromboembolism in the United States. A multi-institutional cohort of patients diagnosed with confirmed pulmonary embolism or deep venous thrombosis during the years 2004 through 2010 was established from 4 large, US-based integrated health care delivery systems. Computerized databases were accessed and medical records reviewed to collect information on patient demographics, clinical risk factors, initial antithrombotic treatment, and vital status. Multivariable Cox regression models were used to estimate the risk of death at 90 days. The cohort comprised 5497 adults with acute venous thromboembolism. Pulmonary embolism was predominantly managed in the hospital setting (95.0%), while 54.5% of patients with lower extremity thrombosis were treated as outpatients. Anticoagulant treatment differed according to thromboembolism type: 2688 patients (92.8%) with pulmonary embolism and 1625 patients (86.9%) with lower extremity thrombosis were discharged on anticoagulants, compared with 286 patients (80.1%) with upper extremity thrombosis and 69 (54.8%) patients with other thrombosis. While 4.5% of patients died during the index episode, 15.4% died within 90 days. Pulmonary embolism was associated with a higher 90-day death risk than lower extremity thrombosis (adjusted hazard ratio 1.23; 95% confidence interval, 1.04-1.47), as was not being discharged on anticoagulants (adjusted hazard ratio 5.56; 95% confidence interval, 4.76-6.67). In this multicenter, community-based study of patients with acute venous thromboembolism, anticoagulant treatment and outcomes varied by thromboembolism type. Although case fatality during the acute episode was relatively low, 15.4% of people with thromboembolism died within 90 days of the index diagnosis.
Authors: Fang MC; Fan D; Sung SH; Witt DM; Schmelzer JR; Williams MS; Yale SH; Baumgartner C; Go AS
Am J Med. 2019 12;132(12):1450-1457.e1. Epub 2019-06-25.
Aggregation of Asian-American subgroups masks meaningful differences in health and health risks among Asian ethnicities: an electronic health record based cohort study
Few large cohort studies have examined the prevalence of diabetes mellitus (DM), hypertension (HTN), coronary artery disease (CAD), obesity, and smoking among middle-aged and older adults in the major Asian-American ethnic groups and Native Hawaiian/Pacific Islanders (PIs). The aim of this study was to evaluate how prevalence of these conditions and risk factors differs across Asian-American and PI ethnic groups and compares with an aggregated All Asian-American racial group. This study used a cohort of 1.4 million adults aged 45 to 84 who were Kaiser Permanente Northern California health plan members during 2016. The cohort included approximately 274,910 Asian-Americans (Chinese, Filipino, Japanese, Korean, Southeast Asian, South Asian, other), 8450 PIs, 795,080 non-Hispanic whites, 107,200 blacks, and 210,050 Latinos. We used electronic health record data to produce age-standardized prevalence estimates of DM, HTN, CAD, obesity (using standard and Asian thresholds), and smoking for men and women in all racial/ethnic subgroups and compared these subgroups to an aggregated All Asian-American racial group and to whites, blacks, and Latinos. We found large differences in health burden across Asian-American ethnic subgroups. For both sexes, there were 16 and > 22 percentage point differences between the lowest and highest prevalence of DM and HTN, respectively. Obesity prevalence among Asian subgroups (based on an Asian BMI ≥ 27.5 kg/m2 threshold) ranged from 14 to 39% among women and 21 to 45% among men. Prevalence of smoking ranged from 1 to 4% among women and 5 to 14% among men. Across all conditions and risk factors, prevalence estimates for Asian-American and PI ethnic groups significantly differed from those for the All Asian-American group. In general, Filipinos and PIs had greater health burden than All Asians, with prevalence estimates approaching those of blacks. In a population of middle-aged and older adult Northern California health plan members, we found substantive differences in prevalence of chronic cardiovascular conditions, obesity, and smoking across Asian-American ethnic groups and between Asian-American ethnic groups and an aggregated All Asian racial group. Our study confirms that reporting statistics for an aggregated Asian-American racial group masks meaningful differences in Asian-American ethnic group health.
Authors: Gordon NP; Lin TY; Rau J; Lo JC
BMC Public Health. 2019 Nov 25;19(1):1551. Epub 2019-11-25.
Research Needs and Priorities for Catheter Ablation of Atrial Fibrillation: A Report from a National Heart, Lung, and Blood Institute Virtual Workshop
Catheter ablation has brought major advances in the management of patients with atrial fibrillation (AF). As evidenced by multiple randomized trials, AF catheter ablation can reduce the risk of recurrent AF and improve quality of life. In some studies, AF ablation significantly reduced cardiovascular hospitalizations. Despite the existing data on AF catheter ablation, numerous knowledge gaps remain in relation to this intervention. This report is based on a recent virtual workshop convened by the National Heart, Lung, and Blood Institute to identify key research opportunities in AF ablation. We outline knowledge gaps related to emerging technologies, the relationship between cardiac structure and function and the success of AF ablation, patient subgroups in whom clinical benefit from ablation varies, and potential platforms to advance clinical research in this area. This report also considers the potential value and challenges of a sham ablation randomized trial. Prioritized research opportunities are identified and highlighted to empower relevant stakeholders to collaborate in designing and conducting effective, cost-efficient, and transformative research to optimize the use and outcomes of AF ablation.
Authors: Al-Khatib SM; Go AS; et al.
Circulation. 2019 Nov 20.
Serum Calcification Propensity and Clinical Events in CKD
Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4. Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T50 with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality. The mean T50 was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T50 was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T50, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T50, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T50, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T50, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T50 was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality. Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3.
Authors: Bundy JD; Go AS; CRIC Study Investigators; et al.
Clin J Am Soc Nephrol. 2019 11 07;14(11):1562-1571. Epub 2019-10-28.
Cardiac Biomarkers and Risk of Incident Heart Failure in Chronic Kidney Disease: The CRIC (Chronic Renal Insufficiency Cohort) Study
Background Cardiac biomarkers may signal mechanistic pathways involved in heart failure (HF), a leading complication in chronic kidney disease. We tested the associations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor-15 (GDF-15), and soluble ST2 (sST2) with incident HF in chronic kidney disease. Methods and Results We examined adults with chronic kidney disease enrolled in a prospective, multicenter study. All biomarkers were measured at baseline. The primary outcome was incident HF. Secondary outcomes included HF with preserved ejection fraction (EF?50%) and reduced ejection fraction (EF<50%). Cox models were used to test the association of each cardiac biomarker with HF, adjusting for demographics, kidney function, cardiovascular risk factors, and medication use. Among 3314 participants, all biomarkers, with the exception of galectin-3, were significantly associated with increased risk of incident HF (hazard ratio per SD higher concentration of log-transformed biomarker): NT-proBNP (hazard ratio, 2.07; 95% CI, 1.79-2.39); hsTnT (hazard ratio, 1.38; 95% CI, 1.21-1.56); GDF-15 (hazard ratio, 1.44; 95% CI, 1.26-1.66) and sST2 (hazard ratio, 1.19; 95% CI, 1.05-1.35). Higher NT-proBNP, hsTnT, and GDF-15 were also associated with a greater risk of HF with reduced EF; while higher NT-proBNP GDF-15 and sST2 were associated with HF with preserved EF. Galectin-3 was not associated with either HF with reduced EF or HF with preserved EF. Conclusions In chronic kidney disease, elevations of NT-proBNP, hsTnT, GDF-15, sST2 were associated with incident HF. There was a borderline association of galectin-3 with incident HF. NT-proBNP and hsTnT were more strongly associated with HF with reduced EF, while the associations of the newer biomarkers GDF-15 and sST2 were stronger for HF with preserved EF.
Authors: Bansal N; Go A; CRIC Study Investigators
J Am Heart Assoc. 2019 11 05;8(21):e012336. Epub 2019-10-24.
The Preconception Period analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium
Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women’s health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.
Authors: Harville EW; Gunderson EP; Wise LA; et al.
Paediatr Perinat Epidemiol. 2019 11;33(6):490-502. Epub 2019-10-28.
Vitamin D Metabolic Ratio and Risks of Death and CKD Progression
Assessment of impaired vitamin D metabolism is limited by lack of functional measures. CYP24A1-mediated vitamin D clearance, calculated as the ratio of serum 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (the vitamin D metabolic ratio, VDMR), is induced by 1,25-dihydroxyvitamin D and may assess tissue-level activity. We tested associations of the VDMR with risks of death and progression to end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD). We studied participants from the Chronic Renal Insufficiency Cohort (CRIC), which included a random subset of 1080 CRIC participants plus additional participants who experienced ESRD or died (case cohort study design). Serum 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 was measured 1 year after enrollment. The primary outcomes included death and progression to ESRD. Using inverse probability weighting, we tested associations of VDMR (24,25[OH]2D3/25[OH]D3) with risks of death and ESRD, adjusting for demographics, comorbidity, and kidney function (estimated glomerular filtration rate [eGFR] and urine protein-to-creatinine ratio [PCR]). There were a total of 708 ESRD events and 650 deaths events over mean (SD) follow-up periods of 4.9 (2.9) years and 6.5 (2.5) years, respectively. Lower VDMR was associated with increased risk of ESRD prior to adjusting for kidney function (hazard ratio [HR], 1.80 per 20 pg/ng lower VDMR; 95% confidence interval [CI], 1.56-2.08), but not with adjustment for kidney function (HR, 0.94 per 20 pg/ng; 95% CI, 0.81-1.10). Lower VDMR was associated with modestly increased mortality risk, including adjustment for kidney function (HR, 1.18 per 20 pg/ng; 95% CI, 1.02-1.36). Lower VDMR, a measure of CYP24A1-mediated vitamin D clearance, was significantly associated with all-cause mortality but not with progression to ESRD in patients with CKD.
Authors: Bansal N; Go AS; CRIC Study Investigators; et al.
Kidney Int Rep. 2019 Nov;4(11):1598-1607. Epub 2019-08-30.
Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration
Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
Authors: Noordam R; Sims M; Redline S; et al.
Nat Commun. 2019 11 12;10(1):5121. Epub 2019-11-12.
Cardiac and Stress Biomarkers and Chronic Kidney Disease Progression: The CRIC Study
Increases in cardiac and stress biomarkers may be associated with loss of kidney function through shared mechanisms involving cardiac and kidney injury. We evaluated the associations of cardiac and stress biomarkers [N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), soluble ST-2 (sST-2)] with progression of chronic kidney disease (CKD). We included 3664 participants with CKD from the Chronic Renal Insufficiency Cohort study. All biomarkers were measured at entry. The primary outcome was CKD progression, defined as progression to end-stage renal disease (ESRD) or 50% decline in estimated glomerular filtration rate (eGFR). Cox models tested the association of each biomarker with CKD progression, adjusting for demographics, site, diabetes, cardiovascular disease, eGFR, urine proteinuria, blood pressure, body mass index, cholesterol, medication use, and mineral metabolism. There were 1221 participants who had CKD progression over a median (interquartile range) follow-up of 5.8 (2.4-8.6) years. GDF-15, but not sST2, was significantly associated with an increased risk of CKD progression [hazard ratios (HRs) are per SD increase in log-transformed biomarker]: GDF-15 (HR, 1.50; 95% CI, 1.35-1.67) and sST2 (HR, 1.07; 95% CI, 0.99-1.14). NT-proBNP and hsTnT were also associated with increased risk of CKD progression, but weaker than GDF-15: NT-proBNP (HR, 1.24; 95% CI, 1.13-1.36) and hsTnT (HR, 1.11; 95% CI, 1.01-1.22). Increases in GDF-15, NT-proBNP, and hsTnT are associated with greater risk for CKD progression. These biomarkers may inform mechanisms underlying kidney injury.
Authors: Bansal N; Go AS; CRIC Study Investigators; et al.
Clin Chem. 2019 11;65(11):1448-1457. Epub 2019-10-02.
Haemoconcentration during treatment of acute heart failure with cardiorenal syndrome: from the CARRESS-HF trial
Authors: Blumer V; Ambrosy AP; Mentz RJ; et al.
Eur J Heart Fail. 2019 11;21(11):1472-1476. Epub 2019-08-27.
Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?
Authors: Ambrosy AP; Fudim M; Chioncel O
Eur J Heart Fail. 2019 11;21(11):1398-1401. Epub 2019-07-22.
Cannabis Use and Markers of Systemic Inflammation The Coronary Artery Risk Development in Young Adults Study
It is unclear whether cannabis use in humans plays a role in the regulation of inflammatory responses. This study aimed to examine cannabis-attributable immunomodulation as manifested in levels of fibrinogen, C-reactive protein (CRP), and interleukin-6 (IL-6). The Coronary Artery Risk Development in Young Adults (CARDIA) study is a cohort of 5115 African-American and Caucasian males and females enrolled in 1985-1986, and followed up for over 25 years, with repeated measures of cannabis use. Fibrinogen levels were measured at year 5, year 7, and year 20, CRP levels were measured at year 7, year 15, year 20, and year 25, and IL-6 levels were measured at year 20. We estimated the association of cannabis use and each biomarker using generalized estimating equations adjusting for demographic factors, tobacco cigarette smoking, alcohol drinking, and body mass index. Compared with never use (reference), recent cannabis use was not associated with any of the biomarkers studied here after adjusting for potential confounding variables. Former cannabis use was inversely associated with fibrinogen levels (β = -5.4; 95% confidence interval [CI], -9.9, -0.9), whereas the associations were weaker for serum CRP (β = -0.02; 95% CI, -0.10, 0.06) and IL-6 (β = -0.06; 95% CI, -0.13, 0.02). A modest inverse association between former cannabis use and fibrinogen was observed. Additional studies are needed to investigate the immunomodulatory effects of cannabis while considering different cannabis preparation and mode of use.
Authors: Alshaarawy O; Sidney S; Auer R; Green D; Soliman EZ; Goff DC; Anthony JC
Am J Med. 2019 11;132(11):1327-1334.e1. Epub 2019-05-29.
Development of an algorithm to detect methotrexate wrong frequency error using computerized health care data
We validated an algorithm to detect frequency errors in computerized healthcare data and estimated the incidence of these errors in an integrated healthcare system. We applied Sentinel System analytic tools on the electronic health records of Kaiser Permanente, Northern California, January 1, 2010, through May 30, 2015,to identify rheumatoid arthritis (RA) patients with new use of methotrexate (365-day baseline period). We identified potential methotrexate frequency errors using ICD-9 code 995.20 (adverse drug event), Current Procedural Terminology (CPT) code 96409 for injection of leucovorin and prescription refill patterns. We performed chart review to confirm the frequency errors, assessed performance for detecting frequency errors, and estimated the incidence of chart-confirmed errors. The study included 24,529 methotrexate dispensings among 3,668 RA patients. Among these, 722 (3%) had one dispensing and 23,807 (97.1%) had ≥2 dispensings during 1-year follow-up period. We flagged 653 (2.7%) with a potential medication error (46 with one dispensing and 607 with ≥2 dispensings). We sampled 94 for chart review, and confirmed three methotrexate errors. All three confirmed frequency errors involved a first methotrexate dispensing followed by injected rescue therapy, leucovorin, (positive predictive value, 60%; 95% confidence interval [CI], 15-95%). No potential errors were found among patients with ≥2 dispensings. We estimated the frequency error incidence among one methotrexate dispensing to be 0.4% (95%CI, 0.1% to 1.2%). Rescue therapy is a specific indicator of methotrexate overdose among first methotrexate dispensings. This method is generalizable to other medications with serious adverse events treated with antidotes.
Authors: Herrinton LJ; Woodworth TS; Eworuke E; Amsden LB; Liu L; Wyeth J; Petrone A; Menzin TJ; Williams J; Goldfien R; Nguyen M
Pharmacoepidemiol Drug Saf. 2019 10;28(10):1361-1368. Epub 2019-08-13.
Vitamin D Status Among Older Women Initiating Osteoporosis Therapy
Authors: Li CF; Ettinger B; Chandra M; Lo JC
J Am Geriatr Soc. 2019 10;67(10):2207-2208. Epub 2019-08-23.
Incident Anemia in Older Adults with Heart Failure Rate, Etiology, and Association with Outcomes
Limited data exist on the epidemiology, evaluation, and prognosis of otherwise unexplained anaemia of the elderly in heart failure (HF). Thus, we aimed to determine the incidence of anaemia, to characterize diagnostic testing patterns for potentially reversible causes of anaemia, and to evaluate the independent association between incident anaemia and long-term morbidity and mortality. Within the Cardiovascular Research Network (CVRN), we identified adults age ≥65 years with diagnosed HF between 2005 and 2012 and no anaemia at entry. Incident anaemia was defined using World Health Organization (WHO) haemoglobin thresholds (<13.0 g/dL in men; <12.0 g/dL in women). All-cause death and hospitalizations for HF and any cause were identified from electronic health records. Among 38 826 older HF patients, 22 163 (57.1%) developed incident anaemia over a median (interquartile range) follow-up of 2.9 (1.2-5.6) years. The crude rate [95% confidence interval (CI)] per 100 person-years of incident anaemia was 26.4 (95% CI 26.0-26.7) and was higher for preserved ejection fraction (EF) [29.2 (95% CI 28.6-29.8)] compared with borderline EF [26.5 (95% CI 25.4-27.7)] or reduced EF [26.6 (95% CI 25.8-27.4)]. Iron indices, vitamin B12 level, and thyroid testing were performed in 20.9%, 14.9%, and 40.2% of patients, respectively. Reduced iron stores, vitamin B12 deficiency, and/or hypothyroidism were present in 29.7%, 3.2%, and 18.6% of tested patients, respectively. In multivariable analyses, incident anaemia was associated with excess mortality [hazard ratio (HR) 2.14, 95% CI 2.07-2.22] as well as hospitalization for HF (HR 1.80, 95% CI 1.72-1.88) and any cause (HR 1.77, 95% CI 1.72-1.83). Among older adults with HF, incident anaemia is common and independently associated with substantially increased risks of morbidity and mortality. Additional research is necessary to clarify the value of routine evaluation and treatment of potentially reversible causes of anaemia.
Authors: Ambrosy AP; Go AS; RBC HEART Investigators; et al.
Eur Heart J Qual Care Clin Outcomes. 2019 10 01;5(4):361-369.
Trends Associated With Large-scale Expansion of Peritoneal Dialysis Within an Integrated Care Delivery Model
Despite favorable national trends in the incidence of end-stage renal disease (ESRD) from 2008 to 2011, ESRD incidence has been increasing recently, and less than 10% of patients with ESRD start renal replacement therapy with peritoneal dialysis (PD) in the United States. Given known and potential advantages of PD over hemodialysis, the Kaiser Permanente Northern California integrated health care delivery system implemented a program to expand use of PD. To describe the system-level approach to expansion of PD use and temporal trends in initiation and persistence of PD and its associated mortality. This retrospective cohort study included adult members of a large integrated health care delivery system in Northern California who initiated chronic dialysis therapy from January 1, 2008, through December 31, 2018. Data were analyzed from March 1, 2018, through May 31, 2019. From 2008 to 2018, Kaiser Permanente Northern California implemented a multidisciplinary, system-wide approach to increase use of PD that included patient and caregiver education, education and support tools for health care professionals, streamlined system-level processes, monitoring, and continuous quality improvement. Temporal trends in the proportion of patients starting chronic dialysis with PD vs hemodialysis compared with national trends. Secondary outcomes included persistence of PD at 1 year in those initiating it and standardized 1-year mortality rates in those initiating PD or hemodialysis. Among 13 500 eligible health plan members in the study population (7840 men [58.1%] and 5660 women [41.9%]; mean [SD] age, 64.3 [14.4] years), initiation of PD increased from 165 of 1089 all new dialysis patients (15.2%) in 2008 to 486 of 1438 (33.8%) in 2018, which was substantially higher than national trends (6.1% in 2008 and 9.7% in 2016). Among the 2974 patients who initiated PD from 2008 to 2017, 2387 (80.3%) continued PD at 1 year after initiation, with a significant increase in age-, sex-, and race-standardized rates from 2008 (69.1%) to 2017 (84.2%). Age-, sex-, and race-standardized 1-year mortality for patients receiving PD and hemodialysis did not change significantly across this 10-year period (17.3% to 15.5% for hemodialysis, P = 0.89 for trend; and 5.5% to 7.3% for PD, P = 0.12 for trend). This study suggests that large-scale expansion of PD is feasible using a multidisciplinary, integrated, coordinated care approach; we believe these findings represent a national opportunity to improve outcomes for patients with advanced kidney disease.
Authors: Pravoverov LV; Zheng S; Parikh R; Tan TC; Bhalla N; Reddy C; Mroz J; Jonelis TY; Go AS
JAMA Intern Med. 2019 Sep 09.
Spironolactone in Acute Heart Failure Patients With Renal Dysfunction and Risk Factors for Diuretic Resistance: From the ATHENA-HF Trial
Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of spironolactone. The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial randomized 360 acute HF patients with reduced or preserved ejection fraction to spironolactone 100 mg daily or usual care for 96 hours. The current analysis assessed the effects of study therapy within tertiles of baseline estimated glomerular filtration rate (eGFR) and subgroups at heightened risk for diuretic resistance. Across eGFR tertiles, there was no incremental benefit of high-dose spironolactone on any efficacy endpoint, including changes in log N-terminal pro-B-type natriuretic peptide and signs and symptoms of congestion (all P for interaction ≥ 0.06). High-dose spironolactone had no significant effect on N-terminal pro-B-type natriuretic peptide reduction regardless of blood pressure, diabetes mellitus status, and loop diuretic dose (all P for interaction ≥ 0.38). In-hospital changes in serum potassium and creatinine were similar between treatment groups for all GFR tertiles (all P for interaction ≥ 0.18). Rates of inpatient worsening HF, 30-day worsening HF, and 60-day all-cause mortality were numerically higher among patients with lower baseline eGFR, but relative effects of study treatment did not differ with renal function (all P for interaction ≥ 0.27). High-dose spironolactone did not improve congestion over usual care among patients with acute HF, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe during the inpatient stay, even when administered at high doses to patients with moderate renal dysfunction.
Authors: Greene, Stephen J; Ambrosy, Andrew P; Butler, Javed; et al.
Can J Cardiol. 2019 09;35(9):1097-1105. Epub 2019-02-07.
Prenatal Opioid Exposure: Neurodevelopmental Consequences and Future Research Priorities
Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.
Authors: Conradt E; Croen LA; Hedderson MM; Lester BM; et al.
Pediatrics. 2019 Sep;144(3).
Depot Medroxyprogesterone Acetate, Oral Contraceptive, Intrauterine Device Use, and Fracture Risk
To assess fracture risk among women with depot medroxyprogesterone acetate (DMPA), oral contraceptive pill (OCP), and intrauterine device (IUD) use. A retrospective cohort study of 308,876 women age 12-45 years who initiated DMPA, combined or progestin-only OCPs, and copper and levonorgestrel IUDs from 2005 to 2015. Cumulative DMPA, OCP, and IUD use was assessed. Time since last DMPA injection was quantified as recent (within 2 years) and past (more than 2 years ago). Crude fracture rate was estimated using a Poisson distribution. Unadjusted and adjusted hazard ratios (HRs) were estimated using cox proportional hazards models. Thirteen percent of women used DMPA, 78.6% combined OCPs, 17.4% progestin-only OCPs, and 26.2% IUDs; 29.5% used more than one method. There were 7,659 fractures in 1,391,251 person-years (5.5/1,000 person-years [95% CI 5.4-5.6]). The fracture rate for women with any DMPA use was 6.6 (95% CI 6.1-7.2) and 7.8 (95% CI 6.0-10.0) for women with recent use and more than 2 years of cumulative use. Women who had recent use with 2 years or less, or more than 2 years of cumulative use had higher fracture risk compared with women who had no DMPA use and used other methods (adjusted HR 1.15 [95% CI 1.01-1.31] and 1.42 [95% CI 1.10-1.83], respectively). Fracture risk was not increased in women with past DMPA use. Women who had more than 2 years cumulative use of combined OCPs and women with any progestin-only OCP use had lower fracture risk compared with women who did not use OCPs and used other methods (adjusted HR 0.85 [95% CI 0.76-0.96] and 0.88 [95% CI 0.80-0.97], respectively). Use of DMPA beyond 2 years should not be considered an absolute contraindication. Although DMPA use was associated with slightly increased fracture risk compared with other methods, the absolute risk of fracture was small and was not observed after discontinuation.
Authors: Raine-Bennett T; Chandra M; Armstrong MA; Alexeeff S; Lo JC
Obstet Gynecol. 2019 09;134(3):581-589.
Duration and stability of metabolically healthy obesity over 30 years
Obese adults who are free from metabolic risk factors may develop risk factors over time. Our objective was to characterize development of obesity and duration of metabolically healthy obese (MHO) over 30 years. Participants in CARDIA who developed obesity (BMI???30?kg/m2) at follow-up exams during years 7, 10, 15, 20, 25, and 30 were analyzed. MHO was defined as obese and having 0 or 1 risk factor: ?SBP/DBP 130/85?mmHg; fasting glucose ?100?mg/dL/5.55?mmol/L; fasting triglycerides (?150?mg/dL/1.69?mmol/L); and HDL-C (men <40?mg/dL/1.036?mmol/L, women <50?mg/dL/1.295?mmol/L) or on any medication(s) for these conditions. MHO duration (years) and obesity duration (years) were estimated for each subsequent time-point; and an overall cumulative duration was also calculated over available follow-up. MHO duration (%) was approximated as MHO duration?÷?obesity duration. Stable MHO was defined as 100% MHO duration over follow-up, while transient MHO was defined as <1-99%. Chi-squared tests were used to compare proportions by sex and race across obesity phenotypes. Multivariable-adjusted ANCOVA, adjusting for baseline BMI, age, race, and sex, was used to analyze obesity duration in all individuals who developed obesity, and also compare MHO duration (%) across race and sex in transient MHO individuals. Of the 987 eligible participants who developed obesity, 51% were African American (AA), 56% were women. Higher percentages of AA were classified as transient MHO, and higher proportions of females were MHO (both p?
Authors: Camhi SM; Must A; Gona PN; Hankinson A; Odegaard A; Reis J; Gunderson EP; Jacobs DR; Carnethon MR
Int J Obes (Lond). 2019 09;43(9):1803-1810. Epub 2018-08-29.
Links Between Childhood Obesity, Gestational Diabetes, and Infant Temperament-Reply
Authors: Faith MS; Hittner JB; Gunderson EP
JAMA Pediatr. 2019 Aug 26.
Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study
Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF (“AF event”) was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease.
Authors: Lamprea-Montealegre JA; Go AS; CRIC Study Investigators; et al.
J Am Heart Assoc. 2019 08 06;8(15):e012200. Epub 2019-08-05.
Transition From Heart Disease to Cancer as the Leading Cause of Death in the United States
Authors: Sidney S; Go AS; Rana JS
Ann Intern Med. 2019 08 06;171(3):225.
A Balancing Act: Preserving Renal Function and the Need for Decongestion
Authors: Fudim M; Ambrosy AP
J Card Fail. 2019 08;25(8):643-644. Epub 2019-06-26.
In-hospital initiation of sacubitril/valsartan in acute decompensated heart failure: being in the right place at the right time
Authors: Ambrosy AP; DeVore AD; Velazquez EJ
Eur J Heart Fail. 2019 08;21(8):1008-1011. Epub 2019-06-19.
Fasting glucose variability in young adulthood and incident diabetes, cardiovascular disease and all-cause mortality
The aim of this study was to determine whether long-term intra-individual variability in fasting glucose (FG) during young adulthood is associated with incident diabetes, cardiovascular disease (CVD) and mortality. We included participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18-30 years at baseline (1985-1986) and followed with eight examinations for up to 30 years. Long-term glucose variability was assessed using the CV (CV-FG) and the absolute difference between successive FG measurements (average real variability; ARV-FG). For participants who developed any event (diabetes, CVD or mortality), FG variability measurement was censored at the examination prior to event ascertainment. We estimated HRs for incident diabetes, CVD and mortality with adjustment for demographics, baseline FG, change in FG (censor – baseline) and time-varying education, smoking, alcohol consumption, BMI, physical activity, systolic BP, BP medications, LDL-cholesterol and cholesterol medications (and incident diabetes and diabetes medications for CVD and mortality outcomes). Among 3769 black and white participants, there were 317 incident diabetes cases (102,677 person-years), 159 incident CVD events (110,314 person-years) and 174 deaths (111,390 person-years). After adjustment, HRs per 1 SD higher ARV-FG were 1.64 (95% CI 1.52, 1.78) for diabetes, 1.15 (95% CI 1.01, 1.31) for CVD and 1.25 (95% CI 1.11, 1.40) for mortality. The HRs per 1 SD higher CV-FG were 1.39 (95% CI 1.21, 1.58) for diabetes, 1.32 (95% CI 1.13, 1.54) for CVD and 1.08 (95% CI 0.92, 1.27) for mortality, after adjustment. The cause-specific HRs per 1 SD higher ARV-FG were 1.29 (95% CI 1.14, 1.47) for non-CVD death and 1.05 (95% CI 0.76, 1.45) for CVD death. We did not observe evidence for effect modification of any association by sex or race. Our results suggest that higher intra-individual FG variability during young adulthood before the onset of diabetes is associated with incident diabetes, CVD and mortality.
Authors: Bancks MP; Carson AP; Lewis CE; Gunderson EP; Reis JP; Schreiner PJ; Yano Y; Carnethon MR
Diabetologia. 2019 08;62(8):1366-1374. Epub 2019-05-22.
Secular Trends in Long-Term Oral Bisphosphonate Use
Authors: Juergens N; Ettinger B; Hui R; Chandra M; Lo JC
J Gen Intern Med. 2019 08;34(8):1383-1384.
Impact of AKI on Urinary Protein Excretion: Analysis of Two Prospective Cohorts
Prior studies of adverse renal consequences of AKI have almost exclusively focused on eGFR changes. Less is known about potential effects of AKI on proteinuria, although proteinuria is perhaps the strongest risk factor for future loss of renal function. We studied enrollees from the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (ASSESS-AKI) study and the subset of the Chronic Renal Insufficiency Cohort (CRIC) study enrollees recruited from Kaiser Permanente Northern California. Both prospective cohort studies included annual ascertainment of urine protein-to-creatinine ratio, eGFR, BP, and medication use. For hospitalized participants, we used inpatient serum creatinine measurements obtained as part of clinical care to define an episode of AKI (i.e., peak/nadir inpatient serum creatinine ≥1.5). We performed mixed effects regression to examine change in log-transformed urine protein-to-creatinine ratio after AKI, controlling for time-updated covariates. At cohort entry, median eGFR was 62.9 ml/min per 1.73 m2 (interquartile range [IQR], 46.9-84.6) among 2048 eligible participants, and median urine protein-to-creatinine ratio was 0.12 g/g (IQR, 0.07-0.25). After enrollment, 324 participants experienced at least one episode of hospitalized AKI during 9271 person-years of follow-up; 50.3% of first AKI episodes were Kidney Disease Improving Global Outcomes stage 1 in severity, 23.8% were stage 2, and 25.9% were stage 3. In multivariable analysis, an episode of hospitalized AKI was independently associated with a 9% increase in the urine protein-to-creatinine ratio. Our analysis of data from two prospective cohort studies found that hospitalization for an AKI episode was independently associated with subsequent worsening of proteinuria.
Authors: Hsu CY; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators and the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study; et al.
J Am Soc Nephrol. 2019 07;30(7):1271-1281. Epub 2019-06-24.
Association Between Progression of Retinopathy and Concurrent Progression of Kidney Disease: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study
Associations between retinopathy and kidney disease have been previously described. The association between the progression of retinopathy and concurrent progression of chronic kidney disease is unknown. To assess the association between progression of retinopathy and concurrent progression of chronic kidney disease (CKD) among persons with CKD enrolled in a prospective cohort study. A total of 1936 patients with chronic kidney disease enrolled in the multicenter, prospective Chronic Renal Insufficiency Cohort (CRIC) Study were invited to have 2 nonmydriatic fundus photography sessions separated by a mean (SD) of 3.5 (0.5) years. The study was conducted from May 12, 2006, to June 29, 2011. Data analysis was performed from March 16, 2016, to November 17, 2017. Fundus photographs obtained at baseline and then at a follow-up at 3.5 years were reviewed by masked graders for presence and severity of retinopathy, and vessel calibers were assessed using standard protocols. The associations of the changes in retinal features with progression of CKD (50% estimated glomerular filtration rate [eGFR] loss or incident end-stage renal disease, and differences in eGFR slope in the same time period) were assessed with univariable and multivariable logistic regression models. Among 1583 CRIC participants who had baseline fundus photography, had additional follow-up in CRIC, and were at risk for retinopathy progression, 1025 patients (64.8%) had follow-up photography. The odds ratio (OR) for CKD progression associated with worsening of retinopathy in comparison with participants with stable retinopathy was 2.24 (95% CI, 1.28-3.91; P = .005) in univariable analysis among participants with baseline and follow-up photography. In the multivariable analysis, the OR was 1.62 (95% CI, 0.77-3.39; P = .20). The multiple imputation analysis provided similar results. Progression of retinopathy appears to be associated with progression of CKD on univariable analysis but not on multivariable analysis suggesting that similar risk factors may be affecting the progression of both retinal and chronic kidney disease.
Authors: Grunwald JE; Lo JC; Chronic Renal Insufficiency Cohort Study Investigators; et al.
JAMA Ophthalmol. 2019 07 01;137(7):767-774.
Treatment of atrial fibrillation with concomitant coronary or peripheral artery disease: Results from the outcomes registry for better informed treatment of atrial fibrillation II
Treatment patterns and outcomes of individuals with vascular disease who have new-onset atrial fibrillation (AF) are not well characterized. Among patients with new-onset AF, we analyzed treatment and outcomes in those with or without vascular disease in the ORBIT-AF II registry. Vascular disease was defined as coronary disease with or without myocardial infarction (MI) or revascularization, or peripheral artery disease. The primary outcomes included major adverse cardiovascular or neurological events (MACNE) and major bleeding. Cox proportional hazard models were used to adjust the difference in patient characteristics. Overall 1920 of 6203 (31.0%) of new-onset AF had vascular disease. In patients with vascular disease, 62.2% of those were treated with direct oral anticoagulants (DOACs) and 23.4% with warfarin. Dual therapy and triple therapy were used in 36.9% and 4.9%, respectively. Vascular disease patients had increased risk of MACNE (adjusted hazard ratio [aHR] 1.83 [95%CIs 1.32-2.55]), but not major bleeding (aHR 1.24 [0.95-1.63]). Among patients with vascular disease, relative to those on warfarin, those treated with DOACs had similar risk for MACNE (aHR 1.20 [0.77-1.87]) but lower risks for bleeding, although it did not reach statistical significance (aHR 0.70 [0.43-1.15]). Concomitant antiplatelet therapy was associated with higher bleeding (aHR 2.27 [1.38-3.73]) with no apparent reduction in MACNE (aHR 1.50 [1.00-2.25]). Most patients with AF and vascular disease were managed with oral anticoagulation. About half of them were also treated with concomitant antiplatelet therapy, which was associated with increased risk of bleeding, without evidence of improved cardiovascular outcomes.
Authors: Inohara T; Go AS; ORBIT AF Patients and Investigators; et al.
Am Heart J. 2019 07;213:81-90. Epub 2019-04-24.
Association of Fitness With Racial Differences in Chronic Kidney Disease
Non-white minorities are at higher risk for chronic kidney disease than non-Hispanic whites. Better cardiorespiratory fitness is associated with slower declines in estimated glomerular filtration rate and a lower incidence of chronic kidney disease. Little is known regarding associations of fitness with racial disparities in chronic kidney disease. A prospective cohort of 3,842 young adults without chronic kidney disease completed a maximal treadmill test at baseline in 1985-1986. Chronic kidney disease status was defined as estimated glomerular filtration rate of <60 mL/min/1.73 m2 during 10-, 15-, 20-, 25-, and 30-year follow-up assessments (through 2006). Analyses were completed in 2019. Multivariable Cox models were used to determine hazard ratios and 95% CI for incidence of chronic kidney disease. Multivariable models included race, gender, age, field center, education, baseline estimated glomerular filtration rate, and time-varying covariates of healthy diet index, smoking status, alcohol intake, BMI, systolic blood pressure, and fasting glucose. Percent attenuation quantified the association of fitness to racial disparities in chronic kidney disease. Chronic kidney disease incidence was higher among blacks (n=83/1,941, 1.61 per 1,000 person years) than whites (43/1,901, 0.82 per 1,000 person years). Every 1-minute shorter treadmill duration was associated with 1.14 (95% CI=1.04, 1.25) times higher risk of chronic kidney disease. Blacks were 1.72 (95% CI=1.13, 2.63) times more likely to develop chronic kidney disease compared with whites. The risk was reduced to 1.54 (95% CI=1.01, 2.39) with fitness added. This suggests that fitness is associated with 20.4% (95% CI=5.8, 43.0%) of the excess risk of chronic kidney disease attributable to race. Low fitness is a modifiable factor that may contribute to the racial disparity in chronic kidney disease.
Authors: Paluch AE; Pool LR; Isakova T; Lewis CE; Mehta R; Schreiner PJ; Sidney S; Wolf M; Carnethon MR
Am J Prev Med. 2019 07;57(1):68-76. Epub 2019-05-21.
Influence of Multimorbidity on Burden and Appropriateness of Implantable Cardioverter-Defibrillator Therapies
To determine whether burden of multiple chronic conditions (MCCs) influences the risk of receiving inappropriate vs appropriate device therapies. Retrospective cohort study. Seven US healthcare delivery systems. Adults with left ventricular systolic dysfunction receiving an implantable cardioverter-defibrillator (ICD) for primary prevention. Data on 24 comorbid conditions were captured from electronic health records and categorized into quartiles of comorbidity burden (0-3, 4-5, 6-7 and 8-16). Incidence of ICD therapies (shock and antitachycardia pacing [ATP] therapies), including appropriateness, was collected for 3 years after implantation. Outcomes included time to first ICD therapy, total ICD therapy burden, and risk of inappropriate vs appropriate ICD therapy. Among 2235 patients (mean age = 69?±?11?years, 75% men), the median number of comorbidities was 6 (interquartile range = 4-8), with 98% having at least two comorbidities. During a mean 2.2 years of follow-up, 18.3% of patients experienced at least one appropriate therapy and 9.9% experienced at least one inappropriate therapy. Higher comorbidity burden was associated with an increased risk of first inappropriate therapy (adjusted hazard ratio [HR] = 1.94 [95% confidence interval {CI} = 1.14-3.31] for 4-5 comorbidities; HR = 2.25 [95% CI = 1.25-4.05] for 6-7 comorbidities; and HR = 2.91 [95% CI = 1.54-5.50] for 8-16 comorbidities). Participants with 8-16 comorbidities had a higher total burden of ICD therapy (adjusted relative risk [RR] = 2.12 [95% CI = 1.43-3.16]), a higher burden of inappropriate therapy (RR = 3.39 [95% CI = 1.67-6.86]), and a higher risk of receiving inappropriate vs appropriate therapy (RR = 1.74 [95% CI = 1.07-2.82]). Comorbidity burden was not significantly associated with receipt of appropriate ICD therapies. Patterns were similar when separately examining shock or ATP therapies. In primary prevention ICD recipients, MCC burden was independently associated with an increased risk of inappropriate but not appropriate device therapies. Comorbidity burden should be considered when engaging patients in shared decision making about ICD implantation.
Authors: Hajduk AM; Go AS; Cardiovascular Research Network Longitudinal Study of Implantable Cardioverter Defibrillators; et al.
J Am Geriatr Soc. 2019 07;67(7):1370-1378. Epub 2019-03-20.
Association of breastfeeding and gestational diabetes mellitus with the prevalence of prediabetes and the metabolic syndrome in offspring of Hispanic mothers
The effects of breastfeeding (BF) on metabolic syndrome (MetS) and diabetes mellitus in children exposed to gestational diabetes mellitus (GDM) in utero have rarely been evaluated. This study assessed BF and GDM in relation to the prevalence of prediabetes and MetS in Hispanic children and adolescents (8-19 y). This is a longitudinal study with 229 Hispanic children (8-13 y) with overweight/obesity, family history of diabetes, and an average of four annual visits (AV). Participants were categorized as follows: never (negative for prediabetes/MetS at all AVs), ever (positive for prediabetes/MetS at any visit), intermittent (positive for prediabetes/MetS at 1-2 AVs), and persistent (positive for prediabetes/MetS at greater than or equal to 3 AVs). Compared with GDM offspring who were not BF (referent), GDM offspring who were BF had lower odds of persistent prediabetes (OR = 0.18; 95% CI, 0.04-0.82; P = 0.02) and MetS (OR = 0.10; 95% CI, 0.02-0.55; P = 0.008). Compared with referent group, non-GDM offspring who were BF, and non-GDM offspring not BF had lower odds of persistent prediabetes (OR = 0.10; 95% CI, 0.03-0.39; P = 0.001; OR = 0.05; 95% CI, 0.01-0.11; P < 0.001) and MetS (OR = 0.14; 95% CI, 0.04-0.59; P = 0.01 and OR = 0.04; 95% CI, 0.01-0.11; P < 0.001). These results show BF is protective against prediabetes and MetS in offspring regardless of GDM status.
Authors: Vandyousefi S; Goran MI; Gunderson EP; Khazaee E; Landry MJ; Ghaddar R; Asigbee FM; Davis JN
Pediatr Obes. 2019 07;14(7):e12515. Epub 2019-02-08.
Trimethylamine N-oxide and risk of heart failure progression: marker or mediator of disease
Authors: Chioncel O; Ambrosy AP
Eur J Heart Fail. 2019 08;21(8):1008-1011. Epub 2019-06-19.
Burden and Outcomes of Heart Failure Hospitalizations in Adults With Chronic Kidney Disease
Data on rates of heart failure (HF) hospitalizations, recurrent hospitalizations, and outcomes related to HF hospitalizations in chronic kidney disease (CKD) are limited. This study examined rates of HF hospitalizations and re-hospitalizations within a large CKD population and evaluated the burden of HF hospitalizations with the risk of subsequent CKD progression and death. The prospective CRIC (Chronic Renal Insufficiency Cohort) study measured the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) at baseline. The crude rates and rate ratios of HF hospitalizations and 30-day HF re-hospitalizations were calculated using Poisson regression models. Cox regression was used to assess the association of the frequency of HF hospitalizations within the first 2 years of follow-up with risk of subsequent CKD progression and death. Among 3,791 participants, the crude rate of HF admissions was 5.8 per 100 person-years (with higher rates of HF with preserved ejection fraction vs. HF with reduced ejection fraction). The adjusted rate of HF was higher with a lower eGFR (vs. eGFR >45 ml/min/1.73 m2); the rate ratios were 1.7 and 2.2 for eGFR 30 to 44 and <30 ml/min/1.73 m2 (vs. >45 ml/min/1.73 m2), respectively. Similarly, the adjusted rates of HF hospitalization were significantly higher in those with higher urine ACR (vs. urine ACR <30 mg/g); the rate ratios were 1.9 and 2.6 for urine ACR 30 to 299 and ≥300 mg/g, respectively. Overall, 20.6% of participants had a subsequent HF re-admission within 30 days. HF hospitalization within 2 years of study entry was associated with greater adjusted risks for CKD progression (1 hospitalization: hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.40 to 2.67; 2+ hospitalizations: HR: 2.14; 95% CI: 1.30 to 3.54) and all-cause death (1 hospitalization: HR: 2.20; 95% CI: 1.71 to 2.84; 2+ hospitalizations: HR: 3.06; 95% CI: 2.23 to 4.18). Within a large U.S. CKD population, the rates of HF hospitalizations and re-hospitalization were high, with even higher rates across categories of lower eGFR and higher urine ACR. Patients with CKD hospitalized with HF had greater risks of CKD progression and death. HF prevention and treatment should be a public health priority to improve CKD outcomes.
Authors: Bansal N; Go AS; CRIC Study Investigators; et al.
J Am Coll Cardiol. 2019 06 04;73(21):2691-2700.
Intake of Vegetables and Fruits Through Young Adulthood Is Associated with Better Cognitive Function in Midlife in the US General Population
Vegetables and fruits (VF) may differentially affect cognitive functions, presumably due to their various nutrient contents, but evidence from epidemiologic studies is limited. The aim of this study was to examine the long-term association between VF intakes, including VF subgroups, in young adulthood and cognitive function in midlife. A biracial cohort of 3231 men and women aged 18-30 y at baseline in 1985-1986 were followed up for 25 y in the Coronary Artery Risk Development in Young Adults Study. Diet was measured at baseline, and in examination years 7 and 20. Cognitive function was assessed at examination year 25 through the use of 3 tests: the Rey Auditory Verbal Learning Test (RAVLT), the Digit Symbol Substitution Test (DSST), and the Stroop test. The mean differences (MDs) with 95% CIs in cognitive scores across intake categories were estimated through the use of the multivariable-adjusted general linear regression model. Excluding potatoes, intake of whole vegetables was significantly associated with a better cognitive performance after adjustment for potential confounders in all 3 cognitive tests (quintile 5 compared with quintile 1-RAVLT, MD: 0.33; 95% CI: 0.01, 0.64; P-trend = 0.08; DSST, MD: 2.84; 95% CI: 0.93, 4.75; P-trend
Authors: Mao X; Chen C; Xun P; Daviglus ML; Steffen LM; Jacobs DR; Van Horn L; Sidney S; Zhu N; Qin B; He K
J Nutr. 2019 Jun 04.
Coronary Artery Calcium From Early Adulthood to Middle Age and Left Ventricular Structure and Function
Background The relationship of coronary artery calcium (CAC) with adverse cardiac remodeling is not well established. We aimed to study the association of CAC in middle age and change in CAC from early adulthood to middle age with left ventricular (LV) function. Methods CAC score was measured by computed tomography at CARDIA study (Coronary Artery Risk Development in Young Adults) year-15 examination and at year-25 examination (Y25) in 3043 and 3189 participants, respectively. CAC score was assessed as a continuous variable and log-transformed to account for nonlinearity. Change in CAC from year-15 examination to Y25 was evaluated as the absolute difference of log-transformed CAC from year-15 examination to Y25. LV structure and function were evaluated by echocardiography at Y25. Results At Y25, mean age was 50.1±3.6 years, 56.6% women, 52.4% black. In the multivariable analysis at Y25, higher CAC was related to higher LV mass (β=1.218; adjusted P=0.007), higher LV end-diastolic volume (β=0.811; adjusted P=0.007), higher LV end-systolic volume (β=0.350; adjusted P=0.048), higher left atrial volume (β=0.214; adjusted P=0.009), and higher E/e’ ratio (β=0.059; adjusted P=0.014). CAC was measured at both year-15 examination and Y25 in 2449 individuals. Higher change in CAC score during follow-up was independently related to higher LV mass index in blacks (β=4.789; adjusted P<0.001), but not in whites (β=1.051; adjusted P=0.283). Conclusions Higher CAC in middle age is associated with higher LV mass and volumes and worse LV diastolic function. Being free of CAC from young adulthood to middle age correlates to better LV function at middle age. Higher change in CAC score during follow-up is independently related to higher LV mass index in blacks.
Authors: Yared GS; Carr JJ; Lima JAC; et al.
Circ Cardiovasc Imaging. 2019 06;12(6):e009228. Epub 2019-06-14.
Using Pharmacy Data and Adherence to Define Long-Term Bisphosphonate Exposure in Women
Assigning drug exposure is a necessary first step in examining bisphosphonate (BP) treatment in observational studies using pharmacy data. To determine whether the choice of adherence level using the proportion of days covered (PDC) affected BP exposure assignment. 10,381 female health plan members who initiated oral BP therapy between 2002 and 2010 and had received 5 consecutive years of treatment were identified and subsequently followed up to 5 additional years. In each 90-day interval of follow-up, a woman was considered “on treatment” if she received the drug for more than a predetermined PDC based on pharmacy days supply and “off treatment” if she received the drug for less than that PDC. Women who continued on therapy above the PDC threshold during follow-up were considered continuously on therapy. Women who were off treatment during the first 90-days of follow-up were classified as off therapy and were followed to determine if they remained continuously off treatment. This study evaluated the extent to which varying the PDC threshold (≥ 0.5, ≥ 0.6, and ≥ 0.7) affected the proportion of women classified as “continuously on” or “continuously off” BP during follow-up. Under PDC thresholds of 0.5, 0.6, and 0.7, 48%, 43%, and 36% of women who remained on follow-up were categorized as continuously on treatment at year 2 of follow-up, and 18%, 14%, and 12% were categorized as continuously on treatment by the end of follow-up. Using these same PDC thresholds, 9%, 12%, and 15% of women were categorized as off therapy during the first quarter of follow-up and were highly likely to remain off therapy: 4%, 5%, and 5% were classified as continuously off therapy at year 2, and 4% of women were classified as such by the end of follow-up for all 3 thresholds. A PDC of 0.6 was chosen as a practical threshold for drug adherence. Varying the PDC to 0.5 or 0.7 resulted in modest changes in the proportions of women considered continuously on BP therapy. This study was supported by a grant from the National Institute of Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (R01AG047230, S1). Lo has received previous research funding from Amgen and Sanofi, outside of the current study. Chandra has received previous research funding from Amgen outside of the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, outside of the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. Ettinger previously served as an expert witness for Teva Pharmaceuticals.
Authors: Izano MA; Neugebauer R; Ettinger B; Hui R; Chandra M; Adams AL; Niu F; Ott SM; Lo JC
J Manag Care Spec Pharm. 2019 Jun;25(6):719-723.
Perceived and objective characteristics of the neighborhood environment are associated with accelerometer-measured sedentary time and physical activity, the CARDIA Study
We investigated cross-sectional and longitudinal associations of neighborhood environment characteristics with accelerometer-measured sedentary time (SED), light-intensity physical activity (LPA), and moderate-to-vigorous intensity physical activity (MVPA). Participants were 2120 men and women in the year 20 (2005-2006) and year 30 CARDIA exams (2015-2016). Year 20 neighborhood characteristics included neighborhood cohesion, resources for physical activity, poverty, and racial residential segregation. Physical activity was measured by accelerometer at years 20 and 30. Multivariable linear regression models examined associations of standardized neighborhood measures at year 20 with SED, LPA, and MVPA assessed that year, and with 10-year changes in SED, LPA, and MVPA. Cross-sectionally, a one standard deviation (SD) increase in cohesion was associated with 4.06 less SED min/day (95% CI: -7.98, -0.15), and 4.46 more LPA min/day (95% CI: 0.88, 8.03). Each one SD increase in resources was associated with 1.19 more MVPA min/day (95% CI: 0.06, 2.31). A one SD increase in poverty was associated with 11.18 less SED min/day (95% CI: -21.16, -1.18) and 10.60 more LPA min/day (95% CI: 1.79, 19.41) among black men. No neighborhood characteristic was associated with 10-year changes in physical activity in the full sample; however, a one SD increase in cohesion was associated with a 10-year decrease of 25.44 SED min/day (95% CI: -46.73, -4.14) and an increase of 19.0 LPA min/day (95% CI, 1.89, 36.10) in black men. Characteristics of the neighborhood environment are associated with accelerometer-measured physical activity. Differences were observed by race and sex, with more robust findings observed in black men.
Authors: Whitaker KM; Xiao Q; Pettee Gabriel K; Gordon Larsen P; Jacobs DR; Sidney S; Reis JP; Barone Gibbs B; Sternfeld B; Kershaw K
Prev Med. 2019 06;123:242-249. Epub 2019-03-30.
Serum Calcification Propensity and Coronary Artery Calcification Among Patients With CKD: The CRIC (Chronic Renal Insufficiency Cohort) Study
Coronary artery calcification (CAC) is prevalent among patients with chronic kidney disease (CKD) and increases risks for cardiovascular disease events and mortality. We hypothesized that a novel serum measure of calcification propensity is associated with CAC among patients with CKD stages 2 to 4. Prospective cohort study. Participants from the Chronic Renal Insufficiency Cohort (CRIC) Study with baseline (n=1,274) and follow-up (n=780) CAC measurements. Calcification propensity, quantified as transformation time (T50) from primary to secondary calciprotein particles, with lower T50 corresponding to higher calcification propensity. Covariates included age, sex, race/ethnicity, clinical site, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, number of antihypertensive medications, current smoking, history of cardiovascular disease, total cholesterol level, and use of statin medications. CAC prevalence, severity, incidence, and progression. Multivariable-adjusted generalized linear models. At baseline, 824 (65%) participants had prevalent CAC. After multivariable adjustment, T50 was not associated with CAC prevalence but was significantly associated with greater CAC severity among participants with prevalent CAC: 1-SD lower T50 was associated with 21% (95% CI, 6%-38%) greater CAC severity. Among 780 participants followed up an average of 3 years later, 65 (20%) without baseline CAC developed incident CAC, while 89 (19%) with baseline CAC had progression, defined as annual increase?100 Agatston units. After multivariable adjustment, T50 was not associated with incident CAC but was significantly associated with CAC progression: 1-SD lower T50 was associated with 28% (95% CI, 7%-53%) higher risk for CAC progression. Potential selection bias in follow-up analyses; inability to distinguish intimal from medial calcification. Among patients with CKD stages 2 to 4, higher serum calcification propensity is associated with more severe CAC and CAC progression.
Authors: Bundy JD; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2019 06;73(6):806-814. Epub 2019-03-29.
Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
A person’s lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
Authors: de Vries PS; Sims M; Morrison AC; et al.
Am J Epidemiol. 2019 06 01;188(6):1033-1054.
Serum Sex Hormones and the Risk of Fracture across the Menopausal Transition: Study of Women’s Health Across the Nation
Sex steroid hormones have been linked to fractures in older women. To test the hypothesis that hormones measured over the menopausal transition predict fractures. Seven US clinical centers. Two thousand nine hundred sixty women (average age, 46.4 ± 2.7 years) who had at least two repeat hormone measures and prospective information on fractures. Fasting serum was collected annually for hormone assays. Estradiol (E2) was measured with a modified direct immunoassay. FSH and SHBG were measured with two-site chemiluminescence immunoassays. Hormones were lagged (visit year -1) and transformed using log base 2. Incident fractures were ascertained at each annual visit. All medications including hormone therapy were time varying covariates. Discrete survival methods were used. Five hundred eight (17.2%) women experienced an incident fracture over an average follow up of 8.8 ± 4.4 years. Women who experienced an incident fracture were more likely to be white, report high alcohol intake and diabetes, and less likely to report premenopausal status at baseline. A woman whose log E2 was twice that of another had a 10% lower risk of fracture independent of covariates, relative risk (95% CI) = 0.90 (0.82, 0.98). Neither FSH nor SHBG were associated with fractures. Serum E2 levels may help to identify women at higher risk of fractures over the menopausal transition. However, hormone assays must be standardized across laboratories for clinical implementation and further work is needed to define E2 thresholds.
Authors: Cauley JA; Ruppert K; Lian Y; Finkelstein JS; Karvonen-Gutierrez CA; Harlow SD; Lo JC; Burnett-Bowie SM; Karlamangla A; Greendale GA
J Clin Endocrinol Metab. 2019 06 01;104(6):2412-2418.
Lipids, Apolipoproteins, and Risk of Atherosclerotic Cardiovascular Disease in Persons With CKD
A large residual risk for atherosclerotic cardiovascular disease (ASCVD) remains in the setting of chronic kidney disease (CKD) despite treatment with statins. We sought to evaluate the associations of lipid and apolipoprotein levels with risk for ASCVD in individuals with CKD. Prospective cohort study. Adults aged 21 to 74 years with non-dialysis-dependent CKD at baseline enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study in 7 clinical study centers in the United States. Baseline total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), HDL-C, and apolipoprotein AI (Apo-AI) values stratified into tertiles. A composite ASCVD event of myocardial infarction or ischemic stroke. Multivariable Cox proportional hazards regression to estimate the risk for ASCVD for each tertile of lipoprotein predictor. Among 3,811 CRIC participants (mean age, 57.7 years; 41.8% white), there were 451 ASCVD events during a median follow-up of 7.9 years. There was increased ASCVD risk among participants with VLDL-C levels in the highest tertile (HR, 1.28; 95% CI, 1.01-1.64), Apo-B levels in the middle tertile (HR, 1.30; 95% CI, 1.03-1.64), HDL-C levels in the middle and lowest tertiles (HRs of 1.40 [95% CI, 1.08-1.83] and 1.77 [95% CI, 1.35-2.33], respectively), and Apo-AI levels in the middle and lowest tertiles (HRs of 1.77 [95% CI, 1.02-1.74] and 1.77 [95% CI, 1.36-2.32], respectively). LDL-C level was not significantly associated with the ASCVD outcome in this population (HR, 1.00 [95% CI, 0.77-1.30] for the highest tertile). Associations based on observational data do not permit inferences about causal associations. Higher VLDL-C and Apo-B levels, as well as lower HDL-C and Apo-AI levels, are associated with increased risk for ASCVD. These findings support future investigations into pharmacologic targeting of lipoproteins beyond LDL-C, such as triglyceride-rich lipoproteins, to reduce residual risk for ASCVD among individuals with CKD.
Authors: Bajaj A; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2019 06;73(6):827-836. Epub 2019-01-25.
Research-based versus clinical serum creatinine measurements and the association of acute kidney injury with subsequent kidney function: findings from the Chronic Renal Insufficiency Cohort study
Observational studies relying on clinically obtained data have shown that acute kidney injury (AKI) is linked to accelerated chronic kidney disease (CKD) progression. However, prior reports lacked uniform collection of important confounders such as proteinuria and pre-AKI kidney function trajectory, and may be susceptible to ascertainment bias, as patients may be more likely to undergo kidney function testing after AKI. We studied 444 adults with CKD who participated in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study and were concurrent members of a large integrated healthcare delivery system. We estimated glomerular filtration rate (eGFR) trajectories using serum creatinine measurements from (i) the CRIC research protocol (yearly) and (ii) routine clinical care. We used linear mixed effects models to evaluate the associations of AKI with acute absolute change in eGFR and post-AKI eGFR slope, and explored whether these varied by source of creatinine results. Models were adjusted for demographic characteristics, diabetes status and albuminuria. During median follow-up of 8.5 years, mean rate of eGFR loss was -0.31 mL/min/1.73 m2/year overall, and 73 individuals experienced AKI (55% Stage 1). A significant interaction existed between AKI and source of serum creatinine for acute absolute change in eGFR level after discharge; in contrast, AKI was independently associated with a faster rate of eGFR decline (mean additional loss of -0.67 mL/min/1.73 m2/year), which was not impacted by source of serum creatinine. AKI is independently associated with subsequent steeper eGFR decline regardless of the serum creatinine source used, but the strength of association is smaller than observed in prior studies after taking into account key confounders such as pre-AKI eGFR slope and albuminuria.
Authors: Hsu RK; Yang J; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators; et al.
Clin Kidney J. 2020 Feb;13(1):55-62. Epub 2019-05-20.
Blood Pressure Control and Cardiovascular Outcomes in Patients With Atrial Fibrillation (From the ORBIT-AF Registry)
Systolic blood pressure (SBP) and its association with clinical outcomes in atrial fibrillation (AF) patients in community practice are poorly characterized. In patients with AF, we sought to (1) examine the prevalence of baseline uncontrolled hypertension and the overall change in SBP control, (2) identify predictors of uncontrolled SBP over 2 years of follow-up, and (3) determine the relation between SBP and clinical outcomes. We analyzed 10,132 patients with AF at 176 clinics in the ORBIT-AF registry between 2010 and 2014, classified as: (1) no history of hypertension; (2) controlled hypertension (baseline SBP <140 mm Hg); (3) and uncontrolled hypertension (baseline SBP >140 mm Hg). Predictors of SBP >140 mm Hg at baseline or in follow-up were identified with pooled logistic regression. Random effects Cox regression models were used to compare cardiovascular outcomes and major bleeding as a function of continuous, time-dependent SBP. Overall 8,383 (83%) of patients with AF had hypertension. Of these, 24.2% (n = 2032) had uncontrolled baseline SBP, with little change over 2 years. Predictors of elevated follow-up SBP included uncontrolled baseline SBP, females, previous percutaneous coronary intervention, and diabetes. For every 5 mm Hg increase in follow-up SBP, the adjusted risk of stroke or systemic embolism or transient ischemic attack (adjusted hazard ratio [aHR] 1.05, 95% confidence interval [CI] 1.01 to 1.08, p = 0.01), myocardial infarction (aHR 1.05, 95% CI 1.00 to 1.11, p = 0.04), and major bleeding (aHR 1.03, 95% CI 1.00 to 1.06, p = 0.04) increased modestly. In conclusion, in patients with AF, higher SBP was associated with increasing adverse events; therefore, more rigorous blood pressure control should be emphasized.
Authors: Vemulapalli S; Go AS; Peterson ED; et al.
Am J Cardiol. 2019 05 15;123(10):1628-1636. Epub 2019-02-23.
Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial
Authors: Morrow DA; Velazquez EJ; DeVore AD; Desai AS; Duffy CI; Ambrosy AP; Gurmu Y; McCague K; Rocha R; Braunwald E
Circulation. 2019 05 07;139(19):2285-2288.
Comparison of Patient-Reported Care Satisfaction, Quality of Warfarin Therapy, and Outcomes of Atrial Fibrillation: Findings From the ORBIT – AF Registry
Background Patient satisfaction with therapy is an important metric of care quality and has been associated with greater medication persistence. We evaluated the association of patient satisfaction with warfarin therapy to other metrics of anticoagulation care quality and clinical outcomes among patients with atrial fibrillation ( AF ). Methods and Results Using data from the ORBIT – AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, patients were identified with AF who were taking warfarin and had completed an Anti-Clot Treatment Scale ( ACTS ) questionnaire, a validated metric of patient-reported burden and benefit of oral anticoagulation. Multivariate regressions were used to determine association of ACTS burden and benefit scores with time in therapeutic international normalized ratio range ( TTR ; both ≥75% and ≥60%), warfarin discontinuation, and clinical outcomes (death, stroke, major bleed, and all-cause hospitalization). Among 1514 patients with AF on warfarin therapy (75±10 years; 42% women; CHA 2 DS 2- VAS c 3.9±1.7), those most burdened with warfarin therapy were younger and more likely to be women, have paroxysmal AF , and to be treated with antiarrhythmic drugs. After adjustment for covariates, ACTS burden scores were independent of TTR ( TTR ≥75%: odds ratio, 1.01 [95% CI , 0.99-1.03]; TTR ≥60%: odds ratio, 1.01 [95% CI , 0.98-1.05]), warfarin discontinuation (odds ratio, 0.99; 95% CI , 0.97-1.01), or clinical outcomes. ACTS benefit scores were also not associated with TTR , warfarin discontinuation, or clinical outcomes. Conclusions In a large registry of patients with AF taking warfarin, ACTS scores provided independent information beyond other traditional metrics of oral anticoagulation care quality and identified patient groups at high risk for dissatisfaction with warfarin therapy.
Authors: Perino AC; Go AS; Mahaffey KW; et al.
J Am Heart Assoc. 2019 05 07;8(9):e011205.
Evaluation of commonly used ectoderm markers in iPSC trilineage differentiation
Patient-derived induced pluripotent stem cells (iPSCs) have become a promising resource for exploring genetics of complex diseases, discovering new drugs, and advancing regenerative medicine. Increasingly, laboratories are creating their own banks of iPSCs derived from diverse donors. However, there are not yet standardized guidelines for qualifying these cell lines, i.e., distinguishing between bona fide human iPSCs, somatic cells, and imperfectly reprogrammed cells. Here, we report the establishment of a panel of 30 iPSCs from CD34+ peripheral blood mononuclear cells, of which 10 were further differentiated in vitro into all three germ layers. We characterized these different cell types with commonly used pluripotent and lineage specific markers, and showed that NES, TUBB3, and OTX2 cannot be reliably used as ectoderm differentiation markers. Our work highlights the importance of marker selection in iPSC authentication, and the need for the field to establish definitive standard assays.
Authors: Kuang YL; Iribarren C; Medina MW; et al.
Stem Cell Res. 2019 05;37:101434. Epub 2019-04-10.
Trends in Readmissions and Length of Stay for Patients Hospitalized With Heart Failure in Canada and the United States
Over the past decade, reducing 30-day readmission rates has been emphasized in the United States (including via the implementation of the Hospital Readmissions Reduction Program) but not Canada. To examine changes that occurred from April 1, 2005, to December 31, 2015, in the United States and Canada for hospitalization length of stay and 30-day readmission rates of patients with heart failure. This cohort study included patients admitted with a primary diagnosis of heart failure to Canadian and US hospitals between April 1, 2005, and December 31, 2015, using International Classification of Diseases, Ninth Revision code 428.xx and Tenth Revision code I50. The study examined secular trends in length of stay and readmissions in both countries and tested for changes after implementation of the Hospital Readmissions Reduction Program using segmented regression models and the association between length of stay and readmissions using patient-level and hospital-level multivariable logistic regression models. Data analysis was completed from February 2018 to August 2018. Thirty-day readmissions. Between 2005 and 2015, mean length of stay declined marginally in Canadian hospitals (from a mean [SD] of 7.5 [5.7] to 7.3 [5.6] days; P < .001) but remained stable in US hospitals (mean [SD], 4.9 [3.7] days to 4.9 [3.5] days). Thirty-day readmission rates declined similarly in Canada (from 4088 of 20 758 patients [19.7%] to 3823 of 21 733 patients [17.6%] for all-cause readmissions; P < .001; and from 1743 of 20 758 patients [8.4%] to 1490 of 21 733 patients [6.9%] for heart failure-specific readmissions; P < .001) and the United States (from 21.2% to 18.5% for all-cause readmissions; from 7.6% to 5.7% for heart failure-specific readmissions; both P < .001). There were small but statistically significant positive correlations between length of stay and 30-day readmissions in both Canada (odds ratio, 1.01 [95% CI, 1.01-1.01]) and the United States (odds ratio, 1.01 [95% CI, 1.01-1.01]). Interrupted time-series analysis comparing readmission rates before and after the Hospital Readmissions Reduction Program implementation revealed no significant difference in either country for all-cause readmission rates before and after October 2012. There was also no change in the slope of the temporal trends; in Canada, all-cause readmissions were decreasing 1.1% per year before implementation and 1.3% after implementation (P = .84 for slope change) compared with 1.6% per year in the United States before implementation and 1.8% per year after October 2012 (P = .60 for slope change). Both Canada and the United States exhibited similar temporal declines in 30-day all-cause readmissions over the past decade. These findings suggest that the Hospital Readmissions Reduction Program did not appear to be associated with this secular trend or length of stay for heart failure in the United States.
Authors: Samsky MD; Ambrosy AP; Youngson E; Liang L; Kaul P; Hernandez AF; Peterson ED; McAlister FA
JAMA Cardiol. 2019 05 01;4(5):444-453.
Natriuretic peptides as a surrogate endpoint in clinical trials - a riddle wrapped in an enigma
Authors: Hardwick AB; Ambrosy AP
Eur J Heart Fail. 2019 05;21(5):621-623. Epub 2019-03-27.
Association of Infant Temperament With Subsequent Obesity in Young Children of Mothers With Gestational Diabetes Mellitus
Infant temperament is associated with excess weight gain or childhood obesity risk in samples of healthy individuals, although the evidence has been inconsistent. To our knowledge, no prior research has examined this topic among children exposed to gestational diabetes mellitus (GDM) in utero. To prospectively evaluate infant temperament in association with overweight and obesity status at ages 2 to 5 years among children born to mothers who experienced GDM. This prospective cohort study took place at Kaiser Permanente Northern California medical centers. We studied singleton infants delivered at 35 weeks’ gestational age or later to mothers who had been diagnosed with GDM. Data were collected from 2009 to 2016, and data analysis occurred from June 2017 to October 2018. The primary exposures in the child’s first year were soothability, distress to limitations, and activity aspects of temperament, as assessed by a validated questionnaire. Modifiable covariates in the child’s first year included breastfeeding intensity and duration monthly ratio scores, along with the timing of the introduction of sugary beverages and complementary foods. The primary outcome was child overweight and obesity status, assessed at ages 2 to 5 years. Multinomial logistic regression models estimated adjusted odds ratios and 95% CIs for infants whose temperaments were measured at 6 to 9 weeks of age and categorized as elevated (≥75th percentile) or not elevated in the 3 domains. We controlled for nonmodifiable and modifiable covariates across models. A total of 382 mother-infant pairs participted, including 130 infants (34.0%) who were non-Hispanic white, 126 infants (33.0%) who were Hispanic, 96 infants (25.1%) who were Asian, 26 infants (6.8%) who were non-Hispanic black, and 4 infants (1.1%) who were of other races/ethnicities. In descriptive analyses, elevated infant soothability and activity temperaments were associated with the early introduction of 100% fruit juice and/or sugar-sweetened beverages (at ages <6 months) and shorter breastfeeding duration (from 0 to <3 months), while elevated distress to limitations was associated with early introduction of complementary foods (at ages <4 months). Elevated soothability consistently was associated with a higher odds of later childhood obesity, with adjusted odds ratios across models ranging from 2.22 (95% CI, 1.04-4.73) to 2.54 (95% CI, 1.28-5.03). Greater breastfeeding intensity and duration (12-month combined) score was associated with lower odds of obesity, independent of infant temperament and other covariates. Among this high-risk population of infants, elevated soothability was associated with early childhood obesity risk, perhaps in part because caregivers use sugary drinks to assuage infants. Soothability temperament may be a novel screening target for early obesity prevention interventions involving responsive feeding and emotion regulation.
Authors: Faith MS; Hittner JB; Hurston SR; Yin J; Greenspan LC; Quesenberry CP; Gunderson EP; SWIFT Offspring Study Investigators
JAMA Pediatr. 2019 05 01;173(5):424-433.
Effects of seafood consumption and toenail mercury and selenium levels on cognitive function among American adults: 25 y of follow up
The aim of this study was to examine the longitudinal association between seafood and intake of long-chain ω-3 polyunsaturated fatty acids (LCω-3 PUFA) and cognitive function and to explore the possible effect modifications owing to mercury (Hg) and selenium (Se) levels. Participants (N = 3231) from the CARDIA (Coronary Artery Risk Development in Young Adults) study underwent baseline examination and were reexamined in eight follow-up visits. Diet was assessed at baseline and in exam years 7 and 20. Toenail Hg and Se were measured at exam year 2. Cognitive function was measured at exam year 25 using three tests: Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and the Stroop test. The general linear regression model was used to examine cumulative average intakes of LCω-3 PUFA and seafood in relation to the cognitive test scores; and to explore the possible effect modifications caused by Hg and Se. LCω-3 PUFA intake was significantly associated with better performance in the DSST test (quintile 5 versus quintile 1; mean difference = 1.74; 95% confidence interval, 0.19-3.29; Ptrend, 0.048]), but not in the RAVLT and Stroop tests. Similar results were observed for intakes of eicosapentaenoic acid, docosahexaenoic acid, and non-fried seafood. The observed associations were more pronounced in participants with body mass index ≥25 kg/m2, but not significantly modified by toenail Hg or Se. This longitudinal study supported the hypothesis that LCω-3 PUFA or non-fried seafood intake is associated with better cognitive performance in psychomotor speed among US adults, especially those who are overweight or obese.
Authors: Mao X; Chen C; Xun P; Daviglus M; Steffen LM; Jacobs DR; Van Horn L; Sidney S; Zhu N; He K
Nutrition. 2019 05;61:77-83. Epub 2018-11-24.
Closing the Evidence Gap in Interstitial Lung Disease: The Promise of Real World Data
Authors: Farrand E; Anstrom KJ; Bernard G; Butte AJ; Iribarren C; Ley B; Martinez FJ; Collard HR
Am J Respir Crit Care Med. 2019 05 01;199(9):1061-1065.
Dietary patterns during adulthood and cognitive performance in midlife: The CARDIA study
To investigate whether dietary patterns (Mediterranean diet [MedDiet], Dietary Approaches to Stop Hypertension [DASH], and A Priori Diet Quality Score [APDQS]) during adulthood are associated with midlife cognitive performance. We studied 2,621 Coronary Artery Risk Development in Young Adults (CARDIA) participants; 45% were black, 57% were female, and mean age was 25 ± 3.5 years at baseline (year 0). Mean diet scores were calculated from diet history at baseline, year 7, and year 20 (mean age 25, 32, and 45 years, respectively). Cognitive function was assessed at years 25 and 30 (mean age 50 and 55 years, respectively). Linear models were used to examine association between tertiles of diet score and change in composite cognitive function and cognitive z scores (verbal memory [Rey Auditory Verbal Learning Test], processing speed [Digit Symbol Substitution Test], and executive function [Stroop Interference test]) and the Montreal Cognitive Assessment (MoCA) at year 30. DASH was not associated with change in cognitive performance. Higher MedDiet and APDQS scores were associated with less decline in cognitive function (MedDiet: low -0.04, middle 0.03, high 0.03, p = 0.03; APDQS: low -0.04, middle -0.00, high 0.06, p < 0.01) and Stroop Interference (MedDiet: low 0.09, middle -0.06, high -0.03; APDQS: low 0.10, middle 0.01, high -0.09, both p < 0.01). Odds ratios (95% confidence interval) for poor global cognitive function (≥1 SD below mean MoCA score) comparing extreme tertiles of diet scores were 0.54 (0.39-0.74) for MedDiet, 0.48 (0.33-0.69) for APDQS, and 0.89 (0.68-1.17) for DASH. Greater adherence to MedDiet and APDQS dietary patterns during adulthood was associated with better midlife cognitive performance. Additional studies are needed to define the combination of foods and nutrients for optimal brain health across the life course.
Authors: McEvoy CT; Hoang T; Sidney S; Steffen LM; Jacobs DR; Shikany JM; Wilkins JT; Yaffe K
Neurology. 2019 04 02;92(14):e1589-e1599. Epub 2019-03-06.
Identifying responders to oral iron supplementation in heart failure with a reduced ejection fraction: a post-hoc analysis of the IRONOUT-HF trial
The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency. The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level >300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation >20% at the end of the study. The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16. This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.
Authors: Ambrosy AP; Lewis GD; Malhotra R; Jones AD; Greene SJ; Fudim M; Coles A; Butler J; Sharma A; Hernandez AF; Mentz RJ
J Cataract Refract Surg. 2019 04;45(4):404-413. Epub 2019-01-09.
Urinary N-Telopeptide as Predictor of Onset of Menopause-Related Bone Loss in Pre- and Perimenopausal Women
The menopause transition (MT) is a period of rapid bone loss and has been proposed to be a time-limited window for early intervention to prevent permanent microarchitectural damage and reduce the risk of subsequent fracture. To intervene early, however, we first need to be able to determine whether menopause-related bone loss is about to begin, in advance of substantial bone loss. The objective of this study was, therefore, to assess whether urinary N-telopeptide (U-NTX) in pre- or early perimenopause can predict the onset of menopause-related bone loss. Repeated U-NTX measurements were obtained during pre- and early perimenopause in 1243 participants from the Study of Women’s Health Across the Nation (SWAN). We examined the ability of U-NTX to predict the onset of significant menopause-related bone loss (categorical outcome, yes versus no) at the lumbar spine (LS) and femoral neck (FN), defined as annualized bone mineral density (BMD) decline at a rate faster than the smallest detectable change in BMD over the 3 to 4 years from the time of U-NTX measurement. Adjusting for age, race/ethnicity, body mass index, urine collection time, starting BMD, and study site in multivariable, modified Poisson regression, every standard deviation increment in U-NTX, measured at baseline in early perimenopausal women, was associated with an 18% and 22% greater risk of significant bone loss at the LS (p = 0.003) and FN (p = 0.003), respectively. The area under the receiver-operator curve for predicting LS and FN bone loss was 0.72 and 0.72, respectively. In mixed-effects analysis of all repeated measures of early perimenopausal U-NTX over follow-up, U-NTX predicted onset of bone loss at the LS (p = 0.002) but not at the FN. We conclude that U-NTX can be used early in the MT to determine if a woman is about to experience significant LS bone loss before there has been substantial skeletal deterioration. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
Authors: Shieh A; Greendale GA; Cauley JA; Karvonen-Gutierrez C; Lo J; Karlamangla AS
JBMR Plus. 2019 Apr;3(4):e10116. Epub 2018-12-30.
Predicting Renal Recovery After Dialysis-Requiring Acute Kidney Injury
After dialysis-requiring acute kidney injury (AKI-D), recovery of sufficient kidney function to discontinue dialysis is an important clinical and patient-oriented outcome. Predicting the probability of recovery in individual patients is a common dilemma. This cohort study examined all adult members of Kaiser Permanente Northern California who experienced AKI-D between January 2009 and September 2015 and had predicted inpatient mortality of <20%. Candidate predictors included demographic characteristics, comorbidities, laboratory values, and medication use. We used logistic regression and classification and regression tree (CART) approaches to develop and cross-validate prediction models for recovery. Among 2214 patients with AKI-D, mean age was 67.1 years, 40.8% were women, and 54.0% were white; 40.9% of patients recovered. Patients who recovered were younger, had higher baseline estimated glomerular filtration rates (eGFR) and preadmission hemoglobin levels, and were less likely to have prior heart failure or chronic liver disease. Stepwise logistic regression applied to bootstrapped samples identified baseline eGFR, preadmission hemoglobin level, chronic liver disease, and age as the predictors most commonly associated with coming off dialysis within 90 days. Our final logistic regression model including these predictors had a correlation coefficient between observed and predicted probabilities of 0.97, with a c-index of 0.64. An alternate CART approach did not outperform the logistic regression model (c-index 0.61). We developed and cross-validated a parsimonious prediction model for recovery after AKI-D with excellent calibration using routinely available clinical data. However, the model's modest discrimination limits its clinical utility. Further research is needed to develop better prediction tools.
Authors: Lee BJ; Hsu CY; Parikh R; McCulloch CE; Tan TC; Liu KD; Hsu RK; Pravoverov L; Zheng S; Go AS
Kidney Int Rep. 2019 Apr;4(4):571-581. Epub 2019-01-28.
Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids
The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
Authors: Bentley AR; Sims M; Cupples LA; et al.
Nat Genet. 2019 04;51(4):636-648. Epub 2019-03-29.
The discovery of novel predictive biomarkers and early-stage pathophysiology for the transition from gestational diabetes to type 2 diabetes
Gestational diabetes mellitus (GDM) affects up to 20% of pregnancies, and almost half of the women affected progress to type 2 diabetes later in life, making GDM the most significant risk factor for the development of future type 2 diabetes. An accurate prediction of future type 2 diabetes risk in the early postpartum period after GDM would allow for timely interventions to prevent or delay type 2 diabetes. In addition, new targets for interventions may be revealed by understanding the underlying pathophysiology of the transition from GDM to type 2 diabetes. The aim of this study is to identify both a predictive signature and early-stage pathophysiology of the transition from GDM to type 2 diabetes. We used a well-characterised prospective cohort of women with a history of GDM pregnancy, all of whom were enrolled at 6-9 weeks postpartum (baseline), were confirmed not to have diabetes via 2 h 75 g OGTT and tested anually for type 2 diabetes on an ongoing basis (2 years of follow-up). A large-scale targeted lipidomic study was implemented to analyse ~1100 lipid metabolites in baseline plasma samples using a nested pair-matched case-control design, with 55 incident cases matched to 85 non-case control participants. The relationships between the concentrations of baseline plasma lipids and respective follow-up status (either type 2 diabetes or no type 2 diabetes) were employed to discover both a predictive signature and the underlying pathophysiology of the transition from GDM to type 2 diabetes. In addition, the underlying pathophysiology was examined in vivo and in vitro. Machine learning optimisation in a decision tree format revealed a seven-lipid metabolite type 2 diabetes predictive signature with a discriminating power (AUC) of 0.92 (87% sensitivity, 93% specificity and 91% accuracy). The signature was highly robust as it includes 45-fold cross-validation under a high confidence threshold (1.0) and binary output, which together minimise the chance of data overfitting and bias selection. Concurrent analysis of differentially expressed lipid metabolite pathways uncovered the upregulation of α-linolenic/linoleic acid metabolism (false discovery rate [FDR] 0.002) and fatty acid biosynthesis (FDR 0.005) and the downregulation of sphingolipid metabolism (FDR 0.009) as being strongly associated with the risk of developing future type 2 diabetes. Focusing specifically on sphingolipids, the downregulation of sphingolipid metabolism using the pharmacological inhibitors fumonisin B1 (FB1) and myriocin in mouse islets and Min6 K8 cells (a pancreatic beta-cell like cell line) significantly impaired glucose-stimulated insulin secretion but had no significant impact on whole-body glucose homeostasis or insulin sensitivity. We reveal a novel predictive signature and associate reduced sphingolipids with the pathophysiology of transition from GDM to type 2 diabetes. Attenuating sphingolipid metabolism in islets impairs glucose-stimulated insulin secretion.
Authors: Khan SR; Mohan H; Liu Y; Batchuluun B; Gohil H; Al Rijjal D; Manialawy Y; Cox BJ; Gunderson EP; Wheeler MB
Diabetologia. 2019 04;62(4):687-703. Epub 2019-01-15.
Large-scale, multi-ethnic genome-wide association study identifies novel loci contributing to asthma susceptibility in adults
Authors: Dahlin A; Iribarren C; Wu AC; et al.
J Allergy Clin Immunol Pract. 2020 05;8(5):1475-1476. Epub 2020-04-06.
Racial Differences in Maintaining Optimal Health Behaviors Into Middle Age
Earlier development of cardiovascular disease risk factors in blacks versus whites may result from differences in maintaining health behaviors. Age-specific racial differences in maintaining health behaviors from ages 18 to 50 years were determined. In 1985-1986, the population-based Coronary Artery Risk Development in Young Adults study enrolled 5,115 participants aged 18-30 years. In 2017, a total of 2,485 blacks and 2,407 whites with one or more optimal health behaviors at baseline who attended one or more of seven follow-up exams over 25 years (i.e., through 2010-2011) were analyzed. The primary outcome, maintaining four or more optimal health behaviors, included BMI <25; never smoking; ≥150 minutes/week of moderate to vigorous physical activity; no/moderate alcohol intake (women/men: zero to seven/zero to 14 drinks per week); and Dietary Approaches to Stop Hypertension diet adherence score ≥15 (i.e., baseline highest quartile). Hazard ratios comparing blacks with whites for maintaining optimal health behaviors were calculated among participants with each optimal behavior at baseline. From ages 18 to 50 years, 2.6% of blacks and 9.2% of whites maintained four or more optimal health behaviors (for optimal BMI: 16.0% and 30.1%, smoking status: 74.6% and 78.4%, physical activity: 17.7% and 21.4%, alcohol intake: 68.4% and 64.6%, diet adherence: 3.9% and 10.3%, respectively). The multivariable adjusted hazard ratio comparing blacks with whites was 0.63 (95% CI=0.56, 0.72) for maintaining four or more optimal health behaviors (for optimal BMI: 0.82 [95% CI=0.66, 1.01], smoking status: 0.57 [95% CI=0.52, 0.62], physical activity: 0.83 [95% CI=0.75, 0.91], alcohol intake: 1.19 [95% CI=1.03, 1.37], diet adherence: 0.71 [95% CI=0.61, 0.82]). Fewer blacks than whites maintained four or more optimal health behaviors until age 50 years, but maintenance was low among both races.
Authors: Booth JN; Spring B; Muntner P; et al.
Am J Prev Med. 2019 03;56(3):368-375.
Applying data science approaches to identify frequent flyers in heart failure: rise of the machines
Authors: Ambrosy AP; Lee KK
Eur J Heart Fail. 2019 03;21(3):319-321. Epub 2019-02-07.
Burden of medical co-morbidities and benefit from surgical revascularization in patients with ischaemic cardiomyopathy
The landmark STICH trial found that surgical revascularization compared to medical therapy alone improved survival in patients with heart failure (HF) of ischaemic aetiology and an ejection fraction (EF) ≤ 35%. However, the interaction between the burden of medical co-morbidities and the benefit from surgical revascularization has not been previously described in patients with ischaemic cardiomyopathy. The STICH trial (ClinicalTrials.gov Identifier: NCT00023595) enrolled patients ≥ 18 years of age with coronary artery disease amenable to coronary artery bypass grafting (CABG) and an EF ≤ 35%. Eligible participants were randomly assigned 1:1 to receive medical therapy (MED) (n = 602) or MED/CABG (n = 610). A modified Charlson co-morbidity index (CCI) based on the availability of data and study definitions was calculated by summing the weighted points for all co-morbid conditions. Patients were divided into mild/moderate (CCI 1-4) and severe (CCI ≥ 5) co-morbidity. Cox proportional hazards models were used to evaluate the association between CCI and outcomes and the interaction between severity of co-morbidity and treatment effect. The study population included 349 patients (29%) with a mild/moderate CCI score and 863 patients (71%) with a severe CCI score. Patients with a severe CCI score had greater functional limitations based on 6-min walk test and impairments in health-related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire. A total of 161 patients (Kaplan-Meier rate = 50%) with a mild/moderate CCI score and 579 patients (Kaplan-Meier rate = 69%) with a severe CCI score died over a median follow-up of 9.8 years. After adjusting for baseline confounders, patients with a severe CCI score were at higher risk for all-cause mortality (hazard ratio 1.44, 95% confidence interval 1.19-1.74; P < 0.001). There was no interaction between CCI score and treatment effect on survival (P = 0.756). More than 70% of patients had a severe burden of medical co-morbidities at baseline, which was independently associated with increased risk of death. There was not a differential benefit of surgical revascularization with respect to survival based on severity of co-morbidity.
Authors: Ambrosy AP; STICH Trial Investigators; et al.
Eur J Heart Fail. 2019 03;21(3):373-381. Epub 2019-01-30.
Use of Measures of Inflammation and Kidney Function for Prediction of Atherosclerotic Vascular Disease Events and Death in Patients With CKD: Findings From the CRIC Study
Traditional risk estimates for atherosclerotic vascular disease (ASVD) and death may not perform optimally in the setting of chronic kidney disease (CKD). We sought to determine whether the addition of measures of inflammation and kidney function to traditional estimation tools improves prediction of these events in a diverse cohort of patients with CKD. Observational cohort study. 2,399 Chronic Renal Insufficiency Cohort (CRIC) Study participants without a history of cardiovascular disease at study entry. Baseline plasma levels of biomarkers of inflammation (interleukin 1? [IL-1?], IL-1 receptor antagonist, IL-6, tumor necrosis factor ? [TNF-?], transforming growth factor ?, high-sensitivity C-reactive protein, fibrinogen, and serum albumin), measures of kidney function (estimated glomerular filtration rate [eGFR] and albuminuria), and the Pooled Cohort Equation probability (PCEP) estimate. Composite of ASVD events (incident myocardial infarction, peripheral arterial disease, and stroke) and death. Cox proportional hazard models adjusted for PCEP estimates, albuminuria, and eGFR. During a median follow-up of 7.3 years, 86, 61, 48, and 323 participants experienced myocardial infarction, peripheral arterial disease, stroke, or death, respectively. The 1-decile greater levels of IL-6 (adjusted HR [aHR], 1.12; 95% CI, 1.08-1.16; P<0.001), TNF-? (aHR, 1.09; 95% CI, 1.05-1.13; P<0.001), fibrinogen (aHR, 1.07; 95% CI, 1.03-1.11; P<0.001), and serum albumin (aHR, 0.96; 95% CI, 0.93-0.99; P<0.002) were independently associated with the composite ASVD-death outcome. A composite inflammation score (CIS) incorporating these 4 biomarkers was associated with a graded increase in risk for the composite outcome. The incidence of ASVD-death increased across the quintiles of risk derived from PCEP, kidney function, and CIS. The addition of eGFR, albuminuria, and CIS to PCEP improved (P=0.003) the area under the receiver operating characteristic curve for the composite outcome from 0.68 (95% CI, 0.66-0.71) to 0.73 (95% CI, 0.71-0.76). Data for cardiovascular death were not available. Biomarkers of inflammation and measures of kidney function are independently associated with incident ASVD events and death in patients with CKD. Traditional cardiovascular risk estimates could be improved by adding markers of inflammation and measures of kidney function.
Authors: Amdur RL; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2019 06;73(6):806-814. Epub 2019-03-29.
Risk factors for medication non-adherence among atrial fibrillation patients
Atrial fibrillation (AF) patients are routinely prescribed medications to prevent and treat complications, including those from common co-occurring comorbidities. However, adherence to such medications may be suboptimal. Therefore, we sought to identify risk factors for general medication non-adherence in a population of patients with atrial fibrillation. Data were collected from a large, ethnically-diverse cohort of Kaiser Permanente Northern and Southern California adult members with incident diagnosed AF between January 1, 2006 and June 30, 2009. Self-reported questionnaires were completed between May 1, 2010 and September 30, 2010, assessing patient socio-demographics, health behaviors, health status, medical history and medication adherence. Medication adherence was assessed using a previously validated 3-item questionnaire. Medication non-adherence was defined as either taking medication(s) as the doctor prescribed 75% of the time or less, or forgetting or choosing to skip one or more medication(s) once per week or more. Electronic health records were used to obtain additional data on medical history. Multivariable logistic regression analyses examined the associations between patient characteristics and self-reported general medication adherence among patients with complete questionnaire data. Among 12,159 patients with complete questionnaire data, 6.3% (n = 771) reported medication non-adherence. Minority race/ethnicity versus non-Hispanic white, not married/with partner versus married/with partner, physical inactivity versus physically active, alcohol use versus no alcohol use, any days of self-reported poor physical health, mental health and/or sleep quality in the past 30 days versus 0 days, memory decline versus no memory decline, inadequate versus adequate health literacy, low-dose aspirin use versus no low-dose aspirin use, and diabetes mellitus were associated with higher adjusted odds of non-adherence, whereas, ages 65-84 years versus < 65 years of age, a Charlson Comorbidity Index score ≥ 3 versus 0, and hypertension were associated with lower adjusted odds of non-adherence. Several potentially preventable and/or modifiable risk factors related to medication non-adherence and a few non-modifiable risk factors were identified. These risk factors should be considered when assessing medication adherence among patients diagnosed with AF.
Authors: Reading SR; Black MH; Singer DE; Go AS; Fang MC; Udaltsova N; Harrison TN; Wei RX; Liu IA; Reynolds K; ATRIA-CVRN Investigators
BMC Cardiovasc Disord. 2019 02 11;19(1):38. Epub 2019-02-11.
Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure
Acute decompensated heart failure accounts for more than 1 million hospitalizations in the United States annually. Whether the initiation of sacubitril-valsartan therapy is safe and effective among patients who are hospitalized for acute decompensated heart failure is unknown. We enrolled patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure at 129 sites in the United States. After hemodynamic stabilization, patients were randomly assigned to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the time-averaged proportional change in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety outcomes were the rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema. Of the 881 patients who underwent randomization, 440 were assigned to receive sacubitril-valsartan and 441 to receive enalapril. The time-averaged reduction in the NT-proBNP concentration was significantly greater in the sacubitril-valsartan group than in the enalapril group; the ratio of the geometric mean of values obtained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril-valsartan group as compared with 0.75 in the enalapril group (percent change, -46.7% vs. -25.3%; ratio of change with sacubitril-valsartan vs. enalapril, 0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001). The greater reduction in the NT-proBNP concentration with sacubitril-valsartan than with enalapril was evident as early as week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). The rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. Among patients with heart failure with reduced ejection fraction who were hospitalized for acute decompensated heart failure, the initiation of sacubitril-valsartan therapy led to a greater reduction in the NT-proBNP concentration than enalapril therapy. Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups. (Funded by Novartis; PIONEER-HF ClinicalTrials.gov number, NCT02554890 .).
Authors: Velazquez EJ; Morrow DA; DeVore AD; Duffy CI; Ambrosy AP; McCague K; Rocha R; Braunwald E; PIONEER-HF Investigators
N Engl J Med. 2019 02 07;380(6):539-548. Epub 2018-11-11.
Left Ventricular Global Longitudinal Strain Can Reliably Be Measured from a Single Apical Four-Chamber View in Patients with Heart Failure
Authors: Alenezi F; Ambrosy AP; Phelan M; Chiswell K; Abudaqa L; Alajmi H; Kisslo J; Velazquez EJ
J Am Soc Nephrol. 2019 09;30(9):1746-1755. Epub 2019-07-10.
Risk Factors for Recurrent Acute Kidney Injury in a Large Population-Based Cohort
Acute kidney injury (AKI) has numerous sequelae. Repeated episodes of AKI may be an important determinant of adverse outcomes, including chronic kidney disease and death. In a population-based cohort study, we sought to determine the incidence of and predictors for recurrent AKI. Retrospective cohort study. 38,659 hospitalized members of Kaiser Permanente Northern California who experienced an episode of AKI from 2006 to 2013. Demographic, clinical, and laboratory data, including baseline kidney function, proteinuria, hemoglobin level, comorbid conditions, and severity of AKI. Incidence and predictors of recurrent AKI. Multivariable Cox proportional hazard regression. 11,048 (28.6%) experienced a second hospitalization complicated by AKI during follow-up (11.2 episodes/100 person-years), with the second episode of AKI occurring a median of 0.6 (interquartile range, 0.2-1.9) years after the first hospitalization. In multivariable analyses, older age, black race, and Hispanic ethnicity were associated with recurrent AKI, along with lower estimated glomerular filtration rate, proteinuria, and anemia. Concomitant conditions, including heart failure, acute coronary syndrome, diabetes, and chronic liver disease, were also multivariable predictors of recurrent AKI. Those who had higher acuity of illness during the initial hospitalization were more likely to have recurrent AKI, but greater AKI severity of the index episode was not independently associated with increased risk for recurrent AKI. In multivariable analysis of matched patients, recurrent AKI was associated with an increased rate of death (HR, 1.66; 95% CI, 1.57-1.77). Analyses were based on clinically available data, rather than protocol-driven timed measurements of kidney function. Recurrent AKI is a common occurrence after a hospitalization complicated by AKI. Based on routinely available patient characteristics, our findings could facilitate identification of the subgroup of patients with AKI who may benefit from more intensive follow-up to potentially avoid recurrent AKI episodes.
Authors: Liu KD; Yang J; Tan TC; Glidden DV; Zheng S; Pravoverov L; Hsu CY; Go AS
Am J Kidney Dis. 2019 02;73(2):163-173. Epub 2018-10-25.
Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume
The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (?genetic?=?-0.59, p-value?=?3.14?×?10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
Authors: Vojinovic D; Stott DJ; Fornage M; et al.
Nat Commun. 2018 09 26;9(1):3945. Epub 2018-09-26.
Associations of Accelerometer-Measured Sedentary Time and Physical Activity With Prospectively Assessed Cardiometabolic Risk Factors: The CARDIA Study
Background Isotemporal substitution examines the effect on health outcomes of replacing sedentary time with light-intensity physical activity or moderate-to-vigorous intensity physical activity; however, existing studies are limited by cross-sectional study designs. Methods and Results Participants were 1922 adults from the CARDIA (Coronary Artery Risk Development in Young Adults) study. Linear regression examined the associations of sedentary, light-intensity physical activity, and moderate-to-vigorous intensity physical activity at year 20 (2005-2006) with waist circumference, blood pressure, glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and a composite risk score at year 30 (2015-2016). Models then examined change in activity with change in cardiometabolic risk over the same 10-year period. Replacing 30 min/day of sedentary time with 30 min/day of light-intensity physical activity at year 20 was associated with a lower composite risk score (-0.01 SD [95% CI, -0.02, -0.00]) at year 30, characterized by lower waist circumference (0.15 cm [95% CI, -0.27, 0.02]), insulin (0.20 ?U/mL [95% CI, -0.35, -0.04]), and higher high-density lipoprotein cholesterol (0.20 mg/dL [95% CI, 0.00, 0.40]; all P<0.05). An increase of 30 min/day in MVPA from year 20 to year 30, when replacing an equivalent increase in sedentary time, was associated with a decrease in the composite risk score (-0.08 [95% CI, -0.13, -0.04]) over the same 10 years, characterized by a decrease in waist circumference (1.52 cm [95% CI, -2.21, -0.84]), insulin (-1.13 ?U/mL [95% CI, -1.95, -0.31]), triglycerides (-6.92 mg/dL [95% CI, -11.69, -2.15]), and an increase in high-density lipoprotein cholesterol (1.59 mg/dL [95% CI, 0.45, 2.73]; all P<0.05). Conclusions Replacement of sedentary time with light-intensity physical activity or moderate-to-vigorous intensity physical activity is associated with improved cardiometabolic health 10 years later.
Authors: Whitaker KM; Pettee Gabriel K; Buman MP; Pereira MA; Jacobs DR; Reis JP; Gibbs BB; Carnethon MR; Staudenmayer J; Sidney S; Sternfeld B
J Am Heart Assoc. 2019 02 19;8(4):e010586.
Survival and Re-intervention Risk by Patient Age and Preoperative Abdominal Aortic Aneurysm (AAA) Diameter Following Endovascular Aneurysm Repair (EVAR)
Endovascular aneurysm repair (EVAR) has become the standard of care for abdominal aortic aneurysm (AAA), but questions remain regarding the benefit in high-risk and elderly patients. The purpose of this study was to examine the effect of age, preoperative AAA diameter, and their interaction on survival and reintervention rates after EVAR. Our integrated health system’s AAA endograft registry was used to identify patients who underwent elective EVAR between 2010 and 2014. Of interest was the effect of patient age at the time of surgery (≤80 vs. >80 years old), preoperative AAA diameter (≤5.5 cm vs. >5.5 cm), and their interaction. Primary endpoints were all-cause mortality and reintervention. Between-within mixed-effects Cox models with propensity score weights were fit. Of 1,967 patients undergoing EVAR, unadjusted rates for survival at 4 years after EVAR was 76.1%, and reintervention-free rate was 86.0%. For mortality, there was insufficient evidence for an interaction between age and AAA size (P = 0.309). Patient age >80 years was associated with 2.53-fold higher mortality risk (hazard ratios [HR] = 2.53; 95% confidence intervals [CI], 1.73-3.70; P < 0.001), whereas AAA > 5.5 cm was associated with 1.75-fold higher mortality risk (HR = 1.75; 95% CI, 1.26-2.45; P = 0.001). For reintervention risk, there were no significant interactions or main effects for age or AAA diameter. Age and AAA diameter are independent predictors of reduced survival after EVAR, but the effect is not amplified when both are present. Age >80 years or AAA size >5.5 cm did not increase the risk of reintervention. No specific AAA size, patient age, or combination thereof was identified that would contraindicate AAA repair.
Authors: Hye RJ; Janarious AU; Chan PH; Cafri G; Chang RW; Rehring TF; Nelken NA; Hill BB
Ann Vasc Surg. 2019 Jan;54:215-225. Epub 2018-08-04.
Racial discrimination in medical care settings and opioid pain reliever misuse in a U.S. cohort: 1992 to 2015
In the United States whites are more likely to misuse opioid pain relievers (OPRs) than blacks, and blacks are less likely to be prescribed OPRs than whites. Our objective is to determine whether racial discrimination in medical settings is protective for blacks against OPR misuse, thus mediating the black-white disparities in OPR misuse. We used data from 3528 black and white adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, an ongoing multi-site cohort. We employ causal mediation methods, with race (black vs white) as the exposure, lifetime discrimination in medical settings prior to year 2000 as the mediator, and OPR misuse after 2000 as the outcome. We found black participants were more likely to report discrimination in a medical setting (20.3% vs 0.9%) and less likely to report OPR misuse (5.8% vs 8.0%, OR = 0.71, 95% CI = 0.55, 0.93, adjusted for covariates). Our mediation models suggest that when everyone is not discriminated against, the disparity is wider with black persons having even lower odds of reporting OPR misuse (OR = 0.63, 95% CI = 0.45, 0.89) compared to their white counterparts, suggesting racial discrimination in medical settings is a risk factor for OPR misuse rather than protective. These results suggest that racial discrimination in a medical setting is a risk factor for OPR misuse rather than being protective, and thus could not explain the seen black-white disparity in OPR misuse.
Authors: Swift SL; Glymour MM; Elfassy T; Lewis C; Kiefe CI; Sidney S; Calonico S; Feaster D; Bailey Z; Zeki Al Hazzouri A
PLoS One. 2019;14(12):e0226490. Epub 2019-12-20.
Diagnostic thresholds for pregnancy hyperglycemia, maternal weight status and the risk of childhood obesity in a diverse Northern California cohort using health care delivery system data
To estimate the risk of childhood obesity associated with the various criteria proposed for diagnosis of gestational diabetes (GDM), and the joint effects with maternal BMI. Cohort study of 46,396 women delivering at the Kaiser Permanente Northern California health care delivery system in 1995-2004 and their offspring, followed through 5-7 years of age. Pregnancy hyperglycemia was categorized according to the screening and oral glucose tolerance test values proposed for the diagnosis of GDM by the International Association of the Diabetes and Pregnancy Study Group (IADPSG), Carpenter Coustan (CC), and the National Diabetes Data Group (NDDG). Childhood obesity was defined by the International Obesity Task Force’s age and sex-specific BMI cut-offs. Poisson regression models estimated the risks of childhood obesity associated with each category of pregnancy glycemia compared to normal screening, and the joint effects of maternal BMI category and GDM by the CC and the IADPSG criteria. Compared with normal screening, increased risks of childhood obesity were observed for abnormal screening [RR (95% CI): 1.30 (1.22, 1.38)], 1+ abnormal values by the IADPSG or CC [1.47 (1.36, 1.59) and 1.48 (1.37, 1.59), respectively], and 2+ values by CC or NDDG [1.52 (1.39, 1.67) and 1.60 (1.43, 1.78), respectively]. Compared to obese women without GDM, obese women with GDM defined by the CC criteria had significantly increased risk of childhood obesity [1.20 (1.07, 1.34)], which was also observed for GDM by the IADSPG [1.18 (1.07, 1.30)], though GDM did not significantly increase the risk of childhood obesity among normal weight or overweight women. The risk of childhood obesity starts to increase at levels of pregnancy glycemia below those used to diagnose GDM and the effect of GDM on childhood obesity risk appears more pronounced in women with obesity. Interventions to reduce obesity and pregnancy hyperglycemia are warranted.
Authors: Ehrlich SF; Hedderson MM; Xu F; Ferrara A
PLoS One. 2019;14(5):e0216897. Epub 2019-05-10.
Temporal Changes in Health Care Utilization among Participants of a Medically Supervised Weight Management Program
Obesity is associated with increased incidence of chronic diseases such as type 2 diabetes mellitus, systemic hypertension, and other risk factors for cardiovascular disease. Obesity is also associated with increased use of outpatient clinical services, a metric of health care utilization. However, little is known of temporal changes in health care utilization among obese participants of a medical weight management program. To assess changes in 3 health care utilization metrics (primary care physician office visits, ambulatory clinic office visits, and health care touches [encounters]) in weight management program participants across 21 Kaiser Permanente Northern California Medical Centers during a 5-year period. Retrospective observational study of 10,693 participants, with a linear-mixed effects model to account for repeated-measures analysis. Five-year temporal changes in the 3 health care metrics. At baseline, the participants’ average age (standard deviation) was 51.1 (12.4) years, and their mean body mass index (standard deviation) was 39.7 (7.2) kg/m2. At the end of 4 months, there was a decrease in primary care visits (p < 0.001), with an increase in ambulatory clinic visits and health care touches (p < 0.001), because of increased weight management visits. At the end of 5 years, there was a 25% to 35% decrease from baseline in all 3 health care utilization metrics (p < 0.0001). Although slightly attenuated, these findings were similar in a risk-adjusted model. Our findings may be useful to other integrated health care delivery systems considering initiating a similar weight management program.
Authors: Krishnaswami A; Sidney S; Sorel M; Smith W; Ashok R
Perm J. 2019;23.
Pre-pregnancy kidney function and subsequent adverse pregnancy outcomes
Renal insufficiency is associated with pregnancy complications including fetal growth restriction, preterm birth (PTB), and pre-eclampsia. To determine the effect of preconception kidney function within the normal range on pregnancy outcome. 1043 (50% black, 50% white) women who participated in the CARDIA study who had kidney function and biochemical analyses measured before at least one pregnancy delivered during the 20 years post-baseline period were included in analysis. Kidney function estimated as glomerular filtration rate (eGFR) via modified CKD-EPI equations, serum creatinine, and urinary albumin/creatinine ratio were evaluated as predictors of infant birthweight, gestational age, birthweight-for-gestational-age, and hypertensive disorders of pregnancy via self-report, using multiple regression with adjustment for confounders (age, race, smoking, BMI, center, parity, systolic blood pressure at baseline). Serum uric acid was also examined at both baseline and year 10. Unadjusted pre-pregnancy eGFR (baseline) was associated with lower average birthweight-for-gestational-age, but this disappeared after adjustment for confounders. A decline in GFR from baseline to year 10 was associated with lower birthweight (adjusted estimate -195 g, p = 0.03 overall), especially among whites. After adjustment for confounders, no association was found with gestational age or hypertensive disorders. No strong evidence for an association between preconception kidney function in the normal range and birthweight or gestational age was found. Possible racial differences in these relationships warrant further examination.
Authors: Harville EW; Catov J; Lewis CE; Bibbins-Domingo K; Gunderson EP
Pregnancy Hypertens. 2019 Jan;15:195-200. Epub 2019-02-01.
Kidney function, proteinuria and breast arterial calcification in women without clinical cardiovascular disease: The MINERVA study
Breast arterial calcification (BAC) may be a predictor of cardiovascular events and is highly prevalent in persons with end-stage kidney disease. However, few studies to date have examined the association between mild-to-moderate kidney function and proteinuria with BAC. We prospectively enrolled women with no prior cardiovascular disease aged 60 to 79 years undergoing mammography screening at Kaiser Permanente Northern California between 10/24/2012 and 2/13/2015. Urine albumin-to-creatinine ratio (uACR), along with specific laboratory, demographic, and medical data, were measured at the baseline visit. Baseline estimated glomerular filtration rate (eGFR), medication history, and other comorbidities were identified from self-report and/or electronic medical records. BAC presence and gradation (mass) was measured by digital quantification of full-field mammograms. Among 3,507 participants, 24.5% were aged ≥70 years, 63.5% were white, 7.5% had eGFR <60 ml/min/1.73m2, with 85.7% having uACR ≥30 mg/g and 3.3% having uACR ≥300 mg/g. The prevalence of any measured BAC (>0 mg) was 27.9%. Neither uACR ≥30 mg/g nor uACR ≥300 were significantly associated with BAC in crude or multivariable analyses. Reduced eGFR was associated with BAC in univariate analyses (odds ratio 1.53, 95% CI: 1.18-2.00), but the association was no longer significant after adjustment for potential confounders. Results were similar in various sensitivity analyses that used different BAC thresholds or analytic approaches. Among women without cardiovascular disease undergoing mammography screening, reduced eGFR and albuminuria were not significantly associated with BAC.
Authors: Parikh RV; Iribarren C; Lee C; Levine-Hall T; Tan TC; Sanchez G; Ding H; Bidgoli FA; Molloi S; Go AS
PLoS ONE. 2019;14(1):e0210973. Epub 2019-01-17.
The Association of Polycystic Ovary Syndrome and Gestational Hypertensive Disorders in a Diverse Community-Based Cohort
To examine the association of polycystic ovary syndrome (PCOS) and pregnancy-induced hypertension (PIH) within a large population of pregnant women in an integrated healthcare system. This retrospective study utilized a source cohort of 1023 women with PCOS and 1023 women without PCOS who had a delivered pregnancy within Kaiser Permanente Northern California. Preexisting hypertension was defined by hypertension diagnosis, treatment, or elevated blood pressure prior to 20 weeks of gestation. The development of PIH, including gestational hypertension, preeclampsia/eclampsia, or HELLP (hemolysis, elevated liver enzymes, and low platelet count), was ascertained by chart review. Among women without preexisting hypertension who had a singleton pregnancy, the association of PCOS and PIH was examined using multivariable logistic regression. Among 1902 women (910 PCOS) with singleton pregnancy, 101 (11.1%) PCOS and 36 (3.6%) non-PCOS women had preexisting hypertension and were excluded. Of the remaining 1765 women, those with PCOS (compared to non-PCOS) were slightly older (mean age 31.2 versus 30.7), more likely to be obese (39.6% versus 15.1%), nulliparous (63.8% versus 43.4%), and conceive with fertility treatment (54.1% versus 1.9%); they also had a higher incidence of PIH (10.8% versus 6.6%), including gestational hypertension (5.8% versus 3.6%) and preeclampsia or HELLP (4.9% versus 3.0%; all p<0.05). PCOS was associated with increased odds of PIH (odds ratio, OR 1.7, 95% confidence interval, CI 1.2-2.4), remaining significant after adjusting for age, race/ethnicity, nulliparity, and fertility treatment; however, findings were attenuated and no longer significant after adjusting for weight status (OR 1.1, CI 0.7-1.7). Maternal PCOS was also associated with preeclampsia/HELLP in unadjusted but not adjusted (OR 1.0, CI 0.5-1.9) analyses. Nulliparity and higher prepregnancy BMI were associated with PIH in both groups. Compared to women without PCOS, women with PCOS are at higher risk for PIH but this association was not independent of weight status.
Authors: Schneider D; Gonzalez JR; Yamamoto M; Yang J; Lo JC
J Pregnancy. 2019;2019:9847057. Epub 2019-01-01.
Shake Rattle & Roll – Design and rationale for a pragmatic trial to improve blood pressure control among blacks with persistent hypertension
In Kaiser Permanente Northern California (KPNC), members had similar access to care and a very high overall rate of hypertension control. However, blacks had poorer blood pressure (BP) control than whites. The Shake Rattle & Roll (SRR) trial aimed to improve BP control rates in blacks and to reduce disparities in hypertension control. SRR was a cluster randomized controlled trial conducted at an urban medical center. All 98 adult primary care physicians (PCP) and their panels of hypertensive black patients were randomized, stratified by panel size, to one of three arms: 1) Usual Care (n?=?33 PCPs, N?=?1129 patients); 2) Enhanced Monitoring arm with an emphasis on improving pharmacotherapy protocol adherence (n?=?34 PCPs, N?=?349 patients); or 3) Lifestyle arm with a culturally tailored diet and lifestyle coaching intervention focusing on the Dietary Approaches to Stop Hypertension eating plan (n?=?31 PCPs, N?=?286 patients). The intervention period was for 12-months post-enrollment. Follow-up was planned for one and three years post-intervention completion. Primary outcome measure was the proportion of participants with controlled BP, defined as <140/90?mmHg, at 12-months post-enrollment. Secondary outcome included adverse cardiovascular events. An intention-to-treat analysis was carried out as the primary analysis. SRR was a uniquely designed trial that included components from both pragmatic and explanatory methods. The pragmatic aspects allow for a more cost-effective way to conduct a clinical trial and easier implementation of successful interventions into clinical practice. However, there were also challenges of having mixed methodology with regards to trial conduction and analysis.
Authors: Nguyen-Huynh MN; Young JD; Alexeeff S; Hatfield MK; Sidney S
Contemp Clin Trials. 2019 01;76:85-92. Epub 2018-11-28.
Longer lactation duration is associated with decreased prevalence of non-alcoholic fatty liver disease in women
Lactation lowers blood glucose and triglycerides, and increases insulin sensitivity. We hypothesized that a longer duration of lactation would be associated with lower prevalence of non-alcoholic fatty liver disease (NAFLD), which is the leading cause of chronic liver disease in the United States. Participants from the Coronary Artery Risk Development in Young Adults cohort study who delivered???1 child post-baseline (Y0: 1985-1986), and underwent CT quantification of hepatic steatosis 25?years following cohort entry (Y25: 2010-2011) were included (n?=?844). The duration of lactation was summed for all post-baseline births, and NAFLD at Y25 was assessed by central review of CT images and defined by liver attenuation???40 Hounsfield Units after exclusion of other causes of hepatic steatosis. Unadjusted and multivariable logistic regression analyses were performed using an a priori set of confounding variables; age, race, education, and baseline body mass index. Of 844 women who delivered after baseline (48% black, 52% white, mean age 49?years at Y25 exam), 32% reported lactation duration of 0 to 1?month, 25% reported >1 to 6?months, 43% reported more than 6?months, while 54 (6%) had NAFLD. Longer lactation duration was inversely associated with NAFLD in unadjusted logistic regression. For women who reported >6?months lactation compared to those reporting 0-1?month, the odds ratio for NAFLD was 0.48 (95% CI 0.25-0.94; p?=?0.03) and the association remained after adjustment for confounders (adjusted odds ratio 0.46; 95% CI 0.22-0.97; p?=?0.04). A longer duration of lactation, particularly greater than 6?months, is associated with lower odds of NAFLD in mid-life and may represent a modifiable risk factor for NAFLD. A longer duration of breastfeeding has been associated with multiple potential health benefits for the mother including reduction in heart disease, diabetes and certain cancers. In this study we found that breastfeeding for longer than 6?months was associated with a lower risk of non-alcoholic fatty liver disease in mid-life.
Authors: Ajmera VH; Terrault NA; VanWagner LB; Sarkar M; Lewis CE; Carr JJ; Gunderson EP
J Hepatol. 2019 01;70(1):126-132. Epub 2018-11-01.
Inflammation and Endothelial Activation in Early Adulthood are Associated with Future Emphysema: The CARDIA Lung Study
Authors: Wells JM; Colangelo LA; Sivarajan L; Thyagarajan B; Dransfield MT; Iribarren C; Reyfman PA; Jacobs DR; Washko GR; Kalhan R
Eur Respir J. 2019 01;53(1). Epub 2019-01-17.
Undiagnosed dysglycemia in patients hospitalized for worsening heart failure: not so sweet after all
Authors: Chioncel O; Ambrosy AP
Eur J Prev Cardiol. 2019 01;26(1):68-71. Epub 2018-10-28.
Insulin resistance since early adulthood and appendicular lean mass in middle-aged adults without diabetes: 20 years of the CARDIA study
To determine the association between 20-year trajectories in insulin resistance (IR) since young adulthood and appendicular lean mass (ALM) at middle-age in adults without diabetes. A prospective cohort study was designed among young and middle-aged US men (n?=?925) and women (n?=?1193). Fasting serum glucose and insulin were measured five times in 1985-2005. IR was determined using the homeostasis model assessment (HOMA). ALM was measured in 2005 and ALM adjusted for BMI (ALM/BMI) was the outcome. Sex-specific analyses were performed. Three HOMA-IR trajectories were identified. Compared to the low-stable group, the adjusted ALM/BMI difference was -0.041 (95% CI: -0.060 to -0.022) and -0.114 (-0.141 to -0.086) in men, and -0.052 (-0.065 to -0.039) and -0.043 (-0.063 to -0.023) in women, respectively, for the medium-increase and high-increase groups. Further adjusting for the treadmill test duration attenuated these estimates to -0.022 (-0.040 to -0.004) and -0.061 (-0.089 to -0.034) in men and -0.026 (-0.038 to -0.014) and -0.007 (-0.026 to 0.012) in women. Compared to the low-stable insulin resistance trajectory between early and middle adulthood, the high-increase trajectory was associated with lower ALM/BMI in middle-aged men, but not women, without diabetes, after adjusting for cardiorespiratory fitness.
Authors: Zhong VW; Bancks MP; Schreiner PJ; Lewis CE; Steffen LM; Meigs JB; Schrader LA; Schorr M; Miller KK; Sidney S; Carnethon MR
J Emerg Med. 2019 Sep;57(3):405-410. Epub 2019-07-30.
Recurrence after hospitalization for acute coronary syndrome among HIV-infected and HIV-uninfected individuals
We evaluated the association of HIV infection and immunodeficiency with acute coronary syndrome (ACS) recurrence, and with all-cause mortality as a secondary outcome, after hospitalization for ACS among HIV-infected and HIV-uninfected individuals. We conducted a retrospective cohort study within Kaiser Permanente Northern California of HIV-infected and HIV-uninfected adults discharged after ACS hospitalization [types: ST-elevation myocardial infarction (STEMI), non-STEMI, or unstable angina] during 1996-2010. We compared the outcomes of ACS recurrence and all-cause mortality within 3 years, both overall by HIV status and stratified by recent CD4 count, with HIV-uninfected individuals as the reference group. Hazard ratios (HRs) were obtained from Cox regression models with adjustment for age, sex, race/ethnicity, year, ACS type, smoking, and cardiovascular risk factors. Among 226 HIV-infected and 86 321 HIV-uninfected individuals with ACS, HIV-infected individuals had a similar risk of ACS recurrence compared with HIV-uninfected individuals [HR 1.08; 95% confidence interval (CI) 0.76-1.54]. HIV infection was independently associated with all-cause mortality after ACS hospitalization overall (HR 2.52; 95% CI 1.81-3.52). In CD4-stratified models, post-ACS mortality was higher for HIV-infected individuals with CD4 counts of 201-499 cells/?L (HR 2.64; 95% CI 1.66-4.20) and < 200 cells/?L (HR 5.41; 95% CI 3.14-9.34), but not those with CD4 counts ? 500 cells/?L (HR 0.67; 95% CI 0.22-2.08), compared with HIV-uninfected individuals (P trend < 0.001). HIV infection and immunodeficiency were not associated with recurrence of ACS after hospitalization. All-cause mortality was higher among HIV-infected compared with HIV-uninfected individuals, but there was no excess mortality risk among HIV-infected individuals with high CD4 counts.
Authors: Marcus JL; Zaroff J; Go AS; Quesenberry CP; Lo JC; Silverberg MJ; et al.
HIV Med. 2019 01;20(1):19-26. Epub 2018-09-04.
The Association Between Change in Serum Bicarbonate and Change in Thyroid Hormone Levels in Patients Receiving Conventional or More Frequent Maintenance Hemodialysis
Correction of metabolic acidosis in patients with chronic kidney disease has been associated with improvement in thyroid function. We examined whether changes in bicarbonate were associated with changes in thyroid function in patients with end-stage renal disease receiving conventional or more frequent haemodialysis. In the Frequent Hemodialysis Network Trials, the relationship between changes in serum bicarbonate, free triiodothyronine (FT3) and free thyroxine (FT4) was examined among 147 and 48 patients with endogenous thyroid function who received conventional (3×/week) or more frequent (6×/week) haemodialysis (Daily Trial) or who received conventional or more frequent nocturnal haemodialysis (Nocturnal Trial). Equilibrated normalized protein catabolic rate (enPCR) was examined to account for nutritional factors affecting both acid load and thyroid function. Increasing dialysis frequency was associated with increased bicarbonate level. Baseline bicarbonate level was not associated with baseline FT3 and FT4. Change in bicarbonate level was not associated with changes in FT3 and FT4 in the Daily Trial nor for FT4 in the Nocturnal Trial (r ≤ 0.14, P > 0.21). While, a significant correlation between change in serum bicarbonate and change in FT3 (r = 0.44, P = 0.02) was observed in the Nocturnal Trial; findings were no longer significant after adjusting for change in enPCR (r = 0.37, P = 0.08). For participants with baseline bicarbonate <23 mmol/L, no association between change in bicarbonate and change in thyroid indices were seen in the Daily Trial; for the Nocturnal Trial, findings were also not significant for change in FT3 and the association between change in bicarbonate and change in FT4 (r = 0.54, P = 0.03) was no longer significant after adjusting for enPCR (r = 0.45, P = 0.11). Changes in bicarbonate were not associated with changes in thyroid hormone levels after adjusting for enPCR, as a marker of nutritional status. Future studies should examine whether improvement in acid base status improves thyroid function in haemodialysis patients with evidence of thyroid hypofunction.
Authors: Molfino A; Beck GJ; Li M; Lo JC; Kaysen GA; FHN Investigators
Nephrology (Carlton). 2019 Jan;24(1):81-87.
Lung Function in Young Adults and Risk of Cardiovascular Events Over 29 Years: The CARDIA Study
Background Diminished peak lung function in young adulthood is a risk factor for future chronic obstructive pulmonary disease. The association between lung disease and cardiovascular disease later in life is well documented. Whether peak lung function measured in young adulthood is associated with risk of future cardiovascular events is unknown. Methods and Results CARDIA (The Coronary Artery Risk Development in Young Adults) study is a prospective, multicenter, community-based, longitudinal cohort study including 4761 participants aged 18 to 30 years with lung function testing we investigated the association between lung health in young adulthood and risk of subsequent cardiovascular events. We performed Cox proportional hazards regression to test the association between baseline and years 10 and 20 pulmonary function with incident cardiovascular events. Linear and logistic regression was performed to explore the associations of lung function with development of risk factors for cardiovascular disease as well as carotid intima-media thickness and coronary artery calcified plaque. At baseline, mean age (± SD ) was 24.9±3.6 years. Baseline forced expiratory volume in 1 second (hazard ratio) per -10-unit decrement in percent predicted forced expiratory volume in 1 second (hazard ratio, 1.18; 95% CI, 1.06-1.31 [ P=0.002]) and FVC per -10-unit decrement in percent predicted FVC (hazard ratio, 1.19; 95% CI, 1.06-1.33 [ P=0.003]) were associated with future cardiovascular events independent of traditional cardiovascular risk factors. Baseline lung function was associated with heart failure and cerebrovascular events but not coronary artery disease events. Conclusions Lung function in young adulthood is independently associated with cardiovascular events into middle age. This association appears to be driven by heart failure and cerebrovascular events rather than coronary heart disease. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00005130.
Authors: Cuttica MJ; Rana JS; Kalhan R; et al.
J Am Med Inform Assoc. 2019 03 01;26(3):219-227.
Is Time From Last Hospitalization for Heart Failure to Placement of a Primary Prevention Implantable Cardioverter-Defibrillator Associated With Patient Outcomes?
Landmark studies have demonstrated the safety and efficacy of implantable cardioverter-defibrillators (ICDs) in selected stable ambulatory patients with heart failure (HF) with a reduced ejection fraction receiving optimal medical therapy. It is not known whether a recent hospitalization for HF before ICD placement is associated with subsequent outcomes. A post hoc analysis was performed of Medicare beneficiaries enrolled in the National Cardiovascular Data Registry’s ICD Registry with a known diagnosis of HF and an ejection fraction ?35% underdoing a new ICD placement for primary prevention. Patients were grouped based on the timing of ICD placement from the last hospitalization for HF. The association between timing of ICD placement and outcomes was assessed by using multivariable logistic regression models. The final analytic cohort included 81?180 patients undergoing initial ICD placement for primary prevention who were currently hospitalized for HF (n=11?563, 14%), hospitalized for HF within 3 months (n=6252, 8%), or hospitalized for HF >3 months previously or had no previous hospitalizations for HF (n=63?365, 78%). Patients currently or recently hospitalized for HF had a higher unadjusted composite periprocedural complication rate (2.60% versus 1.71% versus 1.25%, P<0.001). After adjusting for potential confounders, patients currently hospitalized for HF were at higher risk for death (odds ratio, 2.25; 95% CI, 2.02-2.52; P <0.001) and all-cause readmission (odds ratio, 1.89; 95% CI, 1.79-1.99; P <0.001) at 90 days. Older patients currently or recently hospitalized for HF undergoing initial ICD placement for primary prevention experienced a higher rate of periprocedural complications and were at increased risk of death in comparison with those receiving an ICD without recent HF hospitalization. Additional prospective, real-world, pragmatic, comparative effectiveness studies should be conducted to define the optimal timing of ICD placement.
Authors: Ambrosy AP; Parzynski CS; Friedman DJ; Fudim M; Hernandez AF; Fonarow GC; Masoudi FA; Al-Khatib SM
Clin Chem. 2019 11;65(11):1448-1457. Epub 2019-10-02.
Cardiovascular Events after New-Onset Atrial Fibrillation in Adults with CKD: Results from the Chronic Renal Insufficiency Cohort (CRIC) Study
Atrial fibrillation (AF), the most common sustained arrhythmia in CKD, is associated with poor clinical outcomes in both patients without CKD and patients with dialysis-treated ESRD. However, less is known about AF-associated outcomes in patients with CKD who do not require dialysis. To prospectively examine the association of new-onset AF with subsequent risks of cardiovascular disease events and death among adults with CKD, we studied participants enrolled in the Chronic Renal Insufficiency Cohort Study who did not have AF at baseline. Outcomes included heart failure, myocardial infarction, stroke, and death occurring after diagnosis of AF. We used Cox regression models and marginal structural models to examine the association of incident AF with subsequent risk of cardiovascular disease events and death, adjusting for patient characteristics, laboratory values, and medication use. Among 3080 participants, 323 (10.5%) developed incident AF during a mean 6.1 years of follow-up. Compared with participants who did not develop AF, those who did had higher adjusted rates of heart failure (hazard ratio [HR], 5.17; 95% confidence interval [95% CI], 3.89 to 6.87), myocardial infarction (HR, 3.64; 95% CI, 2.50 to 5.31), stroke (HR, 2.66; 95% CI, 1.50 to 4.74), and death (HR, 3.30; 95% CI, 2.65 to 4.12). These associations remained robust with additional adjustment for biomarkers of inflammation, cardiac stress, and mineral metabolism; left ventricular mass; ejection fraction; and left atrial diameter. Incident AF is independently associated with two- to five-fold increased rates of developing subsequent heart failure, myocardial infarction, stroke, or death in adults with CKD. These findings have important implications for cardiovascular risk reduction.
Authors: Bansal N; Go AS; et al.
J Am Soc Nephrol. 2018 12;29(12):2859-2869. Epub 2018-10-30.
Relationship between timing of trial randomization, protocol completion, and clinical outcomes among patients hospitalized for heart failure: from the ASTRONAUT trial
Authors: Greene SJ; Ambrosy AP; Butler J; et al.
Eur J Heart Fail. 2018 12;20(12):1760-1763. Epub 2018-11-11.
Multimorbidity Burden and Adverse Outcomes in a Community-Based Cohort of Adults with Heart Failure
To assess multimorbidity burden and its association with clinical outcomes in adults with heart failure (HF) according to sex, age, and HF type. Retrospective cohort study. Five healthcare delivery systems across the United States. Adults with HF (N=114,553). We characterized participants with respect to the presence of 26 chronic conditions categorized into quartiles based on overall burden of comorbidity (<5, 5-6, 7-8, ?9). Outcomes included all-cause death and hospitalization for HF or any cause. Multivariable Cox regression was used to evaluate the adjusted association between categorized burden of multimorbidity burden and outcomes. Individuals with more morbidities were more likely to die than those with fewer then 5 morbidities (5-6 morbidities: adjusted hazard ratio (aHR)=1.27 (95% confidence interval (CI)=1.24-1.31; 7-8 morbidities: aHR=1.52, 95% CI=1.48-1.57; ?9 morbidities: aHR=1.92, 95% CI=1.86-1.99). There was a graded, higher adjusted rate of any-cause hospitalization associated with 5 or 6 (aHR=1.28, 95% CI=1.25-1.30), 7 or 8 (aHR=1.47, 95% CI=1.44-1.50), or 9 or more (aHR=1.77, 95% CI=1.73-1.82) morbidities (vs <5). Similar findings were observed for HF-specific hospitalization in those with 5 or 6 (aHR=1.22, 95% CI=1.19-1.26), 7 or 8 (aHR=1.39, 95% CI=1.34-1.44), or 9 or more (aHR 1.68, 95% CI=1.61-1.74) morbidities (vs <5). Consistent findings were seen according to sex, age group, and HF type (preserved, reduced, borderline HF), in the association between categorical burden of multimorbidity and outcomes especially prominent in individuals younger than 65. After adjustment, higher levels of multimorbidity predicted worse HF outcomes and may be an important consideration in strategies to improve clinical and person-centered outcomes. J Am Geriatr Soc 66:2305-2313, 2018.
Authors: Tisminetzky M; Gurwitz JH; Fan D; Reynolds K; Smith DH; Magid DJ; Sung SH; Murphy TE; Goldberg RJ; Go AS
J Am Geriatr Soc. 2018 12;66(12):2305-2313. Epub 2018-09-24.
Central Obesity Increases the Risk of Gestational Diabetes Partially Through Increasing Insulin Resistance
This study examined the associations of central obesity measures, waist to hip ratio (WHR) and waist circumference (WC), in early pregnancy with subsequent risk of gestational diabetes mellitus (GDM) and evaluated the potential mediating role of insulin resistance markers. Within the prospective Pregnancy Environment and Lifestyle Study cohort of 1,750 women, WC and hip circumference were measured at gestational weeks 10 to 13. In a nested case-control study within the cohort, 115 GDM cases and 230 controls had fasting serum insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and adiponectin measurements at gestational weeks 16 to 19. Poisson and conditional logistic regression models were used, adjusting for established risk factors for GDM, including prepregnancy overweight or obesity. For women with WHR
Authors: Zhu Y; Hedderson MM; Quesenberry CP; Feng J; Ferrara A
Obesity (Silver Spring). 2018 Nov 21.
Disparities in the Receipt of Tobacco Treatment Counseling within the US Context of the Affordable Care Act and Meaningful Use Implementation
Disparities in receiving advice to quit smoking and other tobacco use from health professionals may contribute to the continuing gap in smoking prevalence among priority populations. Under the Affordable Care Act (ACA), beginning in 2010, tobacco cessation services are currently covered in private and public health insurance plans. Providers and hospitals are also incentivized through the Meaningful Use of Electronic Health Records (EHRs) to screen and document patients’ tobacco use and deliver brief cessation counseling. This study analyzes trends and correlates of receiving health professionals’ advice to quit and potential disparities among US adult smokers from 2010 to 2015. Data were from the National Health Interview Survey in 2010 and 2015. We analyzed the weighted prevalence of smokers’ receipt of advice to quit smoking and other tobacco use from a health professional in 2010 and 2015 and correlates of receiving advice to quit. Prevalence of receiving advice to quit from a health professional increased from 51.4% in 2010 to 60.6% in 2015. This positive trend was observed across tobacco disparity population groups. Survey year (2015), age (older), ethnicity (non-Hispanic), region (Northeast), poverty level (above 100% poverty level), past quit attempt, daily smoking, cigarettes per day (11+ per day), and psychological distress were associated with higher odds of receiving advice to quit. Based on national level data, receipt of advice to quit from health professionals increased between 2010 and 2015. However, disparities in receiving advice to quit from health professionals persist in certain populations. This study provides important data on the national trends in receipt of health professional advice to quit smoking and other tobacco use in the context of the ACA and Meaningful Use implementation and whether these policies helped to narrow the gaps in receipt of health professional advice among vulnerable populations.
Authors: Tan ASL; Young-Wolff KC; Carter-Harris L; Salloum RG; Banerjee SC
Nicotine Tob Res. 2018 11 15;20(12):1474-1480.
Association of Breast Arterial Calcification Presence and Gradation with the Ankle-Brachial Index among Postmenopausal Women
To examine the association of breast arterial calcification (BAC) with the ankle brachial index (ABI), a sensitive metric of peripheral arterial disease (PAD), among postmenopausal women. Background: BAC is an emerging risk marker of cardiovascular disease (CVD). MINERVA (MultIethNic study of brEast aRterial calcium gradation and cardioVAscular disease) is a cohort of women aged 60 to 79 at baseline (10/24/2012 – 2/13/2015) who were free of symptomatic CVD at baseline. The analytical sample comprised 3,800 women with available ABI, BAC assessment and covariates. We performed cross-sectional logistic regression analysis. 203 women (5.3%) had an ABI < 0.90 indicative of PAD, 26 (0.7%) had an ABI > 1.3 and 94% (n=3,571) had an ABI within normal limits. After adjustment for age, race/ethnicity, body mass index, smoking status, diabetes, hypertension, LDL-C, HDL-C, hs-CRP, estimated-GFR, urinary albumin/creatinine ratio, serum calcium, serum vitamin D and serum PTH, BAC presence remained significantly associated with ABI < 0.90 (OR=1.37; 95% CI, 1.01-1.87; p=0.04). After further adjustment for menopausal hormone therapy, parity and history of breast feeding, the association became marginally significant (OR=1.36; 95% CI, 0.99-1.85; p=0.05). No clear pattern of association was observed for increased gradation of BAC and ABI<0.9, and no significant associations were noted between BAC presence vs. absence or BAC gradation with ABI > 1.3. Among asymptomatic postmenopausal women, presence of BAC was associated with PAD independently of traditional risk factors. Additional prospective studies are required to establish the value of BAC for prediction of incident PAD in the general population.
Authors: Iribarren C; Sanchez G; Lu M; Bidgoli FA; Cho HM; Ding H; Molloi S
Eur J Cardiovasc Med. 2018 Nov;5(5):544-551. Epub 2018-11-16.
Statins for Primary Prevention in Older Adults-Moving Toward Evidence-Based Decision-Making
To determine the efficacy and safety of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) events in older adults, especially those aged 80 and older and with multimorbidity. The National Institute on Aging and the National Heart, Lung and Blood Institute convened A multidisciplinary expert panel from July 31 to August 1, 2017, to review existing evidence, identify knowledge gaps, and consider whether statin safety and efficacy data in persons aged 75 and older without ASCVD are sufficient; whether existing data can inform the feasibility, design, and implementation of future statin trials in older adults; and clinical trial options and designs to address knowledge gaps. This article summarizes the presentations and discussions at that workshop. There is insufficient evidence regarding the benefits and harms of statins in older adults, especially those with concomitant frailty, polypharmacy, comorbidities, and cognitive impairment; a lack of tools to assess ASCVD risk in those aged 80 and older; and a paucity of evidence of the effect of statins on outcomes of importance to older adults, such as statin-associated muscle symptoms, cognitive function, and incident diabetes mellitus. Prospective, traditional, placebo-controlled, randomized clinical trials (RCTs) and pragmatic RCTs seem to be suitable options to address these critical knowledge gaps. Future trials have to consider greater representation of very old adults, women, underrepresented minorities, and individuals of differing health, cognitive, socioeconomic, and educational backgrounds. Feasibility analyses from existing large healthcare networks confirm appropriate power for death and cardiovascular outcomes for future RCTs in this area. Existing data cannot address uncertainties about the benefits and harms of statins for primary ASCVD prevention in adults aged 75 and older, especially those with comorbidities, frailty, and cognitive impairment. Evidence from 1 or more RCTs could address these important knowledge gaps to inform person-centered decision-making. J Am Geriatr Soc 66:2188-2196, 2018.
Authors: Singh S; Zieman S; Go AS; Fortmann SP; Wenger NK; Fleg JL; Radziszewska B; Stone NJ; Zoungas S; Gurwitz JH
J Am Geriatr Soc. 2018 11;66(11):2188-2196. Epub 2018-10-02.
Effect of Variation in Published Stroke Rates on the Net Clinical Benefit of Anticoagulation for Atrial Fibrillation
Stroke rates in patients with nonvalvular atrial fibrillation (AF) who are not receiving anticoagulant therapy vary widely across published studies; the resulting effect on the net clinical benefit of anticoagulation in AF is unknown. To determine the effect of variation in published AF stroke rates on the net clinical benefit of anticoagulation. Markov model decision analysis. Warfarin was the base case, and non-vitamin K antagonist oral anticoagulants (NOACs) were modeled in a secondary analysis. Community-dwelling adults. 33 434 adults with incident AF. Quality-adjusted life-years (QALYs). Of the 33 434 patients, 27 179 had a CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes, stroke, and vascular disease) score of 2 or more. The population benefit of warfarin anticoagulation for these patients was least using stroke rates from the ATRIA (AnTicoagulation and Risk Factors In Atrial Fibrillation) study and greatest using those from the Danish National Patient Registry (6290 QALYs [95% CI, ±2.3%] vs. 24 110 QALYs [CI, ±1.9%]; P < 0.001). The optimal CHA2DS2-VASc score threshold for anticoagulation was 3 or more using stroke rates from ATRIA, 2 or more using those from the Swedish AF cohort study, 1 or more using those from the SPORTIF (Stroke Prevention using ORal Thrombin Inhibitor in atrial Fibrillation) study, and 0 or more using those from the Danish National Patient Registry. Accounting for lower rates of NOAC-associated intracranial hemorrhage decreased optimal CHA2DS2-VASc score thresholds, but these thresholds still varied widely. Measured benefit may not generalize to other populations. Variation in published AF stroke rates for patients not receiving anticoagulant therapy results in multifold variation in the net clinical benefit of anticoagulation. Guidelines should better reflect the uncertainty in current thresholds of stroke risk score for recommending anticoagulation. None.
Authors: Shah SJ; Eckman MH; Aspberg S; Go AS; Singer DE
Ann Intern Med. 2018 10 16;169(8):517-527. Epub 2018-09-25.
Early therapeutic persistence on dabigatran versus warfarin therapy in patients with atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry
Anticoagulation is highly effective for the prevention of stroke in patients with atrial fibrillation (AF) but it is dependent on patients continuing therapy. While studies have demonstrated suboptimal therapeutic persistence on warfarin, few have studied persistence rates with non vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran. We examined rates of continued use of dabigatran versus warfarin over 1 year among AF patients in the ORBIT-AF registry between June 29, 2010 and August 09, 2011. Multivariable logistic regression analysis was used to identify characteristics associated with 1-year persistent use of dabigatran therapy or warfarin. At baseline, 6.4 and 93.6% of 7150 AF patients were on dabigatran and warfarin, respectively. At 12 months, dabigatran-treated patients were less likely to have continued their therapy than warfarin-treated patients [Adjusted persistence rates: 66% (95% CI 60-72) vs. 82% (95% CI 80-84), p < .0001]. Predictors of dabigatran persistence included: CHA2DS2-VASc risk scores ≥ 2 OR 5.69, (95% CI 1.50-21.6) and BMI greater than 25 mg/m2 but less than 38 kg/m2 1.05 (1.01-1.09). Predictors of persistence on warfarin included: African American race (vs. White) 1.53 (1.07-2.19), Hispanic ethnicity (vs. White) 1.66 (1.06-2.60), paroxysmal and persistent AF (vs. new-onset) 1.68 (1.21-2.33) and 1.91 (1.35-2.69) respectively, LVH 1.40 (1.08-1.81), and CHA2DS2-VASc risk scores ≥ 2 1.94 (1.18-3.19). While 1-year persistence rates for dabigatran were lower than warfarin, persistence rates for both agents were not ideal. Future studies evaluating contemporary persistence are needed in order to assist in better targeting interventions aimed to improve anticoagulation persistence.
Authors: Jackson LR; Go AS; Piccini JP; et al.
J Thromb Thrombolysis. 2018 Nov;46(4):435-439.
Characteristics and outcomes of adults with chronic obstructive pulmonary disease and atrial fibrillation
Chronic obstructive pulmonary disease (COPD) is associated with the development of atrial fibrillation (AF), and may complicate treatment of AF. We examined the association between COPD and symptoms, quality of life (QoL), treatment and outcomes among patients with AF. We compared patients with and without a diagnosis of COPD in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a prospective registry that enrolled outpatients with AF not secondary to reversible causes, from both academic and community settings. Among 9749 patients with AF, 1605 (16%) had COPD. Relative to patients without COPD, those with COPD were more likely to be older, current/former smokers (73% vs 43%), have heart failure (54% vs 29%) and coronary artery disease (49% vs 34%). Oral anticoagulant and beta blocker use were similar, whereas digoxin use was more common among patients with COPD. Symptom burden was generally higher, and QoL worse, among patients with COPD (median Atrial Fibrillation Effect on QualiTy-of-Life score 76 vs 83). Patients with COPD had higher risk of all-cause mortality (adjusted HR 1.52 (95% CI 1.32 to 1.74)), cardiovascular mortality (adjusted HR 1.51 (95% CI 1.24 to 1.84)) and cardiovascular hospitalisation (adjusted HR 1.15 (95% CI 1.05 to 1.26)). Patients with COPD also had higher risk of major bleeding events (adjusted HR 1.25 (95% CI 1.05 to 1.50)). There did not appear to be associations between COPD and AF progression, ischaemic events or new-onset heart failure. Among patients with AF, COPD is associated with higher symptom burden, worse QoL, and worse cardiovascular and bleeding outcomes. These associations were not fully explained by cardiovascular risk factors, AF treatment or smoking history. NCT01165710.
Authors: Durheim MT; Go AS; Piccini JP; et al.
Heart. 2018 11;104(22):1850-1858. Epub 2018-06-06.
Understanding functional and social risk characteristics of frail older adults: a cross-sectional survey study
Frailty is a condition of increasing importance, given the aging adult population. With an anticipated shortage of geriatricians, primary care physicians will increasingly need to manage care for frail adults with complex functional risks and social-economic circumstances. We used cross-sectional data from 4551 adults ages 65-90 who responded to the 2014/2015 cycle of the Kaiser Permanente Northern California Member Health Survey (MHS), a self-administered survey that covers multiple health and social characteristics, to create a deficits accumulation model frailty index, classify respondents as frail or non-frail, and then compare prevalence of functional health issues including Activities of Daily Living (ADL)/Instrumental Activities of Daily Living (IADL) and social determinants of health (SDOHs) by frailty status. The overall prevalence of frailty was 14.3%, higher for women than men, increased with age, and more common among those with low levels of education and income. Frail older adults were more likely than non-frail to have ≥ 3 chronic diseases (55.9% vs. 10.1%), obesity (32.7% vs. 22.8%), insomnia (36.4% vs. 8.8%), oral health problems (25.1% vs. 4.7%), balance or walking problems (54.2% vs. 4.9%), ≥ 1 fall (56.1% vs. 19.7%), to use ≥ 1 medication known to increase fall risk (56.7% vs. 26.0%), and to need help with ≥2 ADLs (15.8% vs. 0.8%) and ≥ 2 IADLs (38.4% vs. 0.8%). They were more likely to feel financial strain (26.9% vs. 12.6%) and to use less medication than prescribed (7.4% vs. 3.6%), less medical care than needed (8.3% vs 3.7%), and eat less produce (9.5% vs. 3.2%) due to cost. Nearly 20% of frail adults were unpaid caregivers for an adult with frailty, serious illness or disability. This study examined the prevalence of frailty and identified modifiable and non-modifiable risk factors of health. The frail older adult population is heterogeneous and requires a patient-centered assessment of their circumstances by healthcare providers and caregivers to improve their quality of life, avoid adverse health events, and slow physical and mental decline. The characteristics identified in this study can be proactively used for the assessment of patient health, quality of life, and frailty prevention.
Authors: Lee DR; Santo EC; Lo JC; Ritterman Weintraub ML; Patton M; Gordon NP
BMC Fam Pract. 2018 10 19;19(1):170. Epub 2018-10-19.
Omega 3 polyunsaturated fatty acids and healthy ageing
Authors: Zhu Y; Ferrara A; Forman MR
BMJ. 2018 10 17;363:k4263. Epub 2018-10-17.
Association Between Bariatric Surgery and Macrovascular Disease Outcomes in Patients With Type 2 Diabetes and Severe Obesity
Macrovascular disease is a leading cause of morbidity and mortality for patients with type 2 diabetes, and medical management, including lifestyle changes, may not be successful at lowering risk. To investigate the relationship between bariatric surgery and incident macrovascular (coronary artery disease and cerebrovascular diseases) events in patients with severe obesity and type 2 diabetes. In this retrospective, matched cohort study, patients with severe obesity (body mass index ≥35) aged 19 to 79 years with diabetes who underwent bariatric surgery from 2005 to 2011 in 4 integrated health systems in the United States (n = 5301) were matched to 14 934 control patients on site, age, sex, body mass index, hemoglobin A1c, insulin use, observed diabetes duration, and prior health care utilization, with follow-up through September 2015. Bariatric procedures (76% Roux-en-Y gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) were compared with usual care for diabetes. Multivariable-adjusted Cox regression analysis investigated time to incident macrovascular disease (defined as first occurrence of coronary artery disease [acute myocardial infarction, unstable angina, percutaneous coronary intervention, or coronary artery bypass grafting] or cerebrovascular events [ischemic stroke, hemorrhagic stroke, carotid stenting, or carotid endarterectomy]). Secondary outcomes included coronary artery disease and cerebrovascular outcomes separately. Among a combined 20 235 surgical and nonsurgical patients, the mean (SD) age was 50 (10) years; 76% of the surgical and 75% of the nonsurgical patients were female; and the baseline mean (SD) body mass index was 44.7 (6.9) and 43.8 (6.7) in the surgical and nonsurgical groups, respectively. At the end of the study period, there were 106 macrovascular events in surgical patients (including 37 cerebrovascular and 78 coronary artery events over a median of 4.7 years; interquartile range, 3.2-6.2 years) and 596 events in the matched control patients (including 227 cerebrovascular and 398 coronary artery events over a median of 4.6 years; interquartile range, 3.1-6.1 years). Bariatric surgery was associated with a lower composite incidence of macrovascular events at 5 years (2.1% in the surgical group vs 4.3% in the nonsurgical group; hazard ratio, 0.60 [95% CI, 0.42-0.86]), as well as a lower incidence of coronary artery disease (1.6% in the surgical group vs 2.8% in the nonsurgical group; hazard ratio, 0.64 [95% CI, 0.42-0.99]). The incidence of cerebrovascular disease was not significantly different between groups at 5 years (0.7% in the surgical group vs 1.7% in the nonsurgical group; hazard ratio, 0.69 [95% CI, 0.38-1.25]). In this observational study of patients with type 2 diabetes and severe obesity who underwent surgery, compared with those who did not undergo surgery, bariatric surgery was associated with a lower risk of macrovascular outcomes. The findings require confirmation in randomized clinical trials. Health care professionals should engage patients with severe obesity and type 2 diabetes in a shared decision making conversation about the potential role of bariatric surgery in the prevention of macrovascular events.
Authors: Fisher DP; Sidney S; et al.
JAMA. 2018 10 16;320(15):1570-1582.
Fasting Glucose Variability in Young Adulthood and Cognitive Function in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
To determine whether intraindividual variability in fasting glucose (FG) below the threshold of diabetes is associated with cognitive function in middle adulthood beyond increasing FG. We studied 3,307 CARDIA (Coronary Artery Risk Development Study in Young Adults) participants (age range 18-30 years; 1985-1986) at baseline and calculated two measures of long-term glucose variability: the coefficient of variation about the mean FG (CV-FG) and the absolute difference between successive FG measurements [average real variability (ARV-FG)] before the onset of diabetes over 25 and 30 years of follow-up. Cognitive function was assessed at years 25 (2010-2011) and 30 (2015-2016) with the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment, and category and letter fluency tests. We estimated the association between glucose variability and cognitive function test score with adjustment for clinical and behavioral risk factors, mean FG level, change in FGlevel, and diabetes development, medication use, and duration. After multivariable adjustment, 1-SD increment of CV-FG was associated with worse cognitive scores at year 25: DSST, standardized regression coefficient, -0.95 (95% CI -1.54, -0.36); RAVLT, -0.14 (95% CI -0.27, -0.02); and Stroop Test, 0.49 (95% CI 0.04, 0.94). Findings were similar between CV-FG with each cognitive test score at year 30 and when we used an alternative measure of variability (ARV-FG) that captures variability in successive FG values. Higher intraindividual FG variability during young adulthood below the threshold of diabetes was associated with worse processing speed, memory, and language fluency in midlife independent of FG levels.
Authors: Bancks MP; Carnethon MR; Jacobs DR; Launer LJ; Reis JP; Schreiner PJ; Shah RV; Sidney S; Yaffe K; Yano Y; Allen NB
Diabetes Care. 2018 Oct 10.
A Pre-Pregnancy Biomarker Risk Score Improves Prediction of Future Gestational Diabetes
Previous studies have not examined the ability of multiple preconception biomarkers, considered together, to improve prediction of gestational diabetes mellitus (GDM). To develop a preconception biomarker risk score and assess its association with subsequent GDM. A nested case-control study among a cohort of women with serum collected as part of a health examination (1984 to 1996) and subsequent pregnancy (1984 to 2009). Biomarkers associated with GDM were dichotomized into high/low risk. Integrated health care system. Two controls were matched to each GDM case (n = 256 cases) on year and age at examination, age at pregnancy, and number of pregnancies between examination and index pregnancy. GDM. High-risk levels of sex hormone-binding globulin (SHBG; <44.2 nM), glucose (>90 mg/dL), total adiponectin (<7.2 μg/mL), and homeostasis model assessment-estimated insulin resistance (>3.9) were independently associated with 2.34 [95% confidence interval (CI): 1.50, 3.63], 2.03 (95% CI: 1.29, 3.19), 1.83 (95% CI: 1.16, 2.90), and 1.67 (95% CI: 1.07, 2.62) times the odds of GDM and included in the biomarker risk score. For each unit increase in the biomarker risk score, odds of GDM were 1.94 times greater (95% CI: 1.59, 2.36). A biomarker risk score including only SHBG and glucose was sufficient to improve prediction beyond established risk factors (age, race/ethnicity, body mass index, family history of diabetes, previous GDM; area under the curve = 0.73 vs 0.67, P = 0.002). The improved, predictive ability of the biomarker risk score beyond established risk factors suggests clinical use of the biomarker risk score in identifying women at risk for GDM before conception for targeted prevention strategies.
Authors: Badon SE; Zhu Y; Sridhar SB; Xu F; Lee C; Ehrlich SF; Quesenberry CP; Hedderson MM
J Endocr Soc. 2018 Oct 01;2(10):1158-1169. Epub 2018-09-13.
Cognitive Impairment in Non-Dialysis-Dependent CKD and the Transition to Dialysis: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study
Advanced chronic kidney disease is associated with elevated risk for cognitive impairment. However, it is not known whether and how cognitive impairment is associated with planning and preparation for end-stage renal disease. Retrospective observational study. 630 adults participating in the CRIC (Chronic Renal Insufficiency Cohort) Study who had cognitive assessments in late-stage CKD, defined as estimated glome-rular filtration rate ≤ 20mL/min/1.73m2, and subsequently initiated maintenance dialysis therapy. Predialysis cognitive impairment, defined as a score on the Modified Mini-Mental State Examination lower than previously derived age-based threshold scores. Covariates included age, race/ethnicity, educational attainment, comorbid conditions, and health literacy. Peritoneal dialysis (PD) as first dialysis modality, preemptive permanent access placement, venous catheter avoidance at dialysis therapy initiation, and preemptive wait-listing for a kidney transplant. Multivariable-adjusted logistic regression. Predialysis cognitive impairment was present in 117 (19%) participants. PD was the first dialysis modality among 16% of participants (n=100), 75% had preemptive access placed (n=473), 45% avoided using a venous catheter at dialysis therapy initiation (n=279), and 20% were preemptively wait-listed (n=126). Predialysis cognitive impairment was independently associated with 78% lower odds of PD as the first dialysis modality (adjusted OR [aOR], 0.22; 95% CI, 0.06-0.74; P=0.02) and 42% lower odds of venous catheter avoidance at dialysis therapy initiation (aOR, 0.58; 95% CI, 0.34-0.98; P=0.04). Predialysis cognitive impairment was not independently associated with preemptive permanent access placement or wait-listing. Potential unmeasured confounders; single measure of cognitive function. Predialysis cognitive impairment is associated with a lower likelihood of PD as a first dialysis modality and of venous catheter avoidance at dialysis therapy initiation. Future studies may consider addressing cognitive function when testing strategies to improve patient transitions to dialysis therapy.
Authors: Harhay MN; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2018 10;72(4):499-508. Epub 2018-05-02.
Pharmacotherapy for Atrial Fibrillation in Patients With Chronic Kidney Disease: Insights From ORBIT-AF
Background Chronic kidney disease ( CKD ) is a common comorbidity in patients with atrial fibrillation. The presence of CKD complicates drug selection for stroke prevention and rhythm control. Methods and Results Patients enrolled in ORBIT AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) with baseline renal function and follow-up data were included (N=9019). CKD was defined as an estimated creatinine clearance <60 mL /min. Patient characteristics were compared by CKD status, and Cox proportional hazards modeling was used to examine the association between oral anticoagulant ( OAC ) use and outcomes and antiarrhythmic drug use and outcomes stratified by CKD stages. At enrollment, 3490 (39%) patients had an estimated creatinine clearance <60 mL /min. Patients with CKD were older and had higher CHA 2 DS 2 VAS c and Anticoagulant and Risk Factors in Atrial Fibrillation (ATRIA) scores. A rhythm control strategy was selected less frequently in patients with CKD , while OAC use was lower among Stage IV and V CKD patients. After adjustment, no significant interaction was noted for OAC and CKD on all-cause mortality ( P=0.5442) or cardiovascular death ( P=0.1233), although a trend for increased major bleeding ( P=0.0608) and stroke, systemic embolism or transient ischemic attack ( P=0.0671) was observed. No interaction was noted for antiarrhythmic drug use and CKD status on all-cause mortality ( P=0.9706), or stroke, systemic embolism or transient ischemic attack ( P=0.4218). Conclusions Patients with atrial fibrillation and CKD are less likely to be treated with rhythm control. Patients with advanced CKD are less likely to receive OAC . Finally, outcomes with OAC in patients with advanced CKD may be materially different with higher rates of both bleeding and stroke.
Authors: Washam JB; Go AS; Piccini JP; et al.
J Am Heart Assoc. 2018 09 18;7(18):e008928.
Long-Term Outcomes of Adults With Heart Failure by Left Ventricular Systolic Function Status
Patients with heart failure (HF) and preserved (HFpEF) or borderline preserved ejection fraction (HFbEF) outnumber patients with HF and reduced ejection fraction (HFrEF), but limited data exist on outcomes in community-based populations of these patients. We examined clinical outcomes in a diverse population of adults with HFrEF, HFbEF, and HFpEF. All adults with diagnosed HF from 2005 to 2012 in Kaiser Permanente Northern California were categorized by left ventricular systolic function as HFpEF (EF ≥50%), HFbEF (EF 41-49%), or HFrEF (EF ≤40%). Demographics, clinical characteristics, and therapies were obtained from electronic records. Outcomes included death, HF hospitalization, and HF-related emergency department (ED) visit. In 28,914 eligible HF patients, there were 52% HFpEF, 16% HFbEF, and 32% HFrEF, with mean age 72.8 years and 45% women. During median follow-up of 3.5 years, crude rates (per 100 person-years) of death, HF hospitalization, and HF-related ED visit were 14.5 (95% CI 14.3 to 14.7), 15.8 (15.5 to 16.0), and 38.2 (37.8 to 38.5), respectively. Compared with HFrEF patients, adjusted hazard ratios of death, HF hospitalization, and HF-related ED visit for HFpEF patients were 0.82 (0.79 to 0.85), 0.72 (0.68 to 0.75), and 0.94 (0.90 to 0.99), respectively, and for HFbEF patients were 0.84 (0.79 to 0.88), 0.79 (0.73 to 0.84), and 0.90 (0.84 to 0.96), respectively. In conclusion, within a large community-based HF cohort, adjusted rates of death, HF hospitalization, and HF-related ED visits were similar in HFpEF and HFbEF patients, but higher in HFrEF patients. Regardless of systolic function, however, long-term mortality and morbidity in all HF patients remain high, reinforcing the need for novel strategies to improve long-term outcomes.
Authors: Avula HR; Leong TK; Lee KK; Sung SH; Go AS
Am J Cardiol. 2018 09 15;122(6):1008-1016. Epub 2018-06-21.
Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure
With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.
Authors: Greene SJ; Mentz RJ; Fiuzat M; Butler J; Solomon SD; Ambrosy AP; Mehta C; Teerlink JR; Zannad F; O'Connor CM
Circulation. 2018 09 04;138(10):1039-1053.
Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care: A Matched Cohort Study
Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes. To investigate the relationship between bariatric surgery and incident microvascular complications of T2DM. Retrospective matched cohort study from 2005 to 2011 with follow-up through September 2015. 4 integrated health systems in the United States. Patients aged 19 to 79 years with T2DM who had bariatric surgery (n = 4024) were matched on age, sex, body mass index, hemoglobin A1c level, insulin use, diabetes duration, and intensity of health care use up to 3 nonsurgical participants (n = 11 059). Bariatric procedures (76% gastric bypass, 17% sleeve gastrectomy, and 7% adjustable gastric banding) compared with usual care. Adjusted Cox regression analysis investigated time to incident microvascular disease, defined as first occurrence of diabetic retinopathy, neuropathy, or nephropathy. Median follow-up was 4.3 years for both surgical and nonsurgical patients. Bariatric surgery was associated with significantly lower risk for incident microvascular disease at 5 years (16.9% for surgical vs. 34.7% for nonsurgical patients; adjusted hazard ratio [HR], 0.41 [95% CI, 0.34 to 0.48]). Bariatric surgery was associated with lower cumulative incidence at 5 years of diabetic neuropathy (7.2% for surgical vs. 21.4% for nonsurgical patients; HR, 0.37 [CI, 0.30 to 0.47]), nephropathy (4.9% for surgical vs. 10.0% for nonsurgical patients; HR, 0.41 [CI, 0.29 to 0.58]), and retinopathy (7.2% for surgical vs. 11.2% for nonsurgical patients; HR, 0.55 [CI, 0.42 to 0.73]). Electronic health record databases could misclassify microvascular disease status for some patients. In this large, multicenter study of adults with T2DM, bariatric surgery was associated with lower overall incidence of microvascular disease (including lower risk for neuropathy, nephropathy, and retinopathy) than usual care. National Institute of Diabetes and Digestive and Kidney Diseases.
Authors: O'Brien R; Bogart A; Arterburn D; et al.
Ann Intern Med. 2018 09 04;169(5):300-310. Epub 2018-08-07.
Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort
Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multiethnic population of statin users. We determined the effect of statin dosing on lipid measures utilizing electronic health records in 33 139 statin users from the Kaiser Permanente GERA cohort (Genetic Epidemiology Research on Adult Health and Aging). The relationship between statin defined daily dose and lipid parameter response (percent change) was determined. Defined daily dose and LDL-C response was associated in a log-linear relationship (β, -6.17; SE, 0.09; P
Authors: Oni-Orisan A; Hoffmann TJ; Ranatunga D; Medina MW; Jorgenson E; Schaefer C; Krauss RM; Iribarren C; Risch N
Circ Genom Precis Med. 2018 Sep;11(9):e002043.
Risk of Cardiovascular Disease Among Young Adults: Marijuana Use or the Company it Keeps
Authors: Rana JS; Auer R; Reis JP; Sidney S
J Am Coll Cardiol. 2018 09 25;72(13):1559-1560.
Breastfeeding and later maternal risk of hypertension and cardiovascular disease – The role of overall and abdominal obesity
In this study, we examined how any, full, and partial breastfeeding durations were associated with maternal risk of hypertension and cardiovascular disease (CVD), and how prepregnancy body mass index (BMI) and waist circumference 7 years postpartum influenced these associations. A total of 63,260 women with live-born singleton infants in the Danish National Birth Cohort (1996-2002) were included. Interviews during pregnancy and 6 and 18 months postpartum provided information on prepregnancy weight, height, and the duration of full and partial breastfeeding. Waist circumference was self-reported 7 years postpartum. Cox regression models were used to estimate hazard ratios of incident hypertension and CVD, registered in the National Patient Register from either 18 months or 7 years postpartum through 15 years postpartum. Any breastfeeding ≥4 months was associated with 20-30% lower risks of hypertension and CVD compared to <4 months in both normal/underweight and overweight/obese women. At follow-up starting 7 years postpartum, similar risk reductions were observed after accounting for waist circumference adjusted for BMI. Partial breastfeeding >2 months compared to ≤2 months, following up to 6 months of full breastfeeding, was associated with 10-25% lower risk of hypertension and CVD. Compared with short breastfeeding duration, additional partial breastfeeding was as important as additional full breastfeeding in reducing risk of hypertension and CVD. Altogether, longer duration of breastfeeding was associated with lower maternal risk of hypertension and CVD irrespective of prepregnancy BMI and abdominal adiposity 7 years after delivery. Both full and partial breastfeeding contributed to an improved cardiovascular health in mothers.
Authors: Kirkegaard H; Bliddal M; Støvring H; Rasmussen KM; Gunderson EP; Køber L; Sørensen TIA; Nohr EA
Prev Med. 2018 09;114:140-148. Epub 2018-06-25.
Evolution of Echocardiographic Measures of Cardiac Disease From CKD to ESRD and Risk of All-Cause Mortality: Findings From the CRIC Study
Abnormal cardiac structure and function are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD) and linked with mortality and heart failure. We examined changes in echocardiographic measures during the transition from CKD to ESRD and their associations with post-ESRD mortality. Prospective study. We studied 417 participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) who had research echocardiograms during CKD and ESRD. We measured change in left ventricular mass index, left ventricular ejection fraction (LVEF), diastolic relaxation (normal, mildly abnormal, and moderately/severely abnormal), left ventricular end-systolic (LVESV), end-diastolic (LVEDV) volume, and left atrial volume from CKD to ESRD. All-cause mortality after dialysis therapy initiation. Cox proportional hazard models were used to test the association of change in each echocardiographic measure with postdialysis mortality. Over a mean of 2.9 years between pre- and postdialysis echocardiograms, there was worsening of mean LVEF (52.5% to 48.6%; P<0.001) and LVESV (18.6 to 20.2mL/m2.7; P<0.001). During this time, there was improvement in left ventricular mass index (60.4 to 58.4g/m2.7; P=0.005) and diastolic relaxation (11.11% to 4.94% with moderately/severely abnormal; P=0.02). Changes in left atrial volume (4.09 to 4.15mL/m2; P=0.08) or LVEDV (38.6 to 38.4mL/m2.7; P=0.8) were not significant. Worsening from CKD to ESRD of LVEF (adjusted HR for every 1% decline in LVEF, 1.03; 95% CI, 1.00-1.06) and LVESV (adjusted HR for every 1mL/m2.7 increase, 1.04; 95% CI, 1.02-1.07) were independently associated with greater risk for postdialysis mortality. Some missing or technically inadequate echocardiograms. In a longitudinal study of patients with CKD who subsequently initiated dialysis therapy, LVEF and LVESV worsened and were significantly associated with greater risk for postdialysis mortality. There may be opportunities for intervention during this transition period to improve outcomes.
Authors: Bansal N; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2018 09;72(3):390-399. Epub 2018-05-18.
Prognostic Significance of Nuisance Bleeding in Anticoagulated Patients with Atrial Fibrillation
Bleeding is commonly cited as a reason for stopping oral anticoagulants (OACs). Whether minor bleeding events (nuisance bleeding, NB) in patients with atrial fibrillation on OACs are associated with OAC discontinuation, major bleeding, and stroke/systemic embolism (SSE) is unknown. Within the ORBIT-AF prospective, outpatient registry (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we identified 6771 patients ≥18 years of age at 172 sites with atrial fibrillation and eligible follow-up visits. NB was ascertained from the medical record and was defined as minor bleeding that did not require medical attention (eg, bruising, hemorrhoidal bleeding). We used multivariable pooled logistic regression modeling to evaluate the associations between NB and major bleeding and SSE in the 180 days after documentation of NB. Our unit of analysis was the patient visit, occurring at ≈6-month intervals for a median of 1.5 years following enrollment. Changes in anticoagulation treatment satisfaction after NB were examined descriptively in a subset of patients. The median age of the overall population was 75.0 (interquartile range, 67.0-81.0); 90.0% were white and 42.5% were female. Among 6771 patients (18 560 visits), n=1357 (20.0%) had documented NB, for an incidence rate of 14.8 events per 100 person-years. Over 96.4% of patients remained on OAC therapy after the NB event. Overall, 287 (4.3%) patients experienced major bleeding and 64 (0.96%) had a SSE event during follow-up. NB was not associated with a significant increased risk of major bleeding over 6 months in models adjusting for the ATRIA bleeding score (Anticoagulation and Risk Factors in Atrial Fibrillation) (odds ratio, 1.04; 95% confidence interval, 0.68-1.60; P=0.86). NB was also not associated with increased SSE risk over 6 months in models adjusting for the CHA2DS2-VASc risk score (odds ratio, 1.24; 95% confidence interval, 0.53-2.91; P=0.62). NB is common among patients with atrial fibrillation on OACs. However, NB was not associated with a higher risk of major bleeding or SSE over the next 6 months, suggesting its occurrence should not lead to changes in anticoagulation treatment strategies in OAC-treated patients. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01165710.
Authors: O'Brien EC; Go AS; Hylek EM; et al.
Circulation. 2018 08 28;138(9):889-897.
Stroke Risk and Treatment in Patients with Atrial Fibrillation and Low CHA2DS2-VASc Scores: Findings From the ORBIT-AF I and II Registries
Background Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA2DS2VASc=1) (or women with CHA2DS2VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these “low-risk” patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low-risk CHA2DS2VASc scores. Methods and Results We compared characteristics, treatment strategies, and outcomes among patients with a CHA2DS2VASc=0, CHA2DS2VASc=1, females with a CHA2DS2VASc=2, and CHA2DS2VASc ≥2 in ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA2DS2VASc ≥2 patients (84.2%), those with a CHA2DS2VASc=0 (60.3%), 1 (69.9%), and females with a CHA2DS2VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation ( P<0.0001). Stroke rates were low overall and ranged from 0 per 100 patient-years in those with CHA2DS2VASc=0, 0.8 (95% confidence interval [CI] [0.5-1.2]) in those with CHA2DS2VASc=1, 0.8 (95% CI [0.4-1.6]) in females with a CHA2DS2VASc score=2, and 1.7 (95% CI [1.6-1.9]) in CHA2DS2VASc ≥2. All-cause mortality (per 100 patient-years) was highest in females with a CHA2DS2VASc score=2 (1.4) (95% CI [0.8-2.3]), compared with patients with a CHA2DS2VASc=0 (0.2) (95% CI [0.1-1.0]), and CHA2DS2VASc=1 (1.0) (95% CI [0.7-1.4]), but lower than patients with a CHA2DS2VASc ≥2 (5.7) (95% CI [5.4-6.0]). Conclusion The majority of CHA2DS2VASc=0-1 patients are treated with oral anticoagulation. In addition, the absolute risks of death and stroke/transient ischemic attack were low among both male and females CHA2DS2VASc=0-1 as well as among females with a CHA2DS2VASc score=2. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01701817.
Authors: Jackson LR; Go AS; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Patients and Investigators; et al.
J Am Heart Assoc. 2018 08 21;7(16):e008764.
Improving Postdischarge Outcomes in Acute Heart Failure.
Authors: Chioncel, Ovidiu O; Collins, Sean P SP; Ambrosy, Andrew P AP; Pang, Peter S PS; Antohi, Elena-Laura EL; Iliescu, Vlad Anton VA; Maggioni, Aldo P AP; Butler, Javed J; Mebazaa, Alexandre A
American journal of therapeutics. 2018 Aug 17;25(4):e475-e486. Epub 2018-08-17.
Liraglutide and weight loss among patients with advanced heart failure and a reduced ejection fraction: insights from the FIGHT trial.
AIMS: Obesity is present in up to 45% of patients with heart failure (HF). Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor antagonist, facilitates weight loss in obese patients. The efficacy of liraglutide as a weight loss agent among patients with HF and reduced ejection fraction (HFrEF) and a recent acute HF hospitalization remains unknown.METHODS AND RESULTS: The Functional Impact of GLP-1 for Heart Failure Treatment study randomized 300 patients with HFrEF (ejection fraction ≤ 40%), both with and without diabetes and a recent HF hospitalization to liraglutide or placebo. The primary outcome for this post hoc analysis was the change in weight from baseline to last study visit. We conducted an ‘on-treatment’ analysis of patients with at least one follow-up visit on study drug (123 on liraglutide and 124 on placebo). The median age was 61 years, 21% were female, and 69% of patients had New York Heart Association functional Class III or IV symptoms. The median ejection fraction was 25% (25th, 75th percentile 19-32%). Liraglutide use was associated with a significant weight reduction [liraglutide -1.00 lbs vs. placebo 2.00 lbs; treatment difference -4.10 lbs; 95% confidence interval (CI) -7.94, -0.25; P = 0.0367; percentage treatment difference -2.07%, 95% CI -3.86, -0.28; P = 0.0237]. Similar results were seen after multivariable adjustments. Liraglutide also significantly reduced triglyceride levels (liraglutide 7.5 mg/dL vs. placebo 12.0 mg/dL; treatment difference -33.1 mg/dL; 95% CI -60.7, -5.6; P = 0.019).CONCLUSIONS: Liraglutide is an efficacious weight loss agent in patients with HFrEF. These findings will require further exploration in a well-powered cardiovascular outcomes trial.
Authors: Sharma, Abhinav A; Ambrosy, Andrew P AP; DeVore, Adam D AD; Margulies, Kenneth B KB; McNulty, Steven E SE; Mentz, Robert J RJ; Hernandez, Adrian F AF; Michael Felker, Gary G; Cooper, Lauren B LB; Lala, Anuradha A; Vader, Justin J; Groake, John D JD; Borlaug, Barry A BA; Velazquez, Eric J EJ
ESC heart failure. 2018 Aug 17;122(9):1451-1458. Epub 2018-08-17.
Natural History of Patients Postacute Coronary Syndrome Based on Heart Failure Status.
The natural history of patients hospitalized for acute coronary syndrome (ACS) with pre-existing versus (vs) de novo heart failure (HF) has not been previously reported over an extended duration of follow-up. The IMPROVE-IT trial enrolled 18,144 patients hospitalized for ACS and randomized them to combination simvastatin (40 mg)/ezetimibe (10 mg) vs simvastatin (40 mg). Subjects were divided into 3 groups: pre-existing HF (i.e., defined by past medical history), de novo HF (i.e., defined by Killip class II or greater during index admission), and no HF. The final analytical cohort included 14,792 patients (82%) with HF status recorded at baseline. In total, 790 patients (5.3%) reported a pre-existing diagnosis of HF and 1374 patients (9.3%) experienced de novo HF. Patients with pre-existing or de novo HF were older, more likely to be woman, and had a greater prevalence of atrial fibrillation and diabetes mellitus. The incidences of death/HF-hospitalizations at 5 years were 32%/20% for pre-existing HF, 18%/7% for de novo HF, and 8%/3% for no HF. After adjusting for potential confounders, a history of pre-existing or de novo HF was independently associated with increased risk of death (pre-existing HF: hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.68 to 2.22, p < 0.001; de novo HF: HR 1.51, 95% CI 1.33 to 1.72, p < 0.001) and hospitalizations for HF (pre-existing HF: HR 2.96, 95% CI 2.36 to 3.71, p < 0.001; de novo HF: HR 1.88, 95% CI 1.49 to 2.38, p < 0.001). There was no interaction among baseline HF status (i.e., pre-existing or de novo), lipid lowering therapy (i.e., simvastatin/ezetimibe vs simvastatin alone), and clinical outcomes. In conclusion, patients hospitalized for ACS with pre-existing or de novo HF were older and had a greater burden of medical co-morbidities. In conclusion, HF was independently associated with increased risk of long-term morbidity and mortality with the pre-existing HF cohort demonstrating the highest overall risk.
Authors: Ambrosy, Andrew P AP; Cerbin, Lukasz P LP; Fudim, Marat M; Clare, Robert M RM; Lokhnygina, Yuliya Y; Braunwald, Eugene E; Califf, Robert M RM; Cannon, Christopher P CP; Tershakovec, Andrew M AM; Roe, Matthew T MT; Blazing, Michael A MA
The American journal of cardiology. 2018 Nov 01;122(9):1451-1458. Epub 2018-08-04.
Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging
Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
Authors: Jian X; Risacher SL; neuroCHARGE Working Group; et al.
Stroke. 2018 08;49(8):1812-1819.
Breastfeeding and growth during infancy among offspring of mothers with gestational diabetes mellitus: a prospective cohort study
Breastfeeding (BF) may protect against obesity and type 2 diabetes mellitus in children exposed to maternal diabetes in utero, but its effects on infant growth among this high-risk group have rarely been evaluated. The objective of this study was to evaluate BF intensity and duration in relation to infant growth from birth through 12 months among offspring of mothers with gestational diabetes mellitus (GDM). Prospective cohort of 464 GDM mother-infant dyads (28% White, 36% Hispanic, 26% Asian, 8% Black, 2% other). Weight and length measured at birth, 6-9 weeks, 6 months and 12 months. Categorized as intensive BF or formula feeding (FF) groups at 6-9 weeks (study baseline), and intensity from birth through 12 months as Group 1: consistent exclusive/mostly FF, Group 2: transition from BF to FF within 3-9 months and Group 3: consistent exclusive/mostly BF. Multivariable mixed linear regression models estimated adjusted mean (95% confidence interval) change in z-scores; weight-for-length (WLZ), weight-for-age and length-for-age. Compared with intensive BF at 6-9 weeks, FF showed greater increases in WLZ-scores from 6 to 9 weeks to 6 months [+0.38 (0.13 to 0.62) vs. +0.02 (-0.15 to 0.19); p = 0.02] and birth to 12 months [+1.11 (0.87 to 1.34) vs. +0.53 (0.37 to 0.69); p < 0.001]. For 12-month intensity and duration, Groups 2 and 3 had smaller WLZ-score increases than Group 1 from 6 to 9 weeks to 6 months [-0.05 (-0.27 to 0.18) and +0.07 (-0.19 to 0.23) vs. +0.40 (0.15 to 0.64); p = 0.01 and 0.07], and birth to 12 months [+0.60 (0.39 to 0.82) and +0.59 (0.33 to 0.85) vs. +0.97 (0.75 to 1.19); p < 0.05]. Among offspring of mothers with GDM, high intensity BF from birth through 1 year is associated with slower infant ponderal growth and lower weight gain.
Authors: Gunderson EP; Greenspan LC; Faith MS; Hurston SR; Quesenberry CP; SWIFT Offspring Study Investigators
Pediatr Obes. 2018 08;13(8):492-504. Epub 2018-04-24.
Cardiorespiratory Fitness, Exercise Hemodynamics and Birth Outcomes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Determine associations of cardiorespiratory fitness, exercise systolic blood pressure (SBP) and heart rate recovery (HRR) following a maximal exercise test performed years preceding pregnancy with odds of preterm birth (PTB; <37 weeks' gestation) and small for gestational age (SGA; birthweight <10th percentile) delivery. Prospective, longitudinal. Multi-site, observational cohort study initially consisting of 2787 black and white women aged 18-30 at baseline (1985-86) and followed for 25 years (Y25; 2010-2011). 768 nulliparous women at baseline who reported ≥1 live birth by the Y25 exam. We used Poisson regression to determine associations of exposures with PTB/SGA. PTB and/or SGA births. Women with PTB (n = 143) and/or SGA (n = 88) were younger, had completed fewer years of education and were more likely to be black versus women without PTB/SGA (n = 546). Women with PTB/SGA had lower fitness (501 ± 9 versus 535 ± 6 seconds, P < 0.002) and higher submaximal SBP than women without PTB/SGA (144 ± 1 versus 142 ± 1 mmHg, P < 0.04). After adjustment, no exercise test variables were associated with PTB/SGA, though the association with HRR and submaximal SBP approached significance in the subset of women who completed the exercise test <5 years before the index birth. Neither fitness nor haemodynamic responses to exercise a median of 5 years preceding pregnancy, were associated with PTB/SGA. These findings indicate excess likelihood of PTB/SGA is not detectable by low fitness or exercise haemodynamic responses 5 years preceding pregnancy, but exercise testing, especially HRR and submaximal SBP, may be more useful when conducted closer to the onset of pregnancy. Exercise testing conducted >5 years before pregnancy may not detect women likely to have PTB/SGA.
Authors: Lane-Cordova AD; Carnethon MR; Catov JM; Montag S; Lewis CE; Schreiner PJ; Dude A; Sternfeld B; Badon SE; Greenland P; Gunderson EP
BJOG. 2018 Aug;125(9):1127-1134. Epub 2018-03-02.
Cumulative Incidence of Hypertension by 55 Years of Age in Blacks and Whites: The CARDIA Study
Blacks have higher blood pressure levels compared with whites beginning in childhood. Few data are available on racial differences in the incidence of hypertension from young adulthood through middle age. We calculated the cumulative incidence of hypertension from age 18 to 55 years among participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study. Incident hypertension was defined by the first visit with mean systolic blood pressure ≥130 mm Hg, mean diastolic blood pressure ≥80 mm Hg, or self-reported use of antihypertensive medication. Among 3890 participants without hypertension at baseline (aged 18-30 years), cumulative incidence of hypertension by age 55 years was 75.5%, 75.7%, 54.5%, and 40.0% in black men, black women, white men, and white women, respectively. Among participants with systolic blood pressure/diastolic blood pressure
Authors: Thomas SJ; Li X; Sidney S; Muntner P; et al.
J Am Heart Assoc. 2018 Jul 11;7(14). Epub 2018-07-11.
Occupational cognitive complexity in earlier adulthood is associated with brain structure and cognitive health in midlife: The CARDIA study
In line with cognitive reserve theory, higher occupational cognitive complexity is associated with reduced cognitive decline in older adulthood. How and when occupational cognitive complexity first exerts protective effects during the life span remains unclear. We investigated associations between occupational cognitive complexity during early to midadulthood and brain structure and cognition in midlife. Participants were 669 adults from the Coronary Artery Risk Development in Young Adults study (aged 18-30 years at baseline, 52% female, 38% Black). We calculated scores reflecting occupational cognitive complexity using Census Occupation Codes (years 10 and 15) and Occupational Information Network (O*NET) data. At year 25, participants had structural brain magnetic resonance imaging, diffusion tensor imaging, and cognitive testing (Rey Auditory Verbal Learning Test, Digit Symbol Substitution Test, Stroop). In adjusted mixed models, we examined associations between occupational cognitive complexity during early to midadulthood and midlife brain structure, specifically gray matter volume and white matter fractional anisotropy, and cognition in midlife (all outcomes converted to z-scores). Higher occupational cognitive complexity was associated with greater white matter fractional anisotropy (estimate = 0.10, p = .01) but not gray matter volume. Higher occupational cognitive complexity was associated with better Digit Symbol Substitution Test (estimate = 0.13, p < .001) and Stroop (estimate = 0.09, p = .01) performance but not Rey Auditory Verbal Learning Test performance. Occupational cognitive complexity earlier in adulthood is associated with better white matter integrity, processing speed, and executive function in midlife. These associations may capture how occupational cognitive complexity contributes to cognitive reserve. (PsycINFO Database Record
Authors: Kaup AR; Xia F; Launer LJ; Sidney S; Nasrallah I; Erus G; Allen N; Yaffe K
Neuropsychology. 2018 Jul 09.
Contemporary Burden and Correlates of Symptomatic Paroxysmal Supraventricular Tachycardia
Contemporary data about symptomatic paroxysmal supraventricular tachycardia (PSVT) epidemiology are limited. We characterized prevalence and correlates of symptomatic PSVT within a large healthcare delivery system and estimated national PSVT burden. We identified adults with an encounter for potential PSVT between 2010 and 2015 in Kaiser Permanente Northern California, excluding those with prior known atrial fibrillation or atrial flutter. We adjudicated medical records, ECGs, and other monitoring data to estimate positive predictive values for targeted International Classification of Diseases (ICD), 9th and 10th Revisions codes in inpatient, emergency department, and outpatient settings. Combinations of diagnosis codes and settings were used to calculate PSVT prevalence, and PSVT correlates were identified using multivariable regression. We estimated national rates by applying prevalence estimates in Kaiser Permanente to 2010 US Census data. The highest positive predictive values included codes for “PSVT” in the emergency department (82%), “unspecified cardiac dysrhythmia” in the emergency department (27%), “anomalous atrioventricular excitation” as a primary inpatient diagnosis (33%), and “unspecified paroxysmal tachycardia” as a primary inpatient diagnosis (23%). Prevalence of symptomatic PSVT was 140 per 100 000 (95% confidence interval, 100-179) and was higher for individuals who were older, women, white or black, or who had valvular heart disease, heart failure, diabetes mellitus, lung disease, or prior bleeding. We estimate the national prevalence of symptomatic PSVT to be 168 per 100 000 (95% confidence interval, 120-215). Selected diagnostic codes in inpatient and emergency department settings may be useful to identify symptomatic PSVT episodes. We project that at least 0.168% of US adults experience symptomatic PSVT, and certain characteristics can identify people at higher risk.
Authors: Go AS; Hlatky MA; Liu TI; Fan D; Garcia EA; Sung SH; Solomon MD
J Am Heart Assoc. 2018 07 07;7(14). Epub 2018-07-07.
Association of Burden of Atrial Fibrillation With Risk of Ischemic Stroke in Adults With Paroxysmal Atrial Fibrillation: The KP-RHYTHM Study
Atrial fibrillation is a potent risk factor for stroke, but whether the burden of atrial fibrillation in patients with paroxysmal atrial fibrillation independently influences the risk of thromboembolism remains controversial. To determine if the burden of atrial fibrillation characterized using noninvasive, continuous ambulatory monitoring is associated with the risk of ischemic stroke or arterial thromboembolism in adults with paroxysmal atrial fibrillation. This retrospective cohort study conducted from October 2011 and October 2016 at 2 large integrated health care delivery systems used an extended continuous cardiac monitoring system to identify adults who were found to have paroxysmal atrial fibrillation on 14-day continuous ambulatory electrocardiographic monitoring. The burden of atrial fibrillation was defined as the percentage of analyzable wear time in atrial fibrillation or flutter during the up to 14-day monitoring period. Ischemic stroke and other arterial thromboembolic events occurring while patients were not taking anticoagulation were identified through November 2016 using electronic medical records and were validated by manual review. We evaluated the association of the burden of atrial fibrillation with thromboembolism while not taking anticoagulation after adjusting for the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) or CHA2DS2-VASc stroke risk scores. Among 1965 adults with paroxysmal atrial fibrillation, the mean (SD) age was 69 (11.8) years, 880 (45%) were women, 496 (25%) were persons of color, the median ATRIA stroke risk score was 4 (interquartile range [IQR], 2-7), and the median CHA2DS2-VASc score was 3 (IQR, 1-4). The median burden of atrial fibrillation was 4.4% (IQR ,1.1%-17.23%). Patients with a higher burden of atrial fibrillation were less likely to be women or of Hispanic ethnicity, but had more prior cardioversion attempts compared with those who had a lower burden. After adjusting for either ATRIA or CHA2DS2-VASc stroke risk scores, the highest tertile of atrial fibrillation burden (≥11.4%) was associated with a more than 3-fold higher adjusted rate of thromboembolism while not taking anticoagulants (adjusted hazard ratios, 3.13 [95% CI, 1.50-6.56] and 3.16 [95% CI, 1.51-6.62], respectively) compared with the combined lower 2 tertiles of atrial fibrillation burden. Results were consistent across demographic and clinical subgroups. A greater burden of atrial fibrillation is associated with a higher risk of ischemic stroke independent of known stroke risk factors in adults with paroxysmal atrial fibrillation.
Authors: Go AS; Reynolds K; Yang J; Gupta N; Lenane J; Sung SH; Harrison TN; Liu TI; Solomon MD
JAMA Cardiol. 2018 07 01;3(7):601-608.
Blood Pressure Patterns and Subsequent Coronary Artery Calcification in Women Who Delivered Preterm Births
Women who delivered preterm infants have excess cardiovascular disease, but vascular pathways linking these conditions are not understood. We considered that higher blood pressure over 25 years among women with preterm delivery may be associated with coronary artery calcification (CAC). The CARDIA study (Coronary Artery Risk Development in Young Adults) enrolled 1049 black and white women with births between 1985 and 2010 (n=272 ever preterm [<37 weeks]; n=777 all term births [≥37 weeks]). Latent mixture modeling identified blood pressure trajectories across 20 years, and these were related to CAC at years 20 and 25. Three systolic blood pressure (SBP) patterns were identified: low stable (n=563; 53%), moderate (n=416; 40%), and moderate increasing (n=70; 7%). Women with moderate-increasing SBP were more likely to have delivered preterm compared with those in the low-stable group (40% versus 21%; P<0.0001), and they were more likely to have CAC (38.5% versus 12.2%). The SBP and CAC association varied by preterm birth (P interaction=0.04). Women with preterm delivery and a moderate-increasing SBP had a 2.17-fold higher hazards of CAC (95% confidence interval, 1.14-4.12) compared with women with term births and a lower SBP pattern, adjusted for cardiovascular disease risk factors and other pregnancy features. There was no excess CAC in women with moderate-increasing SBP and term births (adjusted hazard ratio, 1.02; 95% confidence interval, 0.49-2.14). Associations were stronger in women with hypertensive disorders of pregnancy but also detected in those with normotensive preterm deliveries. Women who deliver preterm infants are more likely to follow a high-risk blood pressure pattern throughout the childbearing years that is associated with CAC at midlife.
Authors: Catov JM; Snyder GG; Fraser A; Lewis CE; Liu K; Althouse AD; Bertolet M; Gunderson EP
Hypertension. 2018 07;72(1):159-166. Epub 2018-05-23.
Comparative Trends in Heart Disease, Stroke, and All-Cause Mortality in the United States and a Large Integrated Healthcare Delivery System
Heart disease and stroke remain among the leading causes of death nationally. We examined whether differences in recent trends in heart disease, stroke, and total mortality exist in the United States and Kaiser Permanente Northern California (KPNC), a large integrated healthcare delivery system. The main outcome measures were comparisons of US and KPNC total, age-specific, and sex-specific changes from 2000 to 2015 in mortality rates from heart disease, coronary heart disease, stroke, and all causes. The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system was used to determine US mortality rates. Mortality rates for KPNC were determined from health system, Social Security vital status, and state death certificate databases. Declines in age-adjusted mortality rates were noted in KPNC and the United States for heart disease (36.3% in KPNC vs 34.6% in the United States), coronary heart disease (51.0% vs 47.9%), stroke (45.5% vs 38.2%), and all-cause mortality (16.8% vs 15.6%). However, steeper declines were noted in KPNC than the United States among those aged 45 to 65 years for heart disease (48.3% KPNC vs 23.6% United States), coronary heart disease (55.6% vs 35.9%), stroke (55.8% vs 26.0%), and all-cause mortality (31.5% vs 9.1%). Sex-specific changes were generally similar. Despite significant declines in heart disease and stroke mortality, there remains an improvement gap nationally among those aged less than 65 years when compared with a large integrated healthcare delivery system. Interventions to improve cardiovascular mortality in the vulnerable middle-aged population may play a key role in closing this gap.
Authors: Sidney S; Sorel ME; Quesenberry CP; Jaffe MG; Solomon MD; Nguyen-Huynh MN; Go AS; Rana JS
Am J Med. 2018 07;131(7):829-836.e1. Epub 2018-04-02.
Seasonal patterns of Asthma medication fills among diverse populations of the United States
Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity. We conducted a retrospective cohort study of asthmatics 4-50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age. There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72-1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49-0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16-year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population. A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations.
Authors: Turi KN; Iribarren C; Wu P; et al.
J Asthma. 2018 07;55(7):764-770. Epub 2017-09-07.
Cumulative blood pressure from early adulthood to middle age is associated with left atrial remodelling and subclinical dysfunction assessed by three-dimensional echocardiography: a prospective post hoc analysis from the coronary artery risk development in young adults study
To evaluate the association of cumulative blood pressure (BP) from young adulthood to middle age with left atrial (LA) structure/function as assessed by three-dimensional echocardiography (3DE) in a large longitudinal bi-racial population study. We conducted a prospective post hoc analysis of individuals enrolled at the Coronary Artery Risk Development in Young Adults, which is a multi-centre bi-racial cohort with 30 years of follow-up. Cumulative systolic and diastolic BP levels were defined by summing the product of average millimetres of mercury and the years between each two consecutive clinic visits over 30 years of follow-up. Multivariable linear regression analyses were used to assess the relationship between cumulative systolic and diastolic BP with 3DE LA structure and function, adjusting for demographics and traditional cardiovascular risk factors. A total of 1033 participants were included, mean age was 55.4 ± 3.5 years, 55.2% women, 43.9% blacks. Cumulative systolic BP had stronger correlations than cumulative diastolic BP. Higher cumulative systolic BP was independently associated with higher 3D LA volumes: maximum (β = 1.74, P = 0.004), pre-atrial contraction (β = 1.87, P
Authors: Vasconcellos HD; Sidney S; Lima JAC; et al.
Eur Heart J Cardiovasc Imaging. 2018 Jun 29.
Renal Function and Exercise Training in AmbulatoryHeart Failure Patients With a Reduced Ejection Fraction.
Patients with chronic kidney disease (CKD) and/or end-stage renal disease are less active and experience significant functional limitations. The impact of a structured aerobic exercise intervention on outcomes in ambulatory heart failure (HF) patients with comorbid CKD is unknown. HF-ACTION enrolled 2,331 outpatients with HF and a reduced ejection fraction (i.e., ≤35%) from April 2003 to February 2007 and randomized them to aerobic exercise training versus usual care. Patients were grouped according to the presence of CKD, defined as an estimated glomerular filtration rate
Authors: Ambrosy, Andrew P AP; Mulder, Hillary H; Coles, Adrian A; Krauss, William E WE; Lam, Carolyn S P CSP; McCullough, Peter A PA; Pina, Ileana I; Tromp, Jasper J; Whellan, David J DJ; O'Connor, Christopher M CM; Mentz, Robert J RJ
The American journal of cardiology. 2018 Sep 15;122(6):999-1007. Epub 2018-06-23.
Combination drug therapy in heart failure: greater than the sum of its parts.
Authors: Ambrosy, Andrew P AP; Chioncel, Ovidiu O
European journal of heart failure. 2018 Sep 17;20(9):1323-1325. Epub 2018-06-22.
Contemporary rates and predictors of fast progression of chronic kidney disease in adults with and without diabetes mellitus
Chronic kidney disease (CKD) is highly prevalent but identification of patients at high risk for fast CKD progression before reaching end-stage renal disease in the short-term has been challenging. Whether factors associated with fast progression vary by diabetes status is also not well understood. We examined a large community-based cohort of adults with CKD to identify predictors of fast progression during the first 2 years of follow-up in the presence or absence of diabetes mellitus. Within a large integrated healthcare delivery system in northern California, we identified adults with estimated glomerular filtration rate (eGFR) 30-59 ml/min/1.73 m2 by CKD-EPI equation between 2008 and 2010 who had no previous dialysis or renal transplant, who had outpatient serum creatinine values spaced 10-14 months apart and who did not initiate renal replacement therapy, die or disenroll during the first 2 years of follow-up. Through 2012, we calculated the annual rate of change in eGFR and classified patients as fast progressors if they lost > 4 ml/min/1.73 m2 per year. We used multivariable logistic regression to identify patient characteristics that were independently associated with fast CKD progression stratified by diabetes status. We identified 36,195 eligible adults with eGFR 30-59 ml/min/1.73 m2 and mean age 73 years, 55% women, 11% black, 12% Asian/Pacific Islander and 36% with diabetes mellitus. During 24-month follow-up, fast progression of CKD occurred in 23.0% of patients with diabetes vs. 15.3% of patients without diabetes. Multivariable predictors of fast CKD progression that were similar by diabetes status included proteinuria, age ≥ 80 years, heart failure, anemia and higher systolic blood pressure. Age 70-79 years, prior ischemic stroke, current or former smoking and lower HDL cholesterol level were also predictive in patients without diabetes, while age 18-49 years was additionally predictive in those with diabetes. In a large, contemporary population of adults with eGFR 30-59 ml/min/1.73 m2, accelerated progression of kidney dysfunction within 2 years affected ~ 1 in 4 patients with diabetes and ~ 1 in 7 without diabetes. Regardless of diabetes status, the strongest independent predictors of fast CKD progression included proteinuria, elevated systolic blood pressure, heart failure and anemia.
Authors: Go AS; Yang J; Tan TC; Cabrera CS; Stefansson BV; Greasley PJ; Ordonez JD; Kaiser Permanente Northern California CKD Outcomes Study
BMC Nephrol. 2018 06 22;19(1):146. Epub 2018-06-22.
Respiratory Symptoms in Young Adults and Future Lung Disease: The CARDIA Lung Study
There are limited data on factors in young adulthood that predict future lung disease. To determine the relationship between respiratory symptoms, loss of lung health, and incident respiratory disease in a population-based study of young adults. We examined prospective data from 2,749 participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study who completed respiratory symptom questionnaires at baseline and 2 years later and repeated spirometry measurements over 30 years. Cough or phlegm, episodes of bronchitis, wheeze, shortness of breath, and chest illnesses at both baseline and Year 2 were the main predictor variables in models assessing decline in FEV1 and FVC from Year 5 to Year 30, incident obstructive and restrictive lung physiology, and visual emphysema on thoracic computed tomography scan. After adjustment for covariates, including body mass index, asthma, and smoking, report of any symptom was associated with -2.71 ml/yr excess decline in FEV1 (P < 0.001) and -2.18 in FVC (P < 0.001) as well as greater odds of incident (prebronchodilator) obstructive (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.24-2.14) and restrictive (OR, 1.40; 95% CI, 1.09-1.80) physiology. Cough-related symptoms (OR, 1.56; 95% CI, 1.13-2.16) were associated with greater odds of future emphysema. Persistent respiratory symptoms in young adults are associated with accelerated decline in lung function, incident obstructive and restrictive physiology, and greater odds of future radiographic emphysema.
Authors: Kalhan R; Iribarren C; Washko GR; et al.
Am J Respir Crit Care Med. 2018 06 15;197(12):1616-1624.
10-year changes in accelerometer-based physical activity and sedentary time during midlife: CARDIA Study
To describe 10-year changes in accelerometer-determined physical activity (PA) and sedentary time in a midlife cohort, within and by race/sex groups. Coronary Artery Risk Development in Young Adults participants (n = 962) who wore the accelerometer with valid wear (≥4 of 7 days, ≥10 hours per day) at baseline (2005-06; ages 38-50; ActiGraph 7164) and 10-year follow-up (2015-16; ages 48-60; ActiGraph wGT3X-BT). Data were calibrated to account for accelerometer model differences. Participants (aged 45.0 ± 3.5 years at baseline) experienced reductions in accelerometer counts overall [-65.5 (10.2) ct·min·d-1], and within race/sex groups (all p
Authors: Gabriel KP; Sidney S; Sternfeld B; et al.
Am J Epidemiol. 2018 Jun 11.
Non-recovery from dialysis-requiring acute kidney injury and short-term mortality and cardiovascular risk: a cohort study
The high mortality and cardiovascular disease (CVD) burden in patients with end-stage renal disease (ESRD) is well-documented. Recent literature suggests that acute kidney injury is also associated with CVD. It is unknown whether patients with incident ESRD due to dialysis-requiring acute kidney injury (AKI-D) are at higher short-term risk for death and CVD events, compared with incident ESRD patients without preceding AKI-D. Few studies have examined the impact of recovery from AKI-D on subsequent CVD risk. In this retrospective cohort study, we evaluated adult members of Kaiser Permanente Northern California who initiated dialysis from January 2009 to September 2015. Preceding AKI-D and subsequent outcomes of death and CVD events (acute coronary syndrome, heart failure, ischemic stroke or transient ischemic attack) were identified from electronic health records. We performed multivariable Cox regression models adjusting for demographics, comorbidities, medication use, and laboratory results. Compared to incident ESRD patients who experienced AKI-D (n = 1865), patients with ESRD not due to AKI-D (n = 3772) had significantly lower adjusted rates of death (adjusted hazard ratio [aHR] 0.56, 95% CI: 0.47-0.67) and heart failure hospitalization (aHR 0.45, 0.30-0.70). Compared to AKI-D patients who did not recover and progressed to ESRD, AKI-D patients who recovered (n = 1347) had a 30% lower adjusted relative rate of death (aHR 0.70, 0.55-0.88). Patients who transition to ESRD via AKI-D are a high-risk subgroup that may benefit from aggressive monitoring and medical management, particularly for heart failure. Recovery from AKI-D is independently associated with lower short-term mortality.
Authors: Lee BJ; Hsu CY; Parikh RV; Leong TK; Tan TC; Walia S; Liu KD; Hsu RK; Go AS
BMC Nephrol. 2018 06 11;19(1):134. Epub 2018-06-11.
Acute Kidney Injury and Risk of Heart Failure and Atherosclerotic Events
AKI in the hospital is common and is associated with excess mortality. We examined whether AKI is also independently associated with a higher risk of different cardiovascular events in the first year after discharge. We conducted a retrospective analysis of a cohort between 2006 and 2013 with follow-up through 2014, within Kaiser Permanente Northern California. We identified all adults admitted to 21 hospitals who had one or more in-hospital serum creatinine test result and survived to discharge. Occurrence of AKI was on the basis of Kidney Disease: Improving Global Outcomes diagnostic criteria. Potential confounders were identified from comprehensive inpatient and outpatient, laboratory, and pharmacy electronic medical records. During the 365 days after discharge, we ascertained occurrence of heart failure, acute coronary syndromes, peripheral artery disease, and ischemic stroke events from electronic medical records. Among a matched cohort of 146,941 hospitalized adults, 31,245 experienced AKI. At 365 days postdischarge, AKI was independently associated with higher rates of the composite outcome of hospitalization for heart failure and atherosclerotic events (adjusted hazard ratio [aHR], 1.18; 95% confidence interval [95% CI], 1.13 to 1.25) even after adjustment for demographics, comorbidities, preadmission eGFR and proteinuria, heart failure and sepsis complicating the hospitalization, intensive care unit (ICU) admission, length of stay, and predicted in-hospital mortality. This was driven by an excess risk of subsequent heart failure (aHR, 1.44; 95% CI, 1.33 to 1.56), whereas there was no significant association with follow-up atherosclerotic events (aHR, 1.05; 95% CI, 0.98 to 1.12). AKI is independently associated with a higher risk of cardiovascular events, especially heart failure, after hospital discharge.
Authors: Go AS; Hsu CY; Yang J; Tan TC; Zheng S; Ordonez JD; Liu KD
Clin J Am Soc Nephrol. 2018 06 07;13(6):833-841. Epub 2018-05-17.
Breastfeeding and Future Maternal Health-No Causal Evidence-Reply
Authors: Gunderson EP; Lewis CE
JAMA Intern Med. 2018 06 01;178(6):871-872.
Implementation Research to Address the United States Health Disadvantage: Report of a National Heart, Lung, and Blood Institute Workshop
Four decades ago, U.S. life expectancy was within the same range as other high-income peer countries. However, during the past decades, the United States has fared worse in many key health domains resulting in shorter life expectancy and poorer health-a health disadvantage. The National Heart, Lung, and Blood Institute convened a panel of national and international health experts and stakeholders for a Think Tank meeting to explore the U.S. health disadvantage and to seek specific recommendations for implementation research opportunities for heart, lung, blood, and sleep disorders. Recommendations for National Heart, Lung, and Blood Institute consideration were made in several areas including understanding the drivers of the disadvantage, identifying potential solutions, creating strategic partnerships with common goals, and finally enhancing and fostering a research workforce for implementation research. Key recommendations included exploring why the United States is doing better for health indicators in a few areas compared with peer countries; targeting populations across the entire socioeconomic spectrum with interventions at all levels in order to prevent missing a substantial proportion of the disadvantage; assuring partnership have high-level goals that can create systemic change through collective impact; and finally, increasing opportunities for implementation research training to meet the current needs. Connecting with the research community at large and building on ongoing research efforts will be an important strategy. Broad partnerships and collaboration across the social, political, economic, and private sectors and all civil society will be critical-not only for implementation research but also for implementing the findings to have the desired population impact. Developing the relevant knowledge to tackle the U.S. health disadvantage is the necessary first step to improve U.S. health outcomes.
Authors: Engelgau MM; Siega-Riz AM; Mensah GA; et al.
Glob Heart. 2018 06;13(2):65-72. Epub 2018-04-30.
Association of Pulse Wave Velocity With Chronic Kidney Disease Progression and Mortality: Findings From the CRIC Study (Chronic Renal Insufficiency Cohort)
Patients with chronic kidney diseases (CKDs) are at risk for further loss of kidney function and death, which occur despite reasonable blood pressure treatment. To determine whether arterial stiffness influences CKD progression and death, independent of blood pressure, we conducted a prospective cohort study of CKD patients enrolled in the CRIC study (Chronic Renal Insufficiency Cohort). Using carotid-femoral pulse wave velocity (PWV), we examined the relationship between PWV and end-stage kidney disease (ESRD), ESRD or halving of estimated glomerular filtration rate, or death from any cause. The 2795 participants we enrolled had a mean age of 60 years, 56.4% were men, 47.3% had diabetes mellitus, and the average estimated glomerular filtration rate at entry was 44.4 mL/min per 1.73 m2 During follow-up, there were 504 ESRD events, 628 ESRD or halving of estimated glomerular filtration rate events, and 394 deaths. Patients with the highest tertile of PWV (>10.3 m/s) were at higher risk for ESRD (hazard ratio [95% confidence interval], 1.37 [1.05-1.80]), ESRD or 50% decline in estimated glomerular filtration rate (hazard ratio [95% confidence interval], 1.25 [0.98-1.58]), or death (hazard ratio [95% confidence interval], 1.72 [1.24-2.38]). PWV is a significant predictor of CKD progression and death in people with impaired kidney function. Incorporation of PWV measurements may help define better the risks for these important health outcomes in patients with CKDs. Interventions that reduce aortic stiffness deserve study in people with CKD.
Authors: Townsend RR; CRIC Study Investigators; et al.
Hypertension. 2018 Jun;71(6):1101-1107. Epub 2018-04-30.
Comparison of Two Generations of ActiGraph Accelerometers: The CARDIA Study
This study aimed to examine the comparability of the ActiGraph 7164 and wGT3X-BT wear time, count-based estimates, and average time per day in physical activity of different intensities. We studied 87 Coronary Artery Risk Development in Young Adults (CARDIA) participants 48-60 yr of age who simultaneously wore the 7164 and wGT3X-BT accelerometers at the waist in 2015-2016, with wear time of ≥4 of 7 d, ≥10 h·d for both monitors. Freedson cutpoints (counts per minute) were used to define sedentary (<100), light (100-1951), moderate (1952-5724), and vigorous activity (≥5725). Agreement was evaluated using paired-difference tests, intraclass correlation coefficients, and Bland-Altman plots. Given systematic differences in count-based estimates between monitors, a calibration formula applied to the wGT3X-BT values was obtained by linear regression. Total detected wear time minutes per day was nearly identical between the 7164 and the wGT3X-BT (881.5 ± 70.9 vs 880.3 ± 78.1, P = 0.72). The wGT3X-BT values were calibrated to the 7164 values by dividing counts by 1.088. After calibration, no differences were observed between the 7164 and the wGT3X-BT in total counts per day (310,184 ± 129,189 vs 307,085 ± 135,362, P = 0.48), average counts per min per day (349.5 ± 139.5 vs 346.5 ± 147.2, P = 0.54), sedentary (513.2 ± 93.6 vs 509.6 ± 98.6, P = 0.23), light (335.3 ± 81.5 vs 338.7 ± 81.1, P = 0.22), moderate (31.0 ± 21.9 vs 30.3 ± 23.4, P = 0.31), or moderate-to-vigorous minutes per day (33.1 ± 24.6 vs 32.0 ± 26.0, P = 0.13). A significant difference was observed for vigorous minutes per day (0.2 ± 1.0 vs 0.0 ± 0.3, P < 0.01); however, the absolute difference was marginal. Intraclass correlation coefficients showed excellent agreement for all measures (0.95-0.99). After applying a calibration formula, the 7164 and wGT3X-BT were comparable for total wear time, count-based estimates, and average minutes per day in sedentary, light, moderate, and moderate-to-vigorous activity. Findings illustrate a novel methodological approach to facilitate accelerometer data harmonization.
Authors: Whitaker KM; Pettee Gabriel K; Jacobs DR; Sidney S; Sternfeld B
Med Sci Sports Exerc. 2018 06;50(6):1333-1340.
High-resolution mapping of traffic related air pollution with Google street view cars and incidence of cardiovascular events within neighborhoods in Oakland, CA
Some studies have linked long-term exposure to traffic related air pollutants (TRAP) with adverse cardiovascular health outcomes; however, previous studies have not linked highly variable concentrations of TRAP measured at street-level within neighborhoods to cardiovascular health outcomes. Long-term pollutant concentrations for nitrogen dioxide [NO2], nitric oxide [NO], and black carbon [BC] were obtained by street-level mobile monitoring on 30 m road segments and linked to residential addresses of 41,869 adults living in Oakland during 2010 to 2015. We fit Cox proportional hazard models to estimate the relationship between air pollution exposures and time to first cardiovascular event. Secondary analyses examined effect modification by diabetes and age. Long-term pollutant concentrations [mean, (standard deviation; SD)] for NO2, NO and BC were 9.9 ppb (SD 3.8), 4.9 ppb (SD 3.8), and 0.36 μg/m3 (0.17) respectively. A one SD increase in NO2, NO and BC, was associated with a change in risk of a cardiovascular event of 3% (95% confidence interval [CI] -6% to 12%), 3% (95% CI -5% to 12%), and - 1% (95% CI -8% to 7%), respectively. Among the elderly (≥65 yrs), we found an increased risk of a cardiovascular event of 12% for NO2 (95% CI: 2%, 24%), 12% for NO (95% CI: 3%, 22%), and 7% for BC (95% CI: -3%, 17%) per one SD increase. We found no effect modification by diabetes. Street-level differences in long-term exposure to TRAP were associated with higher risk of cardiovascular events among the elderly, indicating that within-neighborhood differences in TRAP are important to cardiovascular health. Associations among the general population were consistent with results found in previous studies, though not statistically significant.
Authors: Alexeeff SE; Roy A; Shan J; Liu X; Messier K; Apte JS; Portier C; Sidney S; Van Den Eeden SK
Environ Health. 2018 05 15;17(1):38. Epub 2018-05-15.
Weighted Multi-marker Genetic Risk Scores for Incident Coronary Heart Disease among Individuals of African, Latino and East-Asian Ancestry
We examined the clinical utility of two multi-locus genetic risk scores (GRSs) previously validated in Europeans among persons of African (AFR; n = 2,089), Latino (LAT; n = 4,349) and East-Asian (EA; n = 4,804) ancestry. We used data from the GERA cohort (30-79 years old, 68 to 73% female). We utilized two GRSs with 12 and 51 SNPs, respectively, and the Framingham Risk Score (FRS) to estimate 10-year CHD risk. After a median 8.7 years of follow-up, 450 incident CHD events were documented (95 in AFR, 316 in LAT and 39 EA, respectively). In a model adjusting for principal components and risk factors, tertile 3 vs. tertile 1 of GRS_12 was associated with 1.86 (95% CI, 1.15-3.01), 1.52 (95% CI, 1.02-2.25) and 1.19 (95% CI, 0.77-1.83) increased hazard of CHD in AFR, LAT and EA, respectively. Inclusion of the GRSs in models containing the FRS did not increase the C-statistic but resulted in net overall reclassification of 10% of AFR, 7% LAT and EA and in reclassification of 13% of AFR and EA as well as 10% LAT in the intermediate FRS risk subset. Our results support the usefulness of incorporating genetic information into risk assessment for primary prevention among minority subjects in the U.S.
Authors: Iribarren C; Lu M; Jorgenson E; Martínez M; Lluis-Ganella C; Subirana I; Salas E; Elosua R
Sci Rep. 2018 05 01;8(1):6853. Epub 2018-05-01.
Elevated Medium Chain-Acylcarnitines are Associated with Gestational Diabetes, and Early Progression to Type-2 Diabetes, and Induce Pancreatic β-Cell Dysfunction
Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type 2 diabetes (T2D) and linked to peripheral insulin resistance. However, the effect of acylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: 1) women with gestational diabetes mellitus (GDM) and 2) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D, or returned to normoglycemia within a 2-year follow-up period. We observed a specific elevation in serum medium-chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine, among women with GDM and individuals with T2D without alteration in long-chain acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset and that this elevation directly impairs β-cell function.
Authors: Batchuluun B; Al Rijjal D; Prentice KJ; Eversley JA; Burdett E; Mohan H; Bhattacharjee A; Gunderson EP; Liu Y; Wheeler MB
Diabetes. 2018 05;67(5):885-897. Epub 2018-02-07.
Longitudinal Weight Change During CKD Progression and Its Association With Subsequent Mortality
Few studies have investigated the changes in weight that may occur over time among adults with the progression of chronic kidney disease (CKD). Whether such weight changes are independently associated with death after the onset of end-stage renal disease has also not been rigorously examined. Prospective cohort study. We studied 3,933 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a longitudinal cohort of patients with CKD. We also performed similar analyses among 1,067 participants of the African American Study of Kidney Disease and Hypertension (AASK). Estimated glomerular filtration rate (eGFR) and weight change during CKD. Weight and all-cause mortality after dialysis therapy initiation. During a median follow-up of 5.7 years in CRIC, weight change was not linear. Weight was stable until cystatin C-based eGFR (eGFRcys) decreased to <35mL/min/1.73m2; thereafter, weight declined at a mean rate of 1.45 kg (95% CI, 1.19-1.70) for every 10 mL/min/1.73m2 decline in eGFRcys. Among the 770 CRIC participants who began hemodialysis or peritoneal dialysis therapy during follow-up, a >5% annualized weight loss after eGFR decreased to <35mL/min/1.73m2 was associated with a 54% higher risk for death after dialysis therapy initiation (95% CI, 1.17-2.03) compared with those with more stable weight (annualized weight changes within 5% of baseline) in adjusted analysis. Similar findings were observed in the AASK. Inclusion of research participants only; inability to distinguish intentional versus unintentional weight loss. Significant weight loss began relatively early during the course of CKD and was associated with a substantially higher risk for death after dialysis therapy initiation. Further studies are needed to determine whether interventions to optimize weight and nutritional status before the initiation of dialysis therapy will improve outcomes after end-stage renal disease.
Authors: Ku E; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2018 05;71(5):657-665. Epub 2017-12-06.
Lifetime Marijuana Use and Subclinical Atherosclerosis: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Unlike tobacco, the effect of marijuana smoke on subclinical atherosclerosis, a surrogate measure for cardiovascular disease, is not known. This study aimed to determine the association between lifetime exposure to marijuana and measures of subclinical atherosclerosis in mid-life. We used data from the US-based Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of black and white men and women aged 18-30 years at baseline in 1985-86, with up to seven follow-up examinations over 25 years. A total of 3498 participants in the CARDIA study were included in this study. Cumulative years of exposure to marijuana (expressed in ‘marijuana-years’, with 1 marijuana-year equivalent to 365 days of use) using repeated assessments every 2-5 years for 25 years. Abdominal artery calcium (AAC) and coronary artery calcium (CAC) scores were measured by computed tomography at year 25 examination. Among 3117 participants with AAC and CAC measurements, 2627 (84%) reported past marijuana use and 1536 (49%) past daily tobacco smoking. Compared with tobacco smokers, 46% of whom reported 10 or more pack-years of use, only 12% of marijuana users reported 5 or more marijuana-years of use and only 6% reported having used marijuana daily. We found a significant interaction between never and ever tobacco users on the association between cumulative marijuana use and AAC (P = 0.05). Among those who never smoked tobacco, cumulative marijuana-years were not associated with AAC or CAC in models adjusted for demographics, cardiovascular risk factors, licit and illicit drug exposure and depression symptoms. However, among ever tobacco smokers, marijuana exposure was associated with AAC and CAC. At 5 marijuana-years of exposure, using AAC = 0 and CAC = 0 as a reference group, the odds ratio (OR) was 1.97 [95% confidence interval (CI) = 1.21-3.21, P = 0.007] for AAC > 0/CAC = 0 and 1.83 (95% CI = 1.02-3.31, P = 0.04) for CAC > 0), regardless of AAC. Tobacco smoking was associated strongly with both AAC and CAC. Marijuana use appears to be associated with subclinical atherosclerosis, but only among ever tobacco users.
Authors: Auer R; Sidney S; Goff D; Vittinghoff E; Pletcher MJ; Allen NB; Reis JP; Lewis CE; Carr J; Rana JS
Addiction. 2018 05;113(5):845-856. Epub 2018-01-21.
Anxiety, Depression, and Adverse Clinical Outcomes in Patients With Atrial Fibrillation Starting Warfarin: Cardiovascular Research Network WAVE Study
Anxiety and depression are associated with worse outcomes in several cardiovascular conditions, but it is unclear whether they affect outcomes in atrial fibrillation (AF). In a large diverse population of adults with AF, we evaluated the association of diagnosed anxiety and/or depression with stroke and bleeding outcomes. The Cardiovascular Research Network WAVE (Community-Based Control and Persistence of Warfarin Therapy and Associated Rates and Predictors of Adverse Clinical Events in Atrial Fibrillation and Venous Thromboembolism) Study included adults with AF newly starting warfarin between 2004 and 2007 within 5 health delivery systems in the United States. Diagnosed anxiety and depression and other patient characteristics were identified from electronic health records. We identified stroke and bleeding outcomes from hospitalization databases using validated International Classification of Diseases, Ninth Revision (ICD-9), codes. We used multivariable Cox regression to assess the relation between anxiety and/or depression with outcomes after adjustment for stroke and bleeding risk factors. In 25 570 adults with AF initiating warfarin, 490 had an ischemic stroke or intracranial hemorrhage (1.52 events per 100 person-years). In multivariable analyses, diagnosed anxiety was associated with a higher adjusted rate of combined ischemic stroke and intracranial hemorrhage (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28). Results were not materially changed after additional adjustment for patient-level percentage of time in therapeutic anticoagulation range on warfarin (hazard ratio, 1.56; 95% confidence interval, 1.03-2.36). In contrast, neither isolated depression nor combined depression and anxiety were significantly associated with outcomes. Diagnosed anxiety was independently associated with increased risk of combined ischemic stroke and intracranial hemorrhage in adults with AF initiating warfarin that was not explained by differences in risk factors or achieved anticoagulation quality.
Authors: Baumgartner C; Fan D; Fang MC; Singer DE; Witt DM; Schmelzer JR; Williams MS; Gurwitz JH; Sung SH; Go AS
J Am Heart Assoc. 2018 04 14;7(8). Epub 2018-04-14.
Mineralocorticoid Receptor Antagonism in Patients With Atrial Fibrillation: Findings From the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) Registry
Mineralocorticoid receptor antagonist (MRA) therapy may be beneficial to patients with atrial fibrillation (AF), but little is known about their use in patients with AF and subsequent outcomes. In order to better understand MRA use and subsequent outcomes, we performed a retrospective cohort study of the contemporary ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry. AF progression and cardiovascular outcomes were compared using propensity-matched Cox proportional hazards modeling according to MRA use at baseline and new MRA use at follow-up versus patients with no MRA use. Among 7012 patients with nonpermanent AF, 320 patients were taking MRA at enrollment, and 416 patients initiated MRA use during follow-up. The mean patient age was 72.5 years, 56.3% were men, and 70.4% had paroxysmal AF. Among all patients taking MRAs, 434 (59.0%) had heart failure, 655 (89.0%) had hypertension, and 380 (51.6%) had both. After adjustment, new MRA use was not associated with reduced AF progression (hazard ratio, 1.18; 95% confidence interval, 0.88-1.58; P=0.27) but showed a trend towards lower risk of stroke, transient ischemic attack, or systemic embolism (hazard ratio, 0.17; 95% confidence interval, 0.02-1.23; P=0.08). Results were similar for a comparison of new MRA users and baseline MRA users compared with nonusers. In community-based outpatients with AF, the majority of MRA use was for heart failure and hypertension. MRA use also trended towards lower adjusted stroke risk. Future studies should test the hypothesis that MRA use may decrease the risk of stroke in patients with AF.
Authors: Fudim M; Thomas L; Piccini JP; et al.
J Am Heart Assoc. 2018 04 13;7(8). Epub 2018-04-13.
Sudden Death After Hospitalization for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial).
Patients with chronic heart failure with reduced ejection fraction (HFrEF) benefit from medical and device therapies targeting sudden cardiac death (SCD). Contemporary estimates of SCD risk after hospitalization for heart failure are limited. We describe the incidence, timing, and clinical predictors of SCD after hospitalization for HFrEF (≤40%) in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial. Multiple logistic regression analyses tested >30 baseline covariates (including treatment randomization, demographics, comorbid conditions, natriuretic peptides, ejection fraction, and medical and device therapies) to identify predictors of 1-year SCD. Of the 4,024 trial patients discharged alive (97%), there were 268 who experienced SCD (7%) and 703 who experienced non-SCD (17%) during median follow-up of 9.9 months. Implantable cardioverter defibrillator use at baseline was 14.5%. Estimates of SCD at 1, 3, 6, and 12 months were 0.8%, 2.3%, 4.1%, and 7.4%, respectively. Most patients were readmitted before SCD (n = 147, 55%). Male gender, black race, diabetes mellitus, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were potential predictors of 1-year SCD after hospitalization for HFrEF (all p
Authors: Vaduganathan, Muthiah M; Patel, Ravi B RB; Mentz, Robert J RJ; Subacius, Haris H; Chatterjee, Neal A NA; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Maggioni, Aldo P AP; Udelson, James E JE; Swedberg, Karl K; Konstam, Marvin A MA; O'Connor, Christopher M CM; Butler, Javed J; Gheorghiade, Mihai M; Zannad, Faiez F
The American journal of cardiology. 2018 Jul 15;122(2):255-260. Epub 2018-04-11.
A recursive partitioning approach to investigating correlates of self-rated health: The CARDIA Study
Self-rated health (SRH) is an independent predictor of mortality; studies have investigated correlates of SRH to explain this predictive capability. However, the interplay of a broad array of factors that influence health status may not be adequately captured with parametric multivariate regression. This study investigated associations between several health determinants and SRH using recursive partitioning methods. This non-parametric analytic approach aimed to reflect the social-ecological model of health, emphasizing relationships between multiple health determinants, including biological, behavioral, and from social/physical environments. The study sample of 3648 men and women was drawn from the year 15 (2000-2001) data collection of the CARDIA Study, USA, in order to study a young adult sample. Classification tree analysis identified 15 distinct, mutually exclusive, subgroups (eight with a larger proportion of individuals with higher SRH, and seven with a larger proportion of lower SRH), and multi-domain risk and protective factors associated with subgroup membership. Health determinant profiles were not uniform between subgroups, even for those with similar health status. The subgroup with the largest proportion of higher SRH was characterized by several protective factors, whilst that with the largest proportion of lower SRH, with several negative risk factors; certain factors were associated with both higher and lower SRH subgroups. In the full sample, physical activity, education and income were highest ranked by variable importance (random forests analysis) in association with SRH. This exploratory study demonstrates the utility of recursive partitioning methods in studying the joint impact of multiple health determinants. The findings indicate that factors do not affect SRH in the same way across the whole sample. Multiple factors from different domains, and with varying relative importance, are associated with SRH in different subgroups. This has implications for developing and prioritizing appropriate interventions to target conditions and factors that improve self-rated health status.
Authors: Nayak S; Hubbard A; Sidney S; Syme SL
SSM Popul Health. 2018 Apr;4:178-188. Epub 2017-12-15.
Risk factors for progression of coronary artery calcification in patients with chronic kidney disease: The CRIC study
Coronary artery calcification (CAC) is common among patients with chronic kidney disease (CKD) and predicts the risk for cardiovascular disease (CVD). We examined the associations of novel risk factors with CAC progression among patients with CKD. Among 1123 CKD patients in the Chronic Renal Insufficiency Cohort (CRIC) Study, CAC was measured in Agatston units at baseline and a follow-up visit using electron beam computed tomography or multidetector computed tomography. Over an average 3.3-year follow-up, 109 (25.1%) participants without CAC at baseline had incident CAC and 124 (18.0%) participants with CAC at baseline had CAC progression, defined as an annual increase of ≥100 Agatston units. After adjustment for established atherosclerotic risk factors, several novel risk factors were associated with changes in CAC over follow-up. Changes in square root transformed CAC score associated with 1 SD greater level of risk factors were -0.20 (95% confidence interval, -0.31 to -0.10; p < 0.001) for estimated glomerular filtration rate, 0.14 (0.02-0.25; p = 0.02) for 24-h urine albumin, 0.25 (0.15-0.34; p < 0.001) for cystatin C, -0.17 (-0.27 to -0.07; p < 0.001) for serum calcium, 0.14 (0.03-0.24; p = 0.009) for serum phosphate, 0.24 (0.14-0.33; p < 0.001) for fibroblast growth factor-23, 0.13 (0.04-0.23; p = 0.007) for total parathyroid hormone, 0.17 (0.07-0.27; p < 0.001) for interleukin-6, and 0.12 (0.02-0.22; p = 0.02) for tumor necrosis factor-α. Reduced kidney function, calcium and phosphate metabolism disorders, and inflammation, independent of established CVD risk factors, may progress CAC among CKD patients.
Authors: Bundy JD; Go AS; CRIC Study Investigators; et al.
Atherosclerosis. 2018 04;271:53-60. Epub 2018-02-10.
Pre-pregnancy endothelial dysfunction and birth outcomes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Endothelial dysfunction is a form of subclinical cardiovascular disease that may be involved in preterm birth and small-for-gestational-age deliveries. However, concentrations of biomarkers of endothelial dysfunction before pregnancy have rarely been measured. We hypothesized that higher levels of biomarkers of endothelial dysfunction (cellular adhesion molecules and selectins) would be associated with odds of preterm birth and/or small-for-gestational-age deliveries. We included 235 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were nulliparous at Y7, reported ≥1 live birth through Y25, and had ≥1 biomarker measured at Y7. We tested for associations between individual biomarkers and an averaged z-score representing total endothelial dysfunction with preterm birth and/or small-for-gestational-age deliveries using Poisson regression, adjusted for demographic and clinical characteristics at the exam immediately preceding index birth. At Y7, total evidence of endothelial dysfunction was similar in women who did (n = 59) and did not have (n = 176) preterm birth and/or small-for-gestational-age deliveries. There was no association between biomarkers of endothelial dysfunction (either individual biomarker or total score) with odds of preterm birth and/or small-for-gestational-age deliveries after adjustment: IRR = 1.01, 95% CI: 0.74, 1.39, p = 0.93 for total endothelial biomarker score. Associations were not modified by race. We conclude that biomarkers of endothelial dysfunction in nulliparous women, measured ~3 years before pregnancy, did not identify women at risk for preterm birth and/or small-for-gestational-age deliveries. This suggests that the maternal endothelial dysfunction that is believed to contribute to these birth outcomes may not be detectable before pregnancy.
Authors: Lane-Cordova AD; Gunderson EP; Carnethon MR; Catov JM; Reiner AP; Lewis CE; Dude AM; Greenland P; Jacobs DR
Hypertens Res. 2018 Apr;41(4):282-289. Epub 2018-02-15.
Changes in bone mineral density in women with breast cancer receiving aromatase inhibitor therapy
We assessed bone mineral density (BMD) change with aromatase inhibitor (AI) treatment in a contemporary cohort of women with breast cancer treated in Kaiser Permanente Northern California. Percent and estimated annual percent changes in BMD at the total hip and lumbar spine were examined in 676 women receiving AI therapy who had two serial BMD reports available (at least 1 year apart) before and after AI initiation (N = 317) or during continued AI therapy (N = 359). BMD changes were examined at the total hip and lumbar spine and compared by age and clinical subgroups. Women experienced BMD declines after AI initiation or continued therapy, with median annual percent change – 1.2% (interquartile range, IQR – 2.4 to – 0.1%) at the hip and – 1.0% (IQR – 2.3 to 0.1%) at the spine after AI initiation, and – 1.1% (IQR – 2.4 to 0.1%) at the hip and – 0.9% (IQR – 2.4 to 0.5%) at the spine during continued therapy. Higher levels of bone loss were observed among younger (< 55 years) compared with older (≥ 75 years) women at the hip (- 1.6% vs. - 0.8%) and at the spine (- 1.5% vs. - 0.5%) after AI initiation, and at the hip (- 1.4% vs. - 1.2%) and at the spine (- 2.4% vs. - 0.001%) during continued therapy. Small but consistent declines in total hip and lumbar spine BMD were present in breast cancer patients following AI therapy initiation or continued AI therapy. Although the overall rates of osteoporosis were low, greater estimated levels of annual bone loss were evident among women < 55 years.
Authors: Kwan ML; Yao S; Laurent CA; Roh JM; Quesenberry CP; Kushi LH; Lo JC
Breast Cancer Res Treat. 2018 Apr;168(2):523-530. Epub 2017-12-16.
Pre-admission proteinuria impacts risk of non-recovery after dialysis-requiring acute kidney injury
Renal recovery after dialysis-requiring acute kidney injury (AKI-D) is an important clinical and patient-centered outcome. Here we examined whether the pre-admission proteinuria level independently influences risk for non-recovery after AKI-D in a community-based population. All adult members of Kaiser Permanente Northern California who experienced AKI-D between January 1, 2009 and September 30, 2015 were included. Pre-admission proteinuria levels were determined by dipstick up to four years before the AKI-D hospitalization and the outcome was renal recovery (survival and dialysis-independence four weeks and more) at 90 days after initiation of renal replacement therapy. We used multivariable logistic regression to adjust for baseline estimated glomerular filtration rate (eGFR), age, sex, ethnicity, short-term predicted risk of death, comorbidities, and medication use. Among 5,347 adults with AKI-D, the mean age was 66 years, 59% were men, and 50% were white. Compared with negative/trace proteinuria, the adjusted odds ratios for non-recovery (continued dialysis-dependence or death) were 1.47 (95% confidence interval 1.19-1.82) for 1+ proteinuria and 1.92 (1.54-2.38) for 2+ or more proteinuria. Among survivors, the crude probability of recovery ranged from 83% for negative/trace proteinuria with baseline eGFR over 60 mL/min/1.73m2 to 25% for 2+ or more proteinuria with eGFR 15-29 mL/min/1.73m2. Thus, the pre-AKI-D level of proteinuria is a graded, independent risk factor for non-recovery and helps to improve short-term risk stratification for patients with AKI-D.
Authors: Lee BJ; Go AS; Parikh R; Leong TK; Tan TC; Walia S; Hsu RK; Liu KD; Hsu CY
Kidney Int. 2018 04;93(4):968-976. Epub 2018-01-15.
Self-Reported Marijuana Use Over 25 Years and Abdominal Adiposity: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
We investigated the association between cumulative lifetime and current marijuana use with total abdominal adipose tissue (AT), visceral AT, subcutaneous AT, intermuscular AT, and mean liver attenuation (LA) at mid-life. Longitudinal and cross-sectional secondary data analysis of participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA field centers in Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA, USA. CARDIA participants, aged 18-30 years in 1985-1986, who were present at the clinic examination in 2010-2011 (n = 2902). Marijuana use was assessed from responses to self-administered questionnaires at 8 CARDIA examinations over 25 years, determined as cumulative marijuana-years and current use status. Non-contrast computed tomography imaging of the abdomen was obtained in 2010-2011. In 2010-2011, 84% of participants reported a history of marijuana use with 11% reporting use within the past 30 days. Before adjustment, we observed greater cumulative marijuana use was associated with lower total abdominal and subcutaneous AT volume and lower LA and current marijuana use was associated with lower subcutaneous AT. However, after adjustment for age, sex, race, field center, cigarette pack-years and current use, regular alcohol consumption, cumulative drink-years, and physical activity, neither cumulative marijuana use nor current use showed an association with any abdominal adipose depot. Our estimates did not differ by age, sex, or race nor after accounting for cohort attrition. Neither cumulative marijuana use nor current marijuana use is associated with total abdominal, visceral, subcutaneous, or intermuscular adipose tissue, or liver attenuation in mid-life.
Authors: Bancks MP; Auer R; Carr JJ; Goff DC; Kiefe C; Rana JS; Reis J; Sidney S; Terry JG; Schreiner PJ
Addiction. 2018 04;113(4):689-698. Epub 2017-12-07.
Device Therapies Among Patients Receiving Primary Prevention Implantable Cardioverter-Defibrillators in the Cardiovascular Research Network
Primary prevention implantable cardioverter-defibrillators (ICDs) reduce mortality in selected patients with left ventricular systolic dysfunction by delivering therapies (antitachycardia pacing or shocks) to terminate potentially lethal arrhythmias; inappropriate therapies also occur. We assessed device therapies among adults receiving primary prevention ICDs in 7 healthcare systems. We linked medical record data, adjudicated device therapies, and the National Cardiovascular Data Registry ICD Registry. Survival analysis evaluated therapy probability and predictors after ICD implant from 2006 to 2009, with attention to Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups: left ventricular ejection fraction, 31% to 35%; nonischemic cardiomyopathy <9 months' duration; and New York Heart Association class IV heart failure with cardiac resynchronization therapy defibrillator. Among 2540 patients, 35% were <65 years old, 26% were women, and 59% were white. During 27 (median) months, 738 (29%) received ≥1 therapy. Three-year therapy risk was 36% (appropriate, 24%; inappropriate, 12%). Appropriate therapy was more common in men (adjusted hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.43-2.35). Inappropriate therapy was more common in patients with atrial fibrillation (adjusted HR, 2.20; 95% CI, 1.68-2.87), but less common among patients ≥65 years old versus younger (adjusted HR, 0.72; 95% CI, 0.54-0.95) and in recent implants (eg, in 2009 versus 2006; adjusted HR, 0.66; 95% CI, 0.46-0.95). In Centers for Medicare and Medicaid Services Coverage With Evidence Development analysis, inappropriate therapy was less common with cardiac resynchronization therapy defibrillator versus single chamber (adjusted HR, 0.55; 95% CI, 0.36-0.84); therapy risk did not otherwise differ for Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups. In this community cohort of primary prevention patients receiving ICD, therapy delivery varied across demographic and clinical characteristics, but did not differ meaningfully for Centers for Medicare and Medicaid Services Coverage With Evidence Development subgroups.
Authors: Greenlee RT; Go AS; Masoudi FA; et al.
J Am Heart Assoc. 2018 03 26;7(7). Epub 2018-03-26.
Is Time of the Essence? The Impact of Time of Hospital Presentation in Acute Heart Failure: Insights From ASCEND-HF Trial.
OBJECTIVES: As the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF.BACKGROUND: Time of hospital presentation has been shown to impact outcomes among patients hospitalized with many conditions. However, the association among time of presentation and patient characteristics, management, and clinical outcomes among patients hospitalized with AHF has not been well characterized.METHODS: A post hoc analysis of the ASCEND-HF trial was performed, which enrolled 7,141 patients hospitalized for AHF. Patients were divided based on when they presented to the hospital; regular hours were defined as 9 am to 5 pm, Monday through Friday, and off hours were defined as 5 pm to 9 am, Monday through Friday and weekends. Clinical characteristics and outcomes were compared by time of presentation.RESULTS: Overall, 3,298 patients (46%) presented during off hours. Off-hour patients were more likely to have orthopnea (80% vs. 74%, respectively) and rales (56% vs. 49%, respectively) than regular-hour patients. Off-hour patients were more likely to receive intravenous (IV) nitroglycerin (18% vs. 11%, respectively) and IV loop diuretics (92% vs. 86%, respectively) as initial therapy and reported greater relief from dyspnea at 24 h (odds ratio [OR]: 1.14; 95% confidence interval [CI]: 1.04 to 1.24; p = 0.01) than regular-hour patients. After adjustment, off-hour presentation was associated with significantly lower 30-day mortality (OR: 0.74; 95% CI: 0.57 to 0.96; p = 0.03) and 180-day mortality (hazard ratio [HR]: 0.82; 95% CI: 0.72 to 0.94; p = 0.01) but similar 30-day rehospitalization rates (p = 0.40).CONCLUSIONS: In this AHF trial, patients admitted during off hours exhibited a distinct clinical profile, experienced greater dyspnea relief, and had lower post-discharge mortality than regular-hour patients. These findings have implications for future AHF trials.
Authors: Cerbin, Lukasz P LP; Ambrosy, Andrew P AP; Greene, Stephen J SJ; Armstrong, Paul W PW; Butler, Javed J; Coles, Adrian A; DeVore, Adam D AD; Ezekowitz, Justin A JA; Hernandez, Adrian F AF; Metra, Marco M; Starling, Randall C RC; Tang, Wilson W; Teerlink, John R JR; Voors, Adriaan A AA; Wu, Angie A; O'Connor, Christopher M CM; Mentz, Robert J RJ
JACC. Heart failure. 2018 Apr 15;6(4):298-307. Epub 2018-03-07.
A large electronic-health-record-based genome-wide study of serum lipids
A genome-wide association study (GWAS) of 94,674 ancestrally diverse Kaiser Permanente members using 478,866 longitudinal electronic health record (EHR)-derived measurements for untreated serum lipid levels empowered multiple new findings: 121 new SNP associations (46 primary, 15 conditional, and 60 in meta-analysis with Global Lipids Genetic Consortium data); an increase of 33-42% in variance explained with multiple measurements; sex differences in genetic impact (greater impact in females for LDL, HDL, and total cholesterol and the opposite for triglycerides); differences in variance explained among non-Hispanic whites, Latinos, African Americans, and East Asians; genetic dominance and epistatic interaction, with strong evidence for both at the ABO and FUT2 genes for LDL; and tissue-specific enrichment of GWAS-associated SNPs among liver, adipose, and pancreas eQTLs. Using EHR pharmacy data, both LDL and triglyceride genetic risk scores (477 SNPs) were strongly predictive of age at initiation of lipid-lowering treatment. These findings highlight the value of longitudinal EHRs for identifying new genetic features of cholesterol and lipoprotein metabolism with implications for lipid treatment and risk of coronary heart disease.
Authors: Hoffmann TJ; Schaefer C; Iribarren C; Risch N; et al.
Nat Genet. 2018 03;50(3):401-413. Epub 2018-03-05.
Where are they now? Retention strategies over 25 years in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
In 1991, we described the recruitment and goals for a cohort of young adults. At the time, little was known about long-term retention of young, healthy and mobile adults or minorities. We present retention strategies and rates over 25 years, and predictors of participation at the year 25 follow-up examination of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal investigation of coronary artery disease risk factors in a biracial population initially ages 18-30 years recruited from four U.S. centers in 1985. CARDIA has employed a range of strategies to enhance retention, including two contacts per year, multiple tracking methods to locate participants lost-to-follow-up, use of birthday and holiday cards, participant newsletters, examination scheduling accommodations and monetary reimbursements, and a standing committee whose primary purpose has been to continually review retention rates and strategies and identify problems and successes. For 25 years, CARDIA has maintained >90% contact with participants between examinations, over 80% at any 2-year interval, and a 72% 25-year examination attendance rate. Baseline predictors of year 25 examination attendance include white race, female sex, older age, higher education, nonsmoking and moderate alcohol consumption. Consistent use of multiple retention strategies, including attention to contact rates and sharing of best strategies across study centers, has resulted in high retention of a diverse, initially young, biracial cohort.
Authors: Funkhouser E; Wammack J; Roche C; Reis J; Sidney S; Schreiner P
Contemp Clin Trials Commun. 2018 Mar;9:64-70. Epub 2017-12-20.
Thromboprophylaxis for Patients with High-risk Atrial Fibrillation and Flutter Discharged from the Emergency Department
Many patients with atrial fibrillation or atrial flutter (AF/FL) who are high risk for ischemic stroke are not receiving evidence-based thromboprophylaxis. We examined anticoagulant prescribing within 30 days of receiving dysrhythmia care for non-valvular AF/FL in the emergency department (ED). This prospective study included non-anticoagulated adults at high risk for ischemic stroke (ATRIA score ≥7) who received emergency AF/FL care and were discharged home from seven community EDs between May 2011 and August 2012. We characterized oral anticoagulant prescribing patterns and identified predictors of receiving anticoagulants within 30 days of the index ED visit. We also describe documented reasons for withholding anticoagulation. Of 312 eligible patients, 128 (41.0%) were prescribed anticoagulation at ED discharge or within 30 days. Independent predictors of anticoagulation included age (adjusted odds ratio [aOR] 0.89 per year, 95% confidence interval [CI] 0.82-0.96); ED cardiology consultation (aOR 1.89, 95% CI [1.10-3.23]); and failure of sinus restoration by time of ED discharge (aOR 2.65, 95% CI [1.35-5.21]). Reasons for withholding anticoagulation at ED discharge were documented in 139 of 227 cases (61.2%), the most common of which were deferring the shared decision-making process to the patient’s outpatient provider, perceived bleeding risk, patient refusal, and restoration of sinus rhythm. Approximately 40% of non-anticoagulated AF/FL patients at high risk for stroke who presented for emergency dysrhythmia care were prescribed anticoagulation within 30 days. Physicians were less likely to anticoagulate older patients and those with ED sinus restoration. Opportunities exist to improve rates of thromboprophylaxis in this high-risk population.
Authors: Vinson DR; Mark DG; Ballard DW; Reed ME; Go AS; et al.
West J Emerg Med. 2018 Mar;19(2):346-360. Epub 2018-02-12.
Contemporary Procedural Complications, Hospitalizations, and Emergency Visits After Catheter Ablation for Atrial Fibrillation
Contemporary data on complications and resource utilization after atrial fibrillation (AF) ablation are limited. We evaluated rates and risk factors for procedural complication, rehospitalization, and emergency department visits after AF ablation. We identified all adult patients who underwent isolated AF ablation between 2010 and June 2014 in 2 large integrated health-care delivery systems and evaluated rates of acute inpatient complication, 30-day, and 1-year readmission and emergency evaluation. We used multivariable logistic regression to identify predictors of procedural complications, 30-day readmission, or 30-day emergency department evaluation. In 811 AF ablation patients, procedural complications occurred in 2.5% of patients, 9.7% of patients were rehospitalized within 30 days, and 19.1% of patients had an emergency visit within 30 days. At 1 year after AF ablation, 28.9% of patients were readmitted, with 18% of patients readmitted for AF or atrial flutter. At 1 year, 44.5% of patients were seen in an emergency department, with 37.1% related to AF or atrial flutter. Vascular complications and perforation or tamponade were the most common complications, and Hispanic ethnicity, mitral or aortic valvular disease, and diabetes mellitus were the strongest risk factors for adverse outcomes at 30 days after AF ablation. Contemporary rates of acute complication and 1-year readmission after AF ablation have markedly decreased compared with previous community-based studies.
Authors: Freeman JV; Tabada GH; Reynolds K; Sung SH; Liu TI; Gupta N; Go AS
Am J Cardiol. 2018 03 01;121(5):602-608. Epub 2017-12-14.
Comment on ‘Effect of marijuana use on cardiovascular and cerebrovascular mortality’
Authors: Sidney S; Rana JS; Auer R
Eur J Prev Cardiol. 2018 03;25(5):460-461. Epub 2018-01-19.
Lactation Duration and Progression to Diabetes in Women Across the Childbearing Years: The 30-Year CARDIA Study
Lactation duration has shown weak protective associations with incident diabetes (3%-15% lower incidence per year of lactation) in older women based solely on self-report of diabetes, studies initiated beyond the reproductive period are vulnerable to unmeasured confounding or reverse causation from antecedent biochemical risk status, perinatal outcomes, and behaviors across the childbearing years. To evaluate the association between lactation and progression to diabetes using biochemical testing both before and after pregnancy and accounting for prepregnancy cardiometabolic measures, gestational diabetes (GD), and lifestyle behaviors. For this US multicenter, community-based 30-year prospective cohort study, there were 1238 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study of young black and white women ages 18 to 30 years without diabetes at baseline (1985-1986) who had 1 or more live births after baseline, reported lactation duration, and were screened for diabetes up to 7 times during 30 years after baseline (1986-2016). Time-dependent lactation duration categories (none, >0 to 6 months, >6 to <12 months, and ≥12 months) across all births since baseline through 30 years. Diabetes incidence rates per 1000 person-years and adjusted relative hazards (RH) with corresponding 95% CIs, as well as proportional hazards regression models adjusted for biochemical, sociodemographic, and reproductive risk factors, as well as family history of diabetes, lifestyle, and weight change during follow-up. Overall 1238 women were included in this analysis (mean [SD] age, 24.2 [3.7] years; 615 black women). There were 182 incident diabetes cases during 27 598 person-years for an overall incidence rate of 6.6 cases per 1000 person-years (95% CI, 5.6-7.6); and rates for women with GD and without GD were 18.0 (95% CI, 13.3-22.8) and 5.1 (95% CI, 4.2-6.0), respectively (P for difference < .001). Lactation duration showed a strong, graded inverse association with diabetes incidence: adjusted RH for more than 0 to 6 months, 0.75 (95% CI, 0.51-1.09); more than 6 months to less than 12 months, 0.52 (95% CI, 0.31-0.87), and 12 months or more 0.53 (0.29-0.98) vs none (0 days) (P for trend = .01). There was no evidence of effect modification by race, GD, or parity. This study provides longitudinal biochemical evidence that lactation duration is independently associated with lower incidence of diabetes. Further investigation is required to elucidate mechanisms that may explain this relationship.
Authors: Gunderson EP; Lewis CE; Lin Y; Sorel M; Gross M; Sidney S; Jacobs DR; Shikany JM; Quesenberry CP
JAMA Intern Med. 2018 03 01;178(3):328-337.
The role of angiotensin receptor-neprilysin inhibitors in cardiovascular disease-existing evidence, knowledge gaps, and future directions.
Although traditional renin-angiotensin system antagonists including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have revolutionized the treatment of cardiovascular disease (CVD), the pivotal PARADIGM-HF trial demonstrated that sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was superior to an angiotensin-converting enzyme inhibitor in reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction. However, despite international regulatory approval and strong recommendations in the guidelines, uptake of sacubitril/valsartan has been disappointing. Sacubitril/valsartan is now the focus of a large programme of clinical trials testing the hypothesis that ARNIs may supplant conventional renin-angiotensin system inhibitors across the spectrum of CVD, including hypertension, secondary prevention after myocardial infarction, and heart failure with preserved ejection fraction. This review summarizes the existing evidence, knowledge gaps, and future directions of ARNIs in CVD based on discussions between clinical trialists, industry representatives, and regulatory authorities at the 2016 Global CardioVascular Clinical Trialists Forum in Washington, D.C.
Authors: Ambrosy, Andrew P AP; Mentz, Robert J RJ; Fiuzat, Mona M; Cleland, John G F JGF; Greene, Stephen J SJ; O'Connor, Christopher M CM; Teerlink, John R JR; Zannad, Faiez F; Solomon, Scott D SD
European journal of heart failure. 2018 Jun 15;20(6):963-972. Epub 2018-02-21.
Angiotensin receptor-neprilysin inhibitor therapy in heart failure: An end that justifies the means.
Authors: Ambrosy, Andrew P AP; Velazquez, Eric J EJ
American heart journal. 2018 May 17;199(9):176-177. Epub 2018-02-15.
Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease
Chronic kidney disease (CKD) is common in adults with heart failure and is associated with an increased risk of sudden cardiac death. Randomized trials of participants without CKD have demonstrated that implantable cardioverter defibrillators (ICDs) decrease the risk of arrhythmic death in selected patients with reduced left ventricular ejection fraction (LVEF) heart failure. However, whether ICDs improve clinical outcomes in patients with CKD is not well elucidated. To examine the association of primary prevention ICDs with risk of death and hospitalization in a community-based population of potentially ICD-eligible patients who had heart failure with reduced LVEF and CKD. This noninterventional cohort study included adults with heart failure and an LVEF of 40% or less and measures of serum creatinine levels available from January 1, 2005, through December 31, 2012, who were enrolled in 4 Kaiser Permanente health care delivery systems. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2. Patients who received and did not receive an ICD were matched (1:3) on CKD status, age, and high-dimensional propensity score to receive an ICD. Follow-up was completed on December 31, 2013. Data were analyzed from 2015 to 2017. Placement of an ICD. All-cause death, hospitalizations due to heart failure, and any-cause hospitalizations. A total of 5877 matched eligible adults with CKD (1556 with an ICD and 4321 without an ICD) were identified (4049 men [68.9%] and 1828 women [31.1%]; mean [SD] age, 72.9 [8.2] years). In models adjusted for demographics, comorbidity, and cardiovascular medication use, no difference was found in all-cause mortality between patients with CKD in the ICD vs non-ICD groups (adjusted hazard ratio, 0.96; 95% CI, 0.87-1.06). However, ICD placement was associated with increased risk of subsequent hospitalization due to heart failure (adjusted relative risk, 1.49; 95% CI, 1.33-1.60) and any-cause hospitalization (adjusted relative risk, 1.25; 95% CI, 1.20-1.30) among patients with CKD. In a large, contemporary, noninterventional study of community-based patients with heart failure and CKD, ICD placement was not significantly associated with improved survival but was associated with increased risk for subsequent hospitalization due to heart failure and all-cause hospitalization. The potential risks and benefits of ICDs should be carefully considered in patients with heart failure and CKD.
Authors: Bansal N; Szpiro A; Reynolds K; Smith DH; Magid DJ; Gurwitz JH; Masoudi F; Greenlee RT; Tabada GH; Sung SH; Dighe A; Go AS
JAMA Intern Med. 2018 Feb 05.
Predictors of Post-discharge Mortality Among Patients Hospitalized for Acute Heart Failure.
Acute Heart Failure (AHF) is a " multi-event disease" and hospitalisation is a critical event in the clinical course of HF. Despite relatively rapid relief of symptoms, hospitalisation for AHF is followed by an increased risk of death and re-hospitalisation. In AHF, risk stratification from clinically available data is increasingly important in evaluating long-term prognosis. From the perspective of patients, information on the risk of mortality and re-hospitalisation would be helpful in providing patients with insight into their disease. From the perspective of care providers, it may facilitate management decisions, such as who needs to be admitted and to what level of care (i.e. floor, step-down, ICU). Furthermore, risk-stratification may help identify patients who need to be evaluated for advanced HF therapies (i.e. left-ventricle assistance device or transplant or palliative care), and patients who need early a post-discharge follow-up plan. Finally, risk stratification will allow for more robust efforts to identify among risk markers the true targets for therapies that may direct treatment strategies to selected high-risk patients. Further clinical research will be needed to evaluate if appropriate risk stratification of patients could improve clinical outcome and resources allocation.
Authors: Chioncel, Ovidiu O; Collins, Sean P SP; Greene, Stephen J SJ; Pang, Peter S PS; Ambrosy, Andrew P AP; Antohi, Elena-Laura EL; Vaduganathan, Muthiah M; Butler, Javed J; Gheorghiade, Mihai M
Cardiac failure review. 2017 Nov 03;3(2):122-129. Epub 2018-02-03.
Sedentary Behaviors and Cardiometabolic Risk, an Isotemporal Substitution Analysis
Evidence suggests that time spent engaging in sedentary behaviors is associated with a greater risk of adverse cardiometabolic outcomes. We investigated the cross-sectional associations of 6 unique sedentary tasks (watching television, using the computer, completing paperwork, reading, talking on the telephone, and sitting in a car) with cardiometabolic risk factors, and also examined the effect of replacing one type of sedentary behavior with another on the level of cardiometabolic risk. Participants consisted of 3,211 individuals from the Coronary Artery Risk Development in Young Adults Study who visited the clinic between 2010 and 2011. Linear regression models examined the independent and joint associations of sedentary tasks with a composite cardiometabolic risk score, as well as with individual cardiometabolic risk factors (waist circumference, blood pressure, fasting glucose, insulin, triglycerides, and high density lipoprotein cholesterol) after adjusting for physical activity and other covariates. Replacing 2 hours of television viewing with 2 hours spent performing any other sedentary activity was associated with a lower cardiometabolic risk score of 0.06-0.09 standard deviations (all 95% confidence intervals: -0.13, -0.02). No other replacements of one type of sedentary task for another were significant. Study findings indicate that television viewing has a more adverse association with cardiometabolic risk factors than other sedentary behaviors.
Authors: Whitaker KM; Buman MP; Odegaard AO; Carpenter KC; Jacobs DR; Sidney S; Pereira MA
Am J Epidemiol. 2018 02 01;187(2):181-189.
Expanded algorithm for managing patients with acute decompensated heart failure.
Heart failure is a complex disease process, the manifestation of various cardiac and noncardiac abnormalities. General treatment approaches for heart failure have remained the same over the past decades despite the advent of novel therapies and monitoring modalities. In the same vein, the readmission rates for heart failure patients remain high and portend a poor prognosis for morbidity and mortality. In this context, development and implementation of improved algorithms for assessing and treating HF patients during hospitalization remains an unmet need. We propose an expanded algorithm for both monitoring and treating patients admitted for acute decompensated heart failure with the goal to improve post-discharge outcomes and decrease rates of rehospitalizations.
Authors: Njoroge, Joyce N JN; Cheema, Baljash B; Ambrosy, Andrew P AP; Greene, Stephen J SJ; Collins, Sean P SP; Vaduganathan, Muthiah M; Mebazaa, Alexandre A; Chioncel, Ovidiu O; Butler, Javed J; Gheorghiade, Mihai M
Heart failure reviews. 2018 Jul 15;23(4):597-607. Epub 2018-01-10.
Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial.
OBJECTIVE: The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF.BACKGROUND: Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF.METHODS: PIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF 1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia.CONCLUSION: The PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF.
Authors: Velazquez, Eric J EJ; Morrow, David A DA; DeVore, Adam D AD; Ambrosy, Andrew P AP; Duffy, Carol I CI; McCague, Kevin K; Hernandez, Adrian F AF; Rocha, Ricardo A RA; Braunwald, Eugene E
American heart journal. 2018 Apr 15;198(2):145-151. Epub 2018-01-10.
Sudden cardiac death following admission for acute heart failure: adding insult to injury.
Authors: Ambrosy, Andrew P AP; Fudim, Marat M; Chioncel, Ovidiu O
European journal of heart failure. 2018 03 03;20(3):533-535. Epub 2018-01-04.
Liver Enzymes in Early to Mid-pregnancy, Insulin Resistance, and Gestational Diabetes Risk: A Longitudinal Analysis
Background: Liver enzymes may be implicated in glucose homeostasis; liver enzymes progressively change during pregnancy but longitudinal data during pregnancy in relation to insulin resistance and gestational diabetes (GDM) risk are lacking. We investigated longitudinal associations of γ-glutamyl transferase (GGT) and alanine aminotransferase (ALT) with insulin secretion and resistance markers across early to mid-pregnancy and subsequent GDM risk. Methods: Within the prospective Pregnancy Environment and Lifestyle Study cohort, 117 GDM cases were ascertained and matched to 232 non-GDM controls in a nested case-control study. Fasting blood samples were collected at two clinic visits (CV1, gestational weeks 10-13; CV2, gestational weeks 16-19). Linear mixed model and conditional logistic regression were used, adjusting for major risk factors for GDM. Results: In repeated measure analysis, after adjusting for confounders including body mass index and waist-to-hip ratio, GGT per standard deviation increment was associated with elevated fasting glucose and HOMA-IR (% change = 1.51%, 95% CI 0.56-2.46% and 7.43%, 95% CI 1.76-13.11%, respectively) and decreased adiponectin (% change = -2.86%, 95% CI-5.53 to -0.20%) from CV1 to CV2. At CV1 and CV2, GGT levels comparing the highest versus lowest quartile were associated with 3.01-fold (95% CI 1.32-6.85) and 3.51-fold (95% CI 1.37-8.97) increased risk of GDM, respectively. Progressively increased ( Authors: Zhu Y; Hedderson MM; Quesenberry CP; Feng J; Ferrara A Front Endocrinol (Lausanne). 2018;9:581. Epub 2018-10-02.
Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
Authors: Feitosa MF; Sims M; Levy D; et al.
PLoS ONE. 2018;13(6):e0198166. Epub 2018-06-18.
White matter microstructure, white matter lesions, and hypertension: An examination of early surrogate markers of vascular-related brain change in midlife
We examined imaging surrogates of white matter microstructural abnormalities which may precede white matter lesions (WML) and represent a relevant marker of cerebrovascular injury in adults in midlife. In 698 community-dwelling adults (mean age 50 years ±3.5 SD) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study, WML were identified on structural MR and fractional anisotropy (FA), representing WM microstructural integrity, was derived using Diffusion Tensor Imaging. FA and WML maps were overlaid on a parcellated T1-template, based on an expert-delineated brain atlas, which included 42 WM tract ROIs. Analyses occurred in stages: 1) WML were quantified for the different tracts (i.e., frequency, volume, volume relative to tract size); 2) the interdependence of FA in normal appearing WM (NAWM) and WML was examined across tracts; 3) associations of NAWM FA and hypertension status were assessed controlling for WML volume. In the latter analysis, both overall hypertension (i.e. hypertension vs. normotension and prehypertension vs. normotension) and hypertension categorized by antihypertensive treatment status (yes/no) and blood pressure control (e.g., diastolic <90 mmHg, systolic <140 mmHg), were assessed. WML were widely distributed across different WM tracts, however, WML volume was small. Mean NAWM FA was lower in participants with vs. participants without WML in given tracts. Hypertension was significantly associated with lower mean NAWM FA globally across tracts, both before and after adjustment for WML volume. Moreover, the magnitude of this association differed by treatment status and the level of control of the hypertension. In middle-aged adults, NAWM FA could represent a relevant marker of cerebrovascular injury when WML are minimally present.
Authors: Haight T; Meirelles O; Launer LJ; et al.
Neuroimage Clin. 2018;18:753-761. Epub 2018-03-03.
Changes in Biomarker Profile and Left Ventricular Hypertrophy Regression: Results from the Frequent Hemodialysis Network Trials
Regression of left ventricular hypertrophy (LVH) is feasible with more frequent hemodialysis (HD). We aimed to ascertain pathways associated with regression of left ventricular mass (LVM) in patients enrolled in the Frequent HD Network (FHN) trials. This was a post hoc observational cohort study. We hypothesized LVH regression with frequent HD was associated with a different cardiovascular biomarker profile. Regressors were defined as patients who achieved a reduction of more than 10% in LVM at 12 months. Progressors were defined as patients who had a minimum of 10% increase in LVM at 12 months. Among 332 randomized patients, 243 had biomarker data available. Of these, 121 patients did not progress or regress, 77 were regressors, and 45 were progressors. Mean LVM change differed between regressors and progressors by -65.6 (-74.0 to -57.2) g, p < 0.001. Regressors had a median (interquartile range) increase in dialysis frequency (from 3.0 [3.0-3.0] to 4.9 [3-5.7] per week, p = 0.001) and reductions in pre-dialysis systolic (from 149.0 [136.0-162.0] to 136.0 [123.0-152.0] mm Hg, p < 0.001) and diastolic (from 83.0 [71.0-91.0] to 76.0 [68.0-84.0] mm Hg, p < 0.001) blood pressures. Klotho levels increased in regressors versus progressors (76.9 [10.5-143.3] pg/mL, p = 0.024). Tissue inhibitors of metalloproteinase (TIMP)-2 levels fell in regressors compared to progressors (-7,853 [-14,653 to -1,052] pg/mL, p = 0.024). TIMP-1 and log (brain natriuretic -peptide [BNP]) levels also tended to fall in regressors. Changes in LVM correlated inversely with changes in klotho (r = -0.24, p = 0.014). -Conclusions: Markers of collagen turnover and changes in klotho levels are potential novel pathways associated with regression of LVH in the dialysis population, which will require further prospective validation.
Authors: Chan CT; Kaysen GA; Beck GJ; Li M; Lo J; Rocco MV; Kliger AS; FHN Trials
Am J Nephrol. 2018;47(3):208-217. Epub 2018-04-05.
Real-World Effectiveness of a Medically Supervised Weight Management Program in a Large Integrated Health Care Delivery System: Five-Year Outcomes
There are insufficient data on the long-term, nonsurgical, nonpharmacologic treatment of obesity. To determine changes in weight over 5 years in participants enrolled between April 1, 2007, and December 31, 2014, in a medically supervised weight management program at Kaiser Permanente Northern California Medical Centers. The program consisted of 3 phases: Complete meal replacement for 16 weeks; transition phase, 17 to 29 weeks; and lifestyle maintenance phase, 30 to 82 weeks. Retrospective observational study of 10,693 participants (2777 available for analysis at 5 years); no comparator group. Average change in weight from baseline to follow-up. Average age was 51.1 (standard deviation = 12.4) years, and 72.8% were women. Average baseline weight in the entire cohort was 112.9 kg (standard error [SE] = 0.23). Weight (kg) significantly changed over time: 4 months, -17.3 (SE = 0.12); 1 year, -14.2 (SE = 0.12); 2 years, -8.6 (SE = 0.14); 3 years, -6.9 (SE = 0.17); 4 years, -6.5 (SE = 0.16), and 5 years, -6.4 (SE = 0.29); p < 0.0001). In those with 5-year follow-up, weight loss between 5.0 and 9.9% below baseline occurred in 16.3% (SE = 0.004, 95% CI = 15.3% - 17.2%) and weight loss of 10.0% or more of baseline occurred in 35.2% (SE = 0.01, 95% CI = 33.6% - 36.7%). The average weight change of obese adults who participated in a medically supervised weight management program, with available 5-year data, was a statistically and clinically significant 5.8% weight loss from baseline.
Authors: Krishnaswami A; Ashok R; Sidney S; Okimura M; Kramer B; Hogan L; Sorel M; Pruitt S; Smith W
Perm J. 2018;22.
Novel Telestroke Program Improves Thrombolysis for Acute Stroke Across 21 Hospitals of an Integrated Healthcare System
Faster treatment with intravenous alteplase in acute ischemic stroke is associated with better outcomes. Starting in 2015, Kaiser Permanente Northern California redesigned its acute stroke workflow across all 21 Kaiser Permanente Northern California stroke centers to (1) follow a single standardized version of a modified Helsinki model and (2) have all emergency stroke cases managed by a dedicated telestroke neurologist. We examined the effect of Kaiser Permanente Northern California’s Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke program on door-to-needle (DTN) time, alteplase use, and symptomatic intracranial hemorrhage rates. The program was introduced in a staggered fashion from September 2015 to January 2016. We compared DTN times for a seasonally adjusted 9-month period at each center before implementation to the corresponding 9-month calendar period from the start of implementation. The primary outcome was the DTN time for alteplase administration. Secondary outcomes included rate of alteplase administrations per month, symptomatic intracranial hemorrhage, and disposition at time of discharge. This study included 310 patients treated with alteplase in the pre-EXpediting the PRrocess of Evaluating and Stopping Stroke period and 557 patients treated with alteplase in the EXpediting the PRrocess of Evaluating and Stopping Stroke period. After implementation, alteplase administrations increased to 62/mo from 34/mo at baseline (P<0.001). Median DTN time decreased to 34 minutes after implementation from 53.5 minutes prior (P<0.001), and DTN time of <60 minutes was achieved in 87.1% versus 61.0% (P<0.001) of patients. DTN times <30 minutes were much more common in the Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke period (40.8% versus 4.2% before implementation). There was no significant difference in symptomatic intracranial hemorrhage rates in the 2 periods (3.8% versus 2.2% before implementation; P=0.29). Introduction of a standardized modified Helsinki protocol across 21 hospitals using telestroke management was associated with increased alteplase administrations, significantly shorter DTN times, and no increase in adverse outcomes.
Authors: Nguyen-Huynh MN; Klingman JG; Avins AL; Rao VA; Eaton A; Bhopale S; Kim AC; Morehouse JW; Flint AC; KPNC Stroke FORCE Team
Stroke. 2018 Jan;49(1):133-139. Epub 2017-12-15.
MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease: cohort recruitment and baseline characteristics
MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease (MINERVA) was designed to answer the question of whether a novel continuous breast arterial calcification (BAC) mass score improves cardiovascular risk stratification among asymptomatic postmenopausal women. This article describes recruitment and baseline characteristics. MINERVA is a multiethnic longitudinal cohort study. The phenotype data include BAC mass by densitometry applied to digital mammograms, sociodemographic factors, self-reported medical history, medications, parental history, reproductive history, smoking, alcohol consumption, physical activity, anthropometry, ankle-brachial index, blood pressure, laboratory panel, breast volumes, cognitive function, bioelectrical impedance, habitual diet, dietary supplements, sleep, psychosocial factors, and sun exposure. A total of 5145 women aged 60 to 79 years with available digital, uncompressed mammograms were recruited from the membership of Kaiser Permanente of Northern California between October 24, 2012 and February 13, 2015 and completed a baseline clinic visit or an abbreviated phone questionnaire. Of those, 4153 underwent phlebotomy and have blood biomarkers. Overall prevalence of BAC was 26%, and it varied by age and race. The mean (SD) BAC mass was 12 (23) mg and the range 0-342 mg. MINERVA is the first cohort with a continuous measure of BAC. The cohort is large, ethnically diverse, and deeply phenotyped in terms of socioeconomic, behavioral, and clinical factors, and blood biomarkers.
Authors: Iribarren C; Quesenberry C; Molloi S; et al.
Ann Epidemiol. 2018 01;28(1):41-47.e12. Epub 2017-12-05.
Acute Kidney Injury Ascertainment Is Affected by the Use of First Inpatient Versus Outpatient Baseline Serum Creatinine
Authors: Liu KD; Hsu CY; Yang J; Tan TC; Zheng S; Ordonez JD; Go AS
Kidney Int Rep. 2018 Jan;3(1):211-215. Epub 2017-08-31.
Associations of plasma clusterin and Alzheimer’s disease-related MRI markers in adults at mid-life: The CARDIA Brain MRI sub-study
Clinical and epidemiological studies of older persons have implicated clusterin in Alzheimer’s disease (AD) pathogenesis. In the context of identifying early biomarkers of risk, we examined associations of plasma clusterin and characteristics of AD in middle-aged individuals from the community. Subjects were 639 cognitively normal individuals (mean age 50 ± 3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) Brain MRI sub-study. Clusterin was quantified using ELISA (mean 255± 31 ng/ml). Associations were assessed between clusterin and volumes of brain regions known to atrophy in early AD, including entorhinal cortex (ECV), hippocampus (HV), and medial temporal lobe (MTLV) volumes (cm3). Total brain volume (TBV) and volumes of structures affected in later AD were examined for comparison. In multivariable models, higher clusterin had a negative non-linear association with ECV (combined left and right hemispheres), and this association was influenced by the highest clusterin levels. Compared to mean clusterin, 1 and 2 standard deviation (SD) level increases in clusterin were associated with -2.1% (95% CI: -3.3,-0.9) and -7.3% (95% CI: -11.3,-3.3) lower ECV, respectively. Similar relationships were observed between clusterin and HV, although the relationship was stronger for left-side HV than the right-side. However, the association was not significant after adjusting for covariates. Negative non-linear associations between clusterin and MTLV were strongest for the left side: compared to mean clusterin, 1 and 2 SD level increases in clusterin were associated with -0.9% (95% CI: -1.9, 0.1) and -3.7% (95% CI: -7.1, -0.3) lower MTLV. There were no significant associations between clusterin and brain structures affected in later AD. In middle-aged adults unselected for AD, plasma clusterin was associated with lower volume of the entorhinal cortex, an area that atrophies early in AD. Clusterin could be informative as part of a multi-component preclinical marker for AD.
Authors: Haight T; Davatzikos C; Launer LJ; et al.
PLoS ONE. 2018;13(1):e0190478. Epub 2018-01-11.
Association Between Gestational Diabetes and Incident Maternal CKD: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Gestational diabetes mellitus (GDM) is associated with increased risk for diabetes mellitus, metabolic syndrome, and cardiovascular disease. We evaluated whether GDM is associated with incident chronic kidney disease (CKD), controlling for prepregnancy risk factors for both conditions. Prospective cohort. Of 2,747 women (aged 18-30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study in 1985 to 86, we studied 820 who were nulliparous at enrollment, delivered at least 1 pregnancy longer than 20 weeks’ gestation, and had kidney function measurements during 25 years of follow-up. GDM was self-reported by women for each pregnancy. CKD was defined as the development of estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 or urine albumin-creatinine ratio ≥ 25mg/g at any one CARDIA examination in years 10, 15, 20, or 25. HRs for developing CKD were estimated for women who developed GDM versus women without GDM using complementary log-log models, adjusting for prepregnancy age, systolic blood pressure, dyslipidemia, body mass index, smoking, education, eGFR, fasting glucose concentration, physical activity level (all measured at the CARDIA examination before the first pregnancy), race, and family history of diabetes. We explored for an interaction between race and GDM. During a mean follow-up of 20.8 years, 105 of 820 (12.8%) women developed CKD, predominantly increased urine albumin excretion (98 albuminuria only, 4 decreased eGFR only, and 3 both). There was evidence of a GDM-race interaction on CKD risk (P=0.06). Among black women, the adjusted HR for CKD was 1.96 (95% CI, 1.04-3.67) in GDM compared with those without GDM. Among white women, the HR was 0.65 (95% CI, 0.23-1.83). Albuminuria was assessed by single untimed measurements of urine albumin and creatinine. GDM is associated with the subsequent development of albuminuria among black women in CARDIA.
Authors: Dehmer EW; Phadnis MA; Gunderson EP; Lewis CE; Bibbins-Domingo K; Engel SM; Jonsson Funk M; Kramer H; Kshirsagar AV; Heiss G
Am J Kidney Dis. 2018 01;71(1):112-122. Epub 2017-11-08.
Associations between cellular aging markers and metabolic syndrome: findings from the CARDIA study
Metabolic syndrome (MetS) is thought to promote biological aging, which might lead to cardiovascular and aging-related complications. This large-scale study investigated longitudinal relationships between MetS, its components, and cellular aging markers: leukocyte mitochondrial DNA copy number (mtDNAcn) and telomere length (TL). We included 989 participants from the Coronary Artery Risk Development in Young Adults Study. MtDNAcn [study year (Y) 15, Y25] and TL (Y15, Y20, Y25) were measured via quantitative polymerase chain reaction. MetS components [waist circumference, triglycerides, high-density lipoprotein (HDL) cholesterol, systolic blood pressure, and fasting glucose] were determined (Y15, Y20, Y25). Generalized estimated equation and linear regression models, adjusting for sociodemographics and lifestyle, were used to examine associations between MetS and cellular aging at all time points, baseline MetS and 10-year changes in cellular aging, baseline cellular aging and 10-year changes in MetS, and 10-year changes in MetS and 10-year changes in cellular aging. MtDNAcn and TL were negatively associated with age [mtDNAcn unstandardized β (B) = -4.76; P < 0.001; TL B = -51.53; P < 0.001] and positively correlated (r = 0.152; P < 0.001). High triglycerides were associated with low mtDNAcn and low HDL cholesterol with short TL. Greater Y15 waist circumference (B = -7.23; P = 0.05), glucose (B = -13.29; P = 0.001), number of metabolic dysregulations (B = -7.72; P = 0.02), and MetS (B = -28.86; P = 0.006) predicted greater 10-year decrease in mtDNAcn but not TL. The 10-year increase in waist circumference was associated with 10-year telomere attrition (B = -27.61; P = 0.04). Our longitudinal data showed that some metabolic dysregulations were associated with mtDNAcn and TL decreases, possibly contributing to accelerated cellular aging but not the converse.
Authors: Révész D; Verhoeven JE; Picard M; Lin J; Sidney S; Epel ES; Penninx BWJH; Puterman E
J Clin Endocrinol Metab. 2018 01 01;103(1):148-157.
Trends in health care utilization for asthma exacerbations among diverse populations with asthma in the United States
Authors: Stone C; Iribarren C; Wu P; et al.
J Allergy Clin Immunol Pract. 2018 Jan - Feb;6(1):295-297.e5. Epub 2017-09-19.
Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study
Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited. To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice. Retrospective cohort. National U.S. Food and Drug Administration Sentinel network. Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014. Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score-matched patients starting treatment with dabigatran or warfarin. Among 25 289 patients starting dabigatran therapy and 25 289 propensity score-matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran. Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values). In matched adults with atrial fibrillation treated in practice, the incidences of stroke and bleeding with dabigatran versus warfarin were consistent with those seen in trials. The possible relationship between dabigatran and myocardial infarction warrants further investigation. U.S. Food and Drug Administration.
Authors: Go AS; Gagne JJ; et al.
Ann Intern Med. 2017 Dec 19;167(12):845-854. Epub 2017-11-14.
Detecting Risk of Low Health Literacy in Disadvantaged Populations Using Area-based Measures.
Introduction: Socio-economic status (SES) and low health literacy (LHL) are closely correlated. Both are directly associated with clinical and behavioral risk factors and healthcare outcomes. Learning healthcare systems are introducing small-area measures to address the challenges associated with maintaining patient-reported measures of SES and LHL. This study’s purpose was to measure the association between two available census block measures associated with SES and LHL. Understanding the relationship can guide the identification of a multi-purpose area based measure for delivery system use.Methods: A retrospective observational design was deployed using all US Census block groups in Utah. The principal dependent variable was a nationally-standardized health literacy score (HLS). The primary explanatory variable was a state-standardized area deprivation index (ADI). Statistical methods included linear regression and tests of association. Receiver operating characteristic (ROC) analysis was used to develop LHL criteria using ADI.Results: A significant negative association between the HLS and the ADI score remained after adjusting for area-level risk factors (β: -0.21 (95% CI: -0.22, -0.19) p < .001). Eighteen block groups (Conclusions: HLS and ADI use differing measurement criteria but are closely correlated. A state-based ADI detected additional neighborhoods with risk of LHL compared to use of a national HLS. An ADI represents a multi-purpose area measure of social determinants useful for learning health systems tailoring care.
Authors: Knighton, Andrew J; Brunisholz, Kimberly D; Savitz, Samuel T
EGEMS (Washington, DC). 2017 Dec 15;5(3):7. Epub 2017-12-15.
Population-based study of ischemic stroke risk after trauma in children and young adults
To quantify the incidence, timing, and risk of ischemic stroke after trauma in a population-based young cohort. We electronically identified trauma patients (<50 years old) from a population enrolled in a Northern Californian integrated health care delivery system (1997-2011). Within this cohort, we identified cases of arterial ischemic stroke within 4 weeks of trauma and 3 controls per case. A physician panel reviewed medical records, confirmed cases, and adjudicated whether the stroke was related to trauma. We calculated the 4-week stroke incidence and estimated stroke odds ratios (OR) by injury location using logistic regression. From 1,308,009 trauma encounters, we confirmed 52 trauma-related ischemic strokes. The 4-week stroke incidence was 4.0 per 100,000 encounters (95% confidence interval [CI] 3.0-5.2). Trauma was multisystem in 26 (50%). In 19 (37%), the stroke occurred on the day of trauma, and all occurred within 15 days. In 7/28 cases with cerebrovascular angiography at the time of trauma, no abnormalities were detected. In unadjusted analyses, head, neck, chest, back, and abdominal injuries increased stroke risk. Only head (OR 4.1, CI 1.1-14.9) and neck (OR 5.6, CI 1.03-30.9) injuries remained associated with stroke after adjusting for demographics and trauma severity markers (multisystem trauma, motor vehicle collision, arrival by ambulance, intubation). Stroke risk is elevated for 2 weeks after trauma. Onset is frequently delayed, providing an opportunity for stroke prevention during this period. However, in one-quarter of stroke cases with cerebrovascular angiography at the time of trauma, no vascular abnormality was detected.
Authors: Fox CK; Hills NK; Vinson DR; Numis AL; Dicker RA; Sidney S; Fullerton HJ
Neurology. 2017 Dec 05;89(23):2310-2316. Epub 2017-11-08.
Validity of Using Inpatient and Outpatient Administrative Codes to Identify Acute Venous Thromboembolism: The CVRN VTE Study
Administrative data are frequently used to identify venous thromboembolism (VTE) for research and quality reporting. However, the validity of these codes, particularly in outpatients, has not been well-established. To determine how well International Classification of Diseases, Ninth Revision (ICD-9) codes for VTE predict chart-confirmed acute VTE in inpatient and outpatients. We selected 4642 adults with an incident ICD-9 diagnosis of VTE between years 2004 and 2010 from the Cardiovascular Research Network Venous Thromboembolism cohort study. Medical charts were reviewed to determine validity of events. Positive predictive values (PPVs) of ICD-9 codes were calculated as the number of chart-validated VTE events divided by the number with specific VTE codes. Analyses were stratified by VTE type [pulmonary embolism (PE), deep venous thrombosis (DVT)], code position (primary, secondary), and setting [hospital/emergency department (ED), outpatient]. The PPV for any diagnosis of VTE was 64.6% for hospital/ED patients and 30.9% for outpatients. Primary diagnosis codes from hospital/ED patients were more likely to represent acute VTE than secondary diagnosis codes (78.9% vs. 44.4%, P<0.001). Primary hospital/ED codes for PE and lower extremity DVT had higher PPV than for upper extremity DVT (89.1%, 74.9%, and 58.1%, respectively). Outpatient codes were poorly predictive of acute VTE: 28.0% for PE and 53.6% for lower extremity DVT. ICD-9 codes for VTE obtained from outpatient encounters or from secondary diagnosis codes do not reliably reflect acute VTE. More accurate ways of identifying VTE in outpatients are needed before these codes can be adopted for research or policy purposes.
Authors: Fang MC; Fan D; Sung SH; Witt DM; Schmelzer JR; Steinhubl SR; Yale SH; Go AS
Med Care. 2017 12;55(12):e137-e143.
Pregnancy and Subsequent Glucose Intolerance in Women of Childbearing Age: Heeding the Early Warning Signs for Primary Prevention of Cardiovascular Disease in Women
Authors: Gunderson EP; Jaffe MG
JAMA Intern Med. 2017 12 01;177(12):1742-1744.
Trends in bisphosphonate initiation within an integrated healthcare delivery system
In the setting of changing temporal trends in the management of osteoporosis, we examined how select characteristics of new oral bisphosphonate (BP) initiators changed over time among 94,073 women within a large, integrated healthcare organization during the period 2004 to 2012. In the earlier era (2004-2007), approximately half of women younger than 65 years initiating BP therapy (47%-54%) had osteoporosis by bone mineral density (BMD) criteria, but this proportion increased sharply in the later era (2008-2012), with 55% to 81% having osteoporosis. This trend was not evident in older women (≥65 years). The proportion of younger women with prior fracture increased from 15% in 2008 to 32% in 2012, after remaining relatively stable (10%-15%) during the earlier era. Again, this trend was not observed among older women. Thus, among women younger than 65 years, we observed a marked temporal shift in initiation of BP treatment toward women at high risk (including those with prior fracture and those with osteoporosis by BMD testing) and away from those at lower risk (such as those with osteopenia and/or no prior fracture).
Authors: Hosein RJ; Lo JC; Ettinger B; Li BH; Niu F; Hui RL; Adams AL
Am J Manag Care. 2017 Dec 01;23(12):e421-e422. Epub 2017-12-01.
Short-Term Outcomes and Factors Associated With Adverse Events Among Adults Discharged From the Emergency Department After Treatment for Acute Heart Failure
Although 80% of patients with heart failure seen in the emergency department (ED) are admitted, less is known about short-term outcomes and demand for services among discharged patients. We examined adult members of a large integrated delivery system who visited an ED for acute heart failure and were discharged from January 1, 2013, through September 30, 2014. The primary outcome was a composite of repeat ED visit, hospital admission, or death within 7 days of discharge. We identified multivariable baseline patient-, provider-, and facility-level factors associated with adverse outcomes within 7 days of ED discharge using logistic regression. Among 7614 patients, mean age was 77.2 years, 51.9% were women, and 28.4% were people of color. Within 7 days of discharge, 75% had outpatient follow-up (clinic, telephone, or e-mail), 7.1% had an ED revisit, 4.7% were hospitalized, and 1.2% died. Patients who met the primary outcome were more likely to be older, smokers, have a history of hemorrhagic stroke, hypothyroidism, and dementia, and less likely to be treated in a facility with an observation unit. In multivariable analysis, higher comorbidity scores and history of smoking were associated with a higher odds of the primary outcome, whereas treatment in a facility with an observation unit and presence of outpatient follow-up within 7 days were associated with a lower odds. We identified selected hospital and patient characteristics associated with short-term adverse outcomes. Further understanding of these factors may optimize safe outpatient management in ED-treated patients with heart failure.
Authors: Sax DR; Mark DG; Hsia RY; Tan TC; Tabada GH; Go AS
Circ Heart Fail. 2017 Dec;10(12).
Contemporary rates and correlates of statin use and adherence in nondiabetic adults with cardiovascular risk factors: The KP CHAMP study
Statin therapy is highly efficacious in the prevention of fatal and nonfatal atherosclerotic events in persons at increased cardiovascular risk. However, its long-term effectiveness in practice depends on a high level of medication adherence by patients. We identified nondiabetic adults with cardiovascular risk factors between 2008 and 2010 within a large integrated health care delivery system in Northern California. Through 2013, we examined the use and adherence of newly initiated statin therapy based on data from dispensed prescriptions from outpatient pharmacy databases. Among 209,704 eligible adults, 68,085 (32.5%) initiated statin therapy during the follow-up period, with 90.4% receiving low-potency statins. At 12 and 24 months after initiating statins, 84.3% and 80.2%, respectively, were actively receiving statin therapy, but only 42% and 30%, respectively, had no gaps in treatment during those time periods. There was also minimal switching between statins or use of other lipid-lowering therapies for augmentation during follow-up. Age≥50 years, Asian/Pacific Islander race, Hispanic ethnicity, prior myocardial infarction, prior ischemic stroke, hypertension, and baseline low-density lipoprotein cholesterol>100 mg/dL were associated with higher adjusted odds, whereas female gender, black race, current smoking, dementia were associated with lower adjusted odds, of active statin treatment at 12 months after initiation. There remain opportunities for improving prevention in patients at risk for cardiovascular events. Our study identified certain patient subgroups that may benefit from interventions to enhance medication adherence, particularly by minimizing treatment gaps and discontinuation of statin therapy within the first year of treatment.
Authors: Go AS; Fan D; Sung SH; Inveiss AI; Romo-LeTourneau V; Mallya UG; Boklage S; Lo JC
Am Heart J. 2017 Dec;194:25-38. Epub 2017-08-24.
Visit-to-Visit Blood Pressure Variability in Young Adulthood and Hippocampal Volume and Integrity at Middle Age: The CARDIA Study (Coronary Artery Risk Development in Young Adults)
The aims of this study are to assess the relationships of visit-to-visit blood pressure (BP) variability in young adulthood to hippocampal volume and integrity at middle age. We used data over 8 examinations spanning 25 years collected in the CARDIA study (Coronary Artery Risk Development in Young Adults) of black and white adults (age, 18-30 years) started in 1985 to 1986. Visit-to-visit BP variability was defined as by SDBP and average real variability (ARVBP, defined as the absolute differences of BP between successive BP measurements). Hippocampal tissue volume standardized by intracranial volume (%) and integrity assessed by fractional anisotropy were measured by 3-Tesla magnetic resonance imaging at the year-25 examination (n=545; mean age, 51 years; 54% women and 34% African Americans). Mean systolic BP (SBP)/diastolic BP levels were 110/69 mm Hg at year 0 (baseline), 117/73 mm Hg at year 25, and ARVSBP and SDSBP were 7.7 and 7.9 mm Hg, respectively. In multivariable-adjusted linear models, higher ARVSBP was associated with lower hippocampal volume (unstandardized regression coefficient [standard error] with 1-SD higher ARVSBP: -0.006 [0.003]), and higher SDSBP with lower hippocampal fractional anisotropy (-0.02 [0.01]; all P<0.05), independent of cumulative exposure to SBP during follow-up. Conversely, cumulative exposure to SBP and diastolic BP was not associated with hippocampal volume. There was no interaction by sex or race between ARVSBP or SDSBP with hippocampal volume or integrity. In conclusion, visit-to-visit BP variability during young adulthood may be useful in assessing the potential risk for reductions in hippocampal volume and integrity in midlife.
Authors: Yano Y; Pletcher MJ; Launer LJ; et al.
Hypertension. 2017 12;70(6):1091-1098. Epub 2017-10-09.
Comparison of Inappropriate Shocks and Other Health Outcomes Between Single- and Dual-Chamber Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death: Results From the Cardiovascular Research Network Longitudinal Study of Implantable Cardioverter-Defibrillators
In US clinical practice, many patients who undergo placement of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death receive dual-chamber devices. The superiority of dual-chamber over single-chamber devices in reducing the risk of inappropriate ICD shocks in clinical practice has not been established. The objective of this study was to compare risk of adverse outcomes, including inappropriate shocks, between single- and dual-chamber ICDs for primary prevention. We identified patients receiving a single- or dual-chamber ICD for primary prevention who did not have an indication for pacing from 15 hospitals within 7 integrated health delivery systems in the Longitudinal Study of Implantable Cardioverter-Defibrillators from 2006 to 2009. The primary outcome was time to first inappropriate shock. ICD shocks were adjudicated for appropriateness. Other outcomes included all-cause hospitalization, heart failure hospitalization, and death. Patient, clinician, and hospital-level factors were accounted for using propensity score weighting methods. Among 1042 patients without pacing indications, 54.0% (n=563) received a single-chamber device and 46.0% (n=479) received a dual-chamber device. In a propensity-weighted analysis, device type was not significantly associated with inappropriate shock (hazard ratio, 0.91; 95% confidence interval, 0.59-1.38 [P=0.65]), all-cause hospitalization (hazard ratio, 1.03; 95% confidence interval, 0.87-1.21 [P=0.76]), heart failure hospitalization (hazard ratio, 0.93; 95% confidence interval, 0.72-1.21 [P=0.59]), or death (hazard ratio, 1.19; 95% confidence interval, 0.93-1.53 [P=0.17]). Among patients who received an ICD for primary prevention without indications for pacing, dual-chamber devices were not associated with lower risk of inappropriate shock or differences in hospitalization or death compared with single-chamber devices. This study does not justify the use of dual-chamber devices to minimize inappropriate shocks.
Authors: Peterson PN; Go AS; Masoudi FA; et al.
J Am Heart Assoc. 2017 Nov 09;6(11). Epub 2017-11-09.
Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines: Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation)
It is unclear how frequently patients with atrial fibrillation receive guideline-concordant (GC) care and whether guideline concordance is associated with improved outcomes. Using data from ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we determined how frequently patients received care that was concordant with 11 recommendations from the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation guidelines pertaining to antithrombotic therapy, rate control, and antiarrhythmic medications. We also analyzed the association between GC care and clinical outcomes at both the patient level and center level. A total of 9570 patients were included. The median age was 75 years (interquartile range, 67-82), and the median CHA2DS2-VASc score was 4 (interquartile range, 3-5). A total of 5977 patients (62.5%) received care that was concordant with all guideline recommendations for which they were eligible. Rates of GC care were higher in patients treated by providers with greater specialization in arrhythmias (60.0%, 62.4%, and 67.0% for primary care physicians, cardiologists, and electrophysiologists, respectively; P<0.001). During a median of 30 months of follow-up, patients treated with GC care had a higher risk of bleeding hospitalization (hazard ratio=1.21; P=0.021) but a similar risk of death, stroke, major bleeding, and all-cause hospitalization. Over a third of patients with atrial fibrillation in this large outpatient registry received care that differed in some respect from guideline recommendations. There was no apparent association between GC care and improved risk-adjusted outcomes.
Authors: Barnett AS; Go AS; Piccini JP; et al.
Circ Arrhythm Electrophysiol. 2017 Nov;10(11).
Association of early left ventricular dysfunction with advanced magnetic resonance white matter and gray matter brain measures: The CARDIA study
Relations between heart failure and clinically manifested stroke are well known, but the associations between heart and brain early abnormalities are not totally clear. We explore relations of subclinical brain abnormalities with early cardiac dysfunction in a large healthy middle-aged biracial cohort. The CARDIA study enrolled 5115 young adults aged 18-30 years at baseline (1985-1986). We assessed 719 Caucasian and African American participants of the CARDIA study, with echocardiograms and brain MRI at follow-up year 25 (2010-2011). Echocardiography assessed aortic root diameter; LVEF; circumferential, longitudinal, and radial deformation. Cerebral MRI DTI, and, on a subset, ASL perfusion sequences were used to assess white matter fractional anisotropy and gray matter cerebral blood flow (CBF). Linear regression explored relations between cardiac parameters and cerebral measures, adjusting for anthropometrics, risk factors, and brain constitutional variation. Mean age 50 ± 4 years, SBP 118 ± 15 mm Hg; 60% white, and 48% men. Mean CBF was 46 ± 9 mL/100 g/min, and white matter fractional anisotropy was 0.31 ± 0.02. Worse circumferential deformation and larger aortic root were related to worse white matter fractional anisotropy. Worse radial systolic deformation was related to worse CBF in multivariable models. LVEF did not relate to early brain abnormalities. In spite of no apparent effect of LV ejection fraction, early subclinical cardiac dysfunction and brain abnormalities are present and associated in middle-aged generally healthy individuals.
Authors: Armstrong AC; Muller M; Ambale-Venkatesh B; Halstead M; Kishi S; Bryan N; Sidney S; Correia LCL; Gidding SS; Launer LJ; Lima JAC
Echocardiography. 2017 11;34(11):1617-1622. Epub 2017-11-08.
25-Year Physical Activity Trajectories and Development of Subclinical Coronary Artery Disease as Measured by Coronary Artery Calcium: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
To evaluate 25-year physical activity (PA) trajectories from young to middle age and assess associations with the prevalence of coronary artery calcification (CAC). This study includes 3175 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who self-reported PA by questionnaire at 8 follow-up examinations over 25 years (from March 1985-June 1986 through June 2010-May 2011). The presence of CAC (CAC>0) at year 25 was measured using computed tomography. Group-based trajectory modeling was used to identify PA trajectories with increasing age. We identified 3 distinct PA trajectories: trajectory 1, below PA guidelines (n=1813; 57.1%); trajectory 2, meeting PA guidelines (n=1094; 34.5%); and trajectory 3, 3 times PA guidelines (n=268; 8.4%). Trajectory 3 participants had higher adjusted odds of CAC>0 (adjusted odds ratio [OR], 1.27; 95% CI, 0.95-1.70) vs those in trajectory 1. Stratification by race showed that white participants who engaged in PA 3 times the guidelines had higher odds of developing CAC>0 (OR, 1.80; 95% CI, 1.21-2.67). Further stratification by sex showed higher odds for white males (OR, 1.86; 95% CI, 1.16-2.98), and similar but nonsignificant trends were noted for white females (OR, 1.71; 95% CI, 0.79-3.71). However, no such higher odds of CAC>0 for trajectory 3 were observed for black participants. White individuals who participated in 3 times the recommended PA guidelines over 25 years had higher odds of developing coronary subclinical atherosclerosis by middle age. These findings warrant further exploration, especially by race, into possible biological mechanisms for CAC risk at very high levels of PA.
Authors: Laddu DR; Rana JS; Quesenberry CP; Sidney S; et al.
Mayo Clin Proc. 2017 Nov;92(11):1660-1670. Epub 2017-10-16.
Aetiology, timing and clinical predictors of early vs. late readmission following index hospitalization for acute heart failure: insights from ASCEND-HF.
AIMS: Patients hospitalized for heart failure (HF) are at high risk for 30-day readmission. This study sought to examine the timings and causes of readmission within 30 days of an HF hospitalization.METHODS AND RESULTS: Timing and cause of readmission in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial were assessed. Early and late readmissions were defined as admissions occurring within 0-7 days and 8-30 days post-discharge, respectively. Patients who died in hospital or remained hospitalized at day 30 post-randomization were excluded. Patients were compared by timing and cause of readmission. Logistic and Cox proportional hazards regression analyses were used to identify independent risk factors for early vs. late readmission and associations with 180-day outcomes. Of the 6584 patients (92%) in the ASCEND-HF population included in this analysis, 751 patients (11%) were readmitted within 30 days for any cause. Overall, 54% of readmissions were for non-HF causes. The median time to rehospitalization was 11 days (interquartile range: 6-18 days) and 33% of rehospitalizations occurred by day 7. Rehospitalization within 30 days was independently associated with increased risk for 180-day all-cause death [hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.93-2.94; P CONCLUSIONS: In this hospitalized HF trial population, a significant majority of 30-day readmissions were for non-HF causes and one-third of readmissions occurred in the first 7 days. Early and late readmissions within the 30-day timeframe were associated with similarly increased risk for death. Continued efforts to optimize multidisciplinary transitional care are warranted to improve rates of early readmission.
Authors: Fudim, Marat M; O'Connor, Christopher M CM; Dunning, Allison A; Ambrosy, Andrew P AP; Armstrong, Paul W PW; Coles, Adrian A; Ezekowitz, Justin A JA; Greene, Stephen J SJ; Metra, Marco M; Starling, Randall C RC; Voors, Adriaan A AA; Hernandez, Adrian F AF; Michael Felker, G G; Mentz, Robert J RJ
European journal of heart failure. 2018 02 03;20(2):304-314. Epub 2017-10-29.
Lessons learned in acute heart failure.
Acute heart failure (HF) is a global pandemic with more than one million admissions to hospital annually in the US and millions more worldwide. Post-discharge mortality and readmission rates remain unchanged and unacceptably high. Although recent drug development programmes have failed to deliver novel therapies capable of reducing cardiovascular morbidity and mortality in patients hospitalized for worsening chronic HF, hospitalized HF registries and clinical trial databases have generated a wealth of information improving our collective understanding of the HF syndrome. This review will summarize key insights from clinical trials in acute HF and hospitalized HF registries over the last several decades, focusing on improving the management of patients with HF and reduced ejection fraction.
Authors: Cheema, Baljash B; Ambrosy, Andrew P AP; Kaplan, Rachel M RM; Senni, Michele M; Fonarow, Gregg C GC; Chioncel, Ovidiu O; Butler, Javed J; Gheorghiade, Mihai M
European journal of heart failure. 2018 04 03;20(4):630-641. Epub 2017-10-29.
Pre-discharge and early post-discharge troponin elevation among patients hospitalized for heart failure with reduced ejection fraction: findings from the ASTRONAUT trial.
AIMS: Troponin levels are commonly elevated among patients hospitalized for heart failure (HF), but the prevalence and prognostic significance of early post-discharge troponin elevation are unclear. This study sought to describe the frequency and prognostic value of pre-discharge and post-discharge troponin elevation, including persistent troponin elevation from the inpatient to outpatient settings.METHODS AND RESULTS: The ASTRONAUT trial (NCT00894387; https://www.clinicaltrials.gov) enrolled hospitalized HF patients with ejection fraction ≤40% and measured troponin I prior to discharge (i.e. study baseline) and at 1-month follow-up in a core laboratory (elevation defined as >0.04 ng/mL). This analysis included 1469 (91.0%) patients with pre-discharge troponin data. Overall, 41.5% and 29.9% of patients had elevated pre-discharge [median: 0.09 ng/mL; interquartile range (IQR): 0.06-0.19 ng/mL] and 1-month (median: 0.09 ng/mL; IQR: 0.06-0.15 ng/mL) troponin levels, respectively. Among patients with pre-discharge troponin elevation, 60.4% had persistent elevation at 1 month. After adjustment, pre-discharge troponin elevation was not associated with 12-month clinical outcomes. In contrast, 1-month troponin elevation was independently predictive of increased all-cause mortality [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.18-2.13] and cardiovascular mortality or HF hospitalization (HR 1.28, 95% CI 1.03-1.58) at 12 months. Associations between 1-month troponin elevation and outcomes were similar among patients with newly elevated (i.e. normal pre-discharge) and persistently elevated levels (interaction P ≥ 0.16). The prognostic value of 1-month troponin elevation for 12-month mortality was driven by a pronounced association among patients with coronary artery disease (interaction P = 0.009).CONCLUSIONS: In this hospitalized HF population, troponin I elevation was common during index hospitalization and at 1-month follow-up. Elevated troponin I level at 1 month, but not pre-discharge, was independently predictive of increased clinical events at 12 months. Early post-discharge troponin I measurement may offer a practical means of risk stratification and should be investigated as a therapeutic target.
Authors: Greene, Stephen J SJ; Butler, Javed J; Fonarow, Gregg C GC; Subacius, Haris P HP; Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; Triggiani, Marco M; Solomon, Scott D SD; Lewis, Eldrin F EF; Maggioni, Aldo P AP; Böhm, Michael M; Chioncel, Ovidiu O; Nodari, Savina S; Senni, Michele M; Zannad, Faiez F; Gheorghiade, Mihai M;
European journal of heart failure. 2018 02 03;20(2):281-291. Epub 2017-10-17.
Cohort Study of ECG Left Ventricular Hypertrophy Trajectories: Ethnic Disparities, Associations With Cardiovascular Outcomes, and Clinical Utility
ECG left ventricular hypertrophy (LVH) is a well-known predictor of cardiovascular disease. However, no prior study has characterized patterns of presence/absence of ECG LVH (“ECG LVH trajectories”) across the adult lifespan in both sexes and across ethnicities. We examined: (1) correlates of ECG LVH trajectories; (2) the association of ECG LVH trajectories with incident coronary heart disease, transient ischemic attack, ischemic stroke, hemorrhagic stroke, and heart failure; and (3) reclassification of cardiovascular disease risk using ECG LVH trajectories. We performed a cohort study among 75 412 men and 107 954 women in the Northern California Kaiser Permanente Medical Care Program who had available longitudinal exposures of ECG LVH and covariates, followed for a median of 4.8 (range <1-9.3) years. ECG LVH was measured by Cornell voltage-duration product. Adverse trajectories of ECG LVH (persistent, new development, or variable pattern) were more common among blacks and Native American men and were independently related to incident cardiovascular disease with hazard ratios ranging from 1.2 for ECG LVH variable pattern and transient ischemic attack in women to 2.8 for persistent ECG LVH and heart failure in men. ECG LVH trajectories reclassified 4% and 7% of men and women with intermediate coronary heart disease risk, respectively. ECG LVH trajectories were significant indicators of coronary heart disease, stroke, and heart failure risk, independently of level and change in cardiovascular disease risk factors, and may have clinical utility.
Authors: Iribarren C; Round AD; Lu M; Okin PM; McNulty EJ
J Am Heart Assoc. 2017 Oct 05;6(10). Epub 2017-10-05.
Sex hormones and brain volumes in a longitudinal study of middle-aged men in the CARDIA study
Several findings suggest that testosterone (T) is neuroprotective and that declining T levels during aging are associated with cognitive and brain pathologies; however, little is known on T and brain health in middle-age. We examined the relationships of total T, bioavailable T, and sex hormone binding globulin (SHBG) levels with total and regional gray matter (GM) and white matter (WM) volumes in middle-aged men. We also evaluated the association of sex hormone levels with cognitive function. Analysis included 267 community-dwelling men participating in the Coronary Artery Risk Development in Young Adults (CARDIA) brain magnetic resonance imaging (MRI) substudy. Total T, bioavailable T, and SHBG levels were measured at three times from the 2nd to 4th decade of life; brain volumes were measured at the ages of 42-56. Associations were estimated using linear regression models, adjusted for several potential confounders. Higher SHBG levels were associated with greater total WM volume (+3.15 cm3 [95% confidence interval [CI] = 0.01, 6.28] per one standard deviation higher SHBG). Higher SHBG levels were associated with lower total and regional GM volumes overall and significantly with smaller parietal GM volume (-0.96 cm3 [95%CI = -1.71, -0.21]). T levels were not related to brain volumes. Neither T nor SHBG levels were associated with cognitive function. Results suggest a role for SHBG in structural brain outcomes in men and emphasize the value of investigating SHBG levels as modulators of sex hormone and metabolic pathways regulating brain and behavioral characteristics in men.
Authors: Elbejjani M; Schreiner PJ; Siscovick DS; Sidney S; Lewis CE; Bryan NR; Launer LJ
Brain Behav. 2017 Oct;7(10):e00765. Epub 2017-09-20.
Intake of niacin, folate, vitamin B-6, and vitamin B-12 through young adulthood and cognitive function in midlife: the Coronary Artery Risk Development in Young Adults (CARDIA) study
Background: Epidemiologic evidence regarding niacin, folate, vitamin B-6, and vitamin B-12 intake in relation to cognitive function is limited, especially in midlife.Objective: We hypothesize that higher intake of these B vitamins in young adulthood is associated with better cognition later in life.Design: This study comprised a community-based multicenter cohort of black and white men and women aged 18-30 y in 1985-1986 (year 0, i.e., baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3136). We examined participants’ CARDIA diet history at years 0, 7, and 20 to assess nutrient intake, including dietary and supplemental B vitamins. We measured cognitive function at year 25 (mean ± SD age: 50 ± 4 y) through the use of the Rey Auditory Verbal Learning Test (RAVLT) for verbal memory, the Digit Symbol Substitution Test (DSST) for psychomotor speed, and a modified Stroop interference test for executive function. Higher RAVLT and DSST scores and a lower Stroop score indicated better cognitive function. We used multivariable-adjusted linear regressions to estimate mean differences in cognitive scores and 95% CIs.Results: Comparing the highest quintile with the lowest (quintile 5 compared with quintile 1), cumulative total intake of niacin was significantly associated with 3.92 more digits on the DSST (95% CI: 2.28, 5.55; P-trend < 0.01) and 1.89 points lower interference score on the Stroop test (95% CI: -3.10, -0.68; P-trend = 0.05). Total folate was associated with 2.56 more digits on the DSST (95% CI: 0.82, 4.31; P-trend = 0.01). We also found that higher intakes of vitamin B-6 (quartile 5 compared with quartile 1: 2.62; 95% CI: 0.97, 4.28; P-trend = 0.02) and vitamin B-12 (quartile 5 compared with quartile 1: 2.08; 95% CI: 0.52, 3.65; P-trend = 0.02) resulted in better psychomotor speed measured by DSST scores.Conclusion: Higher intake of B vitamins throughout young adulthood was associated with better cognitive function in midlife.
Authors: Qin B; Xun P; Jacobs DR; Zhu N; Daviglus ML; Reis JP; Steffen LM; Van Horn L; Sidney S; He K
Am J Clin Nutr. 2017 Oct;106(4):1032-1040. Epub 2017-08-02.
Thyroid function in end stage renal disease and effects of frequent hemodialysis
End-stage renal disease (ESRD) is associated with perturbations in thyroid hormone concentrations and an increased prevalence of hypothyroidism. Few studies have examined the effects of hemodialysis dose or frequency on endogenous thyroid function. Within the Frequent Hemodialysis Network (FHN) trials, we examined the prevalence of hypothyroidism in patients with ESRD. Among those with endogenous thyroid function (without overt hyper/hypothyroidism or thyroid hormone supplementation), we examined the association of thyroid hormone concentration with multiple parameters of self-reported health status, and physical and cognitive performance, and the effects of hemodialysis frequency on serum thyroid stimulating hormone (TSH), free thyroxine (FT4), and free tri-iodothyronine (FT3) levels. Conventional thrice-weekly hemodialysis was compared to in-center (6 d/wk) hemodialysis (Daily Trial) and Nocturnal (6 nights/wk) home hemodialysis (Nocturnal Trial) over 12 months. Among 226 FHN Trial participants, the prevalence of hypothyroidism was 11% based on thyroid hormone treatment and/or serum TSH ≥8 mIU/mL. Among the remaining 195 participants (147 Daily, 48 Nocturnal) with endogenous thyroid function, TSH concentrations were modestly (directly) correlated with age (r = 0.16, P = 0.03) but not dialysis vintage. Circulating thyroid hormone levels were not associated with parameters of health status or physical and cognitive performance. Furthermore, frequent in-center and nocturnal hemodialysis did not significantly change (baseline to month 12) TSH, FT4, or FT3 concentrations in patients with endogenous thyroid function. Among patients receiving hemodialysis without overt hyper/hypothyroidism or thyroid hormone treatment, thyroid indices were not associated with multiple measures of health status and were not significantly altered with increased dialysis frequency.
Authors: Lo JC; Beck GJ; Kaysen GA; Chan CT; Kliger AS; Rocco MV; Li M; Chertow GM; FHN Study
Hemodial Int. 2017 Oct;21(4):534-541. Epub 2017-03-16.
Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes: ORBIT-AF Registry
Diabetes is a well-established risk factor for thromboembolism in patients with atrial fibrillation (AF), but less is known about how diabetes influences outcomes among AF patients. This study assessed whether symptoms, health status, care, and outcomes differ between AF patients with and without diabetes. The cohort study included 9,749 patients from the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, a prospective, nationwide, outpatient registry of patients with incident and prevalent AF. Outcomes included symptoms, health status, and AF treatment, as well as 2-year risk of death, hospitalization, thromboembolic events, heart failure (HF), and AF progression. Patients with diabetes (29.5%) were younger, more likely to have hypertension, chronic kidney disease, HF, coronary heart disease, and stroke. Compared to patients without diabetes, patients with diabetes also had a lower Atrial Fibrillation Effects on Quality of Life score of 80 (interquartile range [IQR]: 62.5 to 92.6) versus 82.4 (IQR: 67.6 to 93.5; p = 0.025) and were more likely to receive anticoagulation (p < 0.001). Diabetes was associated with higher mortality risk, including overall (adjusted hazard ratio [aHR]: 1.63; 95% confidence interval [CI]: 1.04 to 2.56, for age <70 years vs. aHR: 1.25; 95% CI: 1.09 to 1.44, for age ≥70 years) and cardiovascular (CV) mortality (aHR: 2.20; 95% CI: 1.22 to 3.98, for age <70 years vs. 1.24; 95% CI: 1.02 to 1.51 for age ≥70 years). Diabetes conferred a higher risk of non-CV death, sudden cardiac death, hospitalization, CV hospitalization, and non-CV and nonbleeding-related hospitalization, but no increase in risks of thromboembolic events, bleeding-related hospitalization, new-onset HF, and AF progression. Among AF patients, diabetes was associated with worse AF symptoms and lower quality of life, and increased risk of death and hospitalizations, but not thromboembolic or bleeding events.
Authors: Echouffo-Tcheugui JB; Go AS; Fonarow GC; et al.
J Am Coll Cardiol. 2017 Sep 12;70(11):1325-1335.
Treatment Effectiveness in Heart Failure with Comorbidity: Lung Disease and Kidney Disease
To assess the clinical effectiveness of beta-blocker therapy in individuals with heart failure (HF) and chronic lung disease and of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) in individuals with HF and chronic kidney disease. Retrospective cohort study. Community. Individuals with HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We undertook separate new-user cohort studies to assess the effectiveness of beta-blocker therapy in treating HF and chronic lung disease and ACE-Is and ARBs in treating HF and chronic kidney disease (CKD). Individuals with a chronic lung disease diagnosis were included in the group with HF and chronic lung disease (International Classification of Diseases, Ninth Revision, codes 490-496, 518). Individuals with an estimated glomerular filtration rate less than 60 mL/min per 1.73 m2 were included in the group with HF and CKD. The clinical outcomes of interest were death from any cause, hospitalization for HF, and hospitalization for any reason. We fitted pooled logistic marginal structural models using inverse probability weighting, stratified according to HF type. For individuals with HFrEF with chronic lung disease, beta-blocker therapy was protective against death (relative risk (RR) = 0.58, 95% confidence interval (CI) = 0.44-0.77) and hospitalization for HF (RR = 0.78, 95% CI = 0.60-1.00). For those with HFpEF, no statistically significant associations between beta-blocker therapy use and any of the outcomes were observed. We found ACE-I and ARB use to be protective against all three outcomes of interest in individuals with HFrEF (death from any cause: RR = 0.60, 95% 0.40-0.91; hospitalization for HF: RR = 0.43, 95% CI = 0.28-0.67; hospitalization for any reason: RR = 0.63, 95% CI = 0.45-0.89, respectively) and those with HFpEF (death from any cause: RR = 0.52, 95% CI = 0.33-0.81; hospitalization for HF: RR = 0.35, 95% CI = 0.18-0.68; hospitalization for any reason: RR = 0.67, 95% CI = 0.47-0.95). Large observational studies may allow for identification of important subgroups of individuals with HF that might benefit from existing treatment approaches. Our findings may also better inform the design of more-definitive future observational studies and randomized trials.
Authors: Gurwitz JH; Magid DJ; Smith DH; Tabada GH; Sung SH; Allen LA; McManus DD; Goldberg RJ; Tisminetzky M; Go AS
J Am Geriatr Soc. 2017 Sep 05.
Racial and ethnic differences in hip fracture outcomes in men
To examine temporal trends and racial/ethnic differences in hip fracture incidence and mortality outcome in older men. Retrospective cohort study. We ascertained men 50 years or older with a hip fracture during 2000 to 2010 in a diverse northern California healthcare population. Age, comorbidity index, hip fracture incidence, and all-cause mortality up to 12 months post fracture were examined and compared by race/ethnicity. A total of 6247 men (aged 79.3 ± 9.8 years) experienced a hip fracture during 2000 to 2010: 81.4% were white, 7.5% Hispanic, 3.8% black, and 3.9% Asian. The age-adjusted annual incidence of hip fracture averaged 127 per 100,000, ranging from 116 to 139 per 100,000 during this period. In 2010, the age-adjusted incidence of hip fracture was highest among white men (137), followed by Hispanic (98) and black (80), and was lowest among Asian men (45 per 100,000). Mortality following hip fracture was 11.1%, 19.8%, 25.4%, and 32.9%, within 1, 3, 6, and 12 months, respectively, and increased with age. One-year mortality was similar for whites (33.7%), blacks (32.4%), and Hispanics (31.1%), but lower for Asians (23.1%; P <.05). Adjusting for age, comorbidity index, and calendar year, Asians remained at lower mortality risk compared with whites (adjusted odds ratio, 0.62; 95% confidence interval, 0.45-0.86). Although hip fracture rates were largely stable among older men, contemporary rates of hip fracture were highest for white and lowest for Asian men. One-year mortality was similar for white, black, and Hispanic men, but significantly lower for Asians. Future studies should investigate factors underlying observed ethnic differences in fracture outcome among US men.
Authors: Liu LH; Chandra M; Gonzalez JR; Lo JC
Am J Manag Care. 2017 Sep;23(9):560-564.
Oral anticoagulation management in patients with atrial fibrillation undergoing cardiac implantable electronic device implantation
Oral anticoagulation (OAC) therapy is associated with increased periprocedural risks after cardiac implantable electronic device (CIED) implantation. Patterns of anticoagulation management involving non-vitamin K antagonist oral anticoagulants (NOACs) have not been characterized. Anticoagulation strategies and outcomes differ by anticoagulant type in patients undergoing CIED implantation. Using the nationwide Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we assessed how atrial fibrillation (AF) patients undergoing CIED implantation were cared for and their subsequent outcomes. Outcomes were compared by oral anticoagulant therapy (none, warfarin, or NOAC) as well as by anticoagulation interruption status. Among 9129 AF patients, 416 (5%) underwent CIED implantation during a median follow-up of 30 months (interquartile range, 24-36). Of these, 60 (14%) had implantation on a NOAC. Relative to warfarin therapy, those on a NOAC were younger (70.5 years [range, 65-77.5 years] vs 77 years [range, 70-82 years]), had less valvular heart disease (15.0% vs 31.3%), higher creatinine clearance (67.3 [range, 59.7-99.0] vs 65.8 [range, 50.0-91.6]), were more likely to have persistent AF (26.7% vs 22.9%), and use concomitant aspirin (51.7% vs 35.2%). OAC therapy was commonly interrupted for CIED in 64% (n = 183 of 284) of warfarin patients and 65% (n = 39 of 60) of NOAC patients. Many interrupted patients received intravenous bridging anticoagulation: 33/183 (18%) interrupted warfarin and 4/39 (10%) interrupted NOAC patients. Thirty-day periprocedure bleeding and stroke adverse events were infrequent. Management of anticoagulation among AF patients undergoing CIED implantation is highly variable, with OAC being interrupted in more than half of both warfarin- and NOAC-treated patients. Bleeding and stroke events were infrequent in both warfarin and NOAC-treated patients.
Authors: Black-Maier E; Peterson ED; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators; et al.
Clin Cardiol. 2017 Sep;40(9):746-751. Epub 2017-05-19.
Lipoprotein(a) and Risk of Myocardial Infarction and Death in Chronic Kidney Disease: Findings From the CRIC Study (Chronic Renal Insufficiency Cohort)
To investigate the effect of LPA gene variants and renal function on lipoprotein(a) [Lp(a)] levels in people with chronic kidney disease and determine the association between elevated Lp(a) and myocardial infarction and death in this setting. The CRIC Study (Chronic Renal Insufficiency Cohort) is an ongoing prospective study of 3939 participants with chronic kidney disease. In 3635 CRIC participants with genotype data, carriers of the rs10455872 or rs6930542 variants had a higher median Lp(a) level (mg/dL) compared with noncarriers (73 versus 23; P<0.001 and 56 versus 22; P<0.001, respectively). The 3744 participants (55% male and 41% non-Hispanic White) with available baseline Lp(a) levels were stratified into quartiles of baseline Lp(a) (mg/dL): <9.8, 9.8 to 26.0, 26.1 to 61.3, and >61.3. There were 315 myocardial infarctions and 822 deaths during a median follow-up of 7.5 years. The second quartile had the lowest event rate. After adjusting for potential confounders and using a Cox proportional hazards model, the highest quartile of Lp(a) was associated with increased risk of myocardial infarction (hazard ratio, 1.49; 95% confidence interval, 1.05-2.11), death (hazard ratio, 1.28; 95% confidence interval, 1.05-1.57), and the composite outcome (hazard ratio, 1.29; 95% confidence interval, 1.07-1.56) compared with the second quartile of Lp(a). Among adults with chronic kidney disease, elevated Lp(a) is independently associated with myocardial infarction and death. Future studies exploring pharmacological Lp(a) reduction in this population are warranted.
Authors: Bajaj A; Go AS; Rader DJ; et al.
Arterioscler Thromb Vasc Biol. 2017 Aug 24.
Marijuana Use and Estimated Glomerular Filtration Rate in Young Adults
Marijuana use has become more widely accepted in the United States and has been legalized in many areas. Although it is biologically plausible that marijuana could affect kidney function, epidemiologic data are lacking. We conducted a cohort study among young adults with preserved eGFR (i.e., eGFR≥60 ml/min per 1.73 m2) using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. At scheduled examinations occurring every 5 years and starting at study year 10 (calendar years, 1995-1996), cystatin C was collected over a 10-year period, and urine albumin-to-creatinine ratio was collected over a 15-year period. We investigated the cross-sectional association between current and cumulative marijuana use (in marijuana-years; one marijuana-year equals 365 days of marijuana use) and eGFR by cystatin C (eGFRcys) at year 10. In longitudinal analyses, we investigated the association between cumulative marijuana use and eGFRcys change and rapid (≥3%/year) eGFRcys decline over two 5-year intervals and prevalent albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) over a 15-year period. Past or current marijuana use was reported by 83% (3131 of 3765) of the cohort, and the mean eGFRcys was 111 ml/min per 1.73 m2 at year 10. Over the following 10 years, 504 had rapid eGFRcys decline, and over the following 15 years, 426 had prevalent albuminuria. Compared with no use, daily current use and ≥5 marijuana-years of cumulative use were associated with lower eGFRcys at year 10: -4.5% (95% confidence interval, -8.1 to -0.7%; P=0.02) and -3.0% (95% confidence interval, -5.6 to -0.4%; P=0.03), respectively. Marijuana use was not significantly associated with eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria. Although we identified a modest cross-sectional association between higher marijuana exposure and lower eGFRcys among young adults with preserved eGFR, our findings were largely null and did not demonstrate a longitudinal association between marijuana use and eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_24_CJASNPodcast_17_10.mp3.
Authors: Ishida JH; Auer R; Vittinghoff E; Pletcher MJ; Reis JP; Sidney S; Johansen KL; Bibbins-Domingo K; Peralta CA; Shlipak MG
Clin J Am Soc Nephrol. 2017 Aug 24.
Cardiovascular health in young adulthood and structural brain MRI in midlife: The CARDIA study
To examine the association between the American Heart Association (AHA) Life’s Simple 7 (LS7) metric and brain structure. We determined cardiovascular health (CVH) according to the AHA LS7, assigning 0, 1, or 2 points for meeting poor, intermediate, or ideal criteria for the 7 components (range 0-14) at baseline (aged 18-30 years in 1985-1986) and year 25 follow-up examination for 518 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) brain MRI substudy. Visit-based CVH score and average score was assessed in relation to percent of intracranial volume of normal tissue of the whole brain, gray matter, and white matter, and abnormal tissue volume of white matter at year 25 using multivariable linear, logistic, and quantile regression, after adjustment for age, sex, race, field center, educational attainment, and alcohol consumption. Mean percentage of whole brain volume, normal gray matter, and normal white matter was 81.3% (±2.5), 42.9% (±2.0), and 38.4% (±2.0). Greater CVH score at baseline (per each additional point at year 0: 0.1%, 95% confidence limits 0.01-0.3; p < 0.05) and average CVH score were associated with greater percentage of whole brain volume (per each additional point in average score: 0.2%, 95% confidence limits 0.04-0.3; p < 0.05). Visit-based or average CVH score was not significantly associated with normal gray or white matter volume or abnormal white matter volume. Maintaining ideal levels of cardiovascular health, determined by the LS7, in young adulthood is associated with greater whole brain volume in middle age but not regional differences in structure.
Authors: Bancks MP; Allen NB; Dubey P; Launer LJ; Lloyd-Jones DM; Reis JP; Sidney S; Yano Y; Schreiner PJ
Neurology. 2017 Aug 15;89(7):680-686. Epub 2017-07-19.
Real-world dosing of evidence-based medications for heart failure: embracing guideline recommendations and clinical judgement.
Authors: Ambrosy, Andrew P AP; Gheorghiade, Mihai M
European journal of heart failure. 2017 11 03;19(11):1424-1426. Epub 2017-08-08.
Clinical profiles in acute heart failure: one size fits all or not at all?
Authors: Ambrosy, Andrew P AP; Gheorghiade, Mihai M
European journal of heart failure. 2017 10 03;19(10):1255-1257. Epub 2017-08-08.
Blood Pressure and Risk of Cardiovascular Events in Patients on Chronic Hemodialysis: The CRIC Study (Chronic Renal Insufficiency Cohort)
We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis patients when SBP is measured outside of the dialysis unit (out-of-dialysis-unit-SBP), despite there being a U-shaped association between SBP measured at the dialysis unit (dialysis-unit-SBP) with risk of mortality. Here, we explored the relationship between SBP with cardiovascular events, which has important treatment implications but has not been well elucidated. Among 383 hemodialysis participants enrolled in the prospective CRIC study (Chronic Renal Insufficiency Cohort), multivariable splines and Cox models were used to study the association between SBP and adjudicated cardiovascular events (heart failure, myocardial infarction, ischemic stroke, and peripheral artery disease), controlling for differences in demographics, cardiovascular disease risk factors, and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (r=0.34; P<0.001). We noted a U-shaped association of dialysis-unit-SBP and risk of cardiovascular events, with the nadir risk between 140 and 170 mm Hg. In contrast, there was a linear stepwise association between out-of-dialysis-unit-SBP with risk of cardiovascular events. Participants with out-of-dialysis-unit-SBP ≥128 mm Hg (top 2 quartiles) had >2-fold increased risk of cardiovascular events compared with those with out-of-dialysis-unit-SBP ≤112 mm Hg (3rd SBP quartile: adjusted hazard ratio, 2.08 [95% confidence interval, 1.12-3.87] and fourth SBP quartile: adjusted hazard ratio, 2.76 [95% confidence interval, 1.42-5.33]). In conclusion, among hemodialysis patients, although there is a U-shaped (paradoxical) association of dialysis-unit-SBP and risk of cardiovascular disease, there is a linear association of out-of-dialysis-unit-SBP with risk of cardiovascular disease. Out-of-dialysis-unit blood pressure provides key information and may be an important therapeutic target.
Authors: Bansal N; Go AS; CRIC Study Investigators*; et al.
Hypertension. 2017 08;70(2):435-443. Epub 2017-07-03.
Racial/Ethnic Differences in Left Ventricular Structure and Function in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort
Chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease (CVD) and it is especially common among Blacks. Left ventricular hypertrophy (LVH) is an important subclinical marker of CVD, but there are limited data on racial variation in left ventricular structure and function among persons with CKD. In a cross-sectional analysis of the Chronic Renal Insufficiency Cohort Study, we compared the prevalence of different types of left ventricular remodeling (concentric hypertrophy, eccentric hypertrophy, and concentric remodeling) by race/ethnicity. We used multinomial logistic regression to test whether race/ethnicity associated with different types of left ventricular remodeling independently of potential confounding factors. We identified 1,164 non-Hispanic Black and 1,155 non-Hispanic White participants who completed Year 1 visits with echocardiograms that had sufficient data to categorize left ventricular geometry type. Compared to non-Hispanic Whites, non-Hispanic Blacks had higher mean left ventricular mass index (54.7 ± 14.6 vs. 47.4 ± 12.2 g/m2.7; P < 0.0001) and prevalence of concentric LVH (45.8% vs. 24.9%). In addition to higher systolic blood pressure and treatment with >3 antihypertensive medications, Black race/ethnicity was independently associated with higher odds of concentric LVH compared to White race/ethnicity (odds ratio: 2.73; 95% confidence interval: 2.02, 3.69). In a large, diverse cohort with CKD, we found significant differences in left ventricular mass and hypertrophic morphology between non-Hispanic Blacks and Whites. Future studies will evaluate whether higher prevalence of LVH contribute to racial/ethnic disparities in cardiovascular outcomes among CKD patients.
Authors: Ahmad FS; Go AS; CRIC Study Investigators; et al.
Am J Hypertens. 2017 Aug 01;30(8):822-829.
Heterogeneity in national U.S. mortality trends within heart disease subgroups, 2000-2015
The long-term downward national U.S. trend in heart disease-related mortality slowed substantially during 2011-2014 before turning upward in 2015. Examining mortality trends in the major subgroups of heart disease may provide insight into potentially more targeted and effective prevention and treatment approaches to promote favorable trajectories. We examined national trends between 2000 and 2015 in mortality attributed to major heart disease subgroups including ischemic heart disease, heart failure, and all other types of heart disease. Using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER) data system, we determined national trends in age-standardized mortality rates attributed to ischemic heart disease, heart failure, and other heart diseases from January 1, 2000, to December 31, 2011, and from January 1, 2011, to December 31, 2015. Annual rate of changes in mortality attributed to ischemic heart disease, heart failure, and other heart diseases for 2000-2011 and 2011-2015 were compared. Death attributed to ischemic heart disease declined from 2000 to 2015, but the rate of decline slowed from 4.96% (95% confidence interval 4.77%-5.15%) for 2000-2011 to 2.66% (2.00%-3.31%) for 2011-2015. In contrast, death attributed to heart failure and all other causes of heart disease declined from 2000 to 2011 at annual rates of 1.94% (1.77%-2.11%) and 0.64% (0.44%-0.82%) respectively, but increased from 2011 to 2015 at annual rates of 3.73% (3.21% 4.26%) and 1.89% (1.33-2.46%). Differences in 2000-2011 and 2011-2015 decline rates were statistically significant for all 3 endpoints overall, by sex, and all race/ethnicity groups except Asian/Pacific Islanders (heart failure only significant) and American Indian/Alaskan Natives. While the long-term decline in death attributed to heart disease slowed between 2011 and 2014 nationally before turning upward in 2015, heterogeneity existed in the trajectories attributed to heart disease subgroups, with ischemic heart disease mortality continuing to decline while death attributed to heart failure and other heart diseases switched from a downward to upward trend. While systematic efforts to prevent and treat ischemic heart disease continue to be effective, urgent attention is needed to address the challenge of heart failure.
Authors: Sidney S; Quesenberry CP; Jaffe MG; Sorel M; Go AS; Rana JS
BMC Cardiovasc Disord. 2017 07 18;17(1):192. Epub 2017-07-18.
Building the case for aerobic exercise in ambulatory patients with heart failure and a reduced ejection fraction.
Authors: Cerbin, Lukasz P LP; Ambrosy, Andrew P AP; Mentz, Robert J RJ
American heart journal. 2017 Oct 03;192(2):e3. Epub 2017-07-15.
Contribution of medications and risk factors to QTc interval lengthening in the atherosclerosis risk in communities (ARIC) study.
RATIONALE, AIMS, AND OBJECTIVES: Prolongation of the corrected QT (QTc) interval is associated with increased morbidity and mortality. The association between QTc interval-prolonging medications (QTPMs) and risk factors with magnitude of QTc interval lengthening is unknown. We examined the contribution of risk factors alone and in combination with QTPMs to QTc interval lengthening.METHOD: The Atherosclerosis Risk in Communities study assessed 15 792 participants with a resting, standard 12-lead electrocardiogram and ≥1 measure of QTc interval over 4 examinations at 3-year intervals (1987-1998). From 54 638 person-visits, we excluded participants with QRS ≥ 120 milliseconds (n = 2333 person-visits). We corrected the QT interval using the Bazett and Framingham formulas. We examined QTc lengthening using linear regression for 36 602 person-visit observations for 14 160 cohort members controlling for age ≥ 65 years, female sex, left ventricular hypertrophy, QTc > 500 milliseconds at the prior visit, and CredibleMeds categorized QTPMs (Known, Possible, or Conditional risk). We corrected standard errors for repeat observations per person.RESULTS: Eighty percent of person-visits had at least one risk factor for QTc lengthening. Use of QTPMs increased over the 4 visits from 8% to 17%. Among persons not using QTPMs, history of prolonged QTc interval and female sex were associated with the greatest QTc lengthening, 39 and 12 milliseconds, respectively. In the absence of risk factors, Known QTPMs and ≥2 QTPMs were associated with modest but greater QTc lengthening than Possible or Conditional QTPMs. In the presence of risk factors, ≥2 QTPM further increased QTc lengthening. In combination with risk factors, the association of all QTPM categories with QTc lengthening was greater than QTPMs alone.CONCLUSION: Risk factors, particularly female sex and history of prolonged QTc interval, have stronger associations with QTc interval lengthening than any QTPM category alone. All QTPM categories augmented QTc interval lengthening associated with risk factors.
Authors: Alburikan, Khalid A; Aldemerdash, Ahmed; Savitz, Samuel T; Tisdale, James E; Whitsel, Eric A; Soliman, Elsayed Z; Thudium, Emily M; Sueta, Carla A; Kucharska-Newton, Anna M; Stearns, Sally C; Rodgers, Jo E
Journal of evaluation in clinical practice. 2017 Dec 15;23(6):1274-1280. Epub 2017-07-10.
Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry
The presence of cancer can complicate treatment choices for patients with atrial fibrillation (AF) increasing both the risk of thrombotic and bleeding events. Using data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we aimed to characterize AF patients with cancer, to describe their management and to assess the association between cancer and cardiovascular (CV) outcomes. Among 9749 patients, 23.8% had history of cancer (57% solid malignancy, 1.3% leukaemia, 3.3% lymphoma, 40% other type, and 2.2% metastatic cancer). Patients with history of cancer were older, more likely to have CV disease, CV risk factors, and prior gastrointestinal bleeding. No difference in antiarrhythmic and antithrombotic therapy was observed between those with and without cancer. Patients with history of cancer had a significantly higher risk of death (7.8 vs. 4.9 deaths per 100 patient-years follow-up, P = 0.0003) mainly driven by non-CV death (4.2 vs. 2.4 per 100 patient-years follow-up; P = 0.0004) and higher risk of major bleeding (5.1 vs. 3.5 per 100 patient-years follow-up; P = 0.02) compared with non-cancer patients; no differences were observed in risks of strokes/non-central nervous system embolism (1.96 vs. 1.48, P = 0.74) and CV death (2.89 vs. 2.07, P = 0.35) between the two groups. A history of cancer is common among AF patients with up to one in four patients having both. Antithrombotic therapy, rates of cerebrovascular accident, other thrombotic events and cardiac death were similar in AF patients with or without a history of cancer. Patients with cancer, however, were at higher risk of major bleeding and non-CV death.
Authors: Melloni C; Go AS; ORBIT-AF Steering Committee; et al.
Eur Heart J Qual Care Clin Outcomes. 2017 Jul 01;3(3):192-197.
Research Priorities to Advance the Health and Health Care of Older Adults with Multiple Chronic Conditions
To prioritize research topics relevant to the care of the growing population of older adults with multiple chronic conditions (MCCs). Survey of experts in MCC practice, research, and policy. Topics were derived from white papers, funding announcements, or funded research projects relating to older adults with MCCs. Survey conducted through the Health Care Systems Research Network (HCSRN) and Claude D. Pepper Older Americans Independence Centers (OAICs) Advancing Geriatrics Infrastructure and Network Growth Initiative, a joint endeavor of the HCSRN and OAICs. Individuals affiliated with the HCSRN or OAICs and national MCC experts, including individuals affiliated with funding agencies having MCC-related grant portfolios. A “top box” methodology was used, counting the number of respondents selecting the top response on a 5-point Likert scale and dividing by the total number of responses to calculate a top box percentage for each of 37 topics. The highest-ranked research topics relevant to the health and healthcare of older adults with MCCs were health-related quality of life in older adults with MCCs; development of assessment tools (to assess, e.g., symptom burden, quality of life, function); interactions between medications, disease processes, and health outcomes; disability; implementation of novel (and scalable) models of care; association between clusters of chronic conditions and clinical, financial, and social outcomes; role of caregivers; symptom burden; shared decision-making to enhance care planning; and tools to improve clinical decision-making. Study findings serve to inform the development of a comprehensive research agenda to address the challenges relating to the care of this “high-need, high-cost” population and the healthcare delivery systems responsible for serving it.
Authors: Tisminetzky M; Go AS; Gurwitz JH; et al.
J Am Geriatr Soc. 2017 Jul;65(7):1549-1553. Epub 2017-05-26.
Reference Ranges and Regional Patterns of Left Ventricular Strain and Strain Rate Using Two-Dimensional Speckle-Tracking Echocardiography in a Healthy Middle-Aged Black and White Population: The CARDIA Study
Strain and strain rate are sensitive markers of left ventricular (LV) myocardial function. The aim of this study was to assess reference ranges and regional patterns of LV strain and strain rate using two-dimensional speckle-tracking echocardiography in a large population of black and white subjects. This study involved a retrospective review of prospectively collected images in 557 participants in the Coronary Artery Risk Development in Young Adults study who remained healthy at the year 25 examination. LV deformation parameters were measured in apical four-chamber, apical two-chamber, and parasternal short-axis views in 509, 391, and 521 subjects, respectively. Patients’ mean age was 49.6 ± 3.6 years, 61.6% were women, and 69.5% were white. White women showed the highest LV systolic and diastolic deformation values, reflected by a more negative reference range for apical four-chamber longitudinal strain (-16.4%; 95% prediction interval [PI], -20.8% to -12.0%) and a higher positive reference range for early diastolic strain rate (0.93 1/sec; 95% PI, 0.41 to 1.46 1/sec), respectively. The lowest LV systolic and diastolic deformation values were found in black men, with apical four-chamber longitudinal strain (14.7%; 95% PI, -19.1% to -10.3%) and early diastolic strain rate (0.79 1/sec; 95% PI, 0.42 to 1.16 1/sec). Absolute strain increased from the epicardium toward the endocardium. A base-to-apex gradient of longitudinal strain toward the apex was exhibited in inferior and inferoseptal regions and, in contrast, in the opposite direction in anterior and anterolateral walls. Sex had the strongest influence on LV deformation variability. Strain and strain rate reference values were sex and race related. White women showed the highest reference ranges for LV deformation, while the lowest values were found in black men. Significant layer- and level-specific patterns in regional LV deformation were identified.
Authors: Moreira HT; Gidding SS; Ambale-Venkatesh B; et al.
J Am Soc Echocardiogr. 2017 Jul;30(7):647-658.e2. Epub 2017-05-13.
Association of Changes in Neighborhood-Level Racial Residential Segregation With Changes in Blood Pressure Among Black Adults: The CARDIA Study
Despite cross-sectional evidence linking racial residential segregation to hypertension prevalence among non-Hispanic blacks, it remains unclear how changes in exposure to neighborhood segregation may be associated with changes in blood pressure. To examine the association of changes in neighborhood-level racial residential segregation with changes in systolic and diastolic blood pressure over a 25-year period. This observational study examined longitudinal data of 2280 black participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective investigation of adults aged 18 to 30 years who underwent baseline examinations in field centers in 4 US locations from March 25, 1985, to June 7, 1986, and then were re-examined for the next 25 years. Racial residential segregation was assessed using the Getis-Ord Gi* statistic, a measure of SD between the neighborhood’s racial composition (ie, percentage of black residents) and the surrounding area’s racial composition. Segregation was categorized as high (Gi* >1.96), medium (Gi* 0-1.96), and low (Gi* <0). Fixed-effects linear regression modeling was used to estimate the associations of within-person change in exposure to segregation and within-person change in blood pressure while tightly controlling for time-invariant confounders. Data analyses were performed between August 4, 2016, and February 9, 2017. Within-person changes in systolic and diastolic blood pressure across 6 examinations over 25 years. Of the 2280 participants at baseline, 974 (42.7%) were men and 1306 (57.3%) were women. Of these, 1861 (81.6%) were living in a high-segregation neighborhood; 278 (12.2%), a medium-segregation neighborhood; and 141 (6.2%), a low-segregation neighborhood. Systolic blood pressure increased by a mean of 0.16 (95% CI, 0.06-0.26) mm Hg with each 1-SD increase in segregation score after adjusting for interactions of time with age, sex, and field center. Of the 1861 participants (81.6%) who lived in high-segregation neighborhoods at baseline, reductions in exposure to segregation were associated with reductions in systolic blood pressure. Mean differences in systolic blood pressure were -1.33 (95% CI, -2.26 to -0.40) mm Hg when comparing high-segregation with medium-segregation neighborhoods and -1.19 (95% CI, -2.08 to -0.31) mm Hg when comparing high-segregation with low-segregation neighborhoods after adjustment for time and interactions of time with baseline age, sex, and field center. Changes in segregation were not associated with changes in diastolic blood pressure. Decreases in exposure to racial residential segregation are associated with reductions in systolic blood pressure. This study adds to the small but growing body of evidence that policies that reduce segregation may have meaningful health benefits.
Authors: Kershaw KN; Robinson WR; Gordon-Larsen P; Hicken MT; Goff DC; Carnethon MR; Kiefe CI; Sidney S; Diez Roux AV
JAMA Intern Med. 2017 Jul 01;177(7):996-1002.
Hospitalization for Recently Diagnosed Versus Worsening Chronic Heart Failure: From the ASCEND-HF Trial.
BACKGROUND: It is unclear how patients hospitalized for acute heart failure (HF) who are long-term chronic HF survivors differ from those with more recent HF diagnoses.OBJECTIVES: The goal of this study was to evaluate the influence of HF chronicity on acute HF patient profiles and outcomes.METHODS: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 hospitalized patients with acute HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. The present analysis compared patients according to duration of HF diagnosis before index hospitalization by using pre-specified cutoffs (0 to 1 month [i.e., "recently diagnosed"], >1 to 12 months, >12 to 60 months, and >60 months).RESULTS: Overall, 5,741 (80.4%) patients had documentation of duration of HF diagnosis (recently diagnosed, n = 1,536; >1 to 12 months, n = 1,020; >12 to 60 months, n = 1,653; and >60 months, n = 1,532). Across HF duration groups, mean age ranged from 64 to 66 years, and mean ejection fraction ranged from 29% to 32%. Compared with patients with longer HF duration, recently diagnosed patients were more likely to be women with nonischemic HF etiology, higher baseline blood pressure, better baseline renal function, and fewer comorbidities. After adjustment, compared with recently diagnosed patients, patients with longer HF duration were associated with more persistent dyspnea at 24 h (>1 to 12 months, odds ratio [OR]: 1.20; 95% confidence interval [CI]: 0.97 to 1.48; >12 to 60 months, OR: 1.34; 95% CI: 1.11 to 1.62; and >60 months, OR: 1.31; 95% CI: 1.08 to 1.60) and increased 180-day mortality (>1 to 12 months, hazard ratio [HR]: 1.89; 95% CI: 1.35 to 2.65; >12 to 60 months, HR: 1.82; 95% CI: 1.33 to 2.48; and >60 months, HR: 2.02; 95% CI: 1.47 to 2.77). The influence of HF duration on mortality was potentially more pronounced among female patients (interaction p = 0.05), but did not differ according to age, race, prior ischemic heart disease, or ejection fraction (all interactions, p ≥ 0.23).CONCLUSIONS: In this acute HF trial, patient profile differed according to duration of the HF diagnosis. A diagnosis of HF for ≤1 month before hospitalization was independently associated with greater early dyspnea relief and improved post-discharge survival compared to patients with chronic HF diagnoses. The distinction between de novo or recently diagnosed HF and worsening chronic HF should be considered in the design of future acute HF trials. (A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure; NCT00475852).
Authors: Greene, Stephen J SJ; Hernandez, Adrian F AF; Dunning, Allison A; Ambrosy, Andrew P AP; Armstrong, Paul W PW; Butler, Javed J; Cerbin, Lukasz P LP; Coles, Adrian A; Ezekowitz, Justin A JA; Metra, Marco M; Starling, Randall C RC; Teerlink, John R JR; Voors, Adriaan A AA; O'Connor, Christopher M CM; Mentz, Robert J RJ
Journal of the American College of Cardiology. 2017 Jun 27;69(25):3029-3039. Epub 2017-06-28.
Clinical trials in acute heart failure: beginning of the end or end of the beginning?
Authors: Ambrosy, Andrew P AP; Butler, Javed J; Gheorghiade, Mihai M
European journal of heart failure. 2017 11 03;19(11):1358-1360. Epub 2017-06-28.
Hospital Supplementation Differentially Impacts the Association Between Breastfeeding Intention and Duration Among Women With and Without Gestational Diabetes Mellitus History
Little is known about how in-hospital supplementation with water, infant formula, or sugar water affects the relationship between breastfeeding intentions and duration, and whether this differs by gestational diabetes mellitus (GDM) history. Our study objectives were to assess the associations between GDM and exclusive breastfeeding intentions, hospital supplementation, and breastfeeding duration, including whether hospital supplementation mediates the association between exclusive breastfeeding intentions and breastfeeding duration. Using data from the Infant Feeding Practices Study II (2005-2007), we included women with GDM (n?=?160) and women without GDM or prepregnancy diabetes (no diabetes mellitus [NDM]) (n?=?2,139). We used multivariable logistic and linear regressions to determine the associations between GDM history and exclusive breastfeeding intentions, and between breastfeeding intentions, hospital supplementation, and breastfeeding duration, by GDM. We used mediation analysis to assess whether hospital supplementation mediated the association between exclusive breastfeeding intention and breastfeeding duration, also by GDM. All analyses were adjusted for prepregnancy body mass index. GDM was associated with lower odds of intending to exclusively breastfeed (adjusted odds ratio [AOR] 0.71; 95% confidence interval [CI, 0.51-0.99]). GDM and NDM women who did not intend to exclusively breastfeed had similarly increased odds of hospital supplementation (GDM: AOR 3.52; 95% CI [1.44-8.57], NDM: AOR 3.66; 95% CI [2.93-4.56]). Breastfeeding duration was similar by exclusive breastfeeding intentions and by hospital supplementation, regardless of GDM. Hospital supplementation partially mediated the association between breastfeeding intentions and duration in NDM women, but it did not mediate the association in women with GDM. Breastfeeding intentions, rather than hospital supplementation, are particularly important for women with GDM to optimize breastfeeding outcomes.
Authors: Loewenberg Weisband Y; Rausch J; Kachoria R; Gunderson EP; Oza-Frank R
Breastfeed Med. 2017 Jun 20.
Teaching Nutrition in Graduate Medical Education: An Interactive Workshop
Authors: Nguyen T; Lo JC
J Grad Med Educ. 2017 Jun;9(3):375-376.
In-Hospital Breastfeeding Experiences Among Women with Gestational Diabetes
In-hospital experiences among women with gestational diabetes mellitus (GDM) could impact breastfeeding success. We sought (1) to determine changes in the prevalence of hospital breastfeeding experiences between 2004-2008 and 2009-2011 among women with GDM and women without diabetes; (2) to determine whether GDM is associated with higher occurrence of experiencing Baby-Friendly hospital practices because of their known higher rates of breastfeeding difficulties. Data from the 2004 to 2011 Pregnancy Risk Assessment Monitoring System, a survey of women with a recent live birth from 16 states and New York City, were used based on inclusion of an optional survey question about hospital breastfeeding experiences. We examined the association of in-hospital experiences with GDM within each survey phase using chi-square tests. Weighted multivariable logistic regression was used to determine the association between GDM and hospital breastfeeding experiences. Among 157,187 (8.8% GDM), there were crude differences by GDM status for at least 60% of hospital experiences despite increases in positive hospital experiences between time periods. Women with GDM were less likely to report breastfeeding in the first hour (adjusted odds ratio: 0.83, confidence interval [95% CI] 0.73-0.94), feeding only breast milk in the hospital (0.73, 0.65-0.82), and feeding on demand (0.86, 0.74-0.99) compared with women without diabetes. Women with GDM were significantly more likely to report receiving a pump (1.28, 1.07-1.53) and a formula gift pack (1.17, 1.03-1.34) compared with women without diabetes. Although women with GDM experienced improvements in-hospital breastfeeding experiences over time, disparities in breastfeeding practices remained for five in-patient (hospital) practices that included four negative practices (breastfeeding in the first hour, feeding only breast milk in the hospital, told to feed per mother’s preference, receiving a formula gift pack) and one positive practice (receiving a pump).
Authors: Oza-Frank R; Gunderson EP
Breastfeed Med. 2017 06;12:261-268.
Code-Based Diagnostic Algorithms for Idiopathic Pulmonary Fibrosis: Case Validation and Improvement
Population-based studies of idiopathic pulmonary fibrosis (IPF) in the United States have been limited by reliance on diagnostic code-based algorithms that lack clinical validation. To validate a well-accepted International Classification of Diseases, Ninth Revision, code-based algorithm for IPF using patient-level information and to develop a modified algorithm for IPF with enhanced predictive value. The traditional IPF algorithm was used to identify potential cases of IPF in the Kaiser Permanente Northern California adult population from 2000 to 2014. Incidence and prevalence were determined overall and by age, sex, and race/ethnicity. A validation subset of cases (n = 150) underwent expert medical record and chest computed tomography review. A modified IPF algorithm was then derived and validated to optimize positive predictive value. From 2000 to 2014, the traditional IPF algorithm identified 2,608 cases among 5,389,627 at-risk adults in the Kaiser Permanente Northern California population. Annual incidence was 6.8/100,000 person-years (95% confidence interval [CI], 6.1-7.7) and was higher in patients with older age, male sex, and white race. The positive predictive value of the IPF algorithm was only 42.2% (95% CI, 30.6 to 54.6%); sensitivity was 55.6% (95% CI, 21.2 to 86.3%). The corrected incidence was estimated at 5.6/100,000 person-years (95% CI, 2.6-10.3). A modified IPF algorithm had improved positive predictive value but reduced sensitivity compared with the traditional algorithm. A well-accepted International Classification of Diseases, Ninth Revision, code-based IPF algorithm performs poorly, falsely classifying many non-IPF cases as IPF and missing a substantial proportion of IPF cases. A modification of the IPF algorithm may be useful for future population-based studies of IPF.
Authors: Ley B; Urbania T; Husson G; Vittinghoff E; Brush DR; Eisner MD; Iribarren C; Collard HR
Ann Am Thorac Soc. 2017 Jun;14(6):880-887.
Urine Kidney Injury Biomarkers and Risks of Cardiovascular Disease Events and All-Cause Death: The CRIC Study
CKD is an important risk factor for cardiovascular disease (CVD) and death. We investigated whether select urine kidney injury biomarkers were associated with higher risk of heart failure (HF), CVD, and death in persons with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, andN-acetyl-β-d-glucosaminidase were measured in urine of a subset of CRIC participants (n=2466). We used Cox proportional hazards regression to examine associations between these biomarkers indexed to urinary creatinine (Cr) and (1) HF, (2) a composite of atherosclerotic CVD events (myocardial infarction, ischemic stroke, or peripheral artery disease), and (3) all-cause death. At baseline, mean age of study participants was 59.5±10.8 years, 46% were women, and 34% had a self-reported history of any CVD. Median follow-up was 6.5 (interquartile range, 5.6-6.8) years. A total of 333 HF events, 282 atherosclerotic CVD events, and 440 deaths were observed during a median follow-up of 6.5 (interquartile range, 5.6-6.8) years. Those in the highest two quintiles of KIM-1/Cr levels had a higher risk of HF relative to the lowest quintile (quintile 5 versus quintile 1 adjusted hazard ratio [aHR] of 1.73 [95% confidence interval, 1.05 to 2.85]).N-acetyl-β-d-glucosaminidase/Cr was associated with HF in continuous analyses (aHR per log SD higher 1.18 [95% confidence interval, 1.01 to 1.38]). Only KIM-1/Cr was independently associated with atherosclerotic CVD events (aHR per log SD higher 1.21 [95% confidence interval, 1.02 to 1.41]), whereas both KIM-1/Cr (quintile 5 versus quintile 1 aHR of 1.56 [95% confidence interval, 1.06 to 2.31]) and neutrophil gelatinase-associated lipocalin/Cr (quintile 5 versus quintile 1 aHR of 1.82 [95% confidence interval, 1.19 to 2.8]) were associated with all-cause death. Selected urine kidney injury biomarkers were independently associated with higher risk of HF, CVD events, and death in CRIC. Among the biomarkers examined, only KIM-1/Cr was associated with each outcome. Further work is needed to determine the utility of these biomarkers to improve risk prediction for these adverse outcomes.
Authors: Park M; Go AS; CKD Biomarkers Consortium; et al.
Clin J Am Soc Nephrol. 2017 May 08;12(5):761-771. Epub 2017-03-02.
Detecting Cardiovascular Disease from Mammograms With Deep Learning
Coronary artery disease is a major cause of death in women. Breast arterial calcifications (BACs), detected inmammograms, can be useful riskmarkers associated with the disease. We investigate the feasibility of automated and accurate detection ofBACsinmammograms for risk assessment of coronary artery disease. We develop a 12-layer convolutional neural network to discriminate BAC from non-BAC and apply a pixelwise, patch-based procedure for BAC detection. To assess the performance of the system, we conduct a reader study to provide ground-truth information using the consensus of human expert radiologists. We evaluate the performance using a set of 840 full-field digital mammograms from 210 cases, using both free-responsereceiveroperatingcharacteristic (FROC) analysis and calcium mass quantification analysis. The FROC analysis shows that the deep learning approach achieves a level of detection similar to the human experts. The calcium mass quantification analysis shows that the inferred calcium mass is close to the ground truth, with a linear regression between them yielding a coefficient of determination of 96.24%. Taken together, these results suggest that deep learning can be used effectively to develop an automated system for BAC detection inmammograms to help identify and assess patients with cardiovascular risks.
Authors: Wang J; Ding H; Bidgoli FA; Zhou B; Iribarren C; Molloi S; Baldi P
IEEE Trans Med Imaging. 2017 05;36(5):1172-1181. Epub 2017-01-19.
Testosterone Levels in Pre-Menopausal Women are Associated With Nonalcoholic Fatty Liver Disease in Midlife
Young women with hyperandrogenism have high risk of metabolic co-morbidities, including increased risk of nonalcoholic fatty liver disease (NAFLD). Whether testosterone (the predominant androgen) is associated with NAFLD independent of metabolic co-factors is unclear. Additionally, whether testosterone confers increased risk of NAFLD in women without hyperandrogenism is unknown. Among women in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed whether free testosterone levels measured at Year 2 (1987-1988) were associated with prevalent NAFLD at Year 25 (2010-2011) (n=1052). NAFLD was defined using noncontrast abdominal CT scan with liver attenuation≤40 Hounsfield units after excluding other causes of hepatic fat. The association of free testosterone with prevalent NAFLD was assessed by logistic regression. Increasing quintiles of free testosterone were associated with prevalent NAFLD at Year 25 (adjusted odds ratio (AOR) 1.25, 95% confidence interval (CI) 1.04-1.50, P=0.015), independent of insulin resistance, body mass index, waist circumference, and serum lipids. Importantly, the association persisted among n=955 women without androgen excess (AOR 1.27, 95% CI 1.05-1.53, P=0.016). Visceral adipose tissue (VAT) volume partially mediated the association of free testosterone with NAFLD (mediating effect 41.0%, 95% CI 22-119%). Increasing free testosterone is associated with prevalent NAFLD in middle age, even in women without androgen excess. Visceral adiposity appears to play an important role in the relationship between testosterone and NAFLD in women. Testosterone may provide a potential novel target for NAFLD therapeutics, and future studies in pre-menopausal women should consider the importance of testosterone as a risk factor for NAFLD.
Authors: Sarkar M; Ajmera V; Terrault N; et al.
Am J Gastroenterol. 2017 May;112(5):755-762. Epub 2017-03-14.
Association Between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age
Beyond the risks of smoking, there are limited data on factors associated with change in lung function over time. To determine whether cardiorespiratory fitness was longitudinally associated with preservation of lung health. Prospective data were collected from 3,332 participants in the Coronary Artery Risk Development in Young Adults study aged 18-30 in 1985 who underwent treadmill exercise testing at baseline visit, and 2,735 participants with a second treadmill test 20 years later. The association between cardiorespiratory fitness and covariate adjusted decline in lung function was evaluated. Higher baseline fitness was associated with less decline in lung function. When adjusted for age, height, race-sex group, peak lung function, and years from peak lung function, each additional minute of treadmill duration was associated with 1.00 ml/yr less decline in FEV1 (P < 0.001) and 1.55 ml/yr less decline in FVC (P < 0.001). Greater decline in fitness was associated with greater annual decline in lung function. Each 1-minute decline in treadmill duration between baseline and Year 20 was associated with 2.54 ml/yr greater decline in FEV1 (P < 0.001) and 3.27 ml/yr greater decline in FVC (P < 0.001). Both sustaining higher and achieving relatively increased levels of fitness over 20 years were associated with preservation of lung health. Greater cardiopulmonary fitness in young adulthood, less decline in fitness from young adulthood to middle age, and achieving increased fitness from young adulthood to middle age are associated with less decline in lung health over time. Clinical trial registered with www.clinicaltrials.gov (NCT 00005130).
Authors: Benck LR; Dransfield MT; Kalhan R; et al.
Am J Respir Crit Care Med. 2017 May 01;195(9):1236-1243.
Fitness in Young Adulthood and Long-Term Cardiac Structure and Function: The CARDIA Study
This study sought to evaluate the association between early-life cardiorespiratory fitness (CRF) and measures of left ventricular (LV) structure and function in midlife. Low CRF in midlife is associated with a higher risk of heart failure. However, the unique contributions of early-life CRF toward measures of LV structure and function in middle age are not known. CARDIA (Coronary Artery Risk Development in Young Adults) study participants with a baseline maximal treadmill test and an echocardiogram at year 25 were included. Associations among baseline CRF, CRF change, and echocardiographic LV parameters (global longitudinal strain [GLS] and global circumferential strain, E/e’) were assessed using multivariable linear regression. The study included 3,433 participants. After adjustment for baseline demographic and clinical characteristics, lower baseline CRF was significantly associated with higher LV strain (standardized parameter estimate [Std β] = -0.06; p = 0.03 for GLS) and ratio of early transmitral flow velocity to early peak diastolic mitral annular velocity (E/e’) (Std β = -0.10; p = 0.0001 for lateral E/e’), findings suggesting impaired contractility and elevated diastolic filling pressure in midlife. After additional adjustment for cumulative cardiovascular risk factor burden observed over the follow-up period, the association of CRF with LV strain attenuated substantially (p = 0.36), whereas the association with diastolic filling pressure remained significant (Std β = -0.05; p = 0.02 for lateral E/e’). In a subgroup of participants with repeat CRF tests at year 20, greater decline in CRF was significantly associated with increased abnormalities in GLS (Std β = -0.05; p = 0.02) and higher diastolic filling pressure (Std β = -0.06; p = 0.006 for lateral E/e’) in middle age. CRF in young adulthood and CRF change were associated with measures of LV systolic function and diastolic filling pressure in middle age. Low CRF-associated abnormalities in systolic function were related to the associated higher cardiovascular risk factor burden. In contrast, the inverse association between CRF and LV diastolic filling pressure was independent of cardiovascular risk factor burden.
Authors: Pandey A; Rana JS; Berry JD; et al.
JACC Heart Fail. 2017 May;5(5):347-355. Epub 2017-03-08.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: Pooled analysis of patient-level data from 25 randomized, double-blind, placebo-controlled clinical trials
Authors: Iribarren C; Rothman KJ; Bradley MS; Carrigan G; Eisner MD; Chen H
J Allergy Clin Immunol. 2017 05;139(5):1678-1680. Epub 2017-01-17.
Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study of moderate-to-severe asthma
EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long-term safety of omalizumab in an observational setting, focusing predominantly on malignancies. The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non-omalizumab group (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non-omalizumab-treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non-omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91). This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non-omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded.
Authors: Iribarren C; Rahmaoui A; Long AA; Szefler SJ; Bradley MS; Carrigan G; Eisner MD; Chen H; Omachi TA; Farkouh ME; Rothman KJ
J Allergy Clin Immunol. 2017 May;139(5):1489-1495.e5. Epub 2016-09-14.
Health Literacy and Awareness of Atrial Fibrillation
Atrial fibrillation (AF) is the most common clinically significant arrhythmia in adults and a major risk factor for ischemic stroke. Nonetheless, previous research suggests that many individuals diagnosed with AF lack awareness about their diagnosis and inadequate health literacy may be an important contributing factor to this finding. We examined the association between health literacy and awareness of an AF diagnosis in a large, ethnically diverse cohort of Kaiser Permanente Northern and Southern California adults diagnosed with AF between January 1, 2006 and June 30, 2009. Using self-reported questionnaire data completed between May 1, 2010 and September 30, 2010, awareness of an AF diagnosis was evaluated using the question “Have you ever been told by a doctor or other health professional that you have a heart rhythm problem called atrial fibrillation or atrial flutter?” and health literacy was assessed using a validated 3-item instrument examining problems because of reading, understanding, and filling out medical forms. Of the 12 517 patients diagnosed with AF, 14.5% were not aware of their AF diagnosis and 20.4% had inadequate health literacy. Patients with inadequate health literacy were less likely to be aware of their AF diagnosis compared with patients with adequate health literacy (prevalence ratio=0.96; 95% CI [0.94, 0.98]), adjusting for sociodemographics, health behaviors, and clinical characteristics. Lower health literacy is independently associated with less awareness of AF diagnosis. Strategies designed to increase patient awareness of AF and its complications are warranted among individuals with limited health literacy.
Authors: Reading SR; Go AS; Fang MC; Singer DE; Liu IA; Black MH; Udaltsova N; Reynolds K; Anticoagulation and Risk Factors in Atrial Fibrillation–Cardiovascular Research Network (ATRIA‐CVRN) Investigators
J Am Heart Assoc. 2017 Apr 11;6(4). Epub 2017-04-11.
Kidney function and appropriateness of device therapies in adults with implantable cardioverter defibrillators
Patients with chronic kidney disease (CKD) have higher risk of sudden cardiac death; however, they may not receive implantable cardioverter defibrillators (ICDs), in part due to higher risk of complications. We evaluated whether CKD is associated with greater risk of device-delivered shocks/antitachycardia pacing (ATP) therapies among patients receiving a primary prevention ICD. We studied participants in the observational Cardiovascular Research Network Longitudinal Study of Implantable Cardioverter Defibrillators. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). Outcomes included all delivered shocks/ATPs therapies and type of shock/ATP therapies (inappropriate or appropriate, determined by physician adjudication) within the 3 years. We evaluated the associations between CKD and time to first device therapy, burden of device therapy, and inappropriate versus appropriate device therapy, adjusting for demographics, comorbidity, laboratory values and medication use. Among 2161 participants, 1066 (49.3%) had CKD (eGFR 44±11 mL/min/1.73 m(2)) at ICD implantation. During mean of 2.26±0.89 years, 9.8% and 18.5% of participants had at least one inappropriate and appropriate shock/ATP therapies, respectively. CKD was not associated with time to first shock/ATP therapies (adjusted HR 0.87, 95% CI 0.73 to 1.05), overall burden of shock/ATP therapies (adjusted relative rate 0.93, 95% CI 0.74 to 1.17) or inappropriate versus appropriate shock/ATP therapies (adjusted relative risk 0.88, 95% CI 0.68 to 1.14) compared with not having CKD. In adults receiving a primary prevention ICD, mild-to-moderate CKD was not associated with the timing, burden or appropriateness of subsequent device therapy. Potential concern for inappropriate ICD-delivered therapies should not preclude ICDs among eligible patients with CKD.
Authors: Bansal N; Go AS; et al.
Heart. 2017 Apr;103(7):529-537. Epub 2016-10-14.
Hyperprolactinemia in end-stage renal disease and effects of frequent hemodialysis
End-stage renal disease is associated with elevations in circulating prolactin concentrations, but the association of prolactin concentrations with intermediate health outcomes and the effects of hemodialysis frequency on changes in serum prolactin have not been examined. The FHN Daily and Nocturnal Dialysis Trials compared the effects of conventional thrice weekly hemodialysis with in-center daily hemodialysis (6 days/week) and nocturnal home hemodialysis (6 nights/week) over 12 months and obtained measures of health-related quality of life, self-reported physical function, mental health and cognition. Serum prolactin concentrations were measured at baseline and 12-month follow-up in 70% of the FHN Trial cohort to examine the associations among serum prolactin concentrations and physical, mental and cognitive function and the effects of hemodialysis frequency on serum prolactin. Among 177 Daily Trial and 60 Nocturnal Trial participants with baseline serum prolactin measurements, the median serum prolactin concentration was 65 ng/mL (25th-75th percentile 48-195 ng/mL) and 81% had serum prolactin concentrations >30 ng/mL. While serum prolactin was associated with sex (higher in women), we observed no association between baseline serum prolactin and age, dialysis vintage, and baseline measures of physical, mental and cognitive function. Furthermore, there was no significant effect of hemodialysis frequency on serum prolactin in either of the two trials. Serum prolactin concentrations were elevated in the large majority of patients with ESRD, but were not associated with several measures of health status. Circulating prolactin levels also do not appear to decrease in response to more frequent hemodialysis over a one-year period.
Authors: Lo JC; Beck GJ; Kaysen GA; Chan CT; Kliger AS; Rocco MV; Chertow GM; FHN Study
Hemodial Int. 2017 Apr;21(2):190-196. Epub 2016-10-23.
Genome-wide physical activity interactions in adiposity – A meta-analysis of 200,452 adults
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Authors: Graff M; Sternfeld B; Kilpeläinen TO; et al.
PLoS Genet. 2017 Apr;13(4):e1006528. Epub 2017-04-27.
Inflammation and Arterial Stiffness in Chronic Kidney Disease: Findings From the CRIC Study
Chronic kidney disease (CKD) and arterial stiffness are associated with increased cardiovascular morbidity and mortality. Inflammation is proposed to have a role in the development of arterial stiffness, and CKD is recognized as a proinflammatory state. Arterial stiffness is increased in CKD, and cross-sectional data has suggested a link between increased inflammatory markers in CKD and higher measures of arterial stiffness. However, no large scale investigations have examined the impact of inflammation on the progression of arterial stiffness in CKD. We performed baseline assessments of 5 inflammatory markers in 3,939 participants from the chronic renal insufficiency cohort (CRIC), along with serial measurements of arterial stiffness at 0, 2, and 4 years of follow-up. A total of 2,933 participants completed each of the follow-up stiffness measures. In cross-sectional analysis at enrollment, significant associations with at least 2 measures of stiffness were observed for fibrinogen, interleukin-6, high-sensitivity C-reactive protein, proteinuria, and composite inflammation score after adjustment for confounders. In longitudinal analyses, there were few meaningful correlations between baseline levels of inflammation and changes in metrics of arterial stiffness over time. In a large cohort of CKD participants, we observed multiple significant correlations between initial markers of inflammation and metrics of arterial stiffness, but baseline inflammation did not predict changes in arterial stiffness over time. While well-described biologic mechanisms provide the basis for our understanding of the cross-sectional results, continued efforts to design longitudinal studies are necessary to fully elucidate the relationship between chronic inflammation and arterial stiffening.
Authors: Peyster E; Go AS; CRIC Study Investigators; et al.
Am J Hypertens. 2017 Apr 01;30(4):400-408.
Predicting Hypertension Among Children With Incident Elevated Blood Pressure
To develop a model to predict hypertension risk among children with incident elevated blood pressure (BP); to test the external validity of the model. A retrospective cohort study was conducted in 3 organizations: Kaiser Permanente Colorado was the model derivation site; HealthPartners of Minnesota and Kaiser Permanente Northern California served as external validation sites. During study years 2006 through 2012, all children aged 3 through 17 years with incident elevated BP in an outpatient setting were identified. The predictor variables were demographic and clinical characteristics collected during routine care. Cox proportional hazards regression was used to predict subsequent hypertension, and diagnostic statistics were used to assess model performance. Among 5598 subjects at the derivation site with incident elevated BP, 160 (2.9%) developed hypertension during the study period. Eight characteristics were used to predict hypertension risk: age, sex, race, BP preceding incident elevated BP, body mass index percentile, systolic BP percentile, diastolic BP percentile, and clinical setting of the incident elevated BP. At the derivation site, the model discriminated well between those at higher versus lower risk of hypertension (c-statistic = 0.77). At external validation sites, the observed risk of hypertension was higher than the predicted risk, and the model showed poor discrimination (c-statistic ranged from 0.64 to 0.67). Among children with incident elevated BP, a risk model demonstrated good internal validity with respect to predicting subsequent hypertension. However, the risk model did not perform well at 2 external validation sites, which might limit transportability to other settings.
Authors: Daley MF; Reifler LM; Johnson ES; Sinaiko AR; Margolis KL; Parker ED; Greenspan LC; Lo JC; O'Connor PJ; Magid DJ
Acad Pediatr. 2017 Apr;17(3):275-282. Epub 2017-02-21.
Predicting Adherence and Persistence with Oral Bisphosphonate Therapy in an Integrated Health Care Delivery System
Examining drug exposure is essential to pharmacovigilance, especially for bisphosphonate (BP) therapy. To examine differences in 4 measures of oral BP exposure: treatment discontinuation, adherence, persistence, and nonpersistence. Among women aged ≥ 50 years who initiated oral BP therapy during 2002-2007 with at least 3 years of health plan membership follow-up, discontinuation was defined by evidence of no further treatment during the study observation period. Among those with at least 2 filled BP prescriptions during the study period, adherence was calculated for each year of follow-up using the (modified) proportion of days covered (mPDC) metric that allows for stockpiling of prescription/refills overlap ≤ 30 days supply. Persistence was quantified by treatment duration, allowing a gap of up to 60 days between prescription/refill days covered. Nonpersistence was quantified by the periods without drugs outside this allowable gap. Multivariable logistic regression was used to compare age and race groups and the relationships of early adherence (adherence during the first year) with subsequent adherence. Among 48,390 women initiating oral BP therapy and followed for 3 years, 26.7% discontinued in year 1, and 14.7% of the remaining 35,456 women discontinued in year 2. Discontinuation rates were slightly higher (29.4%, P < 0.001) for women aged ≥ 75 years and somewhat lower (21.1%, P < 0.001) for Asian women. During the first year, 60.4% of the women achieved an mPDC of ≥ 75%, with demographic differences in adherence similar to that seen for treatment discontinuation. Over the 3 years, the median mPDC levels for BP therapy were 86%, 84%, and 85% in years 1, 2, and 3, respectively, for those receiving treatment. Cumulative persistence was 2.3 years (median, IQR = 1.0-3.0) overall and slightly greater for Asian versus white women and lower for older women. There were 18,174 (42.9%) women with at least 1 period of nonpersistence during 3 years follow-up in excess of the 60-day allowable gap between prescription/refills (median cumulative nonpersistence = 0.65, IQR = 0.30-1.25 years). Women with mPDC ≥ 75% during the first year had a 12-fold and 6-fold increased odds of mPDC ≥ 75% during year 2 and year 3, respectively. BP discontinuation rates are highest for women during the first year. Among those continuing treatment in subsequent years, adherence rates were relatively stable. Persistence and adherence varied slightly by age and was somewhat higher in Asians, contributing to differences in cumulative BP exposure. We also found evidence that optimal adherence in the first year was highly predictive of optimal adherence in the subsequent 1-2 years. Hence, subgroups of patients receiving oral BP drugs may require different levels of support and monitoring to maximize treatment benefit, especially based on early patterns of use. This study was supported by grants from the Kaiser Permanente Northern California Community Benefit Program and the National Institutes of Health, 1R01AG047230-01A1. The opinions expressed in this publication are solely the responsibility of the authors and do not represent the official views of Kaiser Permanente or the National Institutes of Health. Hui, Yi, and Chandra have received past research funding from Amgen not related to the current study. Adams has received research funding from Amgen, Merck, and Otsuka not related to the current study. Niu has received research funding from Bristol-Myers Squibb not related to the current study. Ettinger has received past legal fees in litigation involving Fosamax. Lo has received past research funding from Amgen and current research funding from Sanofi not related to the current study. The data from this study were presented at the Academy of Managed Care Pharmacy Annual Meeting; April 19-22, 2016; San Francisco, California. Study concept and design were contributed primarily by Hui and Lo, along with Adams, Niu, Yi, and Ettinger. Hui took the lead in data collection, along with Chandra, and data interpretation was performed by Niu, Yi, and Lo, along with the other authors. The manuscript was written by Hui, Adams, and Lo, along with Niu, Yi, and Ettinger, and revised by Ettinger, Hui, Lo, and Niu, along with the other authors.
Authors: Hui RL; Adams AL; Niu F; Ettinger B; Yi DK; Chandra M; Lo JC
J Manag Care Spec Pharm. 2017 Apr;23(4):503-512.
Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency
Controversy exists regarding the safety of testosterone replacement therapy (TRT) following recent reports of an increased risk of adverse cardiovascular events. To investigate the association between TRT and cardiovascular outcomes in men with androgen deficiency. A retrospective cohort study was conducted within an integrated health care delivery system. Men at least 40 years old with evidence of androgen deficiency either by a coded diagnosis and/or a morning serum total testosterone level of less than 300 ng/dL were included. The eligibility window was January 1, 1999, to December 31, 2010, with follow-up through December 31, 2012. Any prescribed TRT given by injection, orally, or topically. The primary outcome was a composite of cardiovascular end points that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD). Multivariable Cox proportional hazards models were used to investigate the association between TRT and cardiovascular outcomes. An inverse probability of treatment weight, propensity score methodology, was used to balance baseline characteristics. The cohorts consisted of 8808 men (19.8%) ever dispensed testosterone (ever-TRT) (mean age, 58.4 years; 1.4% with prior cardiovascular events) and 35 527 men (80.2%) never dispensed testosterone (never-TRT) (mean age, 59.8 years; 2.0% with prior cardiovascular events). Median follow was 3.2 years (interquartile range [IQR], 1.7-6.6 years) in the never-TRT group vs 4.2 (IQR, 2.1-7.8) years in the ever-TRT group. The rates of the composite cardiovascular end point were 23.9 vs 16.9 per 1000 person-years in the never-TRT and ever-TRT groups, respectively. The adjusted hazard ratio (HR) for the composite cardiovascular end point in the ever-TRT group was 0.67 (95% CI, 0.62-0.73. Similar results were seen when the outcome was restricted to combined stroke events (stroke and TIA) (HR, 0.72; 95% CI, 0.62-0.84) and combined cardiac events (AMI, SCD, unstable angina, revascularization procedures) (HR, 0.66; 95% CI, 0.60-0.72). Among men with androgen deficiency, dispensed testosterone prescriptions were associated with a lower risk of cardiovascular outcomes over a median follow-up of 3.4 years.
Authors: Cheetham TC; An J; Jacobsen SJ; Niu F; Sidney S; Quesenberry CP; VanDenEeden SK
JAMA Intern Med. 2017 Apr 01;177(4):491-499.
Racial Differences in Associations of Blood Pressure Components in Young Adulthood With Incident Cardiovascular Disease by Middle Age: Coronary Artery Risk Development in Young Adults (CARDIA) Study
Data are sparse regarding which blood pressure (BP) components in young adulthood optimally determine cardiovascular disease (CVD) by middle age. To assess which BP components best determine incident CVD events in young adults and determine whether these associations vary by race and age at BP measurement. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, this study assessed the longitudinal race-stratified associations between BP and cardiovascular outcomes. CARDIA is a community-based cohort that recruited black and white individuals (age range, 18-30 years) from March 26, 1985, through June 7, 1986. CARDIA followed up participants for up to 28 years, and 94% of the surviving cohort completed at least 1 telephone interview or examination from August 2009 through August 2014. Blood pressures measubred at baseline (Y0) and 15 years later (Y15). Composite CVD events, including coronary heart disease, stroke, heart failure, and other vascular diseases. A total of 4880 participants participated in the study (mean [SD] age, 24.9 [3.6] years at Y0 and 25.0 [3.6] years at Y15; 2223 male [45.6%] at Y0 and 1800 [44.2%] at Y15; 2657 female [54.4%] at Y0 and 2277 [55.8%] at Y0; 2473 black individuals [50.7%] at Y0 and 1994 [48.9%] at Y15; and 2407 white individuals [49.3%] at Y0 and 2083 [51.1%] at Y15). The mean SBP/DBP was 112/69 mm Hg in blacks and 109/68 mm Hg in whites at Y0 and 117/77 mm Hg in blacks and 110/72 mm Hg in whites at Y15. During a 25-year follow-up from Y0, 210 CVD events occurred (twice as many events in blacks [n = 140] compared with whites), of which 131 (87 in blacks) occurred after Y15. With adjustments for covariates, results from Cox proportional hazards models, including SBP and DBP, jointly suggested that, at Y0, SBP (hazard ratio [HR] per 1-SD increase, 1.32; 95% CI, 1.09-1.61) but not DBP (HR, 1.05; 95% CI, 0.88-1.26) was associated with CVD risk in blacks, whereas DBP (HR, 1.74; 95% CI, 1.21-2.50) but not SBP (HR, 0.82; 95% CI, 0.57-1.18) was associated with CVD risk in whites. At Y15, SBP was the strongest indicator of CVD in blacks (HR, 1.64; 95% CI, 1.25-2.16) and whites (HR, 1.67; 95% CI, 1.02-2.69). This study questions the classic view that DBP is more able to identify future CVD events than SBP in all individuals younger than 50 years. In young adulthood, SBP in black individuals and DBP in white individuals were the most robust indicators of future CVD. In middle-age, SBP in both races identified risk of incident CVD.
Authors: Yano Y; Reis JP; Tedla YG; Goff DC; Jacobs DR; Sidney S; Ning H; Liu K; Greenland P; Lloyd-Jones DM
JAMA Cardiol. 2017 04 01;2(4):381-389.
Association of Coronary Artery Calcium in Adults Aged 32 to 46 Years With Incident Coronary Heart Disease and Death
Coronary artery calcium (CAC) is associated with coronary heart disease (CHD) and cardiovascular disease (CVD); however, prognostic data on CAC are limited in younger adults. To determine if CAC in adults aged 32 to 46 years is associated with incident clinical CHD, CVD, and all-cause mortality during 12.5 years of follow-up. The Coronary Artery Risk Development in Young Adults (CARDIA) Study is a prospective community-based study that recruited 5115 black and white participants aged 18 to 30 years from March 25, 1985, to June 7, 1986. The cohort has been under surveillance for 30 years, with CAC measured 15 (n = 3043), 20 (n = 3141), and 25 (n = 3189) years after recruitment. The mean follow-up period for incident events was 12.5 years, from the year 15 computed tomographic scan through August 31, 2014. Incident CHD included fatal or nonfatal myocardial infarction, acute coronary syndrome without myocardial infarction, coronary revascularization, or CHD death. Incident CVD included CHD, stroke, heart failure, and peripheral arterial disease. Death included all causes. The probability of developing CAC by age 32 to 56 years was estimated using clinical risk factors measured 7 years apart between ages 18 and 38 years. At year 15 of the study among 3043 participants (mean [SD] age, 40.3 [3.6] years; 1383 men and 1660 women), 309 individuals (10.2%) had CAC, with a geometric mean Agatston score of 21.6 (interquartile range, 17.3-26.8). Participants were followed up for 12.5 years, with 57 incident CHD events and 108 incident CVD events observed. After adjusting for demographics, risk factors, and treatments, those with any CAC experienced a 5-fold increase in CHD events (hazard ratio [HR], 5.0; 95% CI, 2.8-8.7) and 3-fold increase in CVD events (HR, 3.0; 95% CI, 1.9-4.7). Within CAC score strata of 1-19, 20-99, and 100 or more, the HRs for CHD were 2.6 (95% CI, 1.0-5.7), 5.8 (95% CI, 2.6-12.1), and 9.8 (95% CI, 4.5-20.5), respectively. A CAC score of 100 or more had an incidence of 22.4 deaths per 100 participants (HR, 3.7; 95% CI, 1.5-10.0); of the 13 deaths in participants with a CAC score of 100 or more, 10 were adjudicated as CHD events. Risk factors for CVD in early adult life identified those above the median risk for developing CAC and, if applied, in a selective CAC screening strategy could reduce the number of people screened for CAC by 50% and the number imaged needed to find 1 person with CAC from 3.5 to 2.2. The presence of CAC among individuals aged between 32 and 46 years was associated with increased risk of fatal and nonfatal CHD during 12.5 years of follow-up. A CAC score of 100 or more was associated with early death. Adults younger than 50 years with any CAC, even with very low scores, identified on a computed tomographic scan are at elevated risk of clinical CHD, CVD, and death. Selective use of screening for CAC might be considered in individuals with risk factors in early adulthood to inform discussions about primary prevention.
Authors: Carr JJ; Jacobs DR; Terry JG; Shay CM; Sidney S; Liu K; Schreiner PJ; Lewis CE; Shikany JM; Reis JP; Goff DC
JAMA Cardiol. 2017 04 01;2(4):391-399.
Cumulative Lifetime Marijuana Use and Incident Cardiovascular Disease in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
To investigate the effects of marijuana in the development of incident cardiovascular and cerebrovascular outcomes. Participants were 5113 adults aged 18 to 30 years at baseline (1985-1986) from the Coronary Artery Risk Development in Young Adults study, who were followed for more than 25 years. We estimated cumulative lifetime exposure to marijuana using repeated assessments collected at examinations every 2 to 5 years. The primary outcome was incident cardiovascular disease (CVD) through 2013. A total of 84% (n = 4286) reported a history of marijuana use. During a median 26.9 years (131 990 person-years), we identified 215 CVD events, including 62 strokes or transient ischemic attacks, 104 cases of coronary heart disease, and 50 CVD deaths. Compared with no marijuana use, cumulative lifetime and recent marijuana use showed no association with incident CVD, stroke or transient ischemic attacks, coronary heart disease, or CVD mortality. Marijuana use was not associated with CVD when stratified by age, gender, race, or family history of CVD. Neither cumulative lifetime nor recent use of marijuana is associated with the incidence of CVD in middle age.
Authors: Reis JP; Auer R; Bancks MP; Goff DC; Lewis CE; Pletcher MJ; Rana JS; Shikany JM; Sidney S
Am J Public Health. 2017 Apr;107(4):601-606. Epub 2017-02-16.
Loss of executive function after dialysis initiation in adults with chronic kidney disease
The association of dialysis initiation with changes in cognitive function among patients with advanced chronic kidney disease is poorly described. To better define this, we enrolled participants with advanced chronic kidney disease from the Chronic Renal Insufficiency Cohort in a prospective study of cognitive function. Eligible participants had a glomerular filtration rate of 20 ml/min/1.73m(2) or less, or dialysis initiation within the past two years. We evaluated cognitive function by a validated telephone battery at regular intervals over two years and analyzed test scores as z scores. Of 212 participants, 123 did not transition to dialysis during follow-up, 37 transitioned to dialysis after baseline, and 52 transitioned to dialysis prior to baseline. In adjusted analyses, the transition to dialysis was associated with a significant loss of executive function, but no significant changes in global cognition or memory. The estimated net difference in cognitive z scores at two years for participants who transitioned to dialysis during follow-up compared to participants who did not transition to dialysis was -0.01 (95% confidence interval -0.13, 0.11) for global cognition, -0.24 (-0.51, 0.03) for memory, and -0.33 (-0.60, -0.07) for executive function. Thus, among adults with advanced chronic kidney disease, dialysis initiation was associated with loss of executive function with no change in other aspects of cognition. Larger studies are needed to evaluate cognition during dialysis initiation.
Authors: Kurella Tamura M; Yaffe K; CRIC Study Investigators; et al.
Kidney Int. 2017 Apr;91(4):948-953. Epub 2017-01-27.
Risks of Adverse Events in Advanced CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study
People with advanced chronic kidney disease are at risk for the development of end-stage renal disease (ESRD), but also many other adverse outcomes, including cardiovascular disease (CVD) events and death. Determination of risk factors that explain the variability in prognosis and timing of these adverse outcomes can aid patient counseling and medical decision making. Prospective research cohort. 1,798 participants with estimated glomerular filtration rates (eGFRs)<30mL/min/1.73m(2) in the CRIC Study were followed up for a median of 5.5 years. Age, race, sex, eGFR, proteinuria, diabetes mellitus, body mass index, ejection fraction, systolic blood pressure, history of CVD, and smoking history. ESRD, CVD (congestive heart failure, stroke, myocardial infarction, and peripheral artery disease), and death. Baseline age of the cohort was 60 years, 46% were women, and 46% were African American. Although 52.3% of participants progressed to ESRD during follow-up, the path by which this occurred was variable. For example, predicted 1-year probabilities for a hypothetical 60-year-old white woman with eGFR of 30mL/min/1.73m(2), urine protein excretion of 1.8g/d, and no diabetes or CVD (risk characteristics similar to the average participant) were 3.3%, 4.1%, and 0.3%, for first developing CVD, ESRD, and death, respectively. For a 40-year-old African American man with similar characteristics but higher systolic blood pressure, the corresponding 1-year probabilities were 2.4%, 13.2%, and 0.1%. For all participants, the development of ESRD or CVD increased the risk for subsequent mortality, with no differences by patient race or body mass index. The CRIC population was specifically recruited for kidney disease, and the vast majority had seen a nephrologist. The prognosis and timing of adverse outcomes in chronic kidney disease vary by patient characteristics. These results may help guide the development of personalized approaches for managing patients with advanced CKD.
Authors: Grams ME; Yang W; Rebholz CM; Wang X; Porter AC; Inker LA; Horwitz E; Sondheimer JH; Hamm LL; He J; Weir MR; Jaar BG; Shafi T; Appel LJ; Hsu CY; CRIC Study Investigators
Am J Kidney Dis. 2017 Mar 30.
Use of Statins in Adults Older Than 75 Years-Reply
Authors: Gurwitz JH; Go AS; Fortmann SP
JAMA. 2017 03 14;317(10):1081.
Racial-Ethnic Differences in Fall Prevalence among Older Women: A Cross-Sectional Survey Study
Falls are the leading cause of hip fracture in older women, with important public health implications. Fall risk increases with age and other clinical factors, and varies by race/ethnicity. International studies suggest that fall risk is lower in Asians, although data are limited in U.S. This study examines racial/ethnic differences in fall prevalence among older U.S. women within a large integrated healthcare delivery system. This cross-sectional study used data from 6277 women ages 65-90 who responded to the 2008 or 2011 Kaiser Permanente Northern California Member Health Survey (KPNC-MHS). The KPNC-MHS is a mailed questionnaire sent to a random sample of adult members stratified by age, gender, and geographic location, representing a population estimate of >200,000 women age ≥65 years. Age, race/ethnicity, self-reported health status, presence of diabetes, arthritis or prior stroke, mobility limitations and number of falls in the past year were obtained from the KPNC-MHS. The independent association of race/ethnicity and recent falls was examined, adjusting for known risk factors. The weighted sample was 76.7% non-Hispanic white, 6.2% Hispanic, 6.8% black and 10.3% Asian. Over 20% reported having fallen during the past year (28.5% non-Hispanic white, 27.8% Hispanic, 23.4% black and 20.1% Asian). Older age was associated with greater fall risk, as was having diabetes (OR 1.24, CI 1.03-1.48), prior stroke (OR 1.51, CI 1.09-2.07), arthritis (OR 1.61, CI 1.39-1.85) and mobility limitations (OR 2.82, CI 2.34-3.39), adjusted for age. Compared to whites, Asian (OR 0.64, CI 0.50-0.81) and black (OR 0.73, CI 0.55-0.95) women were much less likely to have ≥1 fall in the past year, adjusting for age, comorbidities, mobility limitation and poor health status. Asians were also less likely to have ≥2 falls (OR 0.62, CI 0.43-0.88). Among older women, the risk of having a recent fall was substantially lower for black and Asian women when compared to white women. This may contribute to their lower rates of hip fracture. Future studies should examine cultural and behavioral factors that contribute to these observed racial/ethnic differences in fall risk among U.S. women.
Authors: Geng Y; Lo JC; Brickner L; Gordon NP
BMC Geriatr. 2017 Mar 11;17(1):65. Epub 2017-03-11.
Cardiometabolic Risk Factors Among 1.3 Million Adults With Overweight or Obesity, but Not Diabetes, in 10 Geographically Diverse Regions of the United States, 2012-2013
Various phenotypes of overweight and obesity pose various health risks. The objective of this study was to determine the prevalence of 4 commonly measured cardiometabolic risk factors (CRFs) among adults with overweight or obesity, but not diabetes, at the time of the study. We analyzed data for 1,294,174 adults (aged ≥20 y) who were members of one of 4 integrated health systems. Each cohort member had a body mass index in 2012 or 2013 that indicated overweight or obesity. We determined the presence of 4 CRFs within 1 year of the first BMI measurement: elevated blood pressure (systolic ≥130 mm Hg or diastolic >85 mm Hg or ICD-9-CM [International Classification of Diseases, Ninth Revision, Clinical Modification] diagnosis code 401.0-405.9); elevated triglycerides (≥150 mg/dL or ICD-9-CM 272.1); low high-density lipoprotein cholesterol (<40 mg/dL for men or <50 mg/dL for women or ICD-9-CM 272.5); and prediabetes (fasting glucose 100-125 mg/dL or HbA1c 5.7%-6.4% or ICD-9-CM 790.2x). We tested the risk of having 1 or more CRFs after adjusting for obesity class and demographic characteristics with multivariable logistic regression. Among participants with overweight (52.5% of the sample), 18.6% had none of the 4 CRFs. Among the 47.5% of participants with obesity, 9.6% had none; among participants with morbid obesity, 5.8% had none. Age was strongly associated with CRFs in multivariable analysis. Almost 10% of participants with obesity had no CRFs. Overweight or obesity increases cardiometabolic risk, but the number and type of CRFs varied substantially by age, even among participants with morbid obesity.
Authors: Nichols GA; Horberg M; Koebnick C; Young DR; Waitzfelder B; Sherwood NE; Daley MF; Ferrara A
Prev Chronic Dis. 2017 Mar 09;14:E22. Epub 2017-03-09.
Sedentary Behavior, Physical Activity, and Abdominal Adipose Tissue Deposition
We examined whether sedentary lifestyle habits and physical activity level are associated with abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and liver attenuation, independently of one another and potential confounders. This study analyzed 3010 African American and Caucasian men and women, 42-59 yr old, from the Coronary Artery Risk Development in Young Adults (CARDIA) study, who completed multiple-slice abdominal computed tomography in 2010-2011. Participants reported average hours per day sitting (television, computing, paperwork, music, telephone, and car). Physical activity was assessed with the CARDIA physical activity history. VAT, SAT, IMAT, and liver attenuation were estimated from computed tomography. Multivariable general linear regression models regressed means of fat depots on total sedentary time, task-specific sedentary time, and total physical activity. Television viewing was positively, and physical activity inversely, associated with fat depots. For each 1 SD increment in television viewing (1.5 h·d), VAT, SAT, and IMAT were greater by 3.5, 3.4, and 3.9 cm, respectively (P < 0.03 for all). For each 1 SD increment in physical activity (275 exercise units), VAT, SAT, and IMAT were lower by 7.6, 6.7, and 8.1 cm, respectively, and liver attenuation was greater (indicating more liver fat) by 0.5 Hounsfield units (P < 0.01 for all). Total sedentary time was associated with VAT, IMAT, and liver attenuation in White men only after controlling for physical activity, SAT, and other potential confounders (P ≤ 0.01 for all). No other task-specific sedentary behaviors were associated with fat depots. Sedentary behaviors, particularly television viewing, and physical activity levels have distinct, independent associations with fat deposition.
Authors: Whitaker KM; Odegaard AO; Jacobs DR; Sidney S; Pereira MA
Med Sci Sports Exerc. 2017 Mar;49(3):450-458.
Inflammatory Markers and Risk for Cognitive Decline in Chronic Kidney Disease: The CRIC Study
Chronic kidney disease (CKD) is associated with an increased risk of cognitive decline, but the mechanisms remain poorly defined. We sought to determine the relation between serum inflammatory markers and risk of cognitive decline among adults with CKD. We studied 757 adults aged ?55 years with CKD participating in the Chronic Renal Insufficiency Cohort Cognitive study. We measured interleukin (IL)-1?, IL-1 receptor antagonist, IL-6, tumor necrosis factor (TNF)-?, high-sensitivity C-reactive protein (hs-CRP), and fibrinogen in baseline plasma samples. We assessed cognitive function at regular intervals in 4 domains and defined incident impairment as a follow-up score more than 1 SD poorer than the group mean. The mean age of the sample was 64.3 ± 5.6 years, and the mean follow-up was 6.2 ± 2.5 years. At baseline, higher levels of each inflammatory marker were associated with poorer age-adjusted performance. In analyses adjusted for baseline cognition, demographics, comorbid conditions, and kidney function, participants in the highest tertile of hs-CRP, the highest tertile of fibrinogen, and the highest tertile of IL-1? had an increased risk of impairment in attention compared to participants in the lowest tertile of each marker. Participants in the highest versus lowest tertile of TNF-? had a lower adjusted risk of impairment in executive function. There was no association between other inflammatory markers and change in cognitive function. Among adults with CKD, higher levels of hs-CRP, fibrinogen, and IL-1? were associated with a higher risk of impairment in attention. Higher levels of TNF-? were associated with a lower risk of impaired executive function.
Authors: Kurella Tamura M; Go AS; CRIC Study Investigators; et al.
Kidney Int Rep. 2017 Mar;2(2):192-200. Epub 2016-10-31.
Trends in Incidence of Hospitalized Acute Myocardial Infarction in the Cardiovascular Research Network (CVRN)
Monitoring trends in cardiovascular events can provide key insights into the effectiveness of prevention efforts. Leveraging data from electronic health records provides a unique opportunity to examine contemporary, community-based trends in acute myocardial infarction hospitalizations. We examined trends in hospitalized acute myocardial infarction incidence among adults aged ≥25 years in 13 US health plans in the Cardiovascular Research Network. The first hospitalization per member for acute myocardial infarction overall and for ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction was identified by International Classification of Diseases, Ninth Revision, Clinical Modification primary discharge codes in each calendar year from 2000 through 2008. Age- and sex-adjusted incidence was calculated per 100,000 person-years using direct adjustment with 2000 US census data. Between 2000 and 2008, we identified 125,435 acute myocardial infarction hospitalizations. Age- and sex-adjusted incidence rates (per 100,000 person-years) of acute myocardial infarction decreased an average 3.8%/y from 230.5 in 2000 to 168.6 in 2008. Incidence of ST-segment elevation myocardial infarction decreased 8.7%/y from 104.3 in 2000 to 51.7 in 2008, whereas incidence of non-ST-segment elevation myocardial infarction increased from 126.1 to 129.4 between 2000 and 2004 and then decreased thereafter to 116.8 in 2008. Age- and sex-specific incidence rates generally reflected similar patterns, with relatively larger decreases in ST-segment elevation myocardial infarction rates in women compared with men. As compared with 2000, the age-adjusted incidence of ST-segment elevation myocardial infarction in 2008 was 48% lower among men and 61% lower among women. Among a large, diverse, multicenter community-based insured population, there were significant decreases in incidence of hospitalized acute myocardial infarction and the more serious ST-segment elevation myocardial infarctions between 2000 and 2008. Decreases in ST-segment elevation myocardial infarctions were most pronounced among women. While ecologic in nature, these secular decreases likely reflect, at least in part, results of improvement in primary prevention efforts.
Authors: Reynolds K; Go AS; Quesenberry CP; Sidney S; et al.
Am J Med. 2017 Mar;130(3):317-327. Epub 2016-10-14.
The Implication of Coronary Artery Calcium Testing for Cardiovascular Disease Prevention and Diabetes
Over the last two decades coronary artery calcium (CAC) scanning has emerged as a quick, safe, and inexpensive method to detect the presence of coronary atherosclerosis. Data from multiple studies has shown that compared to individuals who do not have any coronary calcifications, those with severe calcifications (i.e., CAC score >300) have a 10-fold increase in their risk of coronary heart disease events and cardiovascular disease. Conversely, those that have a CAC of 0 have a very low event rate (~0.1%/year), with data that now extends to 15 years in some studies. Thus, the most notable implication of identifying CAC in individuals who do not have known cardiovascular disease is that it allows targeting of more aggressive therapies to those who have the highest risk of having future events. Such identification of risk is especially important for individuals who are not on any therapies for coronary heart disease, or when intensification of treatment is being considered but has an uncertain role. This review will highlight some of the recent data on CAC testing, while focusing on the implications of those findings on patient management. The evolving role of CAC in patients with diabetes will also be highlighted.
Authors: Blankstein R; Gupta A; Rana JS; Nasir K
Endocrinol Metab (Seoul). 2017 Mar;32(1):47-57.
Television viewing and hostile personality trait increase the risk of injuries
Individuals with high levels of hostility may be more susceptible to the influence of television on violence and risk taking behaviors. This study aimed to examine whether hostile personality trait modifies the association between TV viewing and injuries. It is a prospective study of 4,196 black and white adults aged 23 to 35 in 1990/1. Cross-lagged panel models were analyzed at three 5-year time periods to test whether TV viewing predicted injuries. Covariates were gender, race, and education. Individuals who watched more TV (0 hours, 1-3 hours, 4-6 hours, and ≥7 hours) were more likely to have a hospitalization for an injury in the following 5 years across each of the three follow-up periods [OR = 1.5 (95%CI = 1.2, 1.9), 1.5 (1.1, 1.9), and 1.9 (1.3, 2.6)]. The cross-lagged effects of TV viewing to injury were significant in the high hostility group [OR = 1.4 (95%CI = 1.1, 1.8), 1.3 (1.0, 1.8), and 2.0 (1.3, 2.9)] but not in the low hostility group [OR = 1.3 (95%CI = 0.6, 2.2), 1.1 (0.6, 2.1), and 1.4 (0.7, 2.8)]. Additionally, a statistically significant difference between the two models (P < 0.001) suggested that hostility moderated the relationship between TV watching and injury. These findings suggest that individuals who watch more TV and have a hostile personality trait may be at a greater risk for injury.
Authors: Fabio A; Chen CY; Dearwater S; Jacobs DR; Erickson D; Matthews KA; Iribarren C; Sidney S; Pereira MA
Int J Inj Contr Saf Promot. 2017 Mar;24(1):44-53. Epub 2015-08-14.
Effect of Race and Ethnicity on Antihypertensive Medication Utilization Among Women in the United States: Study of Women’s Health Across the Nation (SWAN)
Antihypertensive medication use may vary by race and ethnicity. Longitudinal antihypertensive medication use patterns are not well described in women. Participants from the Study of Women’s Health Across the Nation (SWAN), a prospective cohort of women (n=3302, aged 42-52), who reported a diagnosis of hypertension or antihypertensive medication use at any annual visit were included. Antihypertensive medications were grouped by class and examined by race/ethnicity adjusting for potential confounders in logistic regression models. A total of 1707 (51.7%) women, mean age 50.6 years, reported hypertension or used antihypertensive medications at baseline or during follow-up (mean 9.1 years). Compared with whites, blacks were almost 3 times as likely to receive a calcium channel blocker (odds ratio, 2.92; 95% CI, 2.24-3.82) and twice as likely to receive a thiazide diuretic (odds ratio, 2.38; 95% CI, 1.93-2.94). Blacks also had a higher probability of reporting use of ≥2 antihypertensive medications (odds ratio, 1.95; 95% CI, 1.55-2.45) compared with whites. Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and thiazide diuretics increased over time for all racial/ethnic groups. Contrary to our hypothesis, rates of β-blocker usage did not decrease over time. Among this large cohort of multiethnic midlife women, use of antihypertensive medications increased over time, with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers becoming the most commonly used antihypertensive medication, even for blacks. Thiazide diuretic utilization increased over time for all race/ethnic groups as did use of calcium channel blockers among blacks; both patterns are in line with guideline recommendations for the management of hypertension.
Authors: Jackson EA; Ruppert K; Derby CA; Lian Y; Neal-Perry G; Habel LA; Tepper PG; Harlow SD; Solomon DH
J Am Heart Assoc. 2017 Feb 23;6(3). Epub 2017-02-23.
Changing Patterns in Oral Bisphosphonate Initiation in Women between 2004 and 2012
Authors: Lee DR; Ettinger B; Chandra M; Hui RL; Lo JC
J Am Geriatr Soc. 2017 Feb 02.
Use of Oral Anticoagulant Therapy in Older Adults with Atrial Fibrillation After Acute Ischemic Stroke
To explore barriers to anticoagulation in older adults with atrial fibrillation (AF) at high risk of stroke and to identify opportunities for interventions that might increase use of oral anticoagulants (OACs). Retrospective cohort study. Two large community-based AF cohorts. Individuals with ischemic stroke surviving hospitalization (N = 1,405, mean age 79). Using structured chart review, reasons for nonuse of OAC were identified, and 1-year poststroke survival was assessed. Logistic regression was used to identify correlates of OAC nonuse. Median CHA2 DS2 -VASc score was 5, yet 44% of participants were not prescribed an OAC at discharge. The most-frequent (nonmutually exclusive) physician reasons for not prescribing OAC included fall risk (26.7%), poor prognosis (19.3%), bleeding history (17.1%), participant or family refusal (14.9%), older age (11.0%), and dementia (9.4%). Older age (odds ratio (OR) = 8.96, 95% confidence interval (CI) = 5.01-16.04 for aged ≥85 vs <65) and disability (OR = 12.58, 95% CI = 5.82-27.21 for severe vs no deficit) were the most-important independent predictors of nonuse of OACs. By 1 year, 42.5% of those not receiving an OAC at discharge had died, versus 19.1% of those receiving an OAC (P < .001), far higher than recurrent stroke rates. Despite very high stroke risk, more than 40% of participants were not discharged with an OAC. Dominant reasons included fall risk, poor prognosis, older age, and dementia. These individuals' high 1-year mortality rate confirmed their high level of comorbidity. To improve anticoagulation decisions and outcomes in this population, future research should focus on strategies to mitigate fall risk, improve assessment of risks and benefits of anticoagulation in individuals with AF, and determine whether newer anticoagulants are safer in complex elderly and frail individuals.
Authors: McGrath ER; Go AS; Chang Y; Borowsky LH; Fang MC; Reynolds K; Singer DE
J Am Geriatr Soc. 2017 Feb;65(2):241-248. Epub 2016-12-30.
Body Weight Change During and After Hospitalization for Acute Heart Failure: Patient Characteristics, Markers of Congestion, and Outcomes: Findings From the ASCEND-HF Trial.
OBJECTIVES: This study sought to examine the relationships between in-hospital and post-discharge body weight changes and outcomes among patients hospitalized for acute heart failure (AHF).BACKGROUND: Body weight changes during and after hospitalization for AHF and the relationships with outcomes have not been well characterized.METHODS: A post hoc analysis was performed of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial, which enrolled patients admitted for AHF regardless of ejection fraction. In-hospital body weight change was defined as the difference between baseline and discharge/day 10, whereas post-discharge body weight change was defined as the difference between discharge/day 10 and day 30. Spearman rank correlations of weight change, urine output (UOP), and dyspnea relief as assessed by a 7-point Likert scale are described. Logistic and Cox proportional hazards regression was used to evaluate the relationship between weight change and outcomes.RESULTS: Study participants with complete body weight data (n = 4,172) had a mean age of 65 ± 14 years, and 66% were male. Ischemic heart disease was reported in 60% of patients and the average ejection fraction was 30 ± 13%. The median change in body weight was -1.0 kg (interquartile range: -2.1 to 0.0 kg) at 24 h and -2.3 kg (interquartile range: -5.0 to -0.7 kg) by discharge/day 10. At hour 24, there was a weak correlation between change in body weight and UOP (r = -0.381), and minimal correlation between body weight change and dyspnea relief (r = -0.096). After risk adjustment, increasing body weight during hospitalization was associated with a 16% increase per kg in the likelihood of 30-day mortality or HF readmission for patients showing weight loss ≤1 kg or weight gain during hospitalization (odds ratio per kg increase 1.16, 95% confidence interval [CI]: 1.09 to 1.27; p < 0.001). Among the subset of patients experiencing >1-kg increase in body weight post-discharge, increasing body weight was associated with higher risk of 180-day mortality (hazard ratio per kg increase 1.16; 95% CI: 1.09 to 1.23; p < 0.001).CONCLUSIONS: A substantial number of patients experienced minimal weight loss or frank weight gain in the context of an AHF trial, and increasing body weight in this subset of patients was independently associated with a worse post-discharge prognosis.
Authors: Ambrosy, Andrew P AP; Cerbin, Lukasz P LP; Armstrong, Paul W PW; Butler, Javed J; Coles, Adrian A; DeVore, Adam D AD; Dunlap, Mark E ME; Ezekowitz, Justin A JA; Felker, G Michael GM; Fudim, Marat M; Greene, Stephen J SJ; Hernandez, Adrian F AF; O'Connor, Christopher M CM; Schulte, Philip P; Starling, Randall C RC; Teerlink, John R JR; Voors, Adriaan A AA; Mentz, Robert J RJ
JACC. Heart failure. 2017 01 01;5(1):1-13. Epub 2017-01-19.
Global Variations in Patient Populations and Outcomes in Heart Failure Clinical Trials.
PURPOSE OF REVIEW: Heart failure is a global pandemic and there has been a growing effort to enroll patients from different geographical regions in randomized controlled trials. In this review, we examined regional variation in both patient characteristics and outcomes among several of the most recent global heart failure trials RECENT FINDINGS: Retrospective analyses of global heart failure trials have identified marked variations in both baseline characteristics and management of heart failure by region of enrollment. In some trials, this variation has been significant enough to cause differential treatment effects. We summarized key heterogeneity observed in global heart failure clinical trials. Differences in both patient population and organization of these trials abroad pose an important challenge in making interpretations and country-level decisions. As such, we encourage a concerted effort to account for these differences in future research.
Authors: Egwim, Chidiebube C; Dixon, Brittany B; Ambrosy, Andrew P AP; Mentz, Robert J RJ
Current heart failure reports. 2017 02 01;14(1):30-39. Epub 2017-01-19.
Reply: Factors That May Affect Body Change During and After Hospitalization for Acute Heart Failure.
Authors: Cerbin, Lukasz P LP; Ambrosy, Andrew P AP; Mentz, Robert J RJ
JACC. Heart failure. 2017 04 01;5(4):311-312. Epub 2017-01-19.
Aerobic exercise training and general health status in ambulatory heart failure patients with a reduced ejection fraction-Findings from the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION)trial.
BACKGROUND: Although aerobic exercise improves quality of life as assessed by a disease-specific instrument in ambulatory HF patients with a reduced ejection fraction (EF), the impact of an exercise intervention on general health status has not been previously reported.METHODS: A secondary analysis was performed of the HF-ACTION trial (ClinicalTrials.gov Number: NCT00047437), which enrolled 2331 medically stable outpatients with HF and an EF ≤35% and randomized them to aerobic exercise training, consisting of 36 supervised sessions followed by home-based training versus usual care for a median follow-up of 30 months. The EuroQOL 5-dimension questionnaire (EQ-5D) was administered to study participants at baseline, 3 months, and 12 months. EQ-5D includes functional dimensions (ie, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), which were mapped to corresponding utility scores (ie, 0=death and 1=perfect health), and a visual analogue scale (VAS) ranging from 0 (ie, "worst imaginable health state") to 100 (ie, "best imaginable health state").RESULTS: Study participants had a median (25th, 75th) age of 59 (51, 68) years and 71% were male. A history of ischemic heart disease was reported in 51% of participants and the EF was 25% (20%, 30%). Baseline VAS and mapped utility scores were 65±19 and 0.81±0.14. Exercise training led to an improvement in VAS score compared with usual care from baseline to 3 months (exercise training: 6±17 vs usual care: 3±20; P < .0001) and VAS scores (HR 1.05 per 10 point decrease, 95% CI 1.02-1.08; P < .01) at baseline were associated with increased risk of death or hospitalization.CONCLUSION: Ambulatory HF patients with a reduced EF had impaired health status at baseline which was associated with increased morbidity and mortality, in part mitigated by a structured aerobic exercise regimen.
Authors: Ambrosy, Andrew P AP; Cerbin, Lukasz P LP; DeVore, Adam D AD; Greene, Stephen J SJ; Kraus, William E WE; O'Connor, Christopher M CM; Piña, Ileana L IL; Whellan, David J DJ; Wojdyla, Daniel D; Wu, Angie A; Mentz, Robert J RJ
American heart journal. 2017 Apr 01;186(1):130-138. Epub 2017-01-19.
Associations of Conventional Echocardiographic Measures with Incident Heart Failure and Mortality: The Chronic Renal Insufficiency Cohort
Heart failure is the most frequent cardiac complication of CKD. Left ventricular hypertrophy is common and develops early in CKD, but studies have not adequately evaluated the association of left ventricular mass index with heart failure incidence among men and women with CKD. We evaluated echocardiograms of 2567 participants without self-reported heart failure enrolled in the Chronic Renal Insufficiency Cohort Study. Two-dimensional echocardiograms were performed at the year 1 study visit and interpreted at a central core laboratory. Left ventricular mass index was calculated using the linear method, indexed to height2.7, and analyzed using sex-specific quartiles. The primary outcomes of incident heart failure and all-cause mortality were adjudicated over a median of 6.6 (interquartile range, 5.7-7.6) years. Among 2567 participants, 45% were women, and 54% were nonwhite race; mean (SD) age was 59±11 years old, and mean eGFR was 44±17 ml/min per 1.73 m2. During a median follow-up period of 6.6 years, 262 participants developed heart failure, and 470 participants died. Compared with participants in the first quartile of left ventricular mass index, those in the highest quartile had higher rates of incident heart failure (hazard ratio, 3.96; 95% confidence interval, 1.96 to 8.02) and mortality (hazard ratio, 1.86; 95% confidence interval, 1.22 to 2.85), even after adjustment for B-type natriuretic peptide, troponin T, mineral metabolism markers, and other cardiovascular disease risk factors. Those in the lowest quartile of ejection fraction had higher rates of incident heart failure (hazard ratio, 3.01; 95% confidence interval, 1.94 to 4.67) but similar mortality rates (hazard ratio, 1.18; 95% confidence interval, 0.89 to 1.57) compared with those in the highest quartile. Diastolic dysfunction was not significantly associated with heart failure or death. Among persons with CKD and without history of cardiovascular disease, left ventricular mass index is strongly associated with incident heart failure, even after adjustment for major cardiovascular risk factors and biomarkers.
Authors: Dubin RF; Go AS; CRIC Study Investigators; et al.
Clin J Am Soc Nephrol. 2017 Jan 06;12(1):60-68. Epub 2016-11-10.
Sustained Economic Hardship and Cognitive Function: The Coronary Artery Risk Development in Young Adults Study
The relationship between low income and worse health outcomes is evident, yet its association with cognitive outcomes is less explored. Most studies have measured income at one time and none have examined how sustained exposure to low income influences cognition in a relatively young cohort. This study examined the effect of sustained poverty and perceived financial difficulty on cognitive function in midlife. Income data were collected six times between 1985 and 2010 for 3,383 adults from the Coronary Artery Risk Development in Young Adults prospective cohort study. Sustained poverty was defined by the percentage of time participants’ household income was <200% of the federal poverty level-"never" in poverty, "0< to <1/3," "≥1/3 to <100%" or "all-time." In 2010, at a mean age of 50 years, participants underwent a cognitive battery. Data were analyzed in 2015. In demographic-adjusted linear regression models, individuals with all-time poverty performed significantly worse than individuals never in poverty: 0.92 points worse on verbal memory (z-score, -0.28; 95% CI=-0.43, -0.13), 11.60 points worse on processing speed (z-score, -0.72; 95% CI=-0.85, -0.58), and 3.50 points worse on executive function (z-score, -0.32; 95% CI=-0.47, -0.17). Similar results were observed with perceived financial difficulty. Findings were robust when restricted to highly educated participants, suggesting little evidence for reverse causation. Cumulative exposure to low income over 2 decades was strongly associated with worse cognitive function of a relatively young cohort. Poverty and perceived hardship may be important contributors to premature aging among disadvantaged populations.
Authors: Zeki Al Hazzouri A; Elfassy T; Sidney S; Jacobs D; Pérez Stable EJ; Yaffe K
Am J Prev Med. 2017 Jan;52(1):1-9. Epub 2016-09-27.
Risk of Type 2 Diabetes Mellitus following Gestational Diabetes Pregnancy in Women with Polycystic Ovary Syndrome
This study examines gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) and the risk of type 2 diabetes mellitus (DM) following GDM pregnancy. A cohort of 988 pregnant women with PCOS who delivered during 2002-2005 was examined to determine the prevalence and predictors of GDM, with follow-up through 2010 among those with GDM to estimate the risk of DM. Of the 988 pregnant women with PCOS, 192 (19%) developed GDM. Multivariable predictors of GDM included older age, Asian race, prepregnancy obesity, family history of DM, preconception metformin use, and multiple gestation. Among women with PCOS and GDM pregnancy, the incidence of DM was 2.8 (95% confidence interval (CI) 1.9-4.2) per 100 person-years and substantially higher for those who received pharmacologic treatment for GDM (6.6 versus 1.5 per 100 person-years, p < 0.01). The multivariable adjusted risk of DM was fourfold higher in women who received pharmacologic treatment for GDM (adjusted hazard ratio 4.1, 95% CI 1.8-9.6). The five-year incidence of DM was 13.1% overall and also higher in the pharmacologic treatment subgroup (27.0% versus 7.1%, p < 0.01). The strongest predictors of GDM among women with PCOS included Asian race and prepregnancy obesity. Pharmacologic treatment of GDM is associated with fourfold higher risk of subsequent DM.
Authors: Lo JC; Yang J; Gunderson EP; Hararah MK; Gonzalez JR; Ferrara A
J Diabetes Res. 2017;2017:5250162. Epub 2017-12-20.
Gravidity is not associated with telomere length in a biracial cohort of middle-aged women: The Coronary Artery Risk Development in Young Adults (CARDIA) study
Having experienced 2-3 births is associated with reduced mortality versus women with <2 or ≥4 births. The effect of 2-3 births on lifespan may be associated with delayed cellular aging. We hypothesized telomere length, a marker of cellular aging, would be longer in women who had 2-3 pregnancies. Leukocyte telomere length was measured using quantitative real-time polymerase chain reaction in 620 women in CARDIA at the year 15 and 20 exams, expressed as the ratio of telomere repeat copy number to single-copy gene copy number (T/S). Number of pregnancies at the time of telomere length measurement was obtained (mean age = 41±0.1 years, average gravidity = 2.64±0.1 pregnancies). Participants were divided into 4 groups by number of pregnancies: 0, 1, 2-3, and ≥4, to test for differences in telomere length by gravidity group. The mean and SD for telomere length was 0.98 ± 0.20 T/S in the whole cohort. There were no differences in mean telomere length between groups; 0.98±0.02 T/S in women with 0 pregnancies, 1.01±0.02 T/S in women with 1 pregnancy, 0.97±0.01 T/S in women with 2-3 pregnancies, and 0.99±0.02 T/S in women with ≥4 pregnancies (p = 0.51). We defined high-risk (shorter) telomere length as ≤25th percentile, and low-risk (longer) telomere length as ≥75 percentile. There were no differences in the prevalence of high-risk or low-risk telomere length between gravidity groups. Gravidity was not associated with telomere length in early middle age; the protective association of 2-3 births may act through other mechanisms.
Authors: Lane-Cordova AD; Puterman E; Gunderson EP; Chan C; Hou L; Carnethon M
PLoS ONE. 2017;12(10):e0186495. Epub 2017-10-19.
Innovative partnerships to advance public health training in community-based academic residency programs
Collaborative partnerships between community-based academic residency training programs and schools of public health, represent an innovative approach to training future physician leaders in population management and public health. In Kaiser Permanente Northern California, development of residency-Masters in Public Health (MPH) tracks in the Internal Medicine Residency and the Pediatrics Residency programs, with MPH graduate studies completed at the University of California Berkeley School of Public Health, enables physicians to integrate clinical training with formal education in epidemiology, biostatistics, health policy, and disease prevention. These residency-MPH programs draw on more than 50 years of clinical education, public health training, and health services research – creating an environment that sparks inquiry and added value by developing skills in patient-centered care through the lens of population-based outcomes.
Authors: Lo JC; Baudendistel TE; Dandekar A; Le PV; Siu S; Blumberg B
Adv Med Educ Pract. 2017;8:703-706. Epub 2017-10-05.
Dietary variables associated with substantial postpartum weight retention at 1-year among women with GDM pregnancy
An understanding of the dietary behaviors linked to substantial postpartum weight retention, particularly in women diagnosed with gestational diabetes (GDM), is warranted to focus intervention efforts to prevent future type 2 diabetes. This study evaluates the relationship between dietary food intake at 6-9 weeks postpartum (baseline) and odds of substantial postpartum weight retention (≥ 5 kg) at 1-year in women with GDM. The Study of Women, Infant Feeding and Type 2 Diabetes after GDM pregnancy (SWIFT) is a prospective multi-ethnic cohort (75% minority) of 1035 women (aged 20-45 years) with recent GDM who delivered a singleton, live birth (≥35 weeks gestation) and underwent 2-h 75 g OGTTs, anthropometric measurements and other assessments at 6-9 weeks postpartum (baseline) and annually thereafter. Eight hundred and eighty-eight women without diabetes at baseline completed the 18-item PrimeScreen to assess dietary intake and the 13-item Caffeine Survey to assess beverage intake, and completed 1-year follow-up. Average postpartum weight retention was calculated (1-year postpartum weight minus pre-pregnancy weight). Multivariable logistic regression models that estimated baseline dietary intake and odds of substantial postpartum weight retention (SPPWR ≥5 kg above pre-pregnancy weight) versus not SPPWR adjusted for numerous clinical, sociodemographic and behavioral covariates. Compared to eating no fried foods, women who reported eating fried foods ≥5 servings/wk. (n = 32) and 2-4 serv/wk. (n = 208), respectively, had a three-fold and two-fold higher odds of SPPWR (OR = 3.38, 95% CI:1.36-8.38, P = 0.009; OR = 1.99, 95% CI:1.30-3.03, P = 0.02), after adjustment for covariates and other foods and soda intake. Soda intake ≥2 serv/wk. versus none was associated with higher odds of SPPWR (OR = 1.95, 95% CI:1.22-3.11, P = 0.005) adjusted for fried foods and covariates, but was attenuated (OR = 1.61,95% CI:0.98-2.66, p = 0.06) after addition of whole eggs and processed meats. These findings indicate that interventions should focus on reducing fried foods and soda intake during early postpartum periods to reduce substantial postpartum weight retention in high-risk women with GDM. NCT01967030; October 2013, Eunice Kennedy Shriver National Institute of Health and Human Development (NICHD).
Authors: Davis JN; Shearrer GE; Tao W; Hurston SR; Gunderson EP
BMC Obes. 2017;4:31. Epub 2017-08-03.
Circulating Cellular Adhesion Molecules and Cognitive Function: The Coronary Artery Risk Development in Young Adults Study
Higher circulating concentrations of cellular adhesion molecules (CAMs) can be used as markers of endothelial dysfunction. Given that the brain is highly vascularized, we assessed whether endothelial function is associated with cognitive performance. Within the Coronary Artery Risk Development in Young Adults (CARDIA) Study, excluding N = 54 with stroke before year 25, we studied CAMs among N = 2,690 black and white men and women in CARDIA year 7 (1992-1993, ages 25-37) and N = 2,848 in CARDIA year 15 (2000-2001, ages 33-45). We included subjects with levels of circulating soluble CAMs measured in year 7 or 15 and cognitive function testing in year 25 (2010-2011, ages 43-55). Using multiple regression analysis, we evaluated the association between CAMs and year 25 cognitive test scores: Rey Auditory Verbal Learning Test (RAVLT, memory), Digit Symbol Substitution Test (DSST, speed of processing), and the Stroop Test (executive function). All CAM concentrations were greater in year 15 vs. year 7. Adjusting for age, race, sex, education, smoking, alcohol, diet, physical activity, participants in the fourth vs. the first quartile of CARDIA year 7 of circulating intercellular adhesion molecule-1 (ICAM-1) scored worse on RAVLT, DSST, and Stroop Test (p ≤ 0.05) in CARDIA year 25. Other CAMs showed little association with cognitive test scores. Findings were similar for ICAM-1 assessed at year 15. Adjustment for possibly mediating physical factors attenuated the findings. Higher circulating ICAM-1 at average ages 32 and 40 was associated with lower cognitive skills at average age 50. The study is consistent with the hypothesis that endothelial dysfunction is associated with worse short-term memory, speed of processing, and executive function.
Authors: Yoon CY; Steffen LM; Gross MD; Launer LJ; Odegaard A; Reiner A; Sanchez O; Yaffe K; Sidney S; Jacobs DR
Front Cardiovasc Med. 2017;4:37. Epub 2017-05-24.
Race-ethnicity on blood pressure control after ischemic stroke: a prospective cohort study
Disparities in health care access and socioeconomic status (SES) have been associated with racial-ethnic differences in blood pressure (BP) control. We examined post-ischemic stroke BP in a multiethnic cohort with good health care access. We included all hypertensive patients (n = 2972) from a randomized quality improvement trial on secondary stroke prevention, conducted in 14 Kaiser Permanente hospitals in Northern California from 2004-2006 (QUISP). Average age 73.2 ± 12.2 years; 52% female, 66% non-Hispanic white, 14% African-American, 11% Asian, 8% Hispanic, and 1% other. Demographics, diagnoses, health care utilization, BP measurements, and medications were obtained as part of routine care. We used random effects logistic regression models to examine race as a predictor of blood pressure control (<140/90 mm Hg) at 6 months post-discharge, adjusted for SES, age, gender, dementia, antihypertensive therapy, and attendance at follow-up visits. At 6 months, BP was controlled in 52.7% of blacks compared to 61.4% of whites (OR = 0.63, 95% CI, 0.48-0.82, P = .001). Black race remained independently associated with poorer BP control in adjusted analysis, although blacks were as likely to attend post-discharge visits, and more likely to be on any antihypertensive therapy than whites. Greater difficulty in controlling BP and lifestyle differences may account for this difference.
Authors: Nguyen-Huynh MN; Hills NK; Sidney S; Klingman JG; Johnston SC
J Am Soc Hypertens. 2017 Jan;11(1):38-44. Epub 2016-11-17.
Influence of Competing Risks on Estimating the Expected Benefit of Warfarin in Individuals with Atrial Fibrillation Not Currently Taking Anticoagulants: The Anticoagulation and Risk Factors in Atrial Fibrillation Study
To provide greater understanding of the “real world” effect of anticoagulation on stroke risk over several years. Cohort study. Anticoagulation and Risk Factors in Atrial Fibrillation Study community-based cohort. Adults with nonvalvular atrial fibrillation (AF) between 1996 and 2003 (13,559). All events were clinician adjudicated. Extended Cox regression with longitudinal warfarin exposure was used to estimate cause-specific hazard ratios (HRs) for thromboembolism and the competing risk event (all cause death). The Fine and Gray subdistribution regression approach was used to estimate this association while accounting for competing death events. As a secondary analysis, follow-up was limited to 1, 3, and 5 years. The rate of death was much higher in the group not taking warfarin (8.1 deaths/100 person-years (PY)) than in the group taking warfarin (5.5 deaths/100 PY). The cause-specific HR indicated a large reduction in thromboembolism with warfarin use (adjusted HR = 0.57, 95% confidence interval (CI) = 0.50-0.65), although this association was substantially attenuated after accounting for competing death events (adjusted HR = 0.87, 95% CI = 0.77-0.99). In analyses limited to 1 year of follow-up, with fewer competing death events, the results for models that did and did not account for competing risks were similar. Analyses accounting for competing death events may provide a more-realistic estimate of the longer-term stroke prevention benefits of anticoagulants than traditional noncompeting risk analyses for individuals with AF, particularly those who are not currently treated with anticoagulants.
Authors: Ashburner JM; Go AS; Chang Y; Fang MC; Fredman L; Applebaum KM; Singer DE
J Am Geriatr Soc. 2017 Jan;65(1):35-41. Epub 2016-11-12.
Clinical Utility of Multi-marker Genetic Risk Scores for Prediction of Incident Coronary Heart Disease: A Cohort Study among over 51 Thousand Individuals of European Ancestry
We evaluated whether including multilocus genetic risk scores (GRSs) into the Framingham Risk Equation improves the predictive capacity, discrimination, and reclassification of asymptomatic individuals with respect to coronary heart disease (CHD) risk. We performed a cohort study among 51 954 European-ancestry members of a Northern California integrated healthcare system (67% female; mean age 59) free of CHD at baseline (2007-2008). Four GRSs were constructed using between 8 and 51 previously identified genetic variants. After a mean (±SD) follow-up of 5.9 (±1.5) years, 1864 incident CHD events were documented. All GRSs were linearly associated with CHD in a model adjusted by individual risk factors: hazard ratio (95% confidence interval) per SD unit: 1.21 (1.15-1.26) for GRS_8, 1.20 (1.15-1.26) for GRS_12, 1.23 (1.17-1.28) for GRS_36, and 1.23 (1.17-1.28) for GRS_51. Inclusion of the GRSs improved the C statistic (ΔC statistic =0.008 for GRS_8 and GRS_36; 0.007 for GRS_12; and 0.009 for GRS_51; all P<0.001). The net reclassification improvement was 5% for GRS_8, GRS_12, and GRS_36 and 4% for GRS_51 in the entire cohort and was (after correcting for bias) 9% for GRS_8 and GRS_12 and 7% for GRS_36 and GRS_51 when analyzing those classified as intermediate Framingham risk (10%-20%). The number required to treat to prevent 1 CHD after selectively treating with statins up-reclassified subjects on the basis of genetic information was 36 for GRS_8 and GRS_12, 41 for GRS_36, and 43 for GRS_51. Our results demonstrate significant and clinically relevant incremental discriminative/predictive capability of 4 multilocus GRSs for incident CHD among subjects of European ancestry.
Authors: Iribarren C; Lu M; Jorgenson E; Martínez M; Lluis-Ganella C; Subirana I; Salas E; Elosua R
Circ Cardiovasc Genet. 2016 Dec;9(6):531-540. Epub 2016-10-25.
Genome-wide analysis identifies 12 loci influencing human reproductive behavior
The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
Authors: Barban N; Guo X; Mills MC; et al.
Nat Genet. 2016 Dec;48(12):1462-1472. Epub 2016-10-31.
Different components of blood pressure are associated with increased risk of atherosclerotic cardiovascular disease versus heart failure in advanced chronic kidney disease
Blood pressure is a modifiable risk for cardiovascular disease (CVD). Among hemodialysis patients, there is a U-shaped association between blood pressure and risk of death. However, few studies have examined the association between blood pressure and CVD in patients with stage 4 and 5 chronic kidney disease. Here we studied 1795 Chronic Renal Insufficiency Cohort (CRIC) Study participants with estimated glomerular filtration rate <30 ml/min per 1.73 m(2) and not on dialysis. The association of systolic (SBP), diastolic (DBP), and pulse pressure with the risk of physician-adjudicated atherosclerotic CVD (stroke, myocardial infarction, or peripheral arterial disease) and heart failure was tested using Cox regression adjusted for demographics, comorbidity and medications. There was a significant association with higher SBP (adjusted hazard ratio 2.04 [95% confidence interval: 1.46-2.84]) for SBP over 140 vs under 120 mmHg, higher DBP (2.52 [1.54-4.11]) for DBP >90 mm Hg versus <80 mm Hg and higher pulse pressure (2.67 [1.82-3.92]) for pulse pressure >68 mm Hg versus <51 mm Hg with atherosclerotic CVD. For heart failure, there was a significant association with higher pulse pressure only (1.42 [1.05-1.92]) for pulse pressure >68 mm Hg versus <51 mmHg, but not for SBP or DBP. Thus, among participants with stage 4 and 5 chronic kidney disease, there was an independent association between higher SBP, DBP, and pulse pressure with the risk of atherosclerotic CVD, whereas only higher pulse pressure was independently associated with a greater risk of heart failure. Further trials are needed to determine whether aggressive reduction of blood pressure decreases the risk of CVD events in patients with stage 4 and 5 chronic kidney disease.
Authors: Bansal N; Go AS; CRIC Study Investigators; et al.
Kidney Int. 2016 Dec;90(6):1348-1356. Epub 2016-10-04.
Smoking habits and parathyroid hormone concentrations in young adults: The CARDIA study
Conflicting results have been reported concerning a relationship between smoking and serum PTH. Our study objective was to examine whether smoking was associated with serum PTH independent of correlates of PTH among young adults, and explore potential mechanisms. This was a cross-sectional study of healthy individuals, 24-36 years old, examined during 1992 through 1993 in California, USA (a subset of Coronary Artery Risk Development in Young Adults study). Linear regression was used to obtain adjusted means of PTH according to smoking habit (current, former, never). Biomarkers for calcium metabolism and bone turnover (including serum concentrations of osteocalcin, bone-specific alkaline phosphatase, and 24-hour urinary excretion of calcium) and bone mineral density were similarly compared by smoking. 376 participants were analyzed (171 women, 181 black). Over half reported never smoking. We observed lower PTH in current smokers compared to non-smokers and found no evidence of an interaction by race and sex. PTH was lowest in current smokers, intermediate in former smokers, and highest in never smokers (geometric mean PTH: 23.6, 26.7, 27.4 pg/mL, respectively: P for trend, 0.006) after adjusting for potential confounders including calcium intake. Among the biomarkers, serum osteocalcin concentration and 24-hour urinary excretion of calcium were lowest in current smokers. We observed no smoking-related difference in bone mineral density. In this community-based sample of young adult men and women, smoking was associated with significantly lower PTH concentration. The mechanism and clinical implication of the finding, however, remains uncertain.
Authors: Fujiyoshi A; Polgreen LE; Gross MD; Reis JP; Sidney S; Jacobs DR
Bone Rep. 2016 Dec;5:104-109. Epub 2016-4-28.
Characteristics associated with self-rated health in the CARDIA study: Contextualising health determinants by income group
An understanding of factors influencing health in socioeconomic groups is required to reduce health inequalities. This study investigated combinations of health determinants associated with self-rated health (SRH), and their relative importance, in income-based groups. Cross-sectional data from year 15 (2000 – 2001) of the CARDIA study (Coronary Artery Risk Development in Young Adults, USA) – 3648 men and women (mean 40 years) – were split into 5 income-based groups. SRH responses were categorized as ‘higher’/’lower’. Health determinants (medical, lifestyle, and social factors, living conditions) associated with SRH in each group were analyzed using classification tree analysis (CTA). Income and SRH were positively associated (p < 0.05). Data suggested an income-based gradient for lifestyle/medical/social factors/living conditions. Profiles, and relative importance ranking, of multi-domain health determinants, in relation to SRH, differed by income group. The highest ranking variable for each income group was chronic burden-personal health problem (<$25,000); physical activity ($25-50,000; $50-75,000; $100,000 +); and cigarettes/day ($75-100,000). In lower income groups, more risk factors and chronic burden indicators were associated with SRH. Social support, control over life, optimism, and resources for paying for basics/medical care/health insurance were greater (%) with higher income. SRH is a multidimensional measure; CTA is useful for contextualizing risk factors in relation to health status. Findings suggest that for lower income groups, addressing contributors to chronic burden is important alongside lifestyle/medical factors. In a proportionate universalism context, in addition to differences in intensity of public health action across the socioeconomic gradient, differences in the type of interventions to improve SRH may also be important.
Authors: Nayak S; Hubbard A; Sidney S; Syme SL
Prev Med Rep. 2016 Dec;4:199-208. Epub 2016-06-08.
Applying ethnic-specific bone mineral density T-scores to Chinese women in the USA
Caucasian reference data are used to classify bone mineral density in US women of all races. However, use of Chinese American reference data yields lower osteoporosis prevalence in Chinese women. The reduction in osteoporosis labeling may be relevant for younger Chinese women at low fracture risk. Caucasian reference data are used for osteoporosis classification in US postmenopausal women regardless of race, including Asians who tend to have lower bone mineral density (BMD) than women of white race. This study examines BMD classification by ethnic T-scores for Chinese women. Using BMD data in a Northern California healthcare population, Chinese women aged 50-79 years were compared to age-matched white women (1:5 ratio), with femoral neck (FN), total hip (TH), and lumbar spine (LS) T-scores calculated using Caucasian versus Chinese American reference data. Comparing 4039 Chinese and 20,195 white women (44.8 % age 50-59 years, 37.5 % age 60-69 years, 17.7 % age 70-79 years), Chinese women had lower BMD T-scores at the FN, TH, and LS (median T-score 0.29-0.72 units lower across age groups, p < 0.001) using Caucasian reference data. Using Chinese American BMD reference data resulted in an average +0.47, +0.36, and +0.48 units higher FN, TH, and LS T-scores, respectively, reducing the prevalence of osteoporosis (T-score ≤ -2.5) in Chinese women at the FN (16.7 to 6.6 %), TH (9.8 to 3.2 %), and LS (23.2 to 8.9 %); osteoporosis prevalence at any one of three sites fell from 29.6 to 12.6 % (22.4 to 8.1 % for age 50-64 years and 43.2 to 21.0 % for age 65-79 years). Use of Chinese American BMD reference data yields higher (ethnic) T-scores by 0.4-0.5 units, with a large proportion of Chinese women reclassified from osteoporosis to osteopenia. The reduction in osteoporosis labeling with ethnic T-scores may be relevant for younger Chinese women at low fracture risk.
Authors: Lo JC; Kim S; Chandra M; Ettinger B
Osteoporos Int. 2016 12;27(12):3477-3484. Epub 2016-07-28.
Statins for Primary Prevention in Older Adults: Uncertainty and the Need for More Evidence
Authors: Gurwitz JH; Go AS; Fortmann SP
JAMA. 2016 Nov 15;316(19):1971-1972.
Comparison of the ATRIA, CHADS2, and CHA2DS2-VASc stroke risk scores in predicting ischaemic stroke in a large Swedish cohort of patients with atrial fibrillation
Better stroke risk prediction is needed to optimize the anticoagulation decision in atrial fibrillation (AF). The ATRIA stroke risk score (ATRIA) was developed and validated in two large California community AF cohorts. We compared the performance of the ATRIA, CHADS2, and CHA2DS2-VASc scores in a national Swedish AF (SAF) cohort. We examined all Swedish patients hospitalized, or visiting a hospital-based outpatient clinic, with a diagnosis of AF from July 2005 through December 2010. Variables were determined from comprehensive national databases. Risk scores were assessed via C-index (C) and net reclassification improvement (NRI). The cohort included 152 153 AF patients not receiving warfarin. Overall, 11 053 acute ischaemic strokes were observed with mean rate 3.2%/year, higher than the 2%/year in the California cohorts. Using entire point scores, ATRIA had a good C of 0.708 (0.704-0.713), significantly better than CHADS2 0.690 (0.685-0.695) or CHA2DS2-VASc 0.694 (0.690-0.700). Using published cut-points for low/moderate/high risk, C deteriorated but ATRIA remained superior. Net reclassification improvement favoured ATRIA 0.16 (0.14-0.17) vs. CHADS2 and 0.21 (0.20-0.23) vs. CHA2DS2-VASc. Net reclassification improvement decreased when cut-points were altered to better fit the cohort’s stroke rates. In this SAF cohort, the ATRIA score predicted ischaemic stroke risk better than CHADS2 or CHA2DS2-VASc. However, relative performance of the categorical scores varied by population stroke rates. Score cut-points may need to be optimized to better fit local population stroke rates.
Authors: Aspberg S; Chang Y; Atterman A; Bottai M; Go AS; Singer DE
Eur Heart J. 2016 Nov 07;37(42):3203-3210. Epub 2016-03-03.
Marijuana Use and Type 2 Diabetes Mellitus: a Review
Marijuana is used by millions of people, with use likely to increase in the USA because of the trend towards increased decriminalization and legalization. Obesity and diabetes mellitus (DM) rates have increased dramatically in the USA over the past 30 years, with a recent estimate of 29 million individuals with DM. Because there is a plausible link between marijuana use and diabetes due to the known effects of cannabinoids on adipose tissue and glucose/insulin metabolism, it is important to study and understand how marijuana use is related to obesity and diabetes. This paper provides background on the human endocannabinoid system and studies of the association of marijuana use with body mass index/obesity, metabolic syndrome, prediabetes, and diabetes. The studies to date have shown that marijuana use is associated with either lower odds or no difference in the odds of diabetes than non-use.
Authors: Sidney S
Curr Diab Rep. 2016 Nov;16(11):117.
Research Needs to Improve Hypertension Treatment and Control in African Americans
Authors: Whelton PK; Hyman DJ; National Heart, Lung, and Blood Institute Working Group on Research Needs to Improve Hypertension Treatment and Control in African Americans; et al.
Hypertension. 2016 11;68(5):1066-1072. Epub 2016-09-12.
Urinary N-Telopeptide and Rate of Bone Loss Over the Menopause Transition and Early Postmenopause
The purpose of this study was to assess the ability of urinary N-telopeptide (U-NTX) to gauge rate of bone loss across and after the menopause transition (MT). U-NTX measurement was measured in early postmenopause in 604 participants from the Study of Women’s Health Across the Nation (SWAN). We examined the association between U-NTX and annualized rates of decline in lumbar spine and femoral neck bone mineral density (BMD) across the MT (1 year before the final menstrual period [FMP] to time of U-NTX measurement), after the MT (from time of U-NTX measurement to 2 to 4 years later), and over the combined period (from 1 year before FMP to 2 to 4 years after U-NTX measurement). Adjusted for covariates in multivariable linear regression, every standard deviation (SD) increase in U-NTX was associated with 0.6% and 0.4% per year faster declines in lumbar spine and femoral neck BMD across the MT; and 0.3% (lumbar spine) and 0.2% (femoral neck) per year faster declines over the combined period (across and after the MT) (all p < 0.01). Each SD increase in U-NTX was also associated with 44% and 50% greater risk of fast bone loss in the lumbar spine (defined as BMD decline in the fastest 16% of the distribution) across the MT (p < 0.001, c-statistic = 0.80) and over the combined period (across and after the MT) (p = 0.001, c-statistic = 0.80), respectively. U-NTX measured in early postmenopause is most strongly associated with rates of bone loss across the MT, and may aid early identification of women who have experienced fast bone loss during this critical period. © 2016 American Society for Bone and Mineral Research.
Authors: Shieh A; Ishii S; Greendale GA; Cauley JA; Lo JC; Karlamangla AS
J Bone Miner Res. 2016 Nov;31(11):2057-2064. Epub 2016-10-21.
CKD Progression and Mortality among Hispanics and Non-Hispanics
Although recommended approaches to CKD management are achieved less often in Hispanics than in non-Hispanics, whether long-term outcomes differ between these groups is unclear. In a prospective longitudinal analysis of participants enrolled into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies, we used Cox proportional hazards models to determine the association between race/ethnicity, CKD progression (50% eGFR loss or incident ESRD), incident ESRD, and all-cause mortality, and linear mixed-effects models to assess differences in eGFR slope. Among 3785 participants, 13% were Hispanic, 43% were non-Hispanic white (NHW), and 44% were non-Hispanic black (NHB). Over a median follow-up of 5.1 years for Hispanics and 6.8 years for non-Hispanics, 27.6% of all participants had CKD progression, 21.3% reached incident ESRD, and 18.3% died. Hispanics had significantly higher rates of CKD progression, incident ESRD, and mean annual decline in eGFR than did NHW (P<0.05) but not NHB. Hispanics had a mortality rate similar to that of NHW but lower than that of NHB (P<0.05). In adjusted analyses, the risk of CKD progression did not differ between Hispanics and NHW or NHB. However, among nondiabetic participants, compared with NHB, Hispanics had a lower risk of CKD progression (hazard ratio, 0.61; 95% confidence interval, 0.39 to 0.95) and incident ESRD (hazard ratio, 0.50; 95% confidence interval, 0.30 to 0.84). At higher levels of urine protein, Hispanics had a significantly lower risk of mortality than did non-Hispanics (P<0.05). Thus, important differences in CKD progression and mortality exist between Hispanics and non-Hispanics and may be affected by proteinuria and diabetes.
Authors: Fischer MJ; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators; et al.
J Am Soc Nephrol. 2016 Nov;27(11):3488-3497. Epub 2016-05-05.
Can delivery systems use cost-effectiveness analysis to reduce healthcare costs and improve value?
Understanding costs and ensuring that we demonstrate value in healthcare is a foundational presumption as we transform the way we deliver and pay for healthcare in the U.S. With a focus on population health and payment reforms underway, there is increased pressure to examine cost-effectiveness in healthcare delivery. Cost-effectiveness analysis (CEA) is a type of economic analysis comparing the costs and effects (i.e. health outcomes) of two or more treatment options. The result is expressed as a ratio where the denominator is the gain in health from a measure (e.g. years of life or quality-adjusted years of life) and the numerator is the incremental cost associated with that health gain. For higher cost interventions, the lower the ratio of costs to effects, the higher the value. While CEA is not new, the approach continues to be refined with enhanced statistical techniques and standardized methods. This article describes the CEA approach and also contrasts it to optional approaches, in order for readers to fully appreciate caveats and concerns. CEA as an economic evaluation tool can be easily misused owing to inappropriate assumptions, over reliance, and misapplication. Twelve issues to be considered in using CEA results to drive healthcare delivery decision-making are summarized. Appropriately recognizing both the strengths and the limitations of CEA is necessary for informed resource allocation in achieving the maximum value for healthcare services provided.
Authors: Savitz, Lucy A; Savitz, Samuel T
F1000Research. 2016 Dec 15;5(6):1274-1280. Epub 2016-10-25.
Natriuretic peptide-guided management in heart failure.
Heart failure is a clinical syndrome that manifests from various cardiac and noncardiac abnormalities. Accordingly, rapid and readily accessible methods for diagnosis and risk stratification are invaluable for providing clinical care, deciding allocation of scare resources, and designing selection criteria for clinical trials. Natriuretic peptides represent one of the most important diagnostic and prognostic tools available for the care of heart failure patients. Natriuretic peptide testing has the distinct advantage of objectivity, reproducibility, and widespread availability.The concept of tailoring heart failure management to achieve a target value of natriuretic peptides has been tested in various clinical trials and may be considered as an effective method for longitudinal biomonitoring and guiding escalation of heart failure therapies with overall favorable results.Although heart failure trials support efficacy and safety of natriuretic peptide-guided therapy as compared with usual care, the relationship between natriuretic peptide trajectory and clinical benefit has not been uniform across the trials, and certain subgroups have not shown robust benefit. Furthermore, the precise natriuretic peptide value ranges and time intervals of testing are still under investigation. If natriuretic peptides fail to decrease following intensification of therapy, further work is needed to clarify the optimal pharmacologic approach. Despite decreasing natriuretic peptide levels, some patients may present with other high-risk features (e.g. elevated troponin). A multimarker panel investigating multiple pathological processes will likely be an optimal alternative, but this will require prospective validation.Future research will be needed to clarify the type and magnitude of the target natriuretic peptide therapeutic response, as well as the duration of natriuretic peptide-guided therapy in heart failure patients.
Authors: Chioncel, Ovidiu O; Collins, Sean P SP; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; Macarie, Cezar C; Butler, Javed J; Gheorghiade, Mihai M
Journal of cardiovascular medicine (Hagerstown, Md.). 2016 Aug 01;17(8):556-68. Epub 2016-10-17.
Digoxin for Worsening Chronic Heart Failure: Underutilized and Underrated.
Authors: Ambrosy, Andrew P AP; Pang, Peter S PS; Gheorghiade, Mihai M
JACC. Heart failure. 2016 05 01;4(5):365-7. Epub 2016-10-17.
Changes in Dyspnea Status During Hospitalization and Postdischarge Health-Related Quality of Life in Patients Hospitalized for Heart Failure: Findings From the EVEREST Trial.
BACKGROUND: Dyspnea is the most common symptom among hospitalized patients with heart failure and represents a therapeutic target. However, the association between short-term dyspnea relief and postdischarge clinical outcomes and health-related quality of life (HRQOL) remains uncertain.METHODS AND RESULTS: A post hoc analysis was performed of the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which enrolled 4133 patients within 48 hours of admission for heart failure with an ejection fraction ≤40%. Physician-assessed dyspnea was recorded on a daily basis from baseline until discharge or day 7 as none, seldom, frequent, or continuous. Patient-reported dyspnea was measured using a 7-point Likert scale, and patients experiencing moderate or marked dyspnea improvement on day 1 were classified as early responders. The Kansas City Cardiomyopathy Questionnaire summary score, which ranges from 0 to 100, was collected postdischarge at week 1. The primary outcome was unfavorable HRQOL, defined a priori as a Kansas City Cardiomyopathy Questionnaire score CONCLUSIONS: In-hospital physician-assessed, and patient-reported dyspnea was not independently associated with postdischarge HRQOL, survival, or readmissions. Although dyspnea relief remains a goal of therapy for hospitalized patients with heart failure with reduced ejection fraction, this measure may not be a reliable surrogate for long-term patient-centered or hard clinical outcomes.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00071331.
Authors: Ambrosy, Andrew P AP; Khan, Hassan H; Udelson, James E JE; Mentz, Robert J RJ; Chioncel, Ovidiu O; Greene, Stephen J SJ; Vaduganathan, Muthiah M; Subacuis, Haris P HP; Konstam, Marvin A MA; Swedberg, Karl K; Zannad, Faiez F; Maggioni, Aldo P AP; Gheorghiade, Mihai M; Butler, Javed J
Circulation. Heart failure. 2016 05 01;9(5):419-27. Epub 2016-10-17.
Heart Failure Clinical Trials in East and Southeast Asia: Understanding the Importance and Defining the Next Steps.
Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.
Authors: Mentz, Robert J RJ; Roessig, Lothar L; Greenberg, Barry H BH; Sato, Naoki N; Shinagawa, Kaori K; Yeo, Daniel D; Kwok, Bernard W K BW; Reyes, Eugenio B EB; Krum, Henry H; Pieske, Burkert B; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Kelly, Jacob P JP; Zannad, Faiez F; Pitt, Bertram B; Lam, Carolyn S P CS
JACC. Heart failure. 2016 06 01;4(6):419-27. Epub 2016-10-17.
Influence of Clinical Trial Site Enrollment on Patient Characteristics, Protocol Completion, and End Points: Insights From the ASCEND-HF Trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure).
BACKGROUND: Most international acute heart failure trials have failed to show benefit with respect to key end points. The impact of site enrollment and protocol execution on trial performance is unclear.METHODS AND RESULTS: We assessed the impact of varying site enrollment volume among all 7141 acute heart failure patients from the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure). Overall, 398 sites enrolled ≥1 patient, and median enrollment was 12 patients (interquartile range, 5-23). Patients from high enrolling sites (>60 patients/site) tended to have lower ejection fraction, worse New York Heart Association functional class, and lower utilization of guideline-directed medical therapy but fewer comorbidities and lower B-type natriuretic peptide level. Every 10 patient increase (up to 100 patients) in site enrollment correlated with lower likelihood of protocol noncompletion (odds ratio, 0.93; 95% confidence interval [CI], 0.89-0.98). After adjustment, increasing site enrollment predicted higher risk of persistent dyspnea at 6 hours (per 10 patient increase: odds ratio 1.02; 95% CI, 1.01-1.03) but not at 24 hours (odds ratio, 0.99; 95% CI, 0.98-1.00). Higher site enrollment was independently associated with lower risk of 30-day death or rehospitalization (per 10 patient increase: odds ratio, 0.98, 95% CI, 0.96-0.99) but not 180-day mortality (hazard ratio, 0.99; 95% CI, 0.98-1.01). The influence of increasing site enrollment on clinical end points varied across geographic regions with strongest associations in Latin America and Asia-Pacific (all interaction P<0.01).CONCLUSIONS: In this large, acute heart failure trial, site enrollment correlated with protocol completion and was independently associated with trial end points. Individual and regional site performance present challenges to be considered in design of future acute heart failure trials.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00475852.
Authors: Greene, Stephen J SJ; Hernandez, Adrian F AF; Sun, Jie-Lena JL; Metra, Marco M; Butler, Javed J; Ambrosy, Andrew P AP; Ezekowitz, Justin A JA; Starling, Randall C RC; Teerlink, John R JR; Schulte, Phillip J PJ; Voors, Adriaan A AA; Armstrong, Paul W PW; O'Connor, Christopher M CM; Mentz, Robert J RJ
Circulation. Heart failure. 2016 09 01;9(9):552-562. Epub 2016-10-17.
Targeting digoxin dosing to serum concentration: is the bullseye too small?
Authors: Ambrosy, Andrew P AP; Gheorghiade, Mihai M
European journal of heart failure. 2016 08 01;18(8):1082-4. Epub 2016-10-17.
Influence of atrial fibrillation on post-discharge natriuretic peptide trajectory and clinical outcomes among patients hospitalized for heart failure: insights from the ASTRONAUT trial.
AIMS: Change in NT-proBNP level is a common surrogate endpoint in early phase heart failure (HF) trials, but whether this endpoint is influenced by atrial fibrillation/flutter (AFF) is unclear.METHODS AND RESULTS: This analysis included 1358 patients from the ASTRONAUT trial, which randomized patients hospitalized for HF with EF ≤40% to aliskiren or placebo in addition to standard care. Patients were stratified by presence of AFF on baseline ECG. NT-proBNP was measured longitudinally by a core laboratory at baseline, 1 month, 6 months, and 12 months. Compared with non-AFF patients, AFF patients experienced greater reduction from baseline in log-transformed NT-proBNP (interaction P < 0.001), but this difference was not significant after adjustment (interaction P = 0.726). The ability of aliskiren to lower NT-proBNP during follow-up differed by AFF status (interaction P = 0.001), with aliskiren lowering NT-proBNP more than placebo among non-AFF patients only. After adjustment, baseline AFF was not associated with mortality or HF hospitalization at 12 months (all P ≥ 0.152).CONCLUSION: In this hospitalized HF cohort, AFF status did not influence post-discharge NT-proBNP trajectory or clinical outcomes after adjustment for patient characteristics. Aliskiren lowered follow-up NT-proBNP levels in patients without AFF, but had no influence among patients with AFF. This study generates the hypothesis that the ability of a HF trial to meet an NT-proBNP defined endpoint may be influenced by the prevalence of AFF in the population. Because aliskiren did not improve outcomes in patients without AFF, this analysis suggests changes in NT-proBNP induced by investigational therapies may be dissociated from clinical effects.
Authors: Greene, Stephen J SJ; Fonarow, Gregg C GC; Solomon, Scott D SD; Subacius, Haris P HP; Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; Maggioni, Aldo P AP; Böhm, Michael M; Lewis, Eldrin F EF; Zannad, Faiez F; Butler, Javed J; Gheorghiade, Mihai M;
European journal of heart failure. 2017 04 01;19(4):552-562. Epub 2016-10-17.
No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis
In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
Authors: Loley C; Iribarren C; König IR; et al.
Sci Rep. 2016 10 12;6:35278. Epub 2016-10-12.
Influence of Kidney Function Estimation Methods on Eligibility for Edoxaban Population Impact of the US Food and Drug Administration’s Approach for Its Product Labeling
Authors: Pokorney SD; Go AS; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators; et al.
Circulation. 2016 10 11;134(15):1122-1124.
Mortality following hip fracture in Chinese, Japanese, and Filipina women
Authors: Patel MC; Chandra M; Lo JC
Am J Manag Care. 2016 Oct 01;22(10):e358-e359. Epub 2016-10-01.
The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
Authors: Ehret GB; Iribarren C; Munroe PB; et al.
Nat Genet. 2016 Oct;48(10):1171-84. Epub 2016-09-12.
Race/Ethnicity and Cardiovascular Outcomes in Adults With CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic CRIC Studies
Non-Hispanic blacks and Hispanics with end-stage renal disease have a lower risk for death than non-Hispanic whites, but data for racial/ethnic variation in cardiovascular outcomes for non-dialysis-dependent chronic kidney disease are limited. Prospective cohort. 3,785 adults with entry estimated glomerular filtration rates of 20 to 70mL/min/1.73m(2) enrolled in the CRIC (Chronic Renal Insufficiency Cohort) Study. Race/ethnicity (non-Hispanic white, non-Hispanic black, and Hispanic). Cardiovascular outcomes (atherosclerotic events [myocardial infarction, stroke, or peripheral arterial disease] and heart failure) and a composite of each cardiovascular outcome or all-cause death. Multivariable Cox proportional hazards. During a median follow-up of 6.6 years, we observed 506 atherosclerotic events, 551 heart failure events, and 692 deaths. In regression analyses, there were no significant differences in atherosclerotic events among the 3 racial/ethnic groups. In analyses stratified by clinical site, non-Hispanic blacks had a higher risk for heart failure events (HR, 1.59; 95% CI, 1.29-1.95), which became nonsignificant after adjustment for demographic factors and baseline kidney function. In contrast, Hispanics had similar risk for heart failure events as non-Hispanic whites. In analyses stratified by clinical site, compared with non-Hispanic whites, non-Hispanic blacks were at similar risk for atherosclerotic events or death. However, after further adjustment for cardiovascular risk factors, medications, and mineral metabolism markers, non-Hispanic blacks had 17% lower risk for the outcome (HR, 0.83; 95% CI, 0.69-0.99) than non-Hispanic whites, whereas there was no significant association with Hispanic ethnicity. Hispanics were largely recruited from a single center, and the study was underpowered to evaluate the association between Hispanic ethnicity and mortality. There were no significant racial/ethnic differences in adjusted risk for atherosclerotic or heart failure outcomes. Future research is needed to better explain the reduced risk for atherosclerotic events or death in non-Hispanic blacks compared with non-Hispanic whites.
Authors: Lash JP; CRIC Study Investigators; CRIC Study Investigators; et al.
Am J Kidney Dis. 2016 Oct;68(4):545-53. Epub 2016-05-19.
Mild prolonged chronic hyponatremia and risk of hip fracture in the elderly
Hip fractures are among the most serious bone fractures in the elderly, producing significant morbidity and mortality. Several observational studies have found that mild hyponatremia can adversely affect bone, with fractures occurring as a potential complication. We examined if there is an independent association between prolonged chronic hyponatremia (>90 days duration) and risk of hip fracture in the elderly. We performed a retrospective cohort study in adults >60 years of age from a prepaid health maintenance organization who had two or more measurements of plasma sodium between 2005 and 2012. The incidence of hip fractures was assessed in a very restrictive population: subjects with prolonged chronic hyponatremia, defined as plasma sodium values <135 mmol/L, lasting >90 days. Multivariable Cox regression was performed to determine the hazard ratio (HR) for hip fracture risk associated with prolonged chronic hyponatremia after adjustment for the propensity to have hyponatremia, fracture risk factors and relevant baseline characteristics. Among 31 527 eligible patients, only 228 (0.9%) had prolonged chronic hyponatremia. Mean plasma sodium was 132 ± 5 mmol/L in hyponatremic patients and 139 ± 3 mmol/L in normonatremic patients (P < 0.001). The absolute risk for hip fracture was 7/282 in patients with prolonged chronic hyponatremia and 411/313 299 in normonatremic patients. Hyponatremic patients had a substantially elevated rate of hip fracture [adjusted HR 4.52 (95% CI 2.14-9.6)], which was even higher in those with moderate hyponatremia (<130 mmol/L) [adjusted HR 7.61 (95% CI 2.8-20.5)]. Mild prolonged chronic hyponatremia is independently associated with hip fracture risk in the elderly population, although the absolute risk is low. However, proof that correcting hyponatremia will result in a reduction of hip fractures is lacking.
Authors: Ayus JC; Fuentes NA; Negri AL; Moritz ML; Giunta DH; Kalantar-Zadeh K; Nigwekar SU; Thadhani RI; Go AS; De Quiros FG
Nephrol Dial Transplant. 2016 Oct;31(10):1662-9. Epub 2016-03-23.
Measurement Error as Alternative Explanation for the Observation that CrCl/GFR Ratio is Higher at Lower GFR
Overestimation of GFR by urinary creatinine clearance (CrCl) at lower levels of GFR has long been attributed to enhanced creatinine secretion. However, this does not take into consideration the contribution of errors in measured GFR (and CrCl) due to short-term biologic variability or test imprecision. We analyzed cross-sectional data among 1342 participants from the Chronic Renal Insufficiency Cohort study with baseline measurement of GFR by iothalamate clearance (iGFR) and CrCl by 24-hour urine collection. We examined the CrCl/iGFR ratio classified by categories of iGFR and also by categories of CrCl. Overall, mean CrCl/iGFR ratio was 1.13. CrCl/iGFR ratio was higher at lower iGFR categories. In contrast, this ratio was lower at lower CrCl levels. We hypothesize these relationships could be due to measurement error, which is bolstered by replicating these trends in a simulation and modeling exercise in which there was no variation in the ratio of CrCl/iGFR with true kidney function but taking into account the effect of measurement error in both CrCl and iGFR (of magnitudes previously described in the literature). In our simulated data, the observed CrCl/iGFR ratio was higher at lower observed iGFR levels when patients were classified by categories of observed iGFR. When the same patients were classified by categories of observed CrCl, the observed CrCl/iGFR ratio was lower at lower observed CrCl levels. The combined empirical and modeling results suggest that measurement errors (in both CrCl and iGFR) should be considered as an alternative explanation for the longstanding observation that the ratio of CrCl to iGFR gets larger as iGFR decreases.
Authors: Zhang X; McCulloch CE; Lin F; Lin YC; Allen IE; Bansal N; Go AS; Hsu CY
Clin J Am Soc Nephrol. 2016 Sep 07;11(9):1574-81. Epub 2016-08-03.
Sleep Duration and White Matter Quality in Middle-Aged Adults
Sleep duration has been associated with risk of dementia and stroke, but few studies have investigated the relationship between sleep duration and brain MRI measures, particularly in middle age. In a prospective cohort of 613 black and white adults (mean age = 45.4 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, participants reported typical sleep duration, dichotomized into moderate sleep duration (> 6 to ≤ 8 h) and short sleep duration (≤ 6 h) at baseline (2005-2006). Five years later, we obtained brain MRI markers of white matter including fractional anisotropy, mean diffusivity, and white matter hyperintensities. Compared to moderate sleepers, short sleepers had an elevated ratio of white matter hyperintensities to normal tissue in the parietal region (OR = 2.31, 95% CI: 1.47, 3.61) adjusted for age, race/sex, education, hypertension, stroke/TIA, depression, smoking status, and physical activity. White matter diffusivity was also higher, approximately a 0.2 standard deviation difference, in frontal, parietal, and temporal white matter regions, among those reporting shorter sleep duration in (P < 0.05 for all). Short sleep duration was associated with worse markers of white matter integrity in midlife. These mid-life differences in white matter may underlie the link between poor sleep and risk of dementia and stroke.
Authors: Yaffe K; Nasrallah I; Hoang TD; Lauderdale DS; Knutson KL; Carnethon MR; Launer LJ; Lewis CE; Sidney S
Sleep. 2016 Sep 01;39(9):1743-7. Epub 2016-09-01.
25-year weight gain in a racially balanced sample of U.S. adults: The CARDIA study
To examine 25-year trends in weight gain, partitioned by time-related and aging-related changes, during early and middle adulthood. Coronary Artery Risk Development in Young Adults (CARDIA), a prospective, non-nationally representative cohort study conducted at four urban field centers that began in 1985 to 1986 with 5,109 Black (B) and White (W) men (M) and women (W) aged 18 to 30 years, has followed participants for 25 years (aged 43-55 years in 2010-2011). Time-related and aging-related components of weight change were estimated to construct longitudinal models of linear and nonlinear trends. There were nonlinear trends in time-related weight gain in W, with larger weight gains early that attenuated at subsequent exams. Time-related trends were linear in M. There were nonlinear trends in aging-related weight gain in BM, BW, and WM, with the greatest weight gains at younger ages. Aging-related trends were linear in WW. Participants with overweight or obesity in early adulthood had greater attenuation of aging-related weight gain during middle adulthood. These findings partially support recent surveys indicating slower increases in obesity prevalence in recent years. Findings further suggest that aging-related weight gain is greatest in the 20s and may begin attenuating as early as the mid-30s among some groups.
Authors: Dutton GR; Lewis CE; Lewis CE; et al.
Obesity (Silver Spring). 2016 Sep;24(9):1962-8.
How Well Do Stroke Risk Scores Predict Hemorrhage in Patients With Atrial Fibrillation?
The decision to use anticoagulants for atrial fibrillation depends on comparing a patient’s estimated risk of stroke to their bleeding risk. Several of the risk factors in the stroke risk schemes overlap with hemorrhage risk. We compared how well 2 stroke risk scores (CHADS2 and CHA2DS2-VASc) and 2 hemorrhage risk scores (the ATRIA bleeding score and the HAS-BLED score) predicted major hemorrhage on and off warfarin in a cohort of 13,559 community-dwelling adults with AF. Over a cumulative 64,741 person-years of follow-up, we identified a total of 777 incident major hemorrhage events. The ATRIA bleeding score had the highest predictive ability of all the scores in patients on warfarin (c-index of 0.74 [0.72 to 0.76] compared with 0.65 [0.62 to 0.67] for CHADS2, 0.65 [0.62 to 0.67] for CHA2DS2-VASc, and 0.64 [0.61 to 0.66] for HAS-BLED) and in those off warfarin (0.77 [0.74 to 0.79] compared with 0.67 [0.64 to 0.71] for CHADS2, 0.67 [0.64 to 0.70] for CHA2DS2-VASc, and 0.68 [0.65 to 0.71] for HAS-BLED). In conclusion, although CHADS2 and CHA2DS2-VASc stroke scores were better at predicting hemorrhage than chance alone, they were inferior to the ATRIA bleeding score. Our study supports the use of dedicated hemorrhage risk stratification tools to predict major hemorrhage in atrial fibrillation.
Authors: Quinn GR; Singer DE; Chang Y; Go AS; Borowsky LH; Fang MC
Am J Cardiol. 2016 Sep 01;118(5):697-9. Epub 2016-06-15.
A Predictive Metabolic Signature for the Transition from Gestational Diabetes to Type 2 Diabetes
Gestational diabetes mellitus (GDM) affects 3-14% of pregnancies, with 20-50% of these women progressing to type 2 diabetes (T2D) within 5 years. This study sought to develop a metabolomics signature to predict the transition from GDM to T2D. A prospective cohort of 1,035 women with GDM pregnancy were enrolled at 6-9 weeks postpartum (baseline) and were screened for T2D annually for 2 years. Of 1,010 women without T2D at baseline, 113 progressed to T2D within 2 years. T2D developed in another 17 women between 2 and 4 years. A nested case-control design used 122 incident case patients matched to non-case patients by age, prepregnancy BMI, and race/ethnicity. We conducted metabolomics with baseline fasting plasma and identified 21 metabolites that significantly differed by incident T2D status. Machine learning optimization resulted in a decision tree modeling that predicted T2D incidence with a discriminative power of 83.0% in the training set and 76.9% in an independent testing set, which is far superior to measuring fasting plasma glucose levels alone. The American Diabetes Association recommends T2D screening in the early postpartum period via oral glucose tolerance testing after GDM, which is a time-consuming and inconvenient procedure. Our metabolomics signature predicted T2D incidence from a single fasting blood sample. This study represents the first metabolomics study of the transition from GDM to T2D validated in an independent testing set, facilitating early interventions.
Authors: Allalou A; Nalla A; Prentice KJ; Liu Y; Zhang M; Dai FF; Ning X; Osborne LR; Cox BJ; Gunderson EP; Wheeler MB
Diabetes. 2016 Sep;65(9):2529-39. Epub 2016-06-23.
Community-Based Trends in Acute Myocardial Infarction From 2008 to 2014
Authors: Solomon MD; Leong TK; Rana JS; Xu Y; Go AS
J Am Coll Cardiol. 2016 08 09;68(6):666-668.
High-sensitivity cardiac troponin I and incident coronary heart disease among asymptomatic older adults
High-sensitivity cardiac troponin I (hs-cTnI) is a novel biomarker of myocardial injury and ischaemia. Our objective was to ascertain correlates of hs-cTnI and its incremental prognostic utility for incident coronary heart disease (CHD) among older asymptomatic subjects. We performed a cohort study among 1135 asymptomatic control participants in the ADVANCE (Atherosclerotic Disease, VAscular FunctioN and GenetiC Epidemiology) study at Kaiser Permanente Northern California and Stanford University, with follow-up through 31 December 2014. Hs-cTnI was measured in stored baseline (2002-2004) serum samples. After a median follow-up of 11.3 years, 164 CHD events were documented. The most significant correlates of hs-cTnI were black race, body mass index, hypertension, LDL cholesterol and estimated glomerular filtration rate (eGFR) (R(2)=0.16) After adjustment for race/ethnicity, education level, diabetes status, ATP-III Framingham risk score (FRS), C reactive protein and eGFR, each 1 SD increment of log-transformed Hs-cTnI was associated with 1.11 (95% CI 1.01 to 1.23, p=0.04) increased hazard of CHD. The c-statistic increased to 0.70 from 0.68 (p=0.16) and the category-based net reclassification index was 18% (95% CI 8% to 30%) after adding hs-cTnI to the model containing the ATP-III FRS. Hs-cTnI conveys incremental prognostic information for incident CHD among asymptomatic older adults.
Authors: Iribarren C; Chandra M; Rana JS; Hlatky MA; Fortmann SP; Quertermous T; Go AS
Heart. 2016 Aug 01;102(15):1177-82. Epub 2016-03-30.
Recent Trends in Cardiovascular Mortality in the United States and Public Health Goals
Heart disease (HD) and cancer are the 2 leading causes of death in the United States. During the first decade of the 21st century, HD mortality declined at a much greater rate than cancer mortality and it appeared that cancer would overtake HD as the leading cause of death. To determine whether changes in national trends had occurred in recent years in mortality rates due to all cardiovascular disease (CVD), HD, stroke, and cancer and to evaluate the gap between mortality rates from HD and cancer. The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system was used to determine national trends in age-adjusted mortality rates due to all CVD, HD, stroke, and cancer from January 1, 2000, to December 31, 2011, and January 1, 2011, to December 31, 2014, overall, by sex, and by race/ethnicity. The present study was conducted from December 30, 2105, to January 18, 2016. Comparison of annual rates of change and trend in gap between HD and cancer mortality rates. The rate of the decline in all CVD, HD, and stroke mortality decelerated substantially after 2011, and the rate of decline for cancer mortality remained relatively stable. Reported as percentage (95% CI), the annual rates of decline for 2000-2011 were 3.79% (3.61% to 3.97%), 3.69% (3.51% to 3.87%), 4.53% (4.34% to 4.72%), and 1.49% (1.37% to 1.60%) for all CVD, HD, stroke, and cancer mortality, respectively; the rates for 2011-2014 were 0.65% (-0.18% to 1.47%), 0.76% (-0.06% to 1.58%), 0.37% (-0.53% to 1.27%), and 1.55% (1.07% to 2.04%), respectively. Deceleration of the decline in all CVD mortality rates occurred in males, females, and all race/ethnicity groups. For example, the annual rates of decline for total CVD mortality for 2000-2011 were 3.69% (3.48% to 3.89%) for males and 3.98% (3.81% to 4.14%) for females; for 2011-2014, the rates were 0.23% (-0.71% to 1.16%) and 1.17% (0.41% to 1.93%), respectively. The gap between HD and cancer mortality persisted. Deceleration in the decline of all CVD, HD, and stroke mortality rates has occurred since 2011. If this trend continues, strategic goals for lowering the burden of CVD set by the American Heart Association and the Million Hearts Initiative may not be reached.
Authors: Sidney S; Quesenberry CP; Jaffe MG; Sorel M; Nguyen-Huynh MN; Kushi LH; Go AS; Rana JS
JAMA Cardiol. 2016 08 01;1(5):594-9.
Association of Fibroblast Growth Factor 23 With Atrial Fibrillation in Chronic Kidney Disease, From the Chronic Renal Insufficiency Cohort Study
Levels of fibroblast growth factor 23 (FGF23) are elevated in chronic kidney disease (CKD) and strongly associated with left ventricular hypertrophy, heart failure, and death. Whether FGF23 is an independent risk factor for atrial fibrillation in CKD is unknown. To investigate the association of FGF23 with atrial fibrillation in CKD. Prospective cohort study of 3876 individuals with mild to severe CKD who enrolled in the Chronic Renal Insufficiency Cohort Study between June 19, 2003, and September 3, 2008, and were followed up through March 31, 2013. Baseline plasma FGF23 levels. Prevalent and incident atrial fibrillation. The study cohort comprised 3876 participants. Their mean (SD) age was 57.7 (11.0) years, and 44.8% (1736 of 3876) were female. Elevated FGF23 levels were independently associated with increased odds of prevalent atrial fibrillation (n = 660) after adjustment for cardiovascular and CKD-specific factors (odds ratio of highest vs lowest FGF23 quartile, 2.30; 95% CI, 1.69-3.13; P < .001 for linear trend across quartiles). During a median follow-up of 7.6 years (interquartile range, 6.3-8.6 years), 247 of the 3216 participants who were at risk developed incident atrial fibrillation (11.9 events per 1000 person-years). In fully adjusted models, elevated FGF23 was independently associated with increased risk of incident atrial fibrillation after adjustment for demographic, cardiovascular, and CKD-specific factors, and other markers of mineral metabolism (hazard ratio of highest vs lowest FGF23 quartile, 1.59; 95% CI, 1.00-2.53; P = .02 for linear trend across quartiles). The results were unchanged when further adjusted for ejection fraction, but individual adjustments for left ventricular mass index, left atrial area, and interim heart failure events partially attenuated the association of elevated FGF23 with incident atrial fibrillation. Elevated FGF23 is independently associated with prevalent and incident atrial fibrillation in patients with mild to severe CKD. The effect may be partially mediated through a diastolic dysfunction pathway that includes left ventricular hypertrophy, atrial enlargement, and heart failure events.
Authors: Mehta R; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators; et al.
JAMA Cardiol. 2016 08 01;1(5):548-56.
Relation of longitudinal changes in body mass index with atherosclerotic cardiovascular disease risk scores in middle-aged black and white adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study
We assessed whether longitudinal changes in body mass index (BMI) are positively associated with changes in 10-year American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease (ASCVD) risk scores in middle-aged blacks compared to whites. Data were from 1691 participants enrolled in the Coronary Artery Risk Development in Young Adults Study aged 40 years or more in 2000-2001, who had follow-up examinations 5 and 10 years later. The prevalence of obesity increased from 32.3% in 2000-2001 (mean age: 42.8 years) to 41.7% in 2010-2011, higher in blacks than whites. The corresponding change in 10-year ASCVD risk was significantly higher for blacks (men: 4.5%-9.6%, women: 1.7%-5.0%) than whites (men: 2.4%-5.2%, women: 0.7%-1.6%). In 2010-2011, 57.5% of black men had ASCVD risk scores of 7.5% or more compared to white men (14.7%), black women (17.4%), and white women (1.6%). Although BMI trends were positively associated with 10-year change in ASCVD risk scores (0.07% per 1 kg/m(2) increase), it explained very little variance in risk score trends in all race-sex groups. In middle-aged adults, longitudinal changes in BMI had little independent influence on changes in 10-year ASCVD risk scores as its effect may be largely mediated through ASCVD risk factors already accounted for in the risk score.
Authors: Appiah D; Schreiner PJ; Durant RW; Kiefe CI; Loria C; Lewis CE; Williams OD; Person SD; Sidney S
Ann Epidemiol. 2016 Aug;26(8):521-526. Epub 2016-06-17.
Long-Term Microvascular Disease Outcomes in Patients With Type 2 Diabetes After Bariatric Surgery: Evidence for the Legacy Effect of Surgery
To identify and quantify any legacy effect of bariatric surgery on risk of incident microvascular disease in patients with type 2 diabetes. We conducted a retrospective observational cohort study (n = 4,683; 40% racial/ethnic minority) of patients with type 2 diabetes who underwent bariatric surgery from 2001 through 2011. The primary outcome measure was incident microvascular disease defined as a composite indicator of the first occurrence of retinopathy, neuropathy, and/or nephropathy. The Cox proportional hazards framework was used to investigate the associations between type 2 diabetes remission/relapse status and time to microvascular disease. Covariate-adjusted analyses showed that patients who experienced type 2 diabetes remission had 29% lower risk of incident microvascular disease compared with patients who never remitted (hazard ratio [HR] 0.71 [95% CI 0.60, 0.85]). Among patients who experienced a relapse after remission, the length of time spent in remission was inversely related to the risk of incident microvascular disease; for every additional year of time spent in remission prior to relapse, the risk of microvascular disease was reduced by 19% (HR 0.81 [95% CI 0.67, 0.99]) compared with patients who never remitted. Our results indicate that remission of type 2 diabetes after bariatric surgery confers benefits for risk of incident microvascular disease even if patients eventually experience a relapse of their type 2 diabetes. This provides support for a legacy effect of bariatric surgery, where even a transient period of surgically induced type 2 diabetes remission is associated with lower long-term microvascular disease risk.
Authors: Coleman KJ; Theis MK; Arterburn D; et al.
Diabetes Care. 2016 08;39(8):1400-7. Epub 2016-06-06.
Abrupt Decline in Kidney Function Before Initiating Hemodialysisand All-Cause Mortality: The Chronic Renal Insufficiency Cohort (CRIC) Study
It is not clear whether the pattern of kidney function decline in patients with chronic kidney disease (CKD) may relate to outcomes after reaching end-stage renal disease (ESRD). We hypothesize that an abrupt decline in kidney function prior to ESRD predicts early death after initiating maintenance hemodialysis therapy. Prospective cohort study. The Chronic Renal Insufficiency Cohort (CRIC) Study enrolled men and women with mild to moderate CKD. For this study, we studied 661 individuals who developed chronic kidney failure that required hemodialysis therapy initiation. The primary predictor was the presence of an abrupt decline in kidney function prior to ESRD. We incorporated annual estimated glomerular filtration rates (eGFRs) into a mixed-effects model to estimate patient-specific eGFRs at 3 months prior to initiation of hemodialysis therapy. Abrupt decline was defined as having an extrapolated eGFR?30mL/min/1.73m(2) at that time point. All-cause mortality within 1 year after initiating hemodialysis therapy. Multivariable Cox proportional hazards. Among 661 patients with CKD initiating hemodialysis therapy, 56 (8.5%) had an abrupt predialysis decline in kidney function and 69 died within 1 year after initiating hemodialysis therapy. After adjustment for demographics, cardiovascular disease, diabetes, and cancer, abrupt decline in kidney function was associated with a 3-fold higher risk for death within the first year of ESRD (adjusted HR, 3.09; 95% CI, 1.65-5.76). Relatively small number of outcomes; infrequent (yearly) eGFR determinations; lack of more granular clinical data. Abrupt decline in kidney function prior to ESRD occurred in a significant minority of incident hemodialysis patients and predicted early death in ESRD.
Authors: Hsu RK; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2016 Aug;68(2):193-202. Epub 2016-01-29.
Impact of Increased Early Statin Administration on Ischemic Stroke Outcomes: A Multicenter Electronic Medical Record Intervention
Statin administration early in ischemic stroke may influence outcomes. Our aim was to determine the clinical impact of increasing statin administration early in ischemic stroke hospitalization. This is a retrospective analysis of a multicenter electronic medical record (EMR) intervention to increase early statin administration in ischemic stroke across all 20 hospitals of an integrated healthcare delivery system. A stroke EMR order set was modified from an “opt-in” to “opt-out” mode of statin ordering. Outcomes were mortality by 90 days, discharge disposition, and increase in stroke severity. We examined the relationship between intervention and outcome using autoregressive integrated moving average (ARIMA) time-series modeling. The EMR intervention increased both overall in-hospital statin administration (from 87.2% to 90.7%, P<0.001) and early statin administration (from 16.9% to 26.3%, P<0.001). ARIMA models showed a small increase in the rate of survival (difference in probability [Pdiff]=0.02, P=0.016) and discharge to home or rehabilitation facility (Pdiff=0.04, P=0.034) associated with the intervention. The increase in statin administration <8 hours was associated with much larger increases in survival (Pdiff=0.17, P=0.033) and rate of discharge to home or rehabilitation (Pdiff=0.29, P=0.011), as well as a decreased rate of neurological deterioration in-hospital (Pdiff=-0.14, P=0.026). A simple EMR change increased early statin administration in ischemic stroke and was associated with improved clinical outcomes. This is, to our knowledge, the first EMR intervention study to show that a modification of an electronic order set resulted in improved clinical outcomes.
Authors: Flint AC; Conell C; Klingman JG; Rao VA; Chan SL; Kamel H; Cullen SP; Faigeles BS; Sidney S; Johnston SC
J Am Heart Assoc. 2016 Jul 29;5(8). Epub 2016-07-29.
Stability of High-Quality Warfarin Anticoagulation in a Community-Based Atrial Fibrillation Cohort: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study
Warfarin reduces ischemic stroke risk in atrial fibrillation (AF) but increases bleeding risk. Novel anticoagulants challenge warfarin as stroke-preventive therapy for AF. They are available at fixed doses but are more costly. Warfarin anticoagulation at a time in therapeutic range (TTR) ≥70% is similarly as effective and safe as novel anticoagulants. It is unclear whether AF patients with TTR ≥70% will remain stably anticoagulated and avoid the need to switch to a novel anticoagulant. We assessed stability of warfarin anticoagulation in AF patients with an initial TTR ≥70%. Within the community-based Anticoagulation and Risk Factors in AF (ATRIA) cohort followed from 1996 to 2003, we identified 2841 new warfarin users who continued warfarin over 9 months. We excluded months 1 to 3 to achieve a stable dose. For the 987 patients with TTR ≥70% in an initial 6-month period (TTR1; months 4-9), we described the distribution of TTR2 (months 10-15) and assessed multivariable correlates of persistent TTR ≥70%. Of patients with TTR1 ≥70%, 57% persisted with TTR2 ≥70% and 16% deteriorated to TTR2 <50%. Only initial TTR1 ≥90% (adjusted odds ratio 1.47, 95% CI 1.07-2.01) independently predicted TTR2 ≥70%. Heart failure was moderately associated with marked deterioration (TTR2 <50%); adjusted odds ratio 1.45, 95% CI 1.00-2.10. Nearly 60% of AF patients with high-quality TTR1 on warfarin maintained TTR ≥70% over the next 6 months. A minority deteriorated to very poor TTR. Patient features did not strongly predict TTR in the second 6-month period. Our analyses support watchful waiting for AF patients with initial high-quality warfarin anticoagulation before considering alternative anticoagulants.
Authors: Dallalzadeh LO; Go AS; Chang Y; Borowsky LH; Fang MC; Singer DE
J Am Heart Assoc. 2016 Jul 22;5(7). Epub 2016-07-22.
Multimorbidity is strongly associated with long-term but not short-term mortality after cardiac valve replacement
The presence of multimorbidity is known to be related to adverse clinical outcomes. However, its association with mortality in patients undergoing cardiac valve replacement is not known. Multimorbidity (as a continuous variable) was characterized in adults receiving cardiac valve replacement surgery between 2008 and 2012 within Kaiser Permanente Northern California based on information from health plan electronic health records. Our primary outcome was 3-year all-cause mortality after surgery. We used Cox proportional hazards regression to evaluate the independent association of each additional comorbidity with mortality. Among 3686 eligible patients, mean age was 67.9±13.5years and median comorbidity burden was 3 (IQR: 2). The presence of most individual comorbidities except hypertension and hyperlipidemia did not occur in isolation. The unadjusted annual incidence (per 100 person-years) of death increased with higher comorbidity burden: ≤1: 4.61 (95% CI: 3.29-6.45), 2-3: 13.7 (95% CI: 11.9-15.8), 4-5: 23.6 (95% CI: 20.6-26.9), and ≥6: 43.4(95% CI: 34.6-54.4). Advancing age, diabetes mellitus, cerebrovascular accident, heart failure, lung disease, urgent status and use of aldosterone-receptor antagonists were independently associated with an increased risk of mortality. In multivariable analyses, each additional comorbidity was significantly associated with an increased risk of long-term (adjusted hazard ratio (HR) 1.30, 95% CI: 1.22-1.39) but not short-term mortality (HR 0.92, 95% CI: 0.80-1.07). Our study demonstrated that multimorbidity in patients undergoing cardiac valve replacement is significantly associated with long-term but not short-term mortality.
Authors: Krishnaswami A; Go AS; Forman DE; Leong TK; Lee H; Maurer MS; McCulloch CE
Int J Cardiol. 2016 Jul 15;215:417-21. Epub 2016-04-14.
Cognitive Impairment and Progression of CKD
Cognitive impairment is common among patients with chronic kidney disease (CKD); however, its prognostic significance is unclear. We assessed the independent association between cognitive impairment and CKD progression in adults with mild to moderate CKD. Prospective cohort. Adults with CKD participating in the CRIC (Chronic Renal Insufficiency Cohort) Study. Mean age of the sample was 57.7±11.0 years and mean estimated glomerular filtration rate (eGFR) was 45.0±16.9mL/min/1.73m(2). Cognitive function was assessed with the Modified Mini-Mental State Examination at study entry. A subset of participants 55 years and older underwent 5 additional cognitive tests assessing different domains. Cognitive impairment was defined as a score > 1 SD below the mean score on each test. Covariates included demographics, kidney function, comorbid conditions, and medications. Incident end-stage renal disease (ESRD) and incident ESRD or 50% decline in baseline eGFR. In 3,883 CRIC participants, 524 (13.5%) had cognitive impairment at baseline. During a median 6.1 years of follow-up, 813 developed ESRD and 1,062 developed ESRD or a ?50% reduction in eGFR. There was no significant association between cognitive impairment and risk for ESRD (HR, 1.07; 95% CI, 0.87-1.30) or the composite of ESRD or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.89-1.27). Similarly, there was no association between cognitive impairment and the joint outcome of death, ESRD, or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.91-1.23). Among CRIC participants who underwent additional cognitive testing, we found no consistent association between impairment in specific cognitive domains and risk for CKD progression in adjusted analyses. Unmeasured potential confounders, single measure of cognition for younger participants. Among adults with CKD, cognitive impairment is not associated with excess risk for CKD progression after accounting for traditional risk factors.
Authors: Kurella Tamura M; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators; et al.
Am J Kidney Dis. 2016 Jul;68(1):77-83. Epub 2016-03-10.
Cardiovascular Disease Consequences of CKD
Chronic kidney disease, defined as reduced glomerular filtration rate (estimated using serum creatinine- and/or serum cystatin C-based equations) or excess urinary protein excretion, affects approximately 13% of adult Americans and is linked to a variety of clinical complications. Although persons with end-stage renal disease requiring chronic dialysis therapy experience a substantially high cardiovascular burden, whether mild-to-moderate chronic kidney disease is an independent risk factor for fatal and nonfatal cardiovascular events has been more controversial. This review evaluates the current evidence about the clinical and subclinical cardiovascular consequences associated with chronic kidney disease of varying levels of severity. In addition, it discusses the predictors of adverse cardiovascular outcomes while also focusing on recent insights into the relationships between chronic kidney disease and cardiovascular disease from the Chronic Renal Insufficiency Cohort study, a large current prospective cohort study of adults from across the spectrum of chronic kidney disease.
Authors: Go AS
Semin Nephrol. 2016 Jul;36(4):293-304.
Change in Measured GFR Versus eGFR and CKD Outcomes
Measured GFR (mGFR) has long been considered the gold standard measure of kidney function, but recent studies have shown that mGFR is not consistently superior to eGFR in explaining CKD-related comorbidities. The associations between longitudinal changes in mGFR versus eGFR and adverse outcomes have not been examined. We analyzed a subset of 942 participants with CKD in the Chronic Renal Insufficiency Cohort Study who had at least two mGFRs and two eGFRs determined concurrently by iothalamate and creatinine (eGFRcr) or cystatin C, respectively. We compared the associations between longitudinal changes in each measure of kidney function over 2 years and risks of ESRD, nonfatal cardiovascular events, and all-cause mortality using univariate Cox proportional hazards models. The associations for all outcomes except all-cause mortality associated most strongly with longitudinal decline in eGFRcr. Every 5-ml/min per 1.73 m(2) decline in eGFRcr over 2 years associated with 1.54 (95% confidence interval, 1.44 to 1.66; P<0.001) times higher risk of ESRD and 1.23 (95% confidence interval, 1.12 to 1.34; P<0.001) times higher risk for cardiovascular events. All-cause mortality did not associate with longitudinal decline in mGFR or eGFR. When analyzed by tertiles of renal function decline, mGFR did not outperform eGFRcr in the association with any outcome. In conclusion, compared with declines in eGFR, declines in mGFR over a 2-year period, analyzed either as a continuous variable or in tertiles, did not consistently show enhanced association with risk of ESRD, cardiovascular events, or death.
Authors: Ku E; Go AS; CRIC Study Investigators; et al.
J Am Soc Nephrol. 2016 Jul;27(7):2196-204. Epub 2015-11-24.
A Comparison of Self-reported Medication Adherence to Concordance Between Part D Claims and Medication Possession.
OBJECTIVE: Medicare Part D claims indicate medication purchased, but people who are not fully adherent may extend prescription use beyond the interval prescribed. This study assessed concordance between Part D claims and medication possession at a study visit in relation to self-reported medication adherence.MATERIALS AND METHODS: We matched Part D claims for 6 common medications to medications brought to a study visit in 2011-2013 for the Atherosclerosis Risk in Communities study. The combined data consisted of 3027 medication events (claims, medications possessed, or both) for 2099 Atherosclerosis Risk in Communities study participants. Multinomial logistic regression estimated the association of concordance (visit only, Part D only, or both) with self-reported medication adherence while controlling for sociodemographic characteristics, veteran status, and availability under Generic Drug Discount Programs.RESULTS: Relative to participants with high adherence, medication events for participants with low adherence were approximately 25 percentage points less likely to match and more likely to be visit only (PCONCLUSIONS: Part D claims were substantially less likely to be concordant with medications possessed at study visit for participants with low self-reported adherence. This result supports the construction of adherence proxies such as proportion days covered using Part D claims.
Authors: Savitz, Samuel T; Stearns, Sally C; Zhou, Lei; Thudium, Emily; Alburikan, Khalid A; Tran, Richard; Rodgers, Jo E
Medical care. 2017 May ;55(5):500-505. Epub 2016-06-09.
Mind the Gap: Hospitalizations from Multiple Sources in a Longitudinal Study.
BACKGROUND: Medicare claims and prospective studies with self-reported utilization are important sources of hospitalization data for epidemiologic and outcomes research.OBJECTIVES: To assess the concordance of Medicare claims merged with interview-based surveillance data to determine factors associated with source completeness.METHODS: The Atherosclerosis Risk in Communities (ARIC) study recruited 15,792 cohort participants aged 45 to 64 years in the period 1987 to 1989 from four communities. Hospitalization records obtained through cohort report and hospital record abstraction were matched to Medicare inpatient records (MedPAR) from 2006 to 2011. Factors associated with concordance were assessed graphically and using multinomial logit regression.RESULTS: Among fee-for-service enrollees, MedPAR and ARIC hospitalizations matched approximately 67% of the time. For Medicare Advantage enrollees, completeness increased after initiation of hospital financial incentives in 2008 to submit shadow bills for Medicare Advantage enrollees. Concordance varied by geographic site, age, veteran status, proximity to death, study attrition, and whether hospitalizations were within ARIC catchment areas.CONCLUSIONS: ARIC and MedPAR records had good concordance among fee-for-service enrollees, but many hospitalizations were available from only one source. MedPAR hospital records may be missing for veterans or observation stays. Maintaining study participation increases stay completeness, but new sources such as electronic health records may be more efficient than surveillance for mobile elderly populations.
Authors: Savitz, Samuel T; Stearns, Sally C; Groves, Jennifer S; Kucharska-Newton, Anna M; Bengtson, Lindsay G S; Wruck, Lisa
Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2017 06 ;20(6):777-784. Epub 2016-06-09.
Neonatal seizures triple the risk of a remote seizure after perinatal ischemic stroke
To determine incidence rates and risk factors of remote seizure after perinatal arterial ischemic stroke. We retrospectively identified a population-based cohort of children with perinatal arterial ischemic stroke (presenting acutely or in a delayed fashion) from a large Northern Californian integrated health care system. We determined incidence and predictors of a remote seizure (unprovoked seizure after neonatal period, defined as 28 days of life) by survival analyses, and measured epilepsy severity in those with active epilepsy (?1 remote seizure and maintenance anticonvulsant treatment) at last follow-up. Among 87 children with perinatal stroke, 40 (46%) had a seizure in the neonatal period. During a median follow-up of 7.1 years (interquartile range 3.2-10.5), 37 children had ?1 remote seizure. Remote seizure risk was highest during the first year of life, with a 20% (95% confidence interval [CI] 13%-30%) cumulative incidence by 1 year of age, 46% (CI 35%-58%) by 5 years, and 54% (CI 41%-67%) by 10 years. Neonatal seizures increased the risk of a remote seizure (hazard ratio 2.8, CI 1.3-5.8). Children with neonatal seizures had a 69% (CI 48%-87%) cumulative incidence of remote seizure by age 10 years. Among the 24 children with active epilepsy at last follow-up, 8 (33%) were having monthly seizures despite an anticonvulsant and 7 (29%) were on more than one anticonvulsant. Remote seizures and epilepsy, including medically refractory epilepsy, are common after perinatal stroke. Neonatal seizures are associated with nearly 3-fold increased remote seizure risk.
Authors: Fox CK; Glass HC; Sidney S; Smith SE; Fullerton HJ
Neurology. 2016 Jun 07;86(23):2179-86. Epub 2016-05-06.
Obesity and Functioning Among Individuals with Chronic Obstructive Pulmonary Disease (COPD)
In COPD, body composition studies have focused primarily on low BMI. We examined obesity (BMI ≥ 30 kg/m(2)) as a risk factor for poor function and longitudinal functional decline. Data from a longitudinal cohort of adults with COPD (n = 1096) and an age- and sex-matched comparison group collected in two in-person visits ∼49 months apart were analyzed. Two measures of functioning were examined: six-minute walk distance (6MWD) and Short Physical Performance Battery (SPPB). Multivariate regression analyses examined relationships of obesity with functioning. Secondary analyses stratified by GOLD classification (GOLD-0/1, GOLD-2, GOLD-3/4). Obesity (53% of COPD cohort) was associated cross-sectionally with 6MWD and SPPB in COPD, and only with 6MWD in the comparison group. Obesity predicted significant functional decline in 6MWD for individuals with COPD (odds ratio (OR) for decline [95% CI] 1.8 [1.1, 2.9]), but not the comparison group. Secondary analyses revealed that the risk of decline was significant only in those with more severe COPD (GOLD 3/4, OR = 2.3 [1.0, 5.4]). Obesity was highly prevalent and was associated with poor function concurrently and with subsequent decline in 6MWD in COPD. Obesity in COPD should be considered a risk not only for more co-morbidities and greater health care use, but also for functional decline.
Authors: Katz P; Iribarren C; Sanchez G; Blanc PD
COPD. 2016 Jun;13(3):352-9. Epub 2015-12-18.
Cost-Effectiveness of Percutaneous Closure of the Left Atrial Appendage in Atrial Fibrillation Based on Results From PROTECT AF Versus PREVAIL
Randomized trials of left atrial appendage (LAA) closure with the Watchman device have shown varying results, and its cost effectiveness compared with anticoagulation has not been evaluated using all available contemporary trial data. We used a Markov decision model to estimate lifetime quality-adjusted survival, costs, and cost effectiveness of LAA closure with Watchman, compared directly with warfarin and indirectly with dabigatran, using data from the long-term (mean 3.8 year) follow-up of Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation (PROTECT AF) and Prospective Randomized Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation (PREVAIL) randomized trials. Using data from PROTECT AF, the incremental cost-effectiveness ratios compared with warfarin and dabigatran were $20?486 and $23?422 per quality-adjusted life year, respectively. Using data from PREVAIL, LAA closure was dominated by warfarin and dabigatran, meaning that it was less effective (8.44, 8.54, and 8.59 quality-adjusted life years, respectively) and more costly. At a willingness-to-pay threshold of $50?000 per quality-adjusted life year, LAA closure was cost effective 90% and 9% of the time under PROTECT AF and PREVAIL assumptions, respectively. These results were sensitive to the rates of ischemic stroke and intracranial hemorrhage for LAA closure and medical anticoagulation. Using data from the PROTECT AF trial, LAA closure with the Watchman device was cost effective; using PREVAIL trial data, Watchman was more costly and less effective than warfarin and dabigatran. PROTECT AF enrolled more patients and has substantially longer follow-up time, allowing greater statistical certainty with the cost-effectiveness results. However, longer-term trial results and postmarketing surveillance of major adverse events will be vital to determining the value of the Watchman in clinical practice.
Authors: Freeman JV; Hlatky MA; Turakhia MP; et al.
Circ Arrhythm Electrophysiol. 2016 Jun;9(6).
Initial management and outcomes after superficial thrombophlebitis: The Cardiovascular Research Network Venous Thromboembolism study
Although superficial thrombophlebitis (SVTE) is generally considered a benign, self-limited disease, accumulating evidence suggests that it often leads to more serious forms of venous thromboembolism. We reviewed the medical charts of 329 subjects with SVTE from the Cardiovascular Research Network Venous Thromboembolism cohort study to collect information on the acute treatment of SVTE and subsequent diagnosis of deep venous thrombosis within 1 year. All participants received care within Kaiser Permanente Northern California, a large, integrated healthcare delivery system. Fourteen (4.3%) subjects with SVTE received anticoagulants, 148 (45.0%) were recommended antiplatelet agents or nonsteroidal anti-inflammatory drugs, and in 167 (50.8%) there was no documented antithrombotic therapy. In the year after SVTE diagnosis, 19 (5.8%) patients had a subsequent diagnosis of a deep venous thrombosis or pulmonary embolism. In conclusion, clinically significant venous thrombosis within a year after SVTE was uncommon in our study despite infrequent use of antithrombotic therapy. Journal of Hospital Medicine 2016;11:432-434. © 2016 Society of Hospital Medicine.
Authors: Samuelson B; Go AS; Sung SH; Fan D; Fang MC
J Hosp Med. 2016 Jun;11(6):432-4. Epub 2016-02-01.
Preterm Delivery and Metabolic Syndrome in Women Followed From Prepregnancy Through 25 Years Later
To investigate whether women who deliver preterm have excess risk for metabolic dysregulation independent of prepregnancy factors. We conducted a multicenter, longitudinal, observational study of 1,205 women (50% black) in the Coronary Artery Risk Development in Young Adults study with at least one birth between baseline (1985-1986) and year 25 and no metabolic syndrome or diabetes before pregnancy. Cardiometabolic factors were measured prepregnancy and at up to five subsequent examinations. We estimated the relative hazards of incident metabolic syndrome in women with one or more preterm births (less than 37 weeks of gestation, n=295) compared with only term births (37 weeks of gestation or greater, n=910). Self-reported gestational diabetes mellitus, hypertension during pregnancy, and time-dependent weight gain were also considered as covariates. Of 315 cases of metabolic syndrome in 17,717 person-years of follow-up, the incidence rate was higher among women with preterm compared with term births (22.0 compared with 16.4 per 1,000 person-years; relative hazard 2.91 [95% confidence interval (CI) 2.75-3.09]). After adjustment for prepregnancy cardiometabolic factors and covariates, the relative hazard (95% CI) for metabolic syndrome was 1.52 (1.22-1.88) for women with preterm compared with term births. Gestational diabetes mellitus, hypertension during pregnancy, and weight gain only modestly attenuated this association. Elevated blood pressure (36.3% compared with 26.7%, P=.002) and central adiposity (51.5% compared with 44.0%, P=.02) were the individual metabolic syndrome components that were different in women with preterm compared with term births. Women with a history of preterm birth have increased risk of incident metabolic syndrome compared with those with term births, independent of the prepregnancy metabolic status and pregnancy complications.
Authors: Catov JM; Althouse AD; Lewis CE; Harville EW; Gunderson EP
Obstet Gynecol. 2016 Jun;127(6):1127-34.
Getting it Straight: Avoiding Blunders While Criticizing a Peer’s Work
Authors: Achinger SG; Go AS; Ayus JC
Int J Epidemiol. 2016 06;45(3):619-20. Epub 2015-08-14.
Triple Versus Dual Antithrombotic Therapy in Patients With Atrial Fibrillation and Coronary Artery Disease
The role of triple antithrombotic therapy vs dual antithrombotic therapy in patients with both atrial fibrillation and coronary artery disease remains unclear. This study explores the differences in treatment practices and outcomes between triple antithrombotic therapy and dual antithrombotic therapy in patients with atrial fibrillation and coronary artery disease. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (n = 10,135), we analyzed outcomes in patients with coronary artery disease (n = 1827) according to treatment with triple antithrombotic therapy (defined as concurrent therapy with an oral anticoagulant, a thienopyridine, and aspirin) or dual antithrombotic therapy (comprising either an oral anticoagulant and one antiplatelet agent [OAC plus AA] or 2 antiplatelet drugs and no anticoagulant [DAP]). The use of triple antithrombotic therapy, OAC plus AA, and DAP at baseline was 8.5% (n = 155), 80.4% (n = 1468), and 11.2% (n = 204), respectively. Among patients treated with OAC plus AA, aspirin was the most common antiplatelet agent used (90%), followed by clopidogrel (10%) and prasugrel (0.1%). The use of triple antithrombotic therapy was not affected by patient risk of either stroke or bleeding. Patients treated with triple antithrombotic therapy at baseline were hospitalized for all causes (including cardiovascular) more often than patients on OAC plus AA (adjusted hazard ratio 1.75; 95% confidence interval, 1.35-2.26; P <.0001) or DAP (hazard ratio 1.82; 95% confidence interval, 1.25-2.65; P = .0018). Rates of major bleeding or a combined cardiovascular outcome were not significantly different by treatment group. Choice of antithrombotic therapy in patients with atrial fibrillation and coronary artery disease was not affected by patient stroke or bleeding risks. Triple antithrombotic therapy-treated patients were more likely to be hospitalized for all causes than those on OAC plus AA or on DAP.
Authors: Lopes RD; Go AS; Mahaffey KW; et al.
Am J Med. 2016 Jun;129(6):592-599.e1. Epub 2016-01-18.
Intake of fish and long-chain omega-3 polyunsaturated fatty acids and incidence of metabolic syndrome among American young adults: a 25-year follow-up study
Studies suggest that long-chain ?-3 polyunsaturated fatty acid (LC?3PUFA) intake and its primary food source-fish-may have beneficial effects on the individual components of metabolic syndrome (MetS). We examined the longitudinal association between fish or LC?3PUFA intake and MetS incidence. We prospectively followed 4356 American young adults, free from MetS and diabetes at baseline, for incident MetS and its components in relation to fish and LC?3PUFA intake. MetS was defined by the National Cholesterol Education Program/Adult Treatment Panel III criteria. Cox proportional hazards model was used for analyses, controlling for socio-demographic, behavioral, and dietary factors. During the 25-year follow-up, a total of 1069 incident cases of MetS were identified. LC?3PUFA intake was inversely associated with the incidence of MetS in a dose-response manner. The multivariable adjusted hazards ratio (HR) [95 % confidence interval (CI)] of incident MetS was 0.54 (95 % CI 0.44, 0.67; P for linear trend < 0.01) as compared the highest to the lowest quintile of LC?3PUFA intake. A threshold inverse association was found between non-fried fish consumption and the incidence of MetS. The multivariable adjusted HRs (95 % CIs) from the lowest to the highest quintile were 1.00, 0.70 (0.51, 0.95), 0.68 (0.52, 0.91), 0.67 (0.53, 0.86), and 0.71 (0.56, 0.89) (P for linear trend = 0.49). The observed inverse associations were independent of the status of baseline individual components of MetS. Our findings suggest that intakes of LC?3PUFAs and non-fried fish in young adulthood are inversely associated with the incidence of MetS later in life.
Authors: Kim YS; Xun P; Iribarren C; Van Horn L; Steffen L; Daviglus ML; Siscovick D; Liu K; He K
Eur J Nutr. 2016 Jun;55(4):1707-16. Epub 2016-01-27.
Effectiveness of Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Patients With End-Stage Renal Disease
The optimal coronary revascularization strategy (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) in patients with end-stage renal disease (ESRD) remains uncertain. We performed an updated systematic review and meta-analysis of observational studies comparing CABG and PCI in patients with ESRD using a random-effects model for the primary outcome of long-term all-cause mortality. Our review registered through PROSPERO included observational studies published after 2011 to ensure overlap with previous studies and identified 7 new studies for a total of 23. We found that the median sample size in the selected studies was 125 patients (25 to 15,784) with a large variation in the covariate risk adjustment and only 3 studies reporting the indications for the revascularization strategy. CABG was associated with a small reduction in mortality (relative risk 0.92, 95% CI 0.89 to 0.96) with significant heterogeneity demonstrated (p = 0.005, I(2) = 48.6%). Subgroup analysis by categorized “year of study initiation” (<1990, 1991 to 2003, >2004) further confirmed the summary estimate trending toward survival benefit of CABG along with a substantial decrease in heterogeneity after 2004 (p = 0.64, I(2) = 0%). In conclusion, our updated systematic review and meta-analysis demonstrated that in patients with ESRD referred for coronary revascularization, CABG was associated with a small decrease in the relative risk of long-term mortality compared with PCI. The generalizability of the finding to all patients with ESRD referred for coronary revascularization is limited because of a lack of known indications for coronary revascularization, substantial variation in covariate risk adjustment, and lack of randomized clinical trial data.
Authors: Krishnaswami A; Goh AC; Go AS; Lundstrom RJ; Zaroff J; Jang JJ; Allen E
Am J Cardiol. 2016 May 15;117(10):1596-603. Epub 2016-03-02.
Accuracy of the Atherosclerotic Cardiovascular Risk Equation in a Large Contemporary, Multiethnic Population
The accuracy of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Risk Equation for atherosclerotic cardiovascular disease (ASCVD) events in contemporary and ethnically diverse populations is not well understood. The goal of this study was to evaluate the accuracy of the 2013 ACC/AHA Pooled Cohort Risk Equation within a large, multiethnic population in clinical care. The target population for consideration of cholesterol-lowering therapy in a large, integrated health care delivery system population was identified in 2008 and followed up through 2013. The main analyses excluded those with known ASCVD, diabetes mellitus, low-density lipoprotein cholesterol levels <70 or ?190 mg/dl, prior lipid-lowering therapy use, or incomplete 5-year follow-up. Patient characteristics were obtained from electronic medical records, and ASCVD events were ascertained by using validated algorithms for hospitalization databases and death certificates. We compared predicted versus observed 5-year ASCVD risk, overall and according to sex and race/ethnicity. We additionally examined predicted versus observed risk in patients with diabetes mellitus. Among 307,591 eligible adults without diabetes between 40 and 75 years of age, 22,283 were black, 52,917 were Asian/Pacific Islander, and 18,745 were Hispanic. We observed 2,061 ASCVD events during 1,515,142 person-years. In each 5-year predicted ASCVD risk category, observed 5-year ASCVD risk was substantially lower: 0.20% for predicted risk <2.50%; 0.65% for predicted risk 2.50% to <3.75%; 0.90% for predicted risk 3.75% to <5.00%; and 1.85% for predicted risk ?5.00% (C statistic: 0.74). Similar ASCVD risk overestimation and poor calibration with moderate discrimination (C statistic: 0.68 to 0.74) were observed in sex, racial/ethnic, and socioeconomic status subgroups, and in sensitivity analyses among patients receiving statins for primary prevention. Calibration among 4,242 eligible adults with diabetes was improved, but discrimination was worse (C statistic: 0.64). In a large, contemporary "real-world" population, the ACC/AHA Pooled Cohort Risk Equation substantially overestimated actual 5-year risk in adults without diabetes, overall and across sociodemographic subgroups.
Authors: Rana JS; Tabada GH; Solomon MD; Lo JC; Jaffe MG; Sung SH; Ballantyne CM; Go AS
J Am Coll Cardiol. 2016 May 10;67(18):2118-30.
Gestational Diabetes Mellitus Is Strongly Associated With Non-Alcoholic Fatty Liver Disease
Insulin resistance is central to the development of non-alcoholic fatty liver disease (NAFLD), and gestational diabetes mellitus (GDM) is an early marker of insulin resistance. We hypothesized that a history of GDM would identify women at higher risk of NAFLD in middle age. Women from the multicenter Coronary Artery Risk Development in Young Adults (CARDIA) cohort study who delivered ?1 birth, were free of diabetes prior to pregnancy(ies), and underwent CT quantification of hepatic steatosis 25 years following cohort entry (Y25: 2010-2011) were included (n=1,115). History of GDM by self-report, validated in a subsample by review of antenatal glucose testing, and metabolic risk factors were assessed prospectively. NAFLD was defined by liver attenuation (LA)?40 Hounsfield Units on CT scan after exclusion of other causes of hepatic steatosis. Of 1,115 women meeting selection criteria (57% black, 43% white, median age 25 years at baseline), 124 (11%) reported a history of GDM and 75 (7%) met the CT definition for NAFLD at year 25. The crude risk of NAFLD at the 25-year visit was significantly higher in women with GDM compared to those without (14 vs. 5.8%, OR: 2.56, 95% CI: 1.44-4.55, P<0.01). History of GDM remained associated with NAFLD (OR: 2.29, 95% CI: 1.23-4.27, P=0.01) after adjustment for covariates in multivariable logistic regression. Addition of incident diabetes mellitus (DM) into the final model attenuated the association between GDM and NAFLD (OR: 1.48, 95% CI: 0.73-3.02, P=0.28). GDM is a risk marker for NAFLD and represents an opportunity to identify women at risk for NAFLD at a young age and may be mediated by the development of incident DM.
Authors: Ajmera VH; Gunderson EP; VanWagner LB; Lewis CE; Carr JJ; Terrault NA
Am J Gastroenterol. 2016 May;111(5):658-64. Epub 2016-03-22.
Ethnic Differences in Risk of Coronary Heart Disease in a Large Contemporary Population
Racial/ethnic differences in diabetes and cardiovascular disease are well documented, but disease estimates are often confounded by differences in access to quality health care. The objective of this study was to evaluate the ethnic differences in risk of future coronary heart disease in patient populations stratified by status of diabetes mellitus and prior coronary heart disease among those with uniform access to care in an integrated healthcare delivery system in Northern California. A cohort was constructed consisting of 1,344,899 members with self-reported race/ethnicity, aged 30-90 years, and followed from 2002 through 2012. Cox proportional hazard regression models were specified to estimate race/ethnicity-specific hazard ratios for coronary heart disease (with whites as the reference category) separately in four clinical risk categories: (1) no diabetes with no prior coronary heart disease; (2) no diabetes with prior coronary heart disease; (3) diabetes with no prior coronary heart disease; and (4) diabetes with prior coronary heart disease. Analyses were performed in 2015. The median follow-up was 10 years (10,980,800 person-years). Compared with whites, blacks, Latinos, and Asians generally had lower risk of coronary heart disease across all clinical risk categories, with the exception of blacks with prior coronary heart disease and no diabetes having higher risk than whites. Findings were not substantively altered after multivariate adjustments. Identification of health outcomes in a system with uniform access to care reveals residual racial/ethnic differences and point to opportunities to improve health in specific subgroups and to improve health equity.
Authors: Rana JS; Liu JY; Moffet HH; Jaffe MG; Sidney S; Karter AJ
Am J Prev Med. 2016 May;50(5):637-41. Epub 2016-01-28.
Report of the National Heart, Lung, and Blood Institute Working Group: An Integrated Network for Congenital Heart Disease Research
The National Heart, Lung, and Blood Institute convened a working group in January 2015 to explore issues related to an integrated data network for congenital heart disease research. The overall goal was to develop a common vision for how the rapidly increasing volumes of data captured across numerous sources can be managed, integrated, and analyzed to improve care and outcomes. This report summarizes the current landscape of congenital heart disease data, data integration methodologies used across other fields, key considerations for data integration models in congenital heart disease, and the short- and long-term vision and recommendations made by the working group.
Authors: Pasquali SK; Go AS; Kaltman JR; et al.
Circulation. 2016 Apr 5;133(14):1410-8.
Post-discharge Follow-up Characteristics Associated With 30-Day Readmission After Heart Failure Hospitalization
Readmission within 30 days after hospitalization for heart failure (HF) is a major public health problem. To examine whether timing and type of post-discharge follow-up impacts risk of 30-day readmission in adults hospitalized for HF. Nested matched case-control study (January 1, 2006-June 30, 2013). A large, integrated health care delivery system in Northern California. Hospitalized adults with a primary diagnosis of HF discharged to home without hospice care. Outpatient visits and telephone calls with cardiology and general medicine providers in non-emergency department and non-urgent care settings were counted as follow-up care. Statistical adjustments were made for differences in patient sociodemographic and clinical characteristics, acute severity of illness, hospitalization characteristics, and post-discharge medication changes and laboratory testing. Among 11,985 eligible adults, early initial outpatient contact within 7 days after discharge was associated with lower odds of readmission [adjusted odds ratio (OR)=0.81; 95% CI, 0.70-0.94], whereas later outpatient contact between 8 and 30 days after hospital discharge was not significantly associated with readmission (adjusted OR=0.99; 95% CI, 0.82-1.19). Initial contact by telephone was associated with lower adjusted odds of 30-day readmission (adjusted OR=0.85; 95% CI, 0.69-1.06) but was not statistically significant. In adults discharged to home after hospitalization for HF, outpatient follow-up with a cardiology or general medicine provider within 7 days was associated with a lower chance of 30-day readmission.
Authors: Lee KK; Yang J; Hernandez AF; Steimle AE; Go AS
Med Care. 2016 Apr;54(4):365-72.
Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry
Significant racial/ethnic differences exist in the incidence of atrial fibrillation (AF). However, less is known about racial/ethnic differences in quality of life (QoL), treatment, and outcomes associated with AF. Using data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we compared clinical characteristics, QoL, management strategies, and long-term outcomes associated with AF among various racial/ethnic groups. We analyzed 9,542 participants with AF (mean age 74 ± 11 years, 43% women, 91% white, 5% black, 4% Hispanic) from 174 centers. Compared with AF patients identified as white race, patients identified as Hispanic ethnicity and those identified as black race were younger, were more often women, and had more cardiac and noncardiac comorbidities. Black patients were more symptomatic with worse QoL and were less likely to be treated with a rhythm control strategy than other racial/ethnic groups. There were no significant racial/ethnic differences in CHA2DS2-VASc stroke or ATRIA bleeding risk scores and rates of oral anticoagulation use were similar. However, racial and ethnic minority populations treated with warfarin spent a lower median time in therapeutic range of international normalized ratio (59% blacks vs 68% whites vs 62% Hispanics, P < .0001). There was no difference in long-term outcomes associated with AF between the 3 groups at a median follow-up of 2.1 years. Relative to white and Hispanic patients, black patients with AF had more symptoms, were less likely to receive rhythm control interventions, and had lower quality of warfarin management. Despite these differences, clinical events at 2 years were similar by race and ethnicity.
Authors: Golwala H; Go AS; Outcomes Registry for Better Informed Treatment for Atrial Fibrillation (ORBIT-AF) Registry; et al.
Am Heart J. 2016 Apr;174:29-36. Epub 2015-12-30.
The association of race/ethnicity and risk of atypical femur fracture among older women receiving oral bisphosphonate therapy
Several epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women. Using data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age?50years old who initiated oral bisphosphonate therapy during 2002-2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors. Among 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9-14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7-11.5) after adjusting for bisphosphonate duration and current use. Our study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk.
Authors: Lo JC; Hui RL; Grimsrud CD; Chandra M; Neugebauer RS; Gonzalez JR; Budayr A; Lau G; Ettinger B
Bone. 2016 Apr;85:142-7. Epub 2016-01-06.
Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat
To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available. A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P<1.0 × 10(-6)) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10(-7)), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; P=2.42 × 10(-7)). Our sex-specific analyses identified one genome-wide significant (P<5.0 × 10(-8)) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10(-8) to 1.13 × 10(-8)). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.
Authors: Sung YJ; Sternfeld B; Bouchard C; et al.
Int J Obes (Lond). 2016 Apr;40(4):662-74. Epub 2015-10-20.
In-Hospital Diuretic Agent Use and Post-Discharge Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure: Insights From the EVEREST Trial.
OBJECTIVES: The aim of this study was to characterize the association between decongestion therapy and 30-day outcomes in patients hospitalized for heart failure (HF).BACKGROUND: Loop diuretic agents are commonly prescribed for the treatment of symptomatic congestion in patients hospitalized for HF, but the association between loop diuretic agent dose response and post-discharge outcomes has not been well characterized.METHODS: Cox proportional hazards models were used to estimate the association among average loop diuretic agent dose, congestion status at discharge, and 30-day post-discharge all-cause mortality and HF rehospitalization in 3,037 subjects hospitalized with worsening HF enrolled in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) study.RESULTS: In univariate analysis, subjects exposed to high-dose diuretic agents (≥160 mg/day) had greater risk for the combined outcome than subjects exposed to low-dose diuretic agents (18.9% vs. 10.0%; hazard ratio: 2.00; 95% confidence interval: 1.64 to 2.46; p < 0.0001). After adjustment for pre-specified covariates of disease severity, the association between diuretic agent dose and outcomes was not significant (hazard ratio: 1.11; 95% confidence interval: 0.89 to 1.38; p = 0.35). Of the 3,011 subjects with clinical assessments of volume status, 2,063 (69%) had little or no congestion at hospital discharge. Congestion status at hospital discharge did not modify the association between diuretic agent exposure and the combined endpoint (p for interaction = 0.84).CONCLUSIONS: Short-term diuretic agent exposure during hospital treatment for worsening HF was not an independent predictor of 30-day all-cause mortality and HF rehospitalization in multivariate analysis. Congestion status at discharge did not modify the association between diuretic agent dose and clinical outcomes.
Authors: Mecklai, Alicia A; Subačius, Haris H; Konstam, Marvin A MA; Gheorghiade, Mihai M; Butler, Javed J; Ambrosy, Andrew P AP; Katz, Stuart D SD
JACC. Heart failure. 2016 07 01;4(7):580-588. Epub 2016-03-30.
Hostile attitudes and effortful coping in young adulthood predict cognition 25 years later
We studied the relation of early-life (mean age 25 years) and mid-life (mean age 50 years) cognitive function to early measures of hostile attitudes and effortful coping. In 3,126 black and white men and women (born in 1955-1968) from the Coronary Artery Risk Development in Young Adults Study (CARDIA), we used linear regression to examine the association of hostile attitudes (Cook-Medley questionnaire) and effortful coping assessed at baseline (1985-1986) to cognitive ability measured in 1987 and to a composite cognitive Z score of tests of verbal memory, psychomotor speed, and executive function ascertained in midlife (2010-2011). Baseline hostility and effortful coping were prospectively associated with lower cognitive function 25 years later, controlling for age, sex, race, education, long-term exposure to depression, discrimination, negative life events, and baseline cognitive ability. Compared to the lowest quartile, those in the highest quartile of hostility performed 0.21 SD units lower (95% confidence interval [CI] -0.39, -0.02). Those in the highest quartile of effortful coping performed 0.30 SD units lower (95% CI -0.48, -0.12) compared to those in the lowest quartile. Further adjustment for cumulative exposure to cardiovascular risk factors attenuated the association with the cognitive composite Z score for hostility. Worse cognition in midlife was independently associated with 2 psychological characteristics measured in young adulthood. This suggests that interventions that promote positive social interactions may have a role in reducing risk of late-age cognitive impairment.
Authors: Albanese E; Matthews KA; Zhang J; Jacobs DR; Whitmer RA; Wadley VG; Yaffe K; Sidney S; Launer LJ
Neurology. 2016 Mar 29;86(13):1227-34. Epub 2016-03-02.
Elevated BP after AKI
The connection between AKI and BP elevation is unclear. We conducted a retrospective cohort study to evaluate whether AKI in the hospital is independently associated with BP elevation during the first 2 years after discharge among previously normotensive adults. We studied adult members of Northern California, a large integrated health care delivery system, who were hospitalized between 2008 and 2011, had available preadmission serum creatinine and BP measures, and were not known to be hypertensive or have BP>140/90 mmHg. Among 43,611 eligible patients, 2451 experienced AKI defined using observed changes in serum creatinine concentration measured during hospitalization. Survivors of AKI were more likely than those without AKI to have elevated BP–defined as documented BP>140/90 mmHg measured during an ambulatory, nonemergency department visit–during follow-up (46.1% versus 41.2% at 730 days; P<0.001). This difference was evident within the first 180 days (30.6% versus 23.1%; P<0.001). In multivariable models, AKI was independently associated with a 22% (95% confidence interval, 12% to 33%) increase in the odds of developing elevated BP during follow-up, with higher adjusted odds with more severe AKI. Results were similar in sensitivity analyses when elevated BP was defined as having at least two BP readings of >140/90 mmHg or those with evidence of CKD were excluded. We conclude that AKI is an independent risk factor for subsequent development of elevated BP. Preventing AKI during a hospitalization may have clinical and public health benefits beyond the immediate hospitalization.
Authors: Hsu CY; Hsu RK; Yang J; Ordonez JD; Zheng S; Go AS
J Am Soc Nephrol. 2016 Mar;27(3):914-23. Epub 2015-07-01.
The Association of Gestational Diabetes Mellitus With Left Ventricular Structure and Function: The CARDIA Study
Gestational diabetes mellitus (GDM) predicts incident cardiovascular disease (CVD). However, mechanisms linking GDM to CVD beyond intervening incident diabetes are not well understood. We examined the relation of GDM with echocardiographic parameters of left ventricular (LV) structure and function, which are important predictors of future CVD risk. We studied 609 women (43% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who delivered one or more births during follow-up and had echocardiograms in 1990-1991 (mean age 28.8 years) and 2010-2011. During the 20-year follow-up, 965 births were reported, with GDM developing in 64 women (10.5%). In linear regression models adjusted for sociodemographic factors, BMI, physical activity, parity, smoking, use of oral contraceptives, alcohol intake, family history of coronary heart disease, systolic blood pressure, and lipid levels, women with GDM had impaired longitudinal peak strain (-15.0 vs. -15.7%, P = 0.025), circumferential peak strain (-14.8 vs. -15.6%, P = 0.028), lateral e’ wave velocity (11.0 vs. 11.8 cm/s, P = 0.012), and septal e’ wave velocity (8.6 vs. 9.3 cm/s, P = 0.015) in 2010-2011 and a greater 20-year increase in LV mass indexed to body surface area (14.3 vs. 6.0 g/m(2), P = 0.006) compared with women with non-GDM pregnancies. Further adjustment for incident type 2 diabetes after pregnancy did not attenuate these associations. Pregnancy complicated by GDM is independently associated with increased LV mass and impaired LV relaxation and systolic function. Implementation of postpartum cardiovascular health interventions in women with a history of GDM may offer an additional opportunity to reduce future CVD risk.
Authors: Appiah D; Konety SH; Gidding SS; et al.
Diabetes Care. 2016 Mar;39(3):400-7. Epub 2016-01-06.
Change in Weight Status and Development of Hypertension
To examine the association of BMI percentile and change in BMI percentile to change in blood pressure (BP) percentile and development of hypertension (HTN). This retrospective cohort included 101?606 subjects age 3 to 17 years from 3 health systems across the United States. Height, weight, and BPs were extracted from electronic health records, and BMI and BP percentiles were computed with the appropriate age, gender, and height charts. Mixed linear regression estimated change in BP percentile, and proportional hazards regression was used to estimate risk of incident HTN associated with BMI percentile and change in BMI percentile. The largest increases in BP percentile were observed among children and adolescents who became obese or maintained obesity. Over a median 3.1 years of follow-up, 0.3% of subjects developed HTN. Obese children ages 3 to 11 had twofold increased risk of developing HTN compared with healthy weight children. Obese children and adolescents had a twofold increased risk of developing HTN, and severely obese children had a more than fourfold increased risk. Compared with those who maintained a healthy weight, children and adolescents who became obese or maintained obesity had a more than threefold increased risk of incident HTN. We observed a strong, statistically significant association between increasing BMI percentile and increases in BP percentile, with risk of incident HTN associated primarily with obesity. The adverse impact of weight gain and obesity in this cohort over a short period underscores the early need for effective strategies for prevention of overweight and obesity.
Authors: Parker ED; Sinaiko AR; Kharbanda EO; Margolis KL; Daley MF; Trower NK; Sherwood NE; Greenspan LC; Lo JC; Magid DJ; O'Connor PJ
Pediatrics. 2016 Mar;137(3):e20151662. Epub 2016-02-19.
Validity of Using Inpatient and Outpatient Administrative Codes to Identify Acute Venous Thromboembolism: The CVRN VTE Study
Administrative data are frequently used to identify venous thromboembolism (VTE) for research and quality reporting. However, the validity of these codes, particularly in outpatients, has not been well-established. To determine how well International Classification of Diseases, Ninth Revision (ICD-9) codes for VTE predict chart-confirmed acute VTE in inpatient and outpatients. We selected 4642 adults with an incident ICD-9 diagnosis of VTE between years 2004 and 2010 from the Cardiovascular Research Network Venous Thromboembolism cohort study. Medical charts were reviewed to determine validity of events. Positive predictive values (PPVs) of ICD-9 codes were calculated as the number of chart-validated VTE events divided by the number with specific VTE codes. Analyses were stratified by VTE type [pulmonary embolism (PE), deep venous thrombosis (DVT)], code position (primary, secondary), and setting [hospital/emergency department (ED), outpatient]. The PPV for any diagnosis of VTE was 64.6% for hospital/ED patients and 30.9% for outpatients. Primary diagnosis codes from hospital/ED patients were more likely to represent acute VTE than secondary diagnosis codes (78.9% vs. 44.4%, P<0.001). Primary hospital/ED codes for PE and lower extremity DVT had higher PPV than for upper extremity DVT (89.1%, 74.9%, and 58.1%, respectively). Outpatient codes were poorly predictive of acute VTE: 28.0% for PE and 53.6% for lower extremity DVT. ICD-9 codes for VTE obtained from outpatient encounters or from secondary diagnosis codes do not reliably reflect acute VTE. More accurate ways of identifying VTE in outpatients are needed before these codes can be adopted for research or policy purposes.
Authors: Fang MC; Fan D; Sung SH; Witt DM; Schmelzer JR; Steinhubl SR; Yale SH; Go AS
Med Care. 2016 Feb 25.
Electrocardiographic Measures and Prediction of Cardiovascular and Noncardiovascular Death in CKD
Limited studies have assessed the resting 12-lead electrocardiogram (ECG) as a screening test in intermediate risk populations. We evaluated whether a panel of common ECG parameters are independent predictors of mortality risk in a prospective cohort of participants with CKD. The Chronic Renal Insufficiency Cohort (CRIC) study enrolled 3939 participants with eGFR<70 ml/min per 1.73 m(2) from June 2003 to September 2008. Over a median follow-up of 7.5 years, 750 participants died. After adjudicating the initial 497 deaths, we identified 256 cardiovascular and 241 noncardiovascular deaths. ECG metrics were independent risk markers for cardiovascular death (hazard ratio, 95% confidence interval): PR interval ?200 ms (1.62, 1.19-2.19); QRS interval 100-119 ms (1.64, 1.20-2.25) and ?120 ms (1.75, 1.17-2.62); corrected QT (QTc) interval ?450 ms in men or ?460 ms in women (1.72, 1.19-2.49); and heart rate 60-90 beats per minute (1.21, 0.89-1.63) and ?90 beats per minute (2.35, 1.03-5.33). Most ECG measures were stronger markers of risk for cardiovascular death than for all-cause mortality or noncardiovascular death. Adding these intervals to a comprehensive model of cardiorenal risk factors increased the C-statistic for cardiovascular death from 0.77 to 0.81 (P<0.001). Furthermore, adding ECG metrics to the model adjusted for standard risk factors resulted in a net reclassification of 12.1% (95% confidence interval 8.1%-16.0%). These data suggest common ECG metrics are independent risk factors for cardiovascular death and enhance the ability to predict death events in a population with CKD.
Authors: Deo R; Shou H; Soliman EZ; Yang W; Arkin JM; Zhang X; Townsend RR; Go AS; Shlipak MG; Feldman HI
J Am Soc Nephrol. 2016 Feb;27(2):559-69. Epub 2015-07-09.
Sinus Node Dysfunction Is Associated With Higher Symptom Burden and Increased Comorbid Illness: Results From the ORBIT-AF Registry
Patients with sinus node dysfunction (SND) have increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). To date, treatment patterns and outcomes of patients with SND and AF have not been well described. Patients with SND and AF have higher risk of adverse cardiovascular outcomes. Sinus node dysfunction was defined clinically, based on treating physician. Treatment patterns were described and logistic regression analysis performed to assess outcomes. Overall, 1710 (17.7%) out of 9631 patients had SND at enrollment. Patients with SND and AF had increased comorbid medical illnesses, more severe symptoms (European Heart Rhythm Association class IV: 17.5% vs 13.9%; P = 0.0007), and poorer quality of life (median 12-month Atrial Fibrillation Effect on Quality of Life score: 79.6 vs 85.2; P = 0.0008). There were no differences in AF management strategy between patients with SND and those without (rate control, 69.7% vs 67.7%; rhythm control, 30.0% vs 32.0%; P = 0.11). After adjustment, patients with SND were more likely than those without SND to progress from paroxysmal AF at baseline to persistent or permanent AF at any follow-up, or persistent AF at baseline to permanent AF at any follow-up (odds ratio: 1.23, 95% confidence interval: 1.01-1.49, P = 0.035). However, there was no association between SND and major risk-adjusted outcomes. Sinus node dysfunction is present in 1 of 6 patients with AF and is associated with increased comorbidities and higher symptom burden. However, SND is not associated with an increase in major risk-adjusted outcomes.
Authors: Jackson LR; Mahaffey KW; Kowey PR; et al.
Clin Cardiol. 2016 Feb;39(2):119-25. Epub 2015-12-31.
Visit-to-visit variability of blood pressure and death, end-stage renal disease, and cardiovascular events in patients with chronic kidney disease
Visit-to-visit variability of blood pressure (VVV of BP) is an important independent risk factor for premature death and cardiovascular events, but relatively little is known about this phenomenon in patients with chronic kidney disease (CKD) not yet on dialysis. We conducted a retrospective study in a community-based cohort of 114?900 adults with CKD stages 3-4 (estimated glomerular filtration rate 15-59?ml/min per 1.73?m). We hypothesized that VVV of BP would be independently associated with higher risks of death, incident treated end-stage renal disease, and cardiovascular events. We defined systolic VVV of BP using three metrics: coefficient of variation, standard deviation of the mean SBP, and average real variability. The highest versus the lowest quintile of the coefficient of variation was associated with higher adjusted rates of death (hazard ratio 1.22; 95% confidence interval 1.11-1.34) and hemorrhagic stroke (hazard ratio 1.91; confidence interval 1.36-2.68). VVV of BP was inconsistently associated with heart failure, and was not significantly associated with acute coronary syndrome and ischemic stroke. Results were similar when using the other two metrics of VVV of BP. VVV of BP had inconsistent associations with end-stage renal disease, perhaps because of the relatively low incidences of this outcome. Higher VVV of BP is independently associated with higher rates of death and hemorrhagic stroke in patients with moderate to advanced CKD not yet on dialysis.
Authors: Chang TI; Tabada GH; Yang J; Tan TC; Go AS
J Hypertens. 2016 Feb;34(2):244-52.
Racial Differences in the Performance of Existing Risk Prediction Models for Incident Type 2 Diabetes: The CARDIA Study
In 2010, the American Diabetes Association (ADA) added hemoglobin A1c (A1C) to the guidelines for diagnosing type 2 diabetes. However, existing models for predicting diabetes risk were developed prior to the widespread adoption of A1C. Thus, it remains unknown how well existing diabetes risk prediction models predict incident diabetes defined according to the ADA 2010 guidelines. Accordingly, we examined the performance of an existing diabetes prediction model applied to a cohort of African American (AA) and white adults from the Coronary Artery Risk Development Study in Young Adults (CARDIA). We evaluated the performance of the Atherosclerosis Risk in Communities (ARIC) diabetes risk prediction model among 2,456 participants in CARDIA free of diabetes at the 2005-2006 exam and followed for 5 years. We evaluated model discrimination, calibration, and integrated discrimination improvement with incident diabetes defined by ADA 2010 guidelines before and after adding baseline A1C to the prediction model. In the overall cohort, re-estimating the ARIC model in the CARDIA cohort resulted in good discrimination for the prediction of 5-year diabetes risk (area under the curve [AUC] 0.841). Adding baseline A1C as a predictor improved discrimination (AUC 0.841 vs. 0.863, P = 0.03). In race-stratified analyses, model discrimination was significantly higher in whites than AA (AUC AA 0.816 vs. whites 0.902; P = 0.008). Addition of A1C to the ARIC diabetes risk prediction model improved performance overall and in racial subgroups. However, for all models examined, discrimination was better in whites than AA. Additional studies are needed to further improve diabetes risk prediction among AA.
Authors: Lacy ME; Wellenius GA; Carnethon MR; Loucks EB; Carson AP; Luo X; Kiefe CI; Gjelsvik A; Gunderson EP; Eaton CB; Wu WC
Diabetes Care. 2016 Feb;39(2):285-91. Epub 2015-12-01.
Anemia and risk for cognitive decline in chronic kidney disease
Anemia is common among patients with chronic kidney disease (CKD) but its health consequences are poorly defined. The aim of this study was to determine the relationship between anemia and cognitive decline in older adults with CKD. We studied a subgroup of 762 adults age ?55 years with CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) study. Anemia was defined according to the World Health Organization criteria (hemoglobin <13 g/dL for men and <12 g/dL for women). Cognitive function was assessed annually with a battery of six tests. We used logistic regression to determine the association between anemia and baseline cognitive impairment on each test, defined as a cognitive score more than one standard deviation from the mean, and mixed effects models to determine the relation between anemia and change in cognitive function during follow-up after adjustment for demographic and clinical characteristics. Of 762 participants with mean estimated glomerular filtration rate of 42.7?±?16.4 ml/min/1.73 m(2), 349 (46 %) had anemia. Anemia was not independently associated with baseline cognitive impairment on any test after adjustment for demographic and clinical characteristics. Over a median 2.9 (IQR 2.6-3.0) years of follow-up, there was no independent association between anemia and change in cognitive function on any of the six cognitive tests. Among older adults with CKD, anemia was not independently associated with baseline cognitive function or decline.
Authors: Kurella Tamura M; Seliger SL; Yaffe K; et al.
BMC Nephrol. 2016 Jan 28;17:13. Epub 2016-Jan-28.
Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association
Authors: Writing Group Members; Go AS; Stroke Statistics Subcommittee; et al.
Circulation. 2016 Jan 26;133(4):e38-60. Epub 2015-12-16.
Effect of Diabetes and Glycemic Control on Ischemic Stroke Risk in AF Patients: ATRIA Study
Diagnosed diabetes mellitus (DM) is a consistently documented risk factor for ischemic stroke in patients with atrial fibrillation (AF). The purpose of this study was to assess the association between duration of diabetes and elevated hemoglobin A1c (HbA1c) with risk of stroke among diabetic patients with AF. We assessed this association in the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) California community-based cohort of AF patients (study years 1996 to 2003) where all events were clinician adjudicated. We used Cox proportional hazards regression to estimate the rate of ischemic stroke in diabetic patients according to time-varying measures of estimated duration of diabetes (?3 years compared with <3 years) and HbA1c values (?9.0% and 7.0% to 8.9% compared with <7.0%), focusing on periods where patients were not anticoagulated. There were 2,101 diabetic patients included in the duration analysis: 40% with duration <3 years and 60% with duration ?3 years at baseline. Among 1,933 diabetic patients included in the HbA1c analysis, 46% had HbA1c <7.0%, 36% between 7.0% and 8.9%, and 19% ?9.0% at baseline. Duration of diabetes ?3 years was associated with an increased rate of ischemic stroke compared with duration <3 years (adjusted hazard ratio [HR]: 1.74, 95% confidence interval [CI]: 1.10 to 2.76). The increased stroke rate was observed in older (age ?75 years) and younger (age <75 years) individuals. Neither poor glycemic control (HbA1c ?9.0%, adjusted HR: 1.04, 95% CI: 0.57 to 1.92) nor moderately increased HbA1c (7.0% to 8.9%, adjusted HR: 1.21, 95% CI: 0.77 to 1.91) were significantly associated with an increased rate of ischemic stroke compared with patients who had HbA1c <7.0%. Duration of diabetes is a more important predictor of ischemic stroke than glycemic control in patients who have diabetes and AF.
Authors: Ashburner JM; Go AS; Chang Y; Fang MC; Fredman L; Applebaum KM; Singer DE
J Am Coll Cardiol. 2016 Jan 26;67(3):239-47.
Executive Summary: Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association
Authors: Writing Group Members; Go AS; Stroke Statistics Subcommittee; et al.
Circulation. 2016 Jan 26;133(4):447-54.
Serum Osmolality and Postdischarge Outcomes After Hospitalization for Heart Failure.
Serum osmolality may fluctuate with neurohormonal activation and in response to certain therapeutics in patients with heart failure (HF). The clinical relevance of osmolality in patients with HF has not been defined. In this post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan trial, we analyzed serum osmolality measured at discharge in 3,744 patients hospitalized for HF and reduced ejection fraction (EF ≤40%). Median follow-up was 9.9 months. The association between discharge osmolality and all-cause mortality (ACM) and composite cardiovascular mortality or HF hospitalization was nonlinear; and thus, patients were divided into low (≤284), normal (285 to 300), and high (≥300 mOsm/kg) osmolality. Median serum osmolality at discharge was 297 (290 to 304) mOsm/kg. Patients in the low osmolality group (n = 454,12.1%) were more likely to be younger, men, have lower rates of hypertension, coronary artery disease, chronic kidney disease, diabetes, and have lower serum sodium, creatinine, systolic blood pressure, and EF (all p 0.4). In conclusion, low discharge serum osmolality was independently predictive of worse postdischarge mortality and readmission. Further study is required to clarify the clinical utility of serum osmolality in hospitalized patients with HF.
Authors: Vaduganathan, Muthiah M; Marti, Catherine N CN; Mentz, Robert J RJ; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Subacius, Haris P HP; Fonarow, Gregg C GC; Chioncel, Ovidiu O; Bazari, Hasan H; Maggioni, Aldo P AP; Zannad, Faiez F; Konstam, Marvin A MA; Sato, Naoki N; Gheorghiade, Mihai M; Butler, Javed J;
The American journal of cardiology. 2016 Apr 01;117(7):1144-50. Epub 2016-01-14.
Blood Pressure Reactivity to Psychological Stress in Young Adults and Cognition in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
The classic view of blood pressure (BP) reactivity to psychological stress in relation to cardiovascular risks assumes that excess reactivity is worse and lower reactivity is better. Evidence addressing how stress-induced BP reactivity in young adults is associated with midlife cognitive function is sparse. We assessed BP reactivity during a star tracing task and a video game in adults aged 20 to 32 years. Twenty-three years later, cognitive function was assessed with use of the Digit Symbol Substitution Test (a psychomotor speed test), the Rey Auditory Verbal Learning Test (a verbal memory test), and the modified Stroop test (an executive function test). At the time of follow-up, participants (n=3021) had a mean age of 50.2 years; 56% were women, and 44% were black. In linear regression models adjusted for demographic and clinical characteristics including baseline and follow-up resting BP, lower systolic BP (SBP) reactivity during the star tracing and video game was associated with worse Digit Symbol Substitution Test scores (? [SE]: 0.11 [0.02] and 0.05 [0.02], respectively) and worse performance on the Stroop test (? [SE]: -0.06 [0.02] and -0.05 [0.02]; all P<0.01). SBP reactivity was more consistently associated than diastolic BP reactivity with cognitive function scores. The associations between SBP reactivity and cognitive function were mostly similar between blacks and whites. Lower psychological stress-induced SBP reactivity in younger adults was associated with lower cognitive function in midlife. BP reactivity to psychological stressors may have different associations with target organs in hypertension.
Authors: Yano Y; Albanese E; Liu K; et al.
J Am Heart Assoc. 2016 Jan 13;5(1). Epub 2016-01-13.
Association of Age to Mortality and Repeat Revascularization in End-Stage Renal Disease Patients: Implications for Clinicians and Future Health Policies
The clinical effects of age occur over an age continuum, yet age as a primary predictor is often analyzed using arbitrary age cut-points. To assess whether transformation of a continuous variable such as age using a spline function can uncover nonlinear associations between age and cardiovascular outcomes. Observational retrospective cohort study in 1015 Kaiser Permanente Northern California patients with end-stage renal disease after index coronary revascularization. Age, the primary predictor, was modeled by 5 different techniques: 1) dichotomized at 65 years or older; 2) at 80 years or older (as a sensitivity analysis); 3) categorized as younger than 55 years (reference), 55 to 64, 65 to 74, and 75 years or older; 4) linear (every 5 years) variable; and 5) nonlinear by transformation into a cubic spline. Age categories were changed in a sensitivity analysis. Primary and secondary outcomes were all-cause mortality and repeat revascularization, respectively. Graphical assessment demonstrated that age dichotomized at either 65 years and older or 80 years and older led to loss of information. Categorized age underestimated or overestimated risk at the extremes of age. A sensitivity analysis demonstrated that an arbitrary change in the age category led to a different conclusion. Age modeled linearly adequately represented mortality risk but was suboptimal with repeat revascularization. Only the cubic spline demonstrated the nonlinear association between age and repeat revascularization. Employing the continuous variable age as a case study, we have demonstrated that the use of flexible transformations, such as spline functions, can unearth clinically meaningful associations that would not have been possible otherwise. Future research should determine whether incorporation of these methods can improve decision making at a population level.
Authors: Krishnaswami A; Alloggiamento T; Forman DE; Leong TK; Go AS; Mcculloch CE
Perm J. 2016 spring;20(2):4-9. Epub 2016-02-25.
Storage Time and Urine Biomarker Levels in the ASSESS-AKI Study
Although stored urine samples are often used in biomarker studies focused on acute and chronic kidney disease, how storage time impacts biomarker levels is not well understood. 866 subjects enrolled in the NIDDK-sponsored ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Study were included. Samples were processed under standard conditions and stored at -70°C until analyzed. Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and liver fatty acid binding protein (L-FABP) were measured in urine samples collected during the index hospitalization or an outpatient visit 3 months later. Mixed effects models were used to determine the effect of storage time on biomarker levels and stratified by visit. Median storage was 17.8 months (25-75% IQR 10.6-23.7) for samples from the index hospitalization and 14.6 months (IQR 7.3-20.4) for outpatient samples. In the mixed effects models, the only significant association between storage time and biomarker concentration was for KIM-1 in outpatient samples, where each month of storage was associated with a 1.7% decrease (95% CI -3% to -0.3%). There was no relationship between storage time and KIM-1 levels in samples from the index hospitalization. There was no significant impact of storage time over a median of 18 months on urine KIM-1, NGAL, IL-18 or L-FABP in hospitalized samples; a statistically significant effect towards a decrease over time was noted for KIM-1 in outpatient samples. Additional studies are needed to determine whether longer periods of storage at -70°C systematically impact levels of these analytes.
Authors: Liu KD; Hsu CY; ASSESS-AKI Study Investigators; et al.
PLoS ONE. 2016;11(10):e0164832. Epub 2016-10-27.
The Comparative Effectiveness of Diabetes Prevention Strategies to Reduce Postpartum Weight Retention in Women With Gestational Diabetes Mellitus: The Gestational Diabetes’ Effects on Moms (GEM) Cluster Randomized Controlled Trial
To compare the effectiveness of diabetes prevention strategies addressing postpartum weight retention for women with gestational diabetes mellitus (GDM) delivered at the health system level: mailed recommendations (usual care) versus usual care plus a Diabetes Prevention Program (DPP)-derived lifestyle intervention. This study was a cluster randomized controlled trial of 44 medical facilities (including 2,280 women with GDM) randomized to intervention or usual care. The intervention included mailed gestational weight gain recommendations plus 13 telephone sessions between 6 weeks and 6 months postpartum. Primary outcomes included the following: proportion meeting the postpartum goals of 1) reaching pregravid weight if pregravid BMI <25.0 kg/m(2) or 2) losing 5% of pregravid weight if BMI ?25.0 kg/m(2); and pregravid to postpartum weight change. On average, over the 12-month postpartum period, women in the intervention had significantly higher odds of meeting weight goals than women in usual care (odds ratio [OR] 1.28 [95% CI 1.10, 1.47]). The proportion meeting weight goals was significantly higher in the intervention than usual care at 6 weeks (25.5 vs. 22.4%; OR 1.17 [1.01, 1.36]) and 6 months (30.6 vs. 23.9%; OR 1.45 [1.14, 1.83]). Condition differences were reduced at 12 months (33.0 vs. 28.0%; OR 1.25 [0.96, 1.62]). At 6 months, women in the intervention retained significantly less weight than women in usual care (mean 0.39 kg [SD 5.5] vs. 0.95 kg [5.5]; mean condition difference -0.64 kg [95% CI -1.13, -0.14]) and had greater increases in vigorous-intensity physical activity (mean condition difference 15.4 min/week [4.9, 25.8]). A DPP-derived lifestyle intervention modestly reduced postpartum weight retention and increased vigorous-intensity physical activity.
Authors: Ferrara A; Brown SD; Albright CL; Tsai AL; Sternfeld B; Gordon NP; Schmittdiel JA; Gunderson EP; Mevi AA; Quesenberry CP; et al.
Diabetes Care. 2016 Jan;39(1):65-74. Epub 2015-12-09.
Description and initial evaluation of incorporating electronic follow-up of study participants in a longstanding multisite cohort study
The objective of this study was to evaluate a pilot program that allowed Chicago field center participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study to submit follow-up information electronically (eCARDIA). Chicago field center participants who provided email addresses were invited to complete contact information and follow-up questionnaires on medical conditions electronically in 2012-2013. Sociodemographic characteristics were compared between those who did and did not complete follow-up electronically. The number of participant contacts by CARDIA staff needed before follow-up was completed was also evaluated. Blacks and low socioeconomic position individuals were less likely to complete follow-up using the electronic questionnaire. Participants who used the electronic questionnaire for follow-up needed fewer contacts (e.g., median 1 contact compared with 3for contact information follow-up), but they also needed fewer contacts prior to eCARDIA (median 1 before and after eCARDIA). Findings suggest other approaches will be needed to maintain contact and elicit follow-up information from harder-to-reach individuals.
Authors: Kershaw KN; Liu K; Goff DC; Lloyd-Jones DM; Rasmussen-Torvik LJ; Reis JP; Schreiner PJ; Garside DB; Sidney S
BMC Med Res Methodol. 2016;16(1):125. Epub 2016-9-23.
Interleukin-6 Is a Risk Factor for Atrial Fibrillation in Chronic Kidney Disease: Findings from the CRIC Study
Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with chronic kidney disease (CKD). In this study, we examined the association between inflammation and AF in 3,762 adults with CKD, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. AF was determined at baseline by self-report and electrocardiogram (ECG). Plasma concentrations of interleukin(IL)-1, IL-1 Receptor antagonist, IL-6, tumor necrosis factor (TNF)-?, transforming growth factor-?, high sensitivity C-Reactive protein, and fibrinogen, measured at baseline. At baseline, 642 subjects had history of AF, but only 44 had AF in ECG recording. During a mean follow-up of 3.7 years, 108 subjects developed new-onset AF. There was no significant association between inflammatory biomarkers and past history of AF. After adjustment for demographic characteristics, comorbid conditions, laboratory values, echocardiographic variables, and medication use, plasma IL-6 level was significantly associated with presence of AF at baseline (Odds ratio [OR], 1.61; 95% confidence interval [CI], 1.21 to 2.14; P = 0.001) and new-onset AF (OR, 1.25; 95% CI, 1.02 to 1.53; P = 0.03). To summarize, plasma IL-6 level is an independent and consistent predictor of AF in patients with CKD.
Authors: Amdur RL; Barrows IR; CRIC Study Investigators; et al.
PLoS ONE. 2016;11(2):e0148189. Epub 2016-02-03.
Obesity Severity, Dietary Behaviors, and Lifestyle Risks Vary by Race/Ethnicity and Age in a Northern California Cohort of Children with Obesity
Identification of modifiable behaviors is important for pediatric weight management and obesity prevention programs. This study examined obesogenic behaviors in children with obesity in a Northern California obesity intervention program using data from a parent/teen-completed intake questionnaire covering dietary and lifestyle behaviors (frequency of breakfast, family meals, unhealthy snacking and beverages, fruit/vegetable intake, sleep, screen time, and exercise). Among 7956 children with BMI ? 95th percentile, 45.5% were females and 14.2% were 3-5, 44.2% were 6-11, and 41.6% were 12-17 years old. One-quarter (24.9%) were non-Hispanic white, 11.3% were black, 43.5% were Hispanic, and 12.0% were Asian/Pacific Islander. Severe obesity was prevalent (37.4%), especially among blacks, Hispanics, and older children, and was associated with less frequent breakfast and exercise and excess screen time, and in young children it was associated with consumption of sweetened beverages or juice. Unhealthy dietary behaviors, screen time, limited exercise, and sleep were more prevalent in older children and in selected black, Hispanic, and Asian subgroups, where consumption of sweetened beverages or juice was especially high. Overall, obesity severity and obesogenic behaviors increased with age and varied by gender and race/ethnicity. We identified several key prevalent modifiable behaviors that can be targeted by healthcare professionals to reduce obesity when counseling children with obesity and their parents.
Authors: Ford MC; Gordon NP; Howell A; Green CE; Greenspan LC; Chandra M; Mellor RG; Lo JC
J Obes. 2016;2016:4287976. Epub 2016-01-14.
Incidence and timing of potentially high-risk arrhythmias detected through long term continuous ambulatory electrocardiographic monitoring
Ambulatory electrocardiographic (ECG) monitoring is the standard to screen for high-risk arrhythmias. We evaluated the clinical utility of a novel, leadless electrode, single-patient-use ECG monitor that stores up to 14 days of a continuous recording to measure the burden and timing of potentially high-risk arrhythmias. We examined data from 122,815 long term continuous ambulatory monitors (iRhythm ZIO® Service, San Francisco) prescribed from 2011 to 2013 and categorized potentially high-risk arrhythmias into two types: (1) ventricular arrhythmias including non-sustained and sustained ventricular tachycardia and (2) bradyarrhythmias including sinus pauses >3 s, atrial fibrillation pauses >5 s, and high-grade heart block (Mobitz Type II or third-degree heart block). Of 122,815 ZIO® recordings, median wear time was 9.9 (IQR 6.8-13.8) days and median analyzable time was 9.1 (IQR 6.4-13.1) days. There were 22,443 (18.3%) with at least one episode of non-sustained ventricular tachycardia (NSVT), 238 (0.2%) with sustained VT, 1766 (1.4%) with a sinus pause >3 s (SP), 520 (0.4%) with a pause during atrial fibrillation >5 s (AFP), and 1486 (1.2%) with high-grade heart block (HGHB). Median time to first arrhythmia was 74 h (IQR 26-149 h) for NSVT, 22 h (IQR 5-73 h) for sustained VT, 22 h (IQR 7-64 h) for SP, 31 h (IQR 11-82 h) for AFP, and 40 h (SD 10-118 h) for HGHB. A significant percentage of potentially high-risk arrhythmias are not identified within 48-h of ambulatory ECG monitoring. Longer-term continuous ambulatory ECG monitoring provides incremental detection of these potentially clinically relevant arrhythmic events.
Authors: Solomon MD; Yang J; Sung SH; Livingston ML; Sarlas G; Lenane JC; Go AS
BMC Cardiovasc Disord. 2016;16:35. Epub 2016-02-17.
Assessment of algorithms to identify patients with thrombophilia following venous thromboembolism
Routine testing for thrombophilia following venous thromboembolism (VTE) is controversial. The use of large datasets to study the clinical impact of thrombophilia testing on patterns of care and patient outcomes may enable more efficient analysis of this practice in a wide range of settings. We set out to examine how accurately algorithms using International Classification of Diseases 9th Revision (ICD-9) codes and/or pharmacy data reflect laboratory-confirmed thrombophilia diagnoses. A random sample of adult Kaiser Permanente Colorado patients diagnosed with unprovoked VTE between 1/2004 and 12/2010 underwent medical record abstraction of thrombophilia test results. Algorithms using “ICD-9” (positive if a thrombophilia ICD-9 code was present), “Extended anticoagulation (AC)” (positive if AC therapy duration was >6 months), and “ICD-9 & Extended AC” (positive for both) criteria to identify possible thrombophilia cases were tested. Using positive thrombophilia laboratory results as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value of each algorithm were calculated, along with 95% confidence intervals (CIs). In our cohort of 636 patients, sensitivities were low (<50%) for each algorithm. "ICD-9" yielded the highest PPV (41.5%, 95% CI 26.3-57.9%) and a high specificity (95.9%, 95% CI 94.0-97.4%). "Extended AC" had the highest sensitivity but lowest specificity, and "ICD-9 & Extended AC" had the highest specificity but lowest sensitivity. ICD-9 codes for thrombophilia are highly specific for laboratory-confirmed cases, but all algorithms had low sensitivities. Further development of methods to identify thrombophilia patients in large datasets is warranted.
Authors: Delate T; Hsiao W; Kim B; Witt DM; Meyer MR; Go AS; Fang MC
Thromb Res. 2016 Jan;137:97-102. Epub 2015-Nov-10.
Lactation and Progression to Type 2 Diabetes Mellitus After Gestational Diabetes Mellitus: A Prospective Cohort Study
Lactation improves glucose metabolism, but its role in preventing type 2 diabetes mellitus (DM) after gestational diabetes mellitus (GDM) remains uncertain. To evaluate lactation and the 2-year incidence of DM after GDM pregnancy. Prospective, observational cohort of women with recent GDM. (ClinicalTrials.gov: NCT01967030). Integrated health care system. 1035 women diagnosed with GDM who delivered singletons at 35 weeks’ gestation or later and enrolled in the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy from 2008 to 2011. Three in-person research examinations from 6 to 9 weeks after delivery (baseline) and annual follow-up for 2 years that included 2-hour, 75-g oral glucose tolerance testing; anthropometry; and interviews. Multivariable Weibull regression models evaluated independent associations of lactation measures with incident DM adjusted for potential confounders. Of 1010 women without diabetes at baseline, 959 (95%) were evaluated up to 2 years later; 113 (11.8%) developed incident DM. There were graded inverse associations for lactation intensity at baseline with incident DM and adjusted hazard ratios of 0.64, 0.54, and 0.46 for mostly formula or mixed/inconsistent, mostly lactation, and exclusive lactation versus exclusive formula feeding, respectively (P trend = 0.016). Time-dependent lactation duration showed graded inverse associations with incident DM and adjusted hazard ratios of 0.55, 0.50, and 0.43 for greater than 2 to 5 months, greater than 5 to 10 months, and greater than 10 months, respectively, versus 0 to 2 months (P trend = 0.007). Weight change slightly attenuated hazard ratios. Randomized design is not feasible or desirable for clinical studies of lactation. Higher lactation intensity and longer duration were independently associated with lower 2-year incidences of DM after GDM pregnancy. Lactation may prevent DM after GDM delivery. National Institute of Child Health and Human Development.
Authors: Gunderson EP; Lo JC; Sternfeld B; Quesenberry CP; Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy Investigators; et al.
Ann Intern Med. 2015 Dec 15;163(12):889-98. Epub 2015-11-24.
Is migraine a risk factor for pediatric stroke?
Our understanding of risk factors for childhood stroke is incomplete. In adults, migraine with aura is associated with a two-fold increase in ischemic stroke risk. In this cohort study we examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC). Children ages 2-17 years who were members of KPNC for ?6 months between 1997 and 2007 were included. Migraine cohort members had one or more of: an ICD-9 code for migraine, migraine listed as a significant health problem, or a prescription for a migraine-specific medication. The comparison group was children with no evidence of headache. Main outcome measures included stroke incidence rates and incidence rate ratios (IR). Among the 1,566,952 children within KPNC during the study period, 88,164 had migraine, and 1,323,142 had no evidence of headache. Eight migraineurs had a stroke (three (38%) hemorrhagic; five (63%) ischemic). Eighty strokes occurred in children without headache (53 (66%) hemorrhagic; 27 (34%) ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8-5.2). A post-hoc analysis of adolescents (12-17 years) showed an increased risk of ischemic stroke among those with migraine; IR 3.4 (95% CI 1.2-9.5). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2-2.0). There was no statistically significant increase in hemorrhagic or ischemic stroke risk in pediatric migraineurs in this cohort study. A post-hoc analysis found that ischemic stroke risk was significantly elevated in adolescents with migraine. Future studies should focus on identifying risk factors for ischemic stroke among adolescent migraineurs. Based on adult data, we recommend that migraine aura status should be studied as a possible risk factor for ischemic stroke among adolescent migraineurs.
Authors: Gelfand AA; Fullerton HJ; Jacobson A; Sidney S; Goadsby PJ; Kurth T; Pressman A
Cephalalgia. 2015 Dec;35(14):1252-60. Epub 2015-03-09.
Metabolic Dyslipidemia and Risk of Coronary Heart Disease in 28,318 Adults With Diabetes Mellitus and Low-Density Lipoprotein Cholesterol <100 mg/dl
The risk of future coronary heart disease (CHD) in subjects with diabetes and “metabolic dyslipidemia” (high triglyceride [TGs] and low high-density cholesterol levels) remains a matter of concern. Little is known regarding the risk of CHD for this phenotype with low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dl. We analyzed a diabetes cohort of 28,318 members (aged 30 to 90 years) of Kaiser Permanente Northern California during 2002 to 2011 (192,356 person-years [p-y] follow-up), with LDL-C levels <100 mg/dl and without known CHD. We compared the incidence and hazard ratios (HRs) for CHD events in groups using Cox models: normal high-density lipoprotein (HDL) and TG (reference; n = 7,278, 25.7%); normal HDL and high TG (? 150 mg/dl; n = 4,484,15.8%); low HDL (? 50 mg/dl for women and ? 40 mg/dl for men) and normal TG (n = 4,048, 14.3%); low HDL and high TG (metabolic dyslipidemia; n = 12,508, 44%). Patients with metabolic dyslipidemia had the highest age-adjusted CHD events/1,000 p-y (12.7/1,000 p-y and 19.0/1,000 p-y for women and men, respectively). After multivariate adjustment for age, gender, ethnicity, hypertension, smoking, statin use, duration of diabetes, and hemoglobin A1c, we observed an increased CHD risk in women (HR 1.35, 95% confidence interval 1.14 to 1.60) and men (HR 1.62, 95% confidence interval 1.43 to 1.83) with metabolic dyslipidemia compared to those with normal HDL and TG. Even in subjects with an LDL-C <100 mg/dl, presence of metabolic dyslipidemia in adults with diabetes is associated with an increased risk of CHD. In conclusion, effective CHD prevention strategies are needed for adults with diabetes and metabolic dyslipidemia.
Authors: Rana JS; Liu JY; Moffet HH; Solomon MD; Go AS; Jaffe MG; Karter AJ
Am J Cardiol. 2015 Dec 1;116(11):1700-4. Epub 2015-09-10.
Marijuana use and risk of prediabetes and diabetes by middle adulthood: the Coronary Artery Risk Development in Young Adults (CARDIA) study
The impact of marijuana use on metabolic health is largely unknown. This study sought to clarify the cross-sectional and longitudinal associations between self-reported marijuana use, and prediabetes (defined as fasting glucose 5.6-6.9 mmol/l, 2 h glucose post OGTT 7.8-11.0 mmol/l or HbA1c 5.7-6.4% [39-47 mmol/mol]) and diabetes. Data from the community-based Coronary Artery Risk Development in Young Adults (CARDIA) study were used to determine marijuana use and the presence of prediabetes and diabetes among participants. The association between marijuana use and the prevalence of prediabetes and diabetes was examined in 3,034 participants at CARDIA examination year 25 (2010-2011), while the incidence of prediabetes and diabetes according to previous marijuana use was assessed in 3,151 individuals who were free from prediabetes/diabetes at year 7 (1992-1993) and who returned for at least one of the four subsequent follow-up examinations over 18 years. The percentage of individuals who self-reported current use of marijuana declined over the course of the study’s follow-up. After multivariable adjustment, higher odds of prediabetes were found for individuals who reported current use of marijuana (OR 1.65 [95% CI 1.15, 2.38]) and a lifetime use of 100 times or more (OR 1.49 [95% CI 1.06, 2.11]), compared with individuals who reported never using marijuana. There was no association between marijuana use and diabetes at CARDIA examination year 25. Over 18 years of follow-up, a greater risk of prediabetes (but not diabetes) was found for individuals who reported a lifetime use of marijuana of 100 times or more (HR 1.39 [95% CI 1.13, 1.71]), compared with individuals who had never used marijuana. Marijuana use in young adulthood is associated with an increased risk of prediabetes by middle adulthood, but not with the development of diabetes by this age.
Authors: Bancks MP; Pletcher MJ; Kertesz SG; Sidney S; Rana JS; Schreiner PJ
Diabetologia. 2015 Dec;58(12):2736-44. Epub 2015-09-13.
Susceptibility Loci for Clinical CAD and Subclinical Coronary Atherosclerosis Throughout the Life-Course
Recent genome-wide association studies have identified 49 single nucleotide polymorphisms associated with clinical coronary artery disease. The mechanism by which these loci influence risk remains largely unclear. We examined the association between a genetic risk score composed of high-risk alleles at the 49 single nucleotide polymorphisms and the degree of subclinical coronary atherosclerosis in 7798 participants from 6 studies stratified into 4 age groups at the time of assessment (15-34, 35-54, 55-74, and >75 years). Atherosclerosis was quantified by staining and direct visual inspection of the right coronary artery in the youngest group and by scanning for coronary artery calcification in the remaining groups. We defined cases as subjects within the top quartile of degree of atherosclerosis in 3 groups and as subjects with a coronary artery calcium score >0 in the fourth (35-54 years) where less than one quarter had any coronary artery calcium. In our meta-analysis of all strata, we found 1-SD increase in the genetic risk score increased the risk of advanced subclinical coronary atherosclerosis by 36% (P=8.3×10(-25)). This increase in risk was significant in all 4 age groups including the youngest group where atherosclerosis consisted primarily of raised lesions without macroscopic evidence of plaque rupture or thrombosis. Results were similar when we restricted the genetic risk score to 32 single nucleotide polymorphisms not associated with traditional risk factors or when we adjusted for traditional risk factors. A genetic risk score for clinical coronary artery disease is associated with advanced subclinical coronary atherosclerosis throughout the life-course. This association is apparent even at the earliest, uncomplicated stages of atherosclerosis.
Authors: Salfati E; Nandkeolyar S; Fortmann SP; Sidney S; Hlatky MA; Quertermous T; Go AS; Iribarren C; Herrington DM; Goldstein BA; Assimes TL
Circ Cardiovasc Genet. 2015 Dec;8(6):803-11. Epub 2015-09-28.
Thrombophilia testing patterns amongst patients with acute venous thromboembolism
Thrombophilia testing has limited value in determining the selection and duration of anticoagulation therapy for venous thromboembolism (VTE), yet is commonly performed. This study describes the patterns and appropriateness of thrombophilia testing in a large cohort of patients with acute VTE. This was a retrospective study of a random sample of patients with a validated diagnosis of acute VTE diagnosed between January 1, 2004 and December 31, 2010. Events were identified from administrative data and verified via manual review. Patients were grouped by thrombophilia testing status and compared on patient characteristics and thrombophilia testing results and appropriateness. Of 1314 patients with validated VTE, 315 (24%) underwent thrombophilia testing, 62 (20%) of whom had ? 1 positive test. Tested patients were younger and more likely to have had a family history of VTE. Factor V Leiden (17%) and prothrombin G20210A mutation (4%) were the most commonly detected thrombophilias. Only 31 (10%) of tested patients met eligibility criteria for thrombophilia testing (i.e., at least one strong thrombophilic risk factor present) and were tested at least 90 days following unprovoked index VTE. Thrombophilia is commonly evaluated in patients without a clear indication for testing and during times where results may be unreliable. Future studies are needed to assess interventions aimed at reducing inappropriate thrombophilia testing without adversely affecting patient outcomes.
Authors: Meyer MR; Witt DM; Delate T; Johnson SG; Fang M; Go A; Clark NP
Thromb Res. 2015 Dec;136(6):1160-4. Epub 2015-10-21.
The Contemporary Safety and Effectiveness of Lower Extremity Bypass Surgery and Peripheral Endovascular Interventions in the Treatment of Symptomatic Peripheral Arterial Disease
Treatment for symptomatic peripheral artery disease includes lower extremity bypass surgery (LEB) and peripheral endovascular interventions (PVIs); however, limited comparative effectiveness data exist between the 2 therapies. We assessed the safety and effectiveness of LEB and PVI in patients with symptomatic claudication and critical limb ischemia. In a community-based clinical registry at 2 large integrated healthcare delivery systems, we compared 883 patients undergoing PVI and 975 patients undergoing LEB between January 1, 2005 and December 31, 2011. Rates of target lesion revascularization were greater for PVI than for LEB in patients presenting with claudication (12.3±2.7% and 19.0±3.5% at 1 and 3 years versus 5.2±2.4% and 8.3±3.1%, log-rank P<0.001) and critical limb ischemia (19.1±4.8% and 31.6±6.3% at 1 and 3 years versus 10.8±2.5% and 16.0±3.2%, log-rank P<0.001). However, in comparison with PVI, LEB was associated with increased rates of complications up to 30 days following the procedure (37.1% versus 11.9%, P<0.001). There were no differences in amputation rates between the 2 groups. Findings remained consistent in sensitivity analyses by using propensity methods to account for treatment selection. In patients with symptomatic peripheral artery disease, in comparison with LEB, PVI was associated with fewer 30-day procedural complications, higher revascularization rates at 1 and 3 years, and no difference in subsequent amputations.
Authors: Tsai TT; Go AS; Magid DJ; et al.
Circulation. 2015 Nov 24;132(21):1999-2011. Epub 2015-09-11.
Retinopathy and the Risk of Cardiovascular Disease in Patients With Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort Study)
Patients with chronic kidney disease (CKD) experience other diseases such as cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess whether retinopathy predicts future CVD events in a subgroup of the participants of the Chronic Renal Insufficiency Cohort (CRIC) study. In this ancillary investigation, 2,605 participants of the CRIC study were invited to participate, and nonmydriatic fundus photographs were obtained in 1,936 subjects. Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed at a central photograph reading center by trained graders masked to study participant’s information. Patients with a self-reported history of cardiovascular disease were excluded. Incident CVD events were adjudicated using medical records. Kidney function measurements, traditional and nontraditional risk factors, for CVD were obtained. Presence and severity of retinopathy were associated with increased risk of development of any CVD in this population of CKD patients, and these associations persisted after adjustment for traditional risk factors for CVD. We also found a direct relation between increased venular diameter and risk of development of CVD; however, the relation was not statistically significant after adjustment for traditional risk factors. In conclusion, the presence of retinopathy was associated with future CVD events, suggesting that retinovascular pathology may be indicative of macrovascular disease even after adjustment for renal dysfunction and traditional CVD risk factors. Assessment of retinal morphology may be valuable in assessing risk of CVD in patients with CKD, both clinically and in research settings.
Authors: Grunwald JE; Lo JC; CRIC Study Investigators; et al.
Am J Cardiol. 2015 Nov 15;116(10):1527-33. Epub 2015-08-31.
Comparative Effectiveness of Statin Therapy in Chronic Kidney Disease and Acute Myocardial Infarction: a Retrospective Cohort Study
Whether there is a kidney function threshold to statin effectiveness in patients with acute myocardial infarction is poorly understood. Our study sought to help fill this gap in clinical knowledge. We undertook a new-user cohort study of the effectiveness of statin therapy by level of estimated glomerular filtration rate (eGFR) in adults who were hospitalized for myocardial infarction between 2000 and 2008. Data came from the Cardiovascular Research Network. The primary clinical outcomes were 1-year all-cause mortality and cardiovascular hospitalizations, with adverse outcomes of myopathy and development of diabetes mellitus. We calculated incidence rates, the number needed to treat, and used Cox proportional hazards regression with propensity score matching and adjustment to control for confounding, with testing for variation of effect by level of kidney function. Compared with statin non-initiators (n = 5583), statin initiators (n = 5597) had a lower propensity score-adjusted risk for death (hazard ratio 0.79; 95% confidence interval [CI], 0.71-0.88) and cardiovascular hospitalizations (hazard ratio 0.90; 95% CI, 0.82-1.00). We found little evidence of variation in effect by level of eGFR (P = .86 for death; P = .77 for cardiovascular hospitalization). Adverse outcomes were similar for statin initiators and statin non-initiators. The number needed to treat to prevent 1 additional death over 1 year of follow-up ranged from 15 (95% CI, 11-28) for eGFR <30 mL/min/1.73 m(2) requiring statin treatment over 2 years to prevent 1 additional death, to 67 (95% CI, 49-118) for patients with eGFR >90 mL/min/1.73 m(2). Our findings suggest that there is potential for important public health gains by increasing the routine use of statin therapy for patients with lower levels of kidney function.
Authors: Smith DH; Go AS; Sidney S; et al.
Am J Med. 2015 Nov;128(11):1252.e1-1252.e11. Epub 2015-07-11.
Association of Fitness With Incident Dyslipidemias Over 25 Years in the Coronary Artery Risk Development in Young Adults Study
Few studies have examined the longitudinal associations of fitness or changes in fitness on the risk of developing dyslipidemias. This study examined the associations of (1) baseline fitness with 25-year dyslipidemia incidence and (2) 20-year fitness change on dyslipidemia development in middle age in the Coronary Artery Risk Development in Young Adults Study (CARDIA). Multivariable Cox proportional hazards regression models were used to test the association of baseline fitness (1985-1986) with dyslipidemia incidence over 25 years (2010-2011) in CARDIA (N=4,898). Modified Poisson regression models were used to examine the association of 20-year change in fitness with dyslipidemia incidence between Years 20 and 25 (n=2,487). Data were analyzed in June 2014 and February 2015. In adjusted models, the risk of incident low high-density lipoprotein cholesterol (HDL-C); high triglycerides; and high low-density lipoprotein cholesterol (LDL-C) was significantly lower, by 9%, 16%, and 14%, respectively, for each 2.0-minute increase in baseline treadmill endurance. After additional adjustment for baseline trait level, the associations remained significant for incident high triglycerides and high LDL-C in the total population and for incident high triglycerides in both men and women. In race-stratified models, these associations appeared to be limited to whites. In adjusted models, change in fitness did not predict 5-year incidence of dyslipidemias, whereas baseline fitness significantly predicted 5-year incidence of high triglycerides. Our findings demonstrate the importance of cardiorespiratory fitness in young adulthood as a risk factor for developing dyslipidemias, particularly high triglycerides, during the transition to middle age.
Authors: Sarzynski MA; Schuna JM; Carnethon MR; Jacobs DR; Lewis CE; Quesenberry CP; Sidney S; Schreiner PJ; Sternfeld B
Am J Prev Med. 2015 Nov;49(5):745-52. Epub 2015-07-10.
Team-Based Care: A Step in the Right Direction for Hypertension Control
Authors: Sidney S
Am J Prev Med. 2015 Nov;49(5):e81-2. Epub 2015-07-29.
The clinical course of health status and association with outcomes in patients hospitalized for heart failure: insights from ASCEND-HF.
AIMS: A longitudinal and comprehensive analysis of health-related quality of life (HRQOL) was performed during hospitalization for heart failure (HF) or soon after discharge.METHODS AND RESULTS: A post-hoc analysis was performed of the ASCEND-HF trial. The EuroQOL five dimensions questionnaire (EQ-5D) was administered to study participants at baseline, 24 h, discharge/day 10, and day 30. EQ-5D includes functional dimensions mapped to corresponding utility scores (i.e. 0 = death and 1 = perfect health), and a visual analogue scale (VAS) ranging from 0 (i.e. ‘worst imaginable health state’) to 100 (i.e. ‘best imaginable health state’). The association between baseline and discharge EQ-5D measurements and subsequent clinical outcomes including death and rehospitalization were assessed using multivariable logistic regression and Cox proportional hazards regression. A total of 6943 patients (97%) had complete EQ-5D data at baseline. Mapped utility and VAS scores (mean ± SD) increased over time, respectively, from 0.56 ± 0.23 and 45 ± 22 at baseline to 0.67 ± 0.26 and 58 ± 22 at 24 h and to 0.79 ± 0.20 and 68 ± 22 at discharge, and remained stable at day 30. Lower mapped utility scores at baseline [odds ratio (OR) per 0.1 decrease in utility score 1.03, 95% confidence interval (CI) 1.00-1.06] and discharge (OR 1.10, 95% CI 1.05-1.15) and VAS scores at baseline (OR per 10 point decrease 1.05, 95% CI 1.01-1.09) were significantly associated with increased risk of 30-day all-cause death or HF rehospitalization.CONCLUSIONS: Patients hospitalized for HF had severely impaired health status at baseline and, although this improved substantially during admission, health status remained abnormal at discharge.
Authors: Ambrosy, Andrew P AP; Hernandez, Adrian F AF; Armstrong, Paul W PW; Butler, Javed J; Dunning, Allison A; Ezekowitz, Justin A JA; Felker, G Michael GM; Greene, Stephen J SJ; Kaul, Padma P; McMurray, John J JJ; Metra, Marco M; O'Connor, Christopher M CM; Reed, Shelby D SD; Schulte, Phillip J PJ; Starling, Randall C RC; Tang, W H Wilson WH; Voors, Adriaan A AA; Mentz, Robert J RJ
European journal of heart failure. 2016 Mar 01;18(3):306-13. Epub 2015-10-14.
The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ?50y, men >50y, women ?50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (?50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
Authors: Winkler TW; Go AS; Loos RJ; et al.
PLoS Genet. 2015 Oct;11(10):e1005378. Epub 2015-10-01.
Comparing US paediatric and adult weight classification at the transition from late teenage to young adulthood
Although paediatric growth charts are recommended for weight assessment prior to age 20, many teenagers transition earlier to adult care where absolute body mass index (BMI) is used. This study examines concordance of weight classification in older teenagers using paediatric percentiles and adult thresholds. BMI from 23?640 US teens ages 18-19 years were classified using paediatric BMI percentile criteria for underweight (
Authors: Maring B; Lo JC; et al.
Pediatr Obes. 2015 Oct;10(5):371-9. Epub 2015-01-22.
Cost-effectiveness analysis of neurocognitive-sparing treatments for brain metastases.
BACKGROUND: Decisions regarding how to treat patients who have 1 to 3 brain metastases require important tradeoffs between controlling recurrences, side effects, and costs. In this analysis, the authors compared novel treatments versus usual care to determine the incremental cost-effectiveness ratio from a payer’s (Medicare) perspective.METHODS: Cost-effectiveness was evaluated using a microsimulation of a Markov model for 60 one-month cycles. The model used 4 simulated cohorts of patients aged 65 years with 1 to 3 brain metastases. The 4 cohorts had a median survival of 3, 6, 12, and 24 months to test the sensitivity of the model to different prognoses. The treatment alternatives evaluated included stereotactic radiosurgery (SRS) with 3 variants of salvage after recurrence (whole-brain radiotherapy [WBRT], hippocampal avoidance WBRT [HA-WBRT], SRS plus WBRT, and SRS plus HA-WBRT). The findings were tested for robustness using probabilistic and deterministic sensitivity analyses.RESULTS: Traditional radiation therapies remained cost-effective for patients in the 3-month and 6-month cohorts. In the cohorts with longer median survival, HA-WBRT and SRS plus HA-WBRT became cost-effective relative to traditional treatments. When the treatments that involved HA-WBRT were excluded, either SRS alone or SRS plus WBRT was cost-effective relative to WBRT alone. The deterministic and probabilistic sensitivity analyses confirmed the robustness of these results.CONCLUSIONS: HA-WBRT and SRS plus HA-WBRT were cost-effective for 2 of the 4 cohorts, demonstrating the value of controlling late brain toxicity with this novel therapy. Cost-effectiveness depended on patient life expectancy. SRS was cost-effective in the cohorts with short prognoses (3 and 6 months), whereas HA-WBRT and SRS plus HA-WBRT were cost-effective in the cohorts with longer prognoses (12 and 24 months).
Authors: Savitz, Samuel T; Chen, Ronald C; Sher, David J
Cancer. 2015 Dec 01;121(23):4231-9. Epub 2015-09-15.
Bariatric surgery results: reporting clinical characteristics and adverse outcomes from an integrated healthcare delivery system
Limited data have been reported on bariatric surgery within a large, high-volume regional multicenter integrated healthcare delivery system. Review clinical characteristics and short- and intermediate-term outcomes and adverse events from a bariatric surgery program within an integrated healthcare delivery system. Single high-volume, multicenter regional integrated healthcare delivery system. Adult patients who underwent primary bariatric surgery during 2010-2011 were reviewed. Clinical characteristics, outcomes, and weight loss results were extracted from the electronic medical record. A total of 2399 patients were identified within the study period. The 30-day rates of clinical outcomes for Roux-en-Y gastric bypass (RYGB; n = 1313) and sleeve gastrectomy (SG; n = 1018) were 2.9% for readmission, 3.0% for major complications, .8% for reoperation, and 0% for mortality. One-year and 2-year weight loss results were as follows: percent weight loss (%WL) was 31.4 (±SD 8.5) and 34.2±12.0% for SG and 34.1±9.3 and 39.1±11.9 for RYGB; percent excess weight loss (%EBWL) was 64.2±18.0 and 69.8±23.7 for SG and 68.0±19.3 and 77.8±23.7 for RYGB; percent excess body mass index loss (%EBMIL) was 72.9±21.0 and 77.7±22.4 for SG and 76.6±22.1% and 85.6±21.6 for RYGB. Follow-up for each procedure at 1 year was 76% for SG (n = 778) and 80% for RYGB (n = 1052) and at 2 years was 65% for SG (n = 659) and 67% for RYGB (n = 875). A large regional high-volume multicenter bariatric program within an integrated healthcare delivery system can produce excellent short-term results with low rates of short- and intermediate-term adverse outcomes.
Authors: Li RA; Fisher DP; Dutta S; O'Brien RM; Ackerson LM; Sorel ME; Sidney S
Surg Obes Relat Dis. 2015 Sep-Oct;11(5):1119-25. Epub 2015-03-09.
Type II endoleak with or without intervention after endovascular aortic aneurysm repair does not change aneurysm-related outcomes despite sac growth
There is considerable controversy about the significance and appropriate treatment of type II endoleaks (T2Ls) after endovascular aneurysm repair (EVAR). We report our long-term experience with T2L management in a large multicenter registry. Between 2000 and 2010, 1736 patients underwent EVAR, and we recorded the incidence of T2L. Primary outcomes were mortality and aneurysm-related mortality (ARM). Secondary outcomes were change in aneurysm sac size, major adverse events, and reintervention. During the follow-up (median of 32.2 months; interquartile range, 14.2-52.8 months), T2L was identified in 474 patients (27.3%). There were no late abdominal aortic aneurysm ruptures attributable to a T2L. Overall mortality (P = .47) and ARM (P = .26) did not differ between patients with and without T2L. Sac growth (median, 5 mm; interquartile range, 2-10 mm) was seen in 213 (44.9%) of the patients with T2L. Of these patients with a T2L and sac growth, 36 (16.9%) had an additional type of endoleak. Of all patients with T2L, 111 (23.4%) received reinterventions, including 39 patients who underwent multiple procedures; 74% of the reinterventions were performed in patients with sac growth. Reinterventions included lumbar embolization in 66 patients (59.5%), placement of additional stents in 48 (43.2%), open surgical revision in 14 (12.6%), and direct sac injection in 22 (19.8%). The reintervention was successful in 35 patients (31.5%). After patients with other types of endoleak were excluded, no difference in overall all-cause mortality (P = .57) or ARM (P = .09) was observed between patients with T2L-associated sac growth who underwent reintervention and those in whom T2L was left untreated. In our multicenter EVAR registry, overall all-cause mortality and ARM were unaffected by the presence of a T2L. Moreover, patients who were simply observed for T2L-associated sac growth had aneurysm-related outcomes similar to those in patients who underwent reintervention. Our future work will investigate the most cost-effective ways to select patients for intervention besides sac growth alone.
Authors: Walker J; Tucker LY; Goodney P; Candell L; Hua H; Okuhn S; Hill B; Chang RW
J Vasc Surg. 2015 Sep;62(3):551-61. Epub 2015-06-06.
Identifying Barriers and Practical Solutions to Conducting Site-Based Research in North America: Exploring Acute Heart Failure Trials As a Case Study.
Although the prognosis of ambulatory heart failure (HF) has improved dramatically there have been few advances in the management of acute HF (AHF). Despite regional differences in patient characteristics, background therapy, and event rates, AHF clinical trial enrollment has transitioned from North America and Western Europe to Eastern Europe, South America, and Asia-Pacific where regulatory burden and cost of conducting research may be less prohibitive. It is unclear if the results of clinical trials conducted outside of North America are generalizable to US patient populations. This article uses AHF as a paradigm and identifies barriers and practical solutions to successfully conducting site-based research in North America.
Authors: Ambrosy, Andrew P AP; Mentz, Robert J RJ; Krishnamoorthy, Arun A; Greene, Stephen J SJ; Severance, Harry W HW
Heart failure clinics. 2015 Oct 01;11(4):581-9. Epub 2015-08-04.
Hospitalized Heart Failure in the United States: Lessons Learned from Clinical Trial Populations.
Hospitalized heart failure (HHF) patients carry a prognosis comparable to many cancers and constitute more than 1 million hospital admissions annually in the United States. To date, North Americans have comprised a minority of those included in prior hospitalized HF trials and have been repeatedly shown to differ from patients in other areas of the world in terms of clinical characteristics, length of hospital stay, therapy utilization, and post-discharge outcomes. Recognizing the varying patient profiles and outcomes of North Americans enrolled in prior HHF trial programs is critical to optimizing design of future drug development programs and maximizing chances of bringing a novel therapeutic agent to the bedside.
Authors: Greene, Stephen J SJ; AlKhawam, Lora L; Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; Mentz, Robert J RJ
Heart failure clinics. 2015 Oct 01;11(4):591-601. Epub 2015-08-04.
Quality Control and Reproducibility in M-Mode, Two-Dimensional, and Speckle Tracking Echocardiography Acquisition and Analysis: The CARDIA Study, Year 25 Examination Experience
Few large studies describe quality control procedures and reproducibility findings in cardiovascular ultrasound, particularly in novel techniques such as speckle tracking echocardiography (STE). We evaluate the echocardiography assessment performance in the Coronary Artery Risk Development in Young Adults (CARDIA) study Year 25 (Y25) examination (2010-2011) and report findings from a quality control and reproducibility program conducted to assess Field Center image acquisition and reading center (RC) accuracy. The CARDIA Y25 examination had 3475 echocardiograms performed in 4 US Field Centers and analyzed in a RC, assessing standard echocardiography (LA dimension, aortic root, LV mass, LV end-diastolic volume [LVEDV], ejection fraction [LVEF]), and STE (two- and four-chamber longitudinal, circumferential, and radial strains). Reproducibility was assessed using intraclass correlation coefficients (ICC), coefficients of variation (CV), and Bland-Altman plots. For standard echocardiography reproducibility, LV mass and LVEDV consistently had CV above 10% and aortic root below 6%. Intra-sonographer aortic root and LV mass had the most robust values of ICC in standard echocardiography. For STE, the number of properly tracking segments was above 80% in short-axis and four-chamber and 58% in two-chamber views. Longitudinal strain parameters were the most robust and radial strain showed the highest variation. Comparing Field Centers with echocardiography RC STE readings, mean differences ranged from 0.4% to 4.1% and ICC from 0.37 to 0.66, with robust results for longitudinal strains. Echocardiography image acquisition and reading processes in the CARDIA study were highly reproducible, including robust results for STE analysis. Consistent quality control may increase the reliability of echocardiography measurements in large cohort studies.
Authors: Armstrong AC; Lewis CE; Lima JA; et al.
Echocardiography. 2015 Aug;32(8):1233-40. Epub 2014-11-09.
Anatomic runoff score predicts cardiovascular outcomes in patients with lower extremity peripheral artery disease undergoing revascularization
Although the presence, extent, and severity of obstruction in patients with lower extremity peripheral artery disease (LE PAD) affect their functional status, quality of life, and treatment, it is not known if these factors are associated with future cardiovascular events. We empirically created an anatomic runoff score (ARS) to approximate the burden of LE PAD and determined its association with clinical outcomes. We evaluated all patients with LE PAD and bilateral angiography undergoing revascularization in a community-based clinical study. Primary clinical outcomes of interest were (1) a composite of all-cause death, myocardial infarction (MI), and stroke and (2) amputation-free survival. Cox proportional hazards models were created to identify predictors of clinical outcomes. We evaluated 908 patients undergoing angiography, and a total of 260 (28.0%) patients reached the composite end point (45 MI, 63 stroke, and 152 death) during the study period. Anatomic runoff score ranged from 0 to 15 (mean 4.7; SD 2.5) with higher scores indicating a higher burden of disease, and an optimal cutpoint analysis classified patients into low ARS (<5) and high ARS (?5). The unadjusted rates of the primary composite end point and amputation-free survival were nearly 2-fold higher in patients with a high ARS when compared with patients with a low ARS. The most significant predictors of the composite end point (death/MI/stroke) were age (? 10 years; hazard ratio [HR] 1.53; CI 1.32-1.78; P < .001), diabetes mellitus (HR 1.65; CI 1.26-2.18; P < .001), glomerular filtration rate <30 (HR 2.23; CI 1.44-3.44; P < .001), statin use (HR 0.66; CI 0.48-0.88; P < .001), and ARS (? 2 points; HR 1.21; CI 1.08-1.35; P < .001). After adjustment for clinical factors, the LE PAD ARS was an independent predictor of future cardiovascular morbidity and mortality in a broadly representative patient population undergoing revascularization for symptomatic PAD. A clinically useful anatomic scoring system, if validated, may assist clinicians in risk stratification during the course of clinical decision making.
Authors: Jones WS; Go AS; Magid DJ; et al.
Am Heart J. 2015 Aug;170(2):400-8. Epub 2015-05-02.
Serum Fractalkine (CX3CL1) and Cardiovascular Outcomes and Diabetes: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study
Cardiometabolic disease is a major cause of morbidity and mortality in persons with chronic kidney disease (CKD). Fractalkine (CX3CL1) is a potential mediator of both atherosclerosis and metabolic disease. Studies of the relationship of CX3CL1 with risk of cardiovascular disease (CVD) events and metabolic traits are lacking, particularly in the high-risk setting of CKD. Cross-sectional and longitudinal observational analysis. Adults with CKD from 7 US sites participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Quartiles of plasma CX3CL1 levels at baseline. Baseline estimated glomerular filtration rate from a creatinine and cystatin C-based equation, prevalent and incident CVD, diabetes, metabolic syndrome and its criteria, homeostatic model assessment of insulin resistance, hemoglobin A1c level, myocardial infarction, all-cause mortality, and the composite outcome of myocardial infarction/all-cause mortality. Among 3,687 participants, baseline CX3CL1 levels were associated positively with several CVD risk factors and metabolic traits, lower estimated glomerular filtration rate, and higher levels of inflammatory cytokines, as well as prevalent CVD (OR, 1.09; 95% CI, 1.01-1.19; P=0.03). Higher CX3CL1 level also was associated with prevalent diabetes (OR, 1.26; 95% CI, 1.16-1.38; P<0.001) in adjusted models. During a mean follow-up of 6 years, there were 352 deaths, 176 myocardial infarctions, and 484 composite outcomes. In fully adjusted models, 1-SD higher CX3CL1 level increased the hazard for all-cause mortality (1.11; 95% CI, 1.00-1.22; P=0.02) and the composite outcome (1.09; 95% CI, 1.00-1.19; P=0.04). Study design did not allow evaluation of changes over time, correlation with progression of phenotypes, or determination of causality of effect. Circulating CX3CL1 level may contribute to both atherosclerotic CVD and diabetes in a CKD cohort. Further studies are required to establish mechanisms through which CX3CL1 affects the pathogenesis of atherosclerosis and diabetes.
Authors: Shah R; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2015 Aug;66(2):266-73. Epub 2015-03-17.
Maternal prepregnancy waist circumference and BMI in relation to gestational weight gain and breastfeeding behavior: the CARDIA study
Studies suggest that gestational weight gain (GWG) and breastfeeding behavior may influence long-term maternal abdominal fat mass. However, this could be confounded by abdominal fat mass before pregnancy because it is unknown whether abdominal fat mass, independently of body size, affects GWG and breastfeeding behavior. We investigated how maternal prepregnancy fat distribution, described by waist circumference (WC) and body mass index (BMI), is associated with GWG and breastfeeding behavior. We analyzed 1371 live births to 1024 women after enrollment in the Coronary Artery Risk Development in Young Adults study (1985-1996). For each birth, maternal prepregnancy BMI and WC were measured at year 0 (baseline), 2, 5, or 7 examinations. Recalled GWG and breastfeeding behavior were collected at years 7 and 10. GWG was analyzed by using linear regression and breastfeeding behavior by using logistic regression and discrete-time logistic regression. Adjusted for potential confounders, a 1-cm larger WC adjusted for BMI was associated with a 0.19-kg (95% CI: -0.29-, -0.10-kg) lower GWG. In contrast, a 1-unit higher BMI adjusted for WC was associated with a 0.27-kg (95% CI: 0.06-, 0.47-kg) higher GWG. The OR for ever breastfeeding compared with never breastfeeding was 0.93 (95% CI: 0.90, 0.97) per 1-cm larger WC after adjustment for BMI, whereas it was 1.10 (95% CI: 1.02, 1.19) per 1-unit higher BMI adjusted for WC. Maternal prepregnancy body size was differently associated with GWG and breastfeeding behavior depending on the location of the fat mass. Thus, maternal fat distribution may be a more important determinant of GWG and breastfeeding behavior than BMI alone.
Authors: Kirkegaard H; Nohr EA; Rasmussen KM; Stovring H; Sørensen TI; Lewis CE; Gunderson EP
Am J Clin Nutr. 2015 Aug;102(2):393-401. Epub 2015-07-01.
Lactation Duration and Midlife Atherosclerosis
To evaluate lactation duration in relation to subsequent atherosclerosis in women during midlife. The Coronary Artery Risk Development in Young Adults study is a multicenter prospective cohort that enrolled 2,787 women in 1985-1986 (ages 18-30 years, 52% black, 48% white), of whom 2,014 (72%) attended the 20-year follow-up examination in 2005-2006. We selected 846 women (46% black) without heart disease or diabetes at baseline who delivered one or more times after the baseline evaluation, had cardiometabolic risk factors measured at baseline, and had maximum common carotid intima-media thickness (mm) measured at the 20-year follow-up examination in 2005-2006. Lactation duration was summed across all postbaseline births for each woman and (n, women) categorized as: 0 to less than 1 month (n=262), 1 to less than 6 months (n=210), 6 to less than 10 months (n=169), and 10 months or greater (n=205). Multiple linear regression models estimated mean common carotid intima-media thickness (95% confidence interval) and mean differences among lactation duration groups compared with the 0 to less than 1-month group adjusted for prepregnancy obesity, cardiometabolic status, parity, and other risk factors. Lactation duration had a graded inverse association with common carotid intima-media thickness; mean differences between 10 months or greater compared with 0 to less than 1 month ranged from -0.062 mm for unadjusted models (P trend <.001) to -0.029 mm for models fully adjusted for prepregnancy body mass index (BMI) and cardiometabolic risk factors, parity, smoking, and sociodemographics (P trend=.010). Stepwise addition of potential mediators (BMI, systolic blood pressure at the 20-year follow-up examination) modestly attenuated the lactation and common carotid intima-media thickness association to -0.027 and -0.023 mm (P trend=.019 and .054). Shorter lactation duration is associated with subclinical atherosclerosis independent of prepregnancy cardiometabolic risk factors and traditional risk factors. The magnitude of differences in carotid artery intima-media thickness may represent greater vascular aging. Lactation may have long-term benefits that lower cardiovascular disease risk in women. II.
Authors: Gunderson EP; Quesenberry CP; Ning X; Jacobs DR; Gross M; Goff DC; Pletcher MJ; Lewis CE
Obstet Gynecol. 2015 Aug;126(2):381-90.
Intima-Media Thickness and Cognitive Function in Stroke-Free Middle-Aged Adults: Findings From the Coronary Artery Risk Development in Young Adults Study
The relationship between carotid artery intima-media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiological cohort of 2618 stroke-free participants. At the year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized z scores, with negative values indicating worse performance. Mean age at baseline was 45.3 years (SD, 3.6). Greater IMT (per 1 SD difference of 0.12 mm) was significantly associated with worse performance on all cognitive tests (z scores) in unadjusted linear regression models (verbal memory, -0.16; 95% confidence interval [CI], -0.20 to -0.13; processing speed, -0.23; 95% CI, -0.27 to -0.19; and executive function, -0.17; 95% CI, -0.20 to -0.13). In models adjusted for sociodemographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (-0.06; 95% CI, -0.09 to -0.02; P, 0.003) and borderline associated with executive function (-0.03; 95% CI, -0.07 to 0.00; P, 0.07) but not with verbal memory. We observed an association between greater IMT and worse processing speed-a key component of cognitive functioning-at middle age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging.
Authors: Zeki Al Hazzouri A; Vittinghoff E; Sidney S; Reis JP; Jacobs DR; Yaffe K
Stroke. 2015 Aug;46(8):2190-6. Epub 2015-06-23.
Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)
Instruments to assess symptom burden and quality of life among patients with atrial fibrillation (AF) have not been well evaluated in community practice or associated with patient outcomes. Using data from 10 087 AF patients in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), symptom severity was evaluated using the European Heart Rhythm Association (EHRA) classification system, and quality of life was assessed using the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire. The association between AF-related symptoms, quality of life, and outcomes was assessed using Cox regression. The majority of AF patients (61.8%) were symptomatic (EHRA >2) and 16.5% had severe or disabling symptoms (EHRA 3-4). EHRA symptom class was well correlated with the AFEQT score (Spearman correlation coefficient -0.39). Over 1.8 years of follow-up, AF symptoms were associated with a higher risk of hospitalization (adjusted hazard ratio for EHRA ?2 versus EHRA 1 1.23, 95% confidence interval, 1.15-1.31) and a borderline higher risk of major bleeding. Lower quality of life was associated with a higher risk of hospitalization (adjusted hazard ratio for lowest quartile of AFEQT versus highest 1.49, 95% confidence interval, 1.2-1.84), but not other major adverse events, including death. In a community-based study, most patients with AF were symptomatic and had impaired quality of life. Quality of life measured by the AFEQT correlated closely with symptom severity measured by the EHRA class. AF symptoms and lower quality of life were associated with higher risk of hospitalization but not mortality during follow-up.
Authors: Freeman JV; Go AS; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators and Patients; et al.
Circ Cardiovasc Qual Outcomes. 2015 Jul;8(4):393-402. Epub 2015-06-09.
Marriage and parenthood in relation to obesogenic neighborhood trajectories: The CARDIA study
Marriage and parenthood are associated with weight gain and residential mobility. Little is known about how obesity-relevant environmental contexts differ according to family structure. We estimated trajectories of neighborhood poverty, population density, and density of fast food restaurants, supermarkets, and commercial and public physical activity facilities for adults from a biracial cohort (CARDIA, n=4,174, aged 25-50) over 13 years (1992-93 through 2005-06) using latent growth curve analysis. We estimated associations of marriage, parenthood, and race with the observed neighborhood trajectories. Married participants tended to live in neighborhoods with lower poverty, population density, and availability of all types of food and physical activity amenities. Parenthood was similarly but less consistently related to neighborhood characteristics. Marriage and parenthood were more strongly related to neighborhood trajectories in whites (versus blacks), who, in prior studies, exhibit weaker associations between neighborhood characteristics and health. Greater understanding of how interactive family and neighborhood environments contribute to healthy living is needed.
Authors: Boone-Heinonen J; Howard AG; Meyer K; Lewis CE; Kiefe CI; Laroche HH; Gunderson EP; Gordon-Larsen P
Health Place. 2015 Jul;34:229-40. Epub 2015-06-18.
The Kansas City Cardiomyopathy Questionnaire Score Is Associated With Incident Heart Failure Hospitalization in Chronic Kidney Disease Patients Without Previously Diagnosed Heart Failure: The CRIC Study
Chronic kidney disease is a risk factor for heart failure (HF). Patients with chronic kidney disease without diagnosed HF have an increased burden of symptoms characteristic of HF. It is not known whether these symptoms are associated with occurrence of new onset HF. We studied the association of a modified Kansas City Cardiomyopathy Questionnaire with newly identified cases of hospitalized HF among 3093 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study who did not report HF at baseline. The annually updated Kansas City Cardiomyopathy Questionnaire score was categorized into quartiles (Q1-4) with the lower scores representing the worse symptoms. Multivariable-adjusted repeated measure logistic regression models were adjusted for demographic characteristics, clinical risk factors for HF, N-terminal probrain natriuretic peptide level and left ventricular hypertrophy, left ventricular systolic and diastolic dysfunction. Over a mean (±SD) follow-up period of 4.3±1.6 years, there were 211 new cases of HF hospitalizations. The risk of HF hospitalization increased with increasing symptom quartiles; 2.62, 1.85, 1.14, and 0.74 events per 100 person-years, respectively. The median number of annual Kansas City Cardiomyopathy Questionnaire assessments per participant was 5 (interquartile range, 3-6). The annually updated Kansas City Cardiomyopathy Questionnaire score was independently associated with higher risk of incident HF hospitalization in multivariable-adjusted models (odds ratio, 3.30 [1.66-6.52]; P=0.001 for Q1 compared with Q4). Symptoms characteristic of HF are common in patients with chronic kidney disease and are associated with higher short-term risk for new hospitalization for HF, independent of level of kidney function, and other known HF risk factors.
Authors: Mishra RK; Go AS; CRIC Study Investigators; et al.
Circ Heart Fail. 2015 Jul;8(4):702-8. Epub 2015-05-18.
Breastfeeding, PAM50 Tumor Subtype, and Breast Cancer Prognosis and Survival
Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown. We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided. Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes. History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity.
Authors: Kwan ML; Kroenke CH; Habel LA; Gunderson EP; Quesenberry CP; Kushi LH; Caan BJ; et al.
J Natl Cancer Inst. 2015 Jul;107(7). Epub 2015-04-28.
Determinants of Aortic Root Dilatation and Reference Values Among Young Adults Over a 20-Year Period: Coronary Artery Risk Development in Young Adults Study
Aortic size increases with age, but factors related to such dilatation in healthy young adult population have not been studied. We aim to evaluate changes in aortic dimensions and its principal correlates among young adults over a 20-year time period. Reference values for aortic dimensions in young adults by echocardiography are also provided. Healthy Coronary Artery Risk Development in Young Adults (CARDIA) study participants aged 23 to 35 years in 1990-1991 (n=3051) were included after excluding 18 individuals with significant valvular dysfunction. Aortic root diameter (ARD) by M-mode echocardiography at year-5 (43.7% men; age, 30.2 ± 3.6 years) and year-25 CARDIA exams was obtained. Univariable and multivariable analyses were performed to assess associations of ARD with clinical data at years-5 and -25. ARD from year-5 was used to establish reference values of ARD in healthy young adults. ARD at year-25 was greater in men (33.3 ± 3.7 versus 28.7 ± 3.4 mm; P<0.001) and in whites (30.9 ± 4.3 versus 30.5 ± 4.1 mm; P=0.006). On multivariable analysis, ARD at year-25 was positively correlated with male sex, white ethnicity, age, height, weight, 20-year gain in weight, active smoking at baseline, and 20-year increase in diastolic, systolic, and mean arterial pressure. A figure showing the estimated 95th percentile of ARD by age and body surface area stratified by race and sex is provided. This study demonstrates that smoking, blood pressure, and increase in body weight are the main modifiable correlates of aortic root dilation during young adulthood. Our study also provides reference values for ARD in young adults.
Authors: Teixido-Tura G; Lewis CE; Lima JA; et al.
Hypertension. 2015 Jul;66(1):23-9. Epub 2015-05-04.
Patients’ time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry
Time in therapeutic range (TTR) of international normalized ratio (INR) of 2.0 to 3.0 is important for the safety and effectiveness of warfarin anticoagulation. There are few data on TTR among patients with atrial fibrillation (AF) in community-based clinical practice. Using the US Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), we examined TTR (using a modified Rosendaal method) among 5,210 patients with AF on warfarin and treated at 155 sites. Patients were grouped into quartiles based on TTR data. Multivariable logistic regression modeling with generalized estimating equations was used to determine patient and provider factors associated with the lowest (worst) TTR. Overall, 59% of the measured INR values were between 2.0 and 3.0, with an overall mean and median TTR of 65% ± 20% and 68% (interquartile range [IQR] 53%-79%). The median times below and above the therapeutic range were 17% (IQR 8%-29%) and 10% (IQR 3%-19%), respectively. Patients with renal dysfunction, advanced heart failure, frailty, prior valve surgery, and higher risk for bleeding (ATRIA score) or stroke (CHA2DS2-VASc score) had significantly lower TTR (P < .0001 for all). Patients treated at anticoagulation clinics had only slightly higher median TTR (69%) than those not (66%) (P < .0001). Among patients with AF in US clinical practices, TTR on warfarin is suboptimal, and those at highest predicted risks for stroke and bleeding were least likely to be in therapeutic range.
Authors: Pokorney SD; Go AS; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators; et al.
Am Heart J. 2015 Jul;170(1):141-8, 148.e1. Epub 2015-04-01.
Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary AtrialFibrillation Cohort
Although digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial. This study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes. Longitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011. Among 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow-up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99). After adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin's safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed.
Authors: Allen LA; Go AS; ORBIT-AF Investigators; et al.
J Am Coll Cardiol. 2015 Jun 30;65(25):2691-8.
Age and sex differences in long-term outcomes following implantable cardioverter-defibrillator placement in contemporary clinical practice: findings from the cardiovascular research network
Patient sex and age may influence rates of death after receiving an implantable cardioverter-defibrillator for primary prevention. Differences in outcomes other than mortality and whether these differences vary by heart failure symptoms, etiology, and left ventricular ejection fraction are not well characterized. We studied 2954 patients with left ventricular ejection fraction ?0.35 undergoing first-time implantable cardioverter-defibrillator for primary prevention within the Cardiovascular Research Network; 769 patients (26%) were women, and 2827 (62%) were aged >65 years. In a median follow-up of 2.4 years, outcome rates per 1000 patient-years were 109 for death, 438 for hospitalization, and 111 for heart failure hospitalizations. Procedure-related complications occurred in 8.36%. In multivariable models, women had significantly lower risks of death (hazard ratio 0.67, 95% CI 0.56 to 0.80) and heart failure hospitalization (hazard ratio 0.82, 95% CI 0.68 to 0.98) and higher risks for complications (hazard ratio 1.38, 95% CI 1.01 to 1.90) than men; patients aged >65 years had higher risks of death (hazard ratio 1.55, 95% CI 1.30 to 1.86) and heart failure hospitalization (hazard ratio 1.25, 95% CI 1.05 to 1.49) than younger patients. Age and sex differences were generally consistent in strata according to symptoms, etiology, and severity of left ventricular systolic dysfunction, except the higher risk of complications in women, which differed by New York Heart Association classification (P=0.03 for sex-New York Heart Association interaction), and the risk of heart failure hospitalization in older patients, which differed by etiology of heart failure (P=0.05 for age-etiology interaction). The burden of adverse outcomes after receipt of an implantable cardioverter-defibrillator for primary prevention is substantial and varies according to patient age and sex. These differences in outcome generally do not vary according to baseline heart failure characteristics.
Authors: Masoudi FA; Go AS; Greenlee RT; et al.
J Am Heart Assoc. 2015 Jun;4(6):e002005. Epub 2015-06-02.
Gestational Thyrotoxicosis, Antithyroid Drug Use and Neonatal Outcomes within an Integrated Healthcare Delivery System
Increasing attention has focused on the prevalence and outcomes of hyperthyroidism in pregnancy, given concerns for hepatotoxicity and embryopathy associated with antithyroid drugs (ATDs). In an integrated health care delivery system, we examined the prevalence of thyrotoxicosis and gestational ATD use (propylthiouracil [PTU] or methimazole [MMI]) in women with delivered pregnancies from 1996 to 2010. Birth outcomes were compared among all infants and those born to mothers with diagnosed thyrotoxicosis or ATD therapy during gestation, with examination of ATD-associated hepatotoxicity and congenital malformations in the latter subgroups. Among 453,586 mother-infant pairs (maternal age 29.7±6.0 years, 57.1% nonwhite), 3.77 per 1000 women had diagnosed thyrotoxicosis and 1.29 per 1000 had gestational ATD exposure (86.5% PTU, 5.1% MMI, 8.4% both). Maternal PTU-associated hepatotoxicity occurred with a frequency of 1.80 per 1000 pregnancies. Infants of mothers with diagnosed thyrotoxicosis (odds ratio [OR] 1.28, 95% confidence interval [CI 1.05-1.55]) or gestational ATD use (OR 1.31 [1.00-1.72]) had an increased risk of preterm birth compared to those born to mothers without thyrotoxicosis or ATD. The risk of neonatal intensive care unit (NICU) admission was also higher with maternal thyrotoxicosis (OR 1.30 [1.07-1.59]) and ATD exposure (OR 1.64 [CI 1.26-2.13]), adjusting for prematurity. Congenital malformation rates were low and similar among infants born to mothers with thyrotoxicosis or ATD exposure (30-44 per 1000 infants). Gestational ATD exposure occurred in 1.29 per 1000 mother-infant pairs while a much larger number had maternal diagnosed thyrotoxicosis but no drug exposure during pregnancy. Infants of mothers with gestational ATD use or diagnosed thyrotoxicosis were more likely to be preterm and admitted to the NICU. The rates of congenital malformation were low for mothers diagnosed with thyrotoxicosis and did not differ by ATD use. Among women with gestational PTU therapy, the frequency of PTU-associated hepatotoxicity was 1.8 per 1000 delivered pregnancies. These findings from a large, population-based cohort provide generalizable estimates of maternal and infant risks associated with maternal thyrotoxicosis and related pharmacotherapy.
Authors: Lo JC; Rivkees SA; Chandra M; Gonzalez JR; Korelitz JJ; Kuzniewicz MW
Thyroid. 2015 Jun;25(6):698-705. Epub 2015-04-14.
The Complex Relationship of Race to Outcomes in Heart Failure with Preserved Ejection Fraction
An improved understanding of racial differences in the natural history, clinical characteristics, and outcomes of heart failure will have important clinical and public health implications. We assessed how clinical characteristics and outcomes vary across racial groups (whites, blacks, and Asians) in adults with heart failure with preserved ejection fraction. We identified all adults with heart failure with preserved ejection fraction between 2005 and 2008 from 4 health systems in the Cardiovascular Research Network using hospital principal discharge and ambulatory visit diagnoses. Among 13,437 adults with confirmed heart failure with preserved ejection fraction, 85.9% were white, 7.6% were black, and 6.5% were Asian. After adjustment for potential confounders and use of cardiovascular therapies, compared with whites, blacks (adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.85) and Asians (HR, 0.75; 95% CI, 0.64-0.87) had a lower risk of death from any cause. Compared with whites, blacks had a higher risk of hospitalization for heart failure (HR, 1.48; 95% CI, 1.29-1.68); no difference was observed for Asians compared with whites (HR, 1.01; 95% CI, 0.86-1.18). Compared with whites, no significant differences were detected in risk of hospitalization for any cause for blacks (HR, 1.03; 95% CI, 0.95-1.12) and Asians (HR, 0.93; 95% CI, 0.85-1.02). In a diverse population with heart failure with preserved ejection fraction, we observed complex relationships between race and important clinical outcomes. More detailed studies of large populations are needed to fully characterize the epidemiologic picture and to elucidate potential pathophysiologic and treatment-response differences that may relate to race.
Authors: Gurwitz JH; Magid DJ; Smith DH; Hsu G; Sung SH; Allen LA; McManus DD; Goldberg RJ; Go AS; Cardiovascular Research Network PRESERVE Study
Am J Med. 2015 Jun;128(6):591-600. Epub 2014-12-30.
Pulmonary Oedema-Therapeutic Targets.
Pulmonary oedema (PO) is a common manifestation of acute heart failure (AHF) and is associated with a high-acuity presentation and with poor in-hospital outcomes. The clinical picture of PO is dominated by signs of pulmonary congestion, and its pathogenesis has been attributed predominantly to an imbalance in Starling forces across the alveolar-capillary barrier. However, recent studies have demonstrated that PO formation and resolution is critically regulated by active endothelial and alveolar signalling. PO represents a medical emergency and treatment should be individually tailored to the urgency of the presentation and acute haemodynamic characteristics. Although, the majority of patients admitted with PO rapidly improve as result of conventional intravenous (IV) therapies, treatment of PO remains largely opinion based as there is a general lack of good evidence to guide therapy. Furthermore, none of these therapies showed simultaneous benefit for symptomatic relief, haemodynamic improvement, increased survival and end-organ protection. Future research is required to develop innovative pharmacotherapies capable of relieving congestion while simultaneously preventing end-organ damage.
Authors: Chioncel, Ovidiu O; Collins, Sean P SP; Ambrosy, Andrew P AP; Gheorghiade, Mihai M; Filippatos, Gerasimos G
Cardiac failure review. 2015 Apr 01;1(1):38-45. Epub 2015-05-09.
Length of hospital stay and 30-day readmission following heart failure hospitalization: insights from the EVEREST trial.
AIMS: Previous reports have provided conflicting data regarding the relationship between length of stay (LOS) and subsequent readmission risk among patients hospitalized for heart failure (HF).METHODS AND RESULTS: We performed a post-hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial to evaluate the differences in LOS overall and between geographic regions (North America, South America, Western Europe, and Eastern Europe) in association with all-cause and cause-specific [HF, cardiovascular (CV) non-HF, and non-CV] readmissions within 30 days of discharge after HF hospitalization. The present analysis included 4020 patients enrolled from 20 countries who were alive at discharge. Median [interquartile range (IQR)] LOS was 8 (4-11) days. The 30-day readmission rates were 15.7% [95% confidence interval (CI) 14.6-16.8] for all-cause; 5.6% (95% CI 4.9-6.3) for HF; 4.4% (95% CI 3.8-5.1) for CV non-HF; and 5.8% (95% CI 5.1-6.6) for non-CV readmissions. There was a positive correlation between LOS and all-cause readmissions (r = 0.09, 95% CI 0.06-0.12). The adjusted odds ratio for the top (≥14 days) vs. the bottom (≤3 days) quintile for LOS was 1.39 (95% CI 0. 92-2.11) for all-cause readmissions, 0.43 (95% CI 0.24-0.79) for HF, 2.99 (95% CI 1.49-6.02) for CV non-HF, and 1.72 (95% CI 1.05-2.81) for non-CV readmissions. With the exception of Western Europe, these findings remained largely consistent across geographic regions.CONCLUSION: In this large multinational cohort of hospitalized HF patients, longer LOS was associated with a higher risk for all-cause, CV non-HF, and non-CV readmissions, but a lower risk of HF readmissions within 30 days of discharge. These results may inform strategies to reduce readmissions.
Authors: Khan, Hassan H; Greene, Stephen J SJ; Fonarow, Gregg C GC; Kalogeropoulos, Andreas P AP; Ambrosy, Andrew P AP; Maggioni, Aldo P AP; Zannad, Faiez F; Konstam, Marvin A MA; Swedberg, Karl K; Yancy, Clyde W CW; Gheorghiade, Mihai M; Butler, Javed J;
European journal of heart failure. 2015 Oct 01;17(10):1022-31. Epub 2015-05-09.
A multiregional registry experience using an electronic medical record to optimize data capture for longitudinal outcomes in endovascular abdominal aortic aneurysm repair
Registries have been proven useful to assess clinical outcomes, but data entry and personnel expenses are challenging. We developed a registry to track patients undergoing endovascular aortic aneurysm repair (EVAR) in an integrated health care system, leveraging an electronic medical record (EMR) to evaluate clinical practices, device performance, surgical complications, and medium-term outcomes. This study describes the registry design, data collection, outcomes validation, and ongoing surveillance, highlighting the unique integration with the EMR. EVARs in six geographic regions of Kaiser Permanente were entered in the registry. Cases were imported using a screening algorithm of inpatient codes applied to the EMR. Standard note templates containing data fields were used for surgeons to enter preoperative, postoperative, and operative data as part of normal workflows in the operating room and clinics. Clinical content experts reviewed cases and entered any missing data of operative details. Patient comorbidities, aneurysm characteristics, implant details, and surgical outcomes were captured. Patients entered in the registry are followed up for life, and all relevant events are captured. Between January 2010 and June 2013, 2112 procedures were entered in the registry. Surgeon compliance with data entry ranges from 60% to 90% by region but has steadily increased over time. Mean aneurysm size was 5.9 cm (standard deviation, 1.3). Most patients were male (84%), were hypertensive (69%), or had a smoking history (79%). The overall reintervention rate was 10.8%: conversion to open repair (0.9%), EVAR revision (2.6%), other surgical intervention (7.3%). Of the reinterventions, 27% were for endoleaks (I, 34.3%; II, 56.9%; III, 8.8%; IV and V, 0.0%), 10.5% were due to graft malfunction, 3.4% were due to infection, and 2.3% were due to rupture. Leveraging an EMR provides a robust platform for monitoring short-term and midterm outcomes after abdominal aortic aneurysm repair. Use of standardized templates in the EMR allows data entry as part of normal workflow, improving compliance, accuracy, and data capture using limited but expert personnel. Assessment of patient demographics, device performance, practice variation, and postoperative outcomes benefits clinical decision-making by providing complete and adjudicated event reporting. The findings from this large, community-based EVAR registry augment other studies limited to perioperative and short-term outcomes or small patient cohorts.
Authors: Hye RJ; Inui TS; Anthony FF; Kiley ML; Chang RW; Rehring TF; Nelken NA; Hill BB
J Vasc Surg. 2015 May;61(5):1160-6. Epub 2015-02-26.
Fitness Change Effects on Midlife Metabolic Outcomes: The CARDIA Study
Fitness decline, high body mass index (BMI), and insulin resistance (IR) are associated with worsening cardiometabolic risk factors prospectively; modification of the fitness change effect by BMI and IR remains unknown. Participants from the Coronary Artery Risk Development in Young Adults study without diabetes at year 0 (Y0) (n = 2048, 43.4% men; mean age, 25 yr) had fitness quantified by treadmill at Y0 and Y20. Y0 BMI was normal (nBMI <25 kg·m) or high (hBMI ?25 kg·m). Y0 IR status was insulin sensitive (IS) (homeostatic model assessment IR <1.84 (75th percentile)) or insulin resistant (IR) (homeostatic model assessment IR ?1.84). Four groups were established: nBMI/IS, hBMI/IS, nBMI/IR, and hBMI/IR. Y0 fitness was low (<33rd percentile for sex) or average high (?33rd percentile for sex). Fitness change (treadmill time: Y20-Y0) was maintained (increase or decline ?20th percentile for sex) or decreased (decline >20th percentile for sex). The outcomes were incident diabetes and percentage change over 25 yr in weight, waist girth, blood pressure, and lipid profile. Analysis was by multiple linear regression and proportional hazards regression with adjustment for individual characteristics. Maintained fitness after 20 yr was associated with greater increase in HDL cholesterol and less increase in weight, waist girth, blood pressure, and triglycerides than decreased fitness, similarly for the groups defined by BMI and IR. Maintained fitness reduced the rate of incident diabetes in IS but not IR participants. Maintained fitness after 20 yr was associated with more favorable middle-age cardiometabolic risk factors than decreased fitness; this benefit might be blunted by baseline IR.
Authors: Chow L; Eberly LE; Austin E; Carnethon M; Bouchard C; Sternfeld B; Zhu NA; Sidney S; Schreiner P
Med Sci Sports Exerc. 2015 May;47(5):967-73.
Coronary artery bypass grafting and percutaneous coronary intervention in patients with end-stage renal disease
To determine the relative risks of long-term mortality between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) among patients with end-stage renal disease (ESRD). We identified 1015 patients with ESRD who underwent coronary revascularization between 1996 and 2008 within Kaiser Permanente Northern California. We obtained clinical variables from health plan databases, state death certificates and social security administration files. Our primary and secondary outcomes, respectively, were all-cause mortality and repeat revascularization. Our primary predictor was CABG compared with PCI. We used a Cox proportional hazards model for multivariable analyses. The mean age of CABG and PCI patients was similar (64.7 ± 10.6 and 63.4 ± 9.3, respectively, P = 0.06). The CABG group had a higher proportion of diabetics (P = 0.045), and higher nitrate use (P = 0.01). Adjusted for age, gender, race, year of index revascularization, number of vessels intervened, duration of dialysis and baseline comorbidities, patients referred for CABG during the first year had a hazard ratio (HR) of 1.16 [95% confidence interval (CI), 0.80-1.67] for mortality compared with PCI. During Years 1-5, the HR was 0.91 (95% CI, 0.63-1.33) with an overall HR of 0.73 (95% CI, 0.43-1.22). The sub-HR as calculated by the Fine-Gray competing risk model was 0.51 (95% CI, 0.31-0.85). As there are no randomized clinical trials in this area, our observational study adds to the growing body of literature that suggests a significant decrease in repeat revascularization with CABG and at least equivalency in long-term mortality with CABG when compared with PCI in ESRD patients.
Authors: Krishnaswami A; McCulloch CE; Tawadrous M; Jang JJ; Lee H; Melikian V; Yee G; Leong TK; Go AS
Eur J Cardiothorac Surg. 2015 May;47(5):e193-8.
Impact of bariatric surgery on life expectancy in severely obese patients with diabetes: a decision analysis
To create a decision analytic model to estimate the balance between treatment risks and benefits for severely obese patients with diabetes. Bariatric surgery leads to many desirable metabolic changes, but long-term impact of bariatric surgery on life expectancy in patients with diabetes has not yet been quantified. We developed a Markov state transition model with multiple Cox proportional hazards models and logistic regression models as inputs to compare bariatric surgery versus no surgical treatment for severely obese diabetic patients. The model is informed by data from 3 large cohorts: (1) 159,000 severely obese diabetic patients (4185 had bariatric surgery) from 3 HMO Research Network sites; (2) 23,000 subjects from the Nationwide Inpatient Sample; and (3) 18,000 subjects from the National Health Interview Survey linked to the National Death Index. In our main analyses, we found that a 45-year-old woman with diabetes and a body mass index (BMI) of 45 kg/m gained an additional 6.7 years of life expectancy with bariatric surgery (38.4 years with surgery vs 31.7 years without surgery). Sensitivity analyses revealed that the gain in life expectancy decreased with increasing BMI, until a BMI of 62 kg/m is reached, at which point nonsurgical treatment was associated with greater life expectancy. Similar results were seen for both men and women in all age groups. For most severely obese patients with diabetes, bariatric surgery seems to improve life expectancy; however, surgery may reduce life expectancy for the super obese with BMIs over 62 kg/m.
Authors: Schauer DP; Arterburn DE; Livingston EH; Coleman KJ; Sidney S; Fisher D; O?Connor P; Fischer D; Eckman MH
Ann Surg. 2015 May;261(5):914-9.
Serum 25 Hydroxyvitamin D, Bone Mineral Density and Fracture Risk Across the Menopause
Low levels of serum 25 Hydroxyvitamin D [25(OH)D] have been linked to greater fracture risk in older women. This study aimed to determine whether higher 25(OH)D is associated with slower loss of bone mineral density (BMD) and lower fracture risk during the menopausal transition. This was a prospective cohort study at five clinical centers in the United States. Mean age was 48.5 ± 2.7 years. The fracture analysis included 124 women with an incident traumatic fracture, 88 with incident nontraumatic fracture, and 1532 women without incident fractures; average followup was 9.5 years. BMD analysis included 922 women with a documented final menstrual period. Serum 25(OH)D was measured by liquid chromatography tandem mass spectrometry at the third annual clinic visit. BMD was measured and incident fractures ascertained at each annual visit. The mean 25(OH)D was 21.8 ng/mL; seven-hundred two (43%) of the women had 25(OH)D values <20 ng/mL. There was no significant association between 25(OH)D and traumatic fractures. In multivariate adjusted hazards models, the hazard ratio (HR) for nontraumatic fractures (95% confidence interval [CI]) was 0.72 (0.54-0.96) for each 10-ng/mL increase in 25(OH)D. Comparing women whose 25(OH)D was ?20 vs <20 ng/mL, the HR (95% CI) for fracture was 0.54 (0.32-0.89). Changes in lumbar spine and femoral neck bone mineral density across menopause were not significantly associated with serum 25(OH)D level. Serum 25(OH)D levels are inversely associated with nontraumatic fracture in mid-life women. Vitamin D supplementation is warranted in midlife women with 25(OH)D levels <20 ng/mL.
Authors: Cauley JA; Greendale GA; Ruppert K; Lian Y; Randolph JF; Lo JC; Burnett-Bowie SA; Finkelstein JS
J Clin Endocrinol Metab. 2015 May;100(5):2046-54. Epub 2015-02-26.
Adherence to endovascular aortic aneurysm repair device instructions for use guidelines has no impact on outcomes
Prior reports have suggested unfavorable outcomes after endovascular aortic aneurysm repair (EVAR) performed outside of the recommended instructions for use (IFU) guidelines. We report our long-term EVAR experience in a large multicenter registry with regard to adherence to IFU guidelines. Between 2000 and 2010, 489 of 1736 patients who underwent EVAR had preoperative anatomic measurements obtained from the M2S, Inc, imaging database (West Lebanon, NH). We examined outcomes in these patients with regard to whether they had met the device-specific IFU criteria. Primary outcomes were all-cause mortality and aneurysm-related mortality. Secondary outcomes were endoleak status, adverse events, reintervention, and aneurysm sac size change. The median follow-up for the 489 patients was 3.1 years (interquartile range, 1.6-5.0 years); 58.1% (n = 284) had EVAR performed within IFU guidelines (IFU-adherent group), and 41.9% (n = 205) had EVAR performed outside of IFU guidelines (IFU-nonadherent group). Preoperative anatomic data showed that 62.4% of the IFU-nonadherent group had short neck length, 10.2% had greater angulation than recommended, 7.3% did not meet neck diameter criteria, and 20% had multiple anatomic issues. A small portion (n = 49; 10%) of the 489 patients were lost to follow-up because of leaving membership enrollment (n = 28), moving outside the region (n = 10), or discontinuing image surveillance (n = 11). There was no significant difference in any of the primary or secondary outcomes between the IFU-adherent and IFU-nonadherent groups. Aneurysm sac size change at any time point during follow-up also did not differ significantly between the two groups. A Cox proportional hazard model showed that IFU nonadherence was not predictive of all-cause mortality (hazard ratio, 1.0; P = .91). Similarly, IFU nonadherence was not identified as a risk factor for aneurysm-related mortality or adverse events in stepwise Cox proportional hazards models. In our cohort of EVAR patients with detailed preoperative anatomic information and long-term follow-up, overall mortality and aneurysm-related mortality were unaffected by IFU adherence. In addition, rates of endoleak and reintervention after initial EVAR were similar, suggesting that lack of IFU-based anatomic suitability was not a driver of outcomes.
Authors: Walker J; Tucker LY; Goodney P; Candell L; Hua H; Okuhn S; Hill B; Chang RW
J Vasc Surg. 2015 May;61(5):1151-9. Epub 2015-02-03.
Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain
In genome-wide association studies (GWAS) five putative risk loci are associated with intracranial aneurysm. As brain arteriovenous malformations (AVM) and intracranial aneurysms are both intracranial vascular diseases and AVMs often have associated aneurysms, we investigated whether these loci are also associated with sporadic brain AVM. We included 506 patients (168 Dutch, 338 American) and 1548 controls, all Caucasians. Controls had been recruited as part of previous GWAS. Dutch patients were genotyped by KASPar assay and US patients by Affymetrix SNP 6.0 array. Associations in each cohort were tested by univariable logistic regression modelling, with subgroup analysis in 205 American cases with aneurysm data. Meta-analysis was performed by a Mantel-Haenszel fixed-effect method. In the Dutch cohort none of the single nucleotide polymorphisms (SNPs) were associated with AVMs. In the American cohort, genotyped SNPs near SOX-17 (OR 0.74; 95% CI 0.56-0.98), RBBP8 (OR 0.76; 95% CI 0.62-0.94) and an imputed SNP near CDKN2B-AS1 (OR 0.79; 95% CI 0.64-0.98) were significantly associated with AVM. The association with SNPs near SOX-17 and CDKN2B-AS1 but not RBBP8 were strongest in patients with AVM with associated aneurysms. In the meta-analysis we found no significant associations between allele frequencies and AVM occurrence, but rs9298506, near SOX-17 approached statistical significance (OR 0.77; 95% CI 0.57-1.03, p=0.08). Our meta-analysis of two Caucasian cohorts did not show an association between five aneurysm-associated loci and sporadic brain AVM. Possible involvement of SOX-17 and RBBP8, genes involved in cell cycle progression, deserves further investigation.
Authors: Kremer PH; Zaroff JG; Klijn CJ; et al.
J Neurol Neurosurg Psychiatr. 2015 May;86(5):524-9. Epub 2014-07-21.
Association of spontaneous bleeding and myocardial infarction with long-term mortality after percutaneous coronary intervention
Platelet inhibition after percutaneous coronary intervention (PCI) reduces the risk of myocardial infarction (MI) but increases the risk of bleeding. MIs and bleeds during the index hospitalization for PCI are known to negatively affect long-term outcomes. The impact of spontaneous bleeding occurring after discharge on long-term mortality is unknown. This study sought to examine, in a real-world cohort, the association between spontaneous major bleeding or MI after PCI and long-term mortality. We conducted a retrospective cohort study of patients ?30 years of age who underwent a PCI between 1996 and 2008 in an integrated healthcare delivery system. We used extended Cox regression to examine the associations of spontaneous bleeding and MI with all-cause mortality, after adjustment for time-updated demographics, comorbidities, periprocedural events, and longitudinal medication exposure. Among 32,906 patients who had a PCI and survived the index hospitalization, 530 had bleeds and 991 had MIs between 7 and 365 days post-discharge. There were 4,048 deaths over a mean follow-up of 4.42 years. The crude annual death rate after a spontaneous bleed (9.5%) or MI (7.6%) was higher than among patients who experienced neither event (2.6%). Bleeding was associated with an increased rate of death (adjusted hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.30 to 2.00), similar to that after an MI (HR: 1.91; 95% CI: 1.62 to 2.25). The association of bleeding with death remained significant after additional adjustment for the longitudinal use of antiplatelet agents. Spontaneous bleeding after a PCI was independently associated with higher long-term mortality, and conveyed a risk comparable to that of an MI during follow-up. This tradeoff between efficacy and safety bolsters the argument for personalizing antiplatelet therapy after PCI on the basis of the patient’s long-term risk of both thrombotic and bleeding events.
Authors: Kazi DS; Leong TK; Chang TI; Solomon MD; Hlatky MA; Go AS
J Am Coll Cardiol. 2015 Apr 14;65(14):1411-20.
Multi-Ethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI
The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
Authors: Verhaaren BF; Sigurdsson S; Fornage M; et al.
Circ Cardiovasc Genet. 2015 Apr;8(2):398-409. Epub 2015-02-07.
Excess body mass index- and waist circumference-years and incident cardiovascular disease: The CARDIA study
To determine the influence of the total cumulative exposure to excess overall and abdominal adiposity on the incidence of cardiovascular disease (CVD). Prospective study of 4,061 white and black adults without CVD at baseline in 1985-1986 (age 18-30 years) from the multicenter, community-based CARDIA study. Time-varying excess body mass index (BMI)- and waist circumference (WC)-years were calculated as products of the degree and duration of excess overall (BMI???25 kg/m(2)) and abdominal adiposity [WC >94 cm (men) and >80 cm (women)], respectively, collected at up to eight examinations. During a median of 24.8 years, there were 125 incident CVD, 62 coronary heart disease (CHD), and 33 heart failure (HF) events. Adjusted hazard ratios for CVD, CHD, and HF for each additional 50 excess BMI-years were 1.20 (1.08, 1.34), 1.25 (1.07, 1.46), and 1.45 (1.23, 1.72), respectively. For each 50 excess WC-years, these hazard ratios were 1.10 (1.04, 1.18), 1.13 (1.03, 1.24), and 1.22 (1.11, 1.34), respectively. Akaike information criterion values were lowest in models containing time-varying excess BMI- or WC-years compared to those including time-varying BMI or WC only. Excess BMI- and WC-years are predictors of the risk of CVD and may provide a better indicator of the cumulative exposure to excess adiposity than BMI or WC only.
Authors: Reis JP; Gunderson EP; Rana JS; Liu K; et al.
Obesity (Silver Spring). 2015 Apr;23(4):879-85. Epub 2015-03-09.
High-Sensitivity Troponin T and N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) and Risk of Incident Heart Failure in Patients with CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study
High-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predict heart failure (HF) in the general population. However, the interpretation of levels of these biomarkers as predictors of HF is uncertain among patients with CKD. Here, we investigated whether hsTnT and NT-proBNP are associated with incident HF among patients with CKD. In a prospective cohort analysis, we studied 3483 people with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study recruited from June of 2003 to August of 2008 who were free of HF at baseline. We used Cox regression to examine the association of baseline levels of hsTnT and NT-proBNP with incident HF after adjustment for demographic factors, traditional cardiovascular risk factors, markers of kidney disease, pertinent medication use, and mineral metabolism markers. At baseline, hsTnT levels ranged from ?5.0 to 378.7 pg/ml, and NT-proBNP levels ranged from ?5 to 35,000 pg/ml. Compared with those who had undetectable hsTnT, participants in the highest quartile (>26.5 ng/ml) had a significantly higher rate of HF (hazard ratio, 4.77; 95% confidence interval, 2.49 to 9.14). Similarly, compared with those in the lowest NT-proBNP quintile (<47.6 ng/ml), participants in the highest quintile (>433.0 ng/ml) experienced a substantially higher rate of HF (hazard ratio, 9.57; 95% confidence interval, 4.40 to 20.83). In conclusion, hsTnT and NT-proBNP were strongly associated with incident HF among a diverse cohort of individuals with mild to severe CKD. Elevations in these biomarkers may indicate subclinical changes in volume and myocardial stress that subsequently contribute to clinical HF.
Authors: Bansal N; Go AS; Feldman HI; et al.
J Am Soc Nephrol. 2015 Apr;26(4):946-56. Epub 2014-10-02.
International REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure (REPORT-HF): rationale for and design of a global registry.
AIMS: The clinical characteristics, initial presentation, management, and outcomes of patients hospitalized with new-onset (first diagnosis) heart failure (HF) or decompensation of chronic HF are poorly understood worldwide. REPORT-HF (International REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure) is a global, prospective, and observational study designed to characterize patient trajectories longitudinally during and following an index hospitalization for HF.METHODS: Data collection for the registry will be conducted at ∼300 sites located in ∼40 countries. Comprehensive data including demographics, clinical presentation, co-morbidities, treatment patterns, quality of life, in-hospital and post-discharge outcomes, and health utilization and costs will be collected. Enrolment of ∼20 000 adult patients hospitalized with new-onset (first diagnosis) HF or decompensation of chronic HF over a 3-year period is planned with subsequent 3 years follow-up.PERSPECTIVE: The REPORT-HF registry will explore the clinical characteristics, management, and outcomes of HF worldwide. This global research programme may have implications for the formulation of public health policy and the design and conduct of international clinical trials.
Authors: Filippatos, Gerasimos G; Khan, Sadiya Sana SS; Ambrosy, Andrew P AP; Cleland, John G F JG; Collins, Sean P SP; Lam, Carolyn S P CS; Angermann, Christiane E CE; Ertl, Georg G; Dahlström, Ulf U; Hu, Dayi D; Dickstein, Kenneth K; Perrone, Sergio V SV; Ghadanfar, Mathieu M; Bermann, Georgina G; Noe, Adele A; Schweizer, Anja A; Maier, Thomas T; Gheorghiade, Mihai M
European journal of heart failure. 2015 May 01;17(5):527-33. Epub 2015-03-10.
Trends in mortality following hip fracture in older women
To examine contemporary trends in mortality following hip fracture among older postmenopausal women in an integrated healthcare delivery system. Retrospective cohort study of 13,550 women aged ?65 years with hip fracture during 2000 to 2010. Demographic factors, comorbidity index score, fracture history, early rehospitalization, and all-cause mortality within 1 year following hip fracture were examined using health plan databases and records. Temporal trends, risk factors, and the association of race/ethnicity and mortality within 1 year post fracture were examined using multivariable logistic regression. Among 13,550 women with hip fracture, 84.6% were aged ?75 years: 83.6% were white, 2.8% black, 5.6% Hispanic, 4.5% Asian, and 3.5% of other/unknown race. Following hip fracture, 2.4% died during the index hospitalization, while 12.3% were rehospitalized within 30 days of discharge. Infection, pneumonia, and cardiovascular conditions were the most common nonorthopedic indications for readmission. Mortality rates at 6 months (17%) and 1 year (22.8%) following hip fracture were high and increased with age. Greater comorbidity and early rehospitalization were associated with increased mortality risk, while Asian and Hispanic race/ethnicity were associated with lower mortality risk (vs white). Temporal trends demonstrated a small but significant reduction in mortality risk during 2004 to 2010. While hip fracture morbidity and mortality remain high, temporal trends suggest recent declines in mortality risk, with risk of death following hip fracture lower for Asian and Hispanic women. Future studies should examine potential benefits of targeted interventions within integrated healthcare settings and factors contributing to observed racial/ethnic differences in post fracture survival.
Authors: Lo JC; Srinivasan S; Chandra M; Patton M; Budayr A; Liu LH; Lau G; Grimsrud CD
Am J Manag Care. 2015 Mar 01;21(3):e206-14. Epub 2015-03-01.
Race-Ethnic and Sex Differences in Left Ventricular Structure and Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
We investigated race-ethnic and sex-specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age. The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985-1986 (Year-0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year-25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle-tracking echocardiography. In the multivariable models, we used, in addition to race-ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year-0 and -25 examinations as independent predictors of echocardiographic outcomes at the Year-25 examination (LV end-diastolic volume [LVEDV]/height, LV end-systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race-ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment. African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial-ethnic differences are partially but not completely explained by established cardiovascular risk factors.
Authors: Kishi S; Wu CO; Lima JA; et al.
J Am Heart Assoc. 2015 Mar;4(3):e001264. Epub 2015-03-13.
Genetic studies of body mass index yield new insights for obesity biology
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ?2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Authors: Locke AE; Go AS; Speliotes EK; et al.
Nature. 2015 Feb 12;518(7538):197-206.
New genetic loci link adipose and insulin biology to body fat distribution
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Authors: Shungin D; Go AS; Mohlke KL; et al.
Nature. 2015 Feb 12;518(7538):187-96.
Age, sex, and racial influences on the Beckman Coulter AccuTnI+3 99th percentile
Beckman Coulter recently released a new cardiac troponin I (cTnI) assay, AccuTnI+3, for the Access 2 and DxI platforms. We validated the stated 99th percentile (20ng/l) using a large population of healthy adults representative of the Northern California population. Within a large sample of healthy adult members receiving care at Kaiser Permanente, cTnI was quantified in residual specimens using the AccuTnI+3 assay. Patients were selected based on pre-defined criteria extracted from a comprehensive electronic medical record. All specimens with a cTnI concentration >30ng/l were repeated; specimens that had a reproducible result >30ng/l were subject to heterophile blocking procedure. 99th percentiles were calculated based on age, sex, race and body mass index categories. Among 1764 tested subjects, the 99th percentile for all samples was 25ng/l. Sex differences were observed; the male and female 99th percentiles were 31 and 21ng/l, respectively (p=0.001). Age (range evaluated 18-89y, median 47y) also had a significant influence on the value (p=0.003), but there were no significant differences by race. False positive results were detected in 0.9% of specimens (0.6% "fliers" and 0.3% heterophile antibodies), corresponding to 52% of all results >30ng/l. Among a large, representative cohort of healthy adults, we found a 99th percentile value consistent with prior studies based on highly selected small patient samples. Sex and age-specific upper reference limits for cTnI should be considered. In this cohort, about half the findings above the 99th percentile were false positives. Avoiding reporting erroneous results requires implementation of quality indicators.
Authors: Greene DN; Leong TK; Collinson PO; Kamer SM; Huang K; Lorey TS; Go AS
Clin Chim Acta. 2015 Feb 12;444C:149-153. Epub 2015-2-12.
Digoxin and Risk of Death in Adults with Atrial Fibrillation: The ATRIA-CVRN Study
Digoxin remains commonly used for rate control in atrial fibrillation, but limited data exist supporting this practice and some studies have shown an association with adverse outcomes. We examined the independent association between digoxin and risks of death and hospitalization in adults with incident atrial fibrillation and no heart failure. We performed a retrospective cohort study of 14,787 age, sex, and high-dimensional propensity score-matched adults with incident atrial fibrillation and no previous heart failure or digoxin use in the AnTicoagulation and Risk factors In Atrial fibrillation-Cardiovascular Research Network (ATRIA-CVRN) study within Kaiser Permanente Northern and Southern California. We examined the independent association between newly initiated digoxin and the risks of death and hospitalization using extended Cox regression. During a median 1.17 (interquartile range, 0.49-1.97) years of follow-up among matched patients with atrial fibrillation, incident digoxin use was associated with higher rates of death (8.3 versus 4.9 per 100 person-years; P<0.001) and hospitalization (60.1 versus 37.2 per 100 person-years; P<0.001). Incident digoxin use was independently associated with a 71% higher risk of death (hazard ratio, 1.71; 95% confidence interval, 1.52-1.93) and a 63% higher risk of hospitalization (hazard ratio, 1.63; 95% confidence interval, 1.56-1.71). Results were consistent in subgroups of age and sex and when using intent-to-treat or on-treatment analytic approaches. In adults with atrial fibrillation, digoxin use was independently associated with higher risks of death and hospitalization. Given other available rate control options, digoxin should be used with caution in the management of atrial fibrillation.
Authors: Freeman JV; Reynolds K; Fang M; Udaltsova N; Steimle A; Pomernacki NK; Borowsky LH; Harrison TN; Singer DE; Go AS
Circ Arrhythm Electrophysiol. 2015 Feb;8(1):49-58. Epub 2014-11-20.
Community-Based Case-Control Study of Childhood Stroke Risk Associated With Congenital Heart Disease
A better understanding of the stroke risk factors in children with congenital heart disease (CHD) could inform stroke prevention strategies. We analyzed pediatric stroke associated with CHD in a large community-based case-control study. From 2.5 million children (aged <20 years) enrolled in a Northern California integrated healthcare plan, we identified children with ischemic and hemorrhagic strokes and randomly selected age- and facility-matched stroke-free controls (3 per case). We determined exposure to CHD (diagnosed before stroke) and used conditional logistic regression to analyze stroke risk factors. CHD was identified in 15 of 412 cases (4%) versus 7 of 1236 controls (0.6%). Cases of childhood stroke (occurring between ages 29 days to 20 years) with CHD had 19-fold (odds ratio, 19; 95% confidence interval 4.2-83) increased stroke risk compared to controls. History of CHD surgery was associated with >30-fold (odds ratio, 31; confidence interval 4-241) increased risk of stroke in children with CHD when compared with controls. After excluding perioperative strokes, the history of CHD surgery still increased the childhood stroke risk (odds ratio, 13; confidence interval 1.5-114). The majority of children with stroke and CHD were outpatients at the time of stroke, and almost half the cases who underwent cardiac surgery had their stroke >5 years after the most recent procedure. An estimated 7% of ischemic and 2% of hemorrhagic childhood strokes in the population were attributable to CHD. CHD is an important childhood stroke risk factor. Children who undergo CHD surgery remain at elevated risk outside the perioperative period and would benefit from optimized long-term stroke prevention strategies.
Authors: Fox CK; Sidney S; Fullerton HJ
Stroke. 2015 Feb;46(2):336-40. Epub 2014-12-16.
Urine Neutrophil Gelatinase-Associated Lipocalin and Risk of Cardiovascular Disease and Death in CKD: Results From the Chronic Renal Insufficiency Cohort (CRIC) Study
Chronic kidney disease is common and is associated with increased cardiovascular disease risk. Currently, markers of renal tubular injury are not used routinely to describe kidney health and little is known about the risk of cardiovascular events and death associated with these biomarkers independent of glomerular filtration-based markers (such as serum creatinine or albuminuria). Cohort study, CRIC (Chronic Renal Insufficiency Cohort) Study. 3,386 participants with estimated glomerular filtration rate of 20 to 70mL/min/1.73m(2) enrolled from June 2003 through August 2008. Urine neutrophil gelatinase-associated lipocalin (NGAL) concentration. Adjudicated heart failure event, ischemic atherosclerotic event (myocardial infarction, ischemic stroke, or peripheral artery disease), and death through March 2011. Urine NGAL measured at baseline with a 2-step assay using chemiluminescent microparticle immunoassay technology on an ARCHITECT i2000SR (Abbott Laboratories). There were 428 heart failure events (during 16,383 person-years of follow-up), 361 ischemic atherosclerotic events (during 16,584 person-years of follow-up), and 522 deaths (during 18,214 person-years of follow-up). In Cox regression models adjusted for estimated glomerular filtration rate, albuminuria, demographics, traditional cardiovascular disease risk factors, and cardiac medications, higher urine NGAL levels remained associated independently with ischemic atherosclerotic events (adjusted HR for the highest [>49.5ng/mL] vs lowest [?6.9ng/mL] quintile, 1.83 [95% CI, 1.20-2.81]; HR per 0.1-unit increase in log urine NGAL, 1.012 [95% CI, 1.001-1.023]), but not heart failure events or deaths. Urine NGAL was measured only once. Among patients with chronic kidney disease, urine levels of NGAL, a marker of renal tubular injury, were associated independently with future ischemic atherosclerotic events, but not with heart failure events or deaths.
Authors: Liu KD; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2015 Feb;65(2):267-74. Epub 2014-10-11.
Effect of minor liver function test abnormalities and values within the normal range on survival in heart failure.
Liver function test (LFT) abnormalities are often observed in patients with heart failure (HF). However, the relation of LFTs with outcomes has not been well described. Patients of the VA Palo Alto Health Care System (3 inpatient facilities and 7 community clinics) with a complete set of LFTs in the 60 days before a first HF diagnosis were included in the analysis from January 2005 to April 2013. A total of 2,096 patients met inclusion criteria. Patients were a mean of 71 ± 12 years old, 97% were men, 57% had a previous diagnosis of ischemic heart disease, and the mean left ventricular ejection fraction was 51 ± 12%. The median (twenty fifth and seventy fifth) values were albumin 3.6 g/dl (3.3, 3.9), alanine transaminase 21 IU/L (16, 30), aspartate transaminase 24 IU/L (20,31), AP 70 IU/L (57, 87), and total bilirubin 0.8 mg/dl (0.6, 1.0). There were 851 deaths (41%) over a mean duration of 41 ± 27 months. Mortality significantly increased with lower values of albumin and alanine transaminase and higher levels of aspartate transaminase and AP. The association with total bilirubin was not significant. In conclusion, many LFT values in the "normal" range are independently associated with decreased survival beyond traditional risk factors for mortality in HF.
Authors: Ambrosy, Andrew P AP; Dunn, Timothy P TP; Heidenreich, Paul A PA
The American journal of cardiology. 2015 Apr 01;115(7):938-41. Epub 2015-01-28.
Executive summary: heart disease and stroke statistics-2015 update: a report from the american heart association
Authors: Mozaffarian D; Go AS; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2015 Jan 27;131(4):434-41.
Heart Disease and Stroke Statistics-2015 Update: A Report From the American Heart Association
Authors: Mozaffarian D; Go AS; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2015 Jan 27;131(4):e29-322. Epub 2014-12-17.
Gastrointestinal symptoms, inflammation and hypoalbuminemia in chronic kidney disease patients: a cross-sectional study
Few studies have focused on investigating hypoalbuminemia in patients during earlier stages of chronic kidney disease (CKD). In particular, little is known about the role of gastrointestinal (GI) symptoms. Our goal in this paper is to study how GI symptoms relate to serum albumin levels in CKD, especially in the context of and compared with inflammation. We performed a cross-sectional study of 3599 patients with chronic kidney disease enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. All subjects were asked to complete the Modification of Diet in Renal Disease (MDRD) study patient symptom form. Our main predictor is GI symptom score. Serum level of C-reactive protein (CRP) was measured as well. Main outcome measures are serum albumin levels and prevalence of hypoalbuminemia. Of the participants assessed, mean serum albumin was 3.95?±?0.46 g/dL; 12.7 % had hypoalbuminemia. Patients with lower estimated glomerular filtration rate (eGFR) were likely to have more GI symptoms (apparent at an eGFR <45 ml/min/1.73 m(2)). Patients with worse GI symptoms had lower dietary protein intake. GI symptoms, like inflammation, were risk factors for lower serum albumin levels. However, adding GI symptom score or CRP into the multivariable regression analysis, did not attenuate the association between lower eGFR and lower albumin or hypoalbuminemia. Increased prevalence of GI symptoms become apparent among CKD patients at relatively high eGFR levels (45 ml/min/1.73 m(2)), long before ESRD. Patients with more severe GI symptoms scores are more likely to have hypoalbuminemia. But our data do not support GI symptoms/decreased protein intake or inflammation as being the main determinants of serum albumin level in CKD patients.
Authors: Zhang X; Bansal N; Go AS; Hsu CY
BMC Nephrol. 2015;16:211. Epub 2015-12-11.
The study of women, infant feeding and type 2 diabetes after GDM pregnancy and growth of their offspring (SWIFT Offspring study): prospective design, methodology and baseline characteristics
Breastfeeding is associated with reduced risk of becoming overweight or obese later in life. Breastfed babies grow more slowly during infancy than formula-fed babies. Among offspring exposed in utero to maternal glucose intolerance, prospective data on growth during infancy have been unavailable. Thus, scientific evidence is insufficient to conclude that breastfeeding reduces the risk of obesity among the offspring of diabetic mothers (ODM). To address this gap, we devised the Study of Women, Infant Feeding and Type 2 Diabetes after GDM Pregnancy and Growth of their Offspring, also known as the SWIFT Offspring Study. This prospective, longitudinal study recruited mother-infant pairs from the SWIFT Study, a prospective study of women with recent gestational diabetes mellitus (GDM). The goal of the SWIFT Offspring Study is to determine whether breastfeeding intensity and duration, compared with formula feeding, are related to slower growth of GDM offspring during the first year life. This article details the study design, participant eligibility, data collection, and methodologies. We also describe the baseline characteristics of the GDM mother-infant pairs. The study enrolled 466 mother-infant pairs among GDM deliveries in northern California from 2009-2011. Participants attended three in-person study exams at 6-9 weeks, 6 months and 12 months after delivery for infant anthropometry (head circumference, body weight, length, abdominal circumference and skinfold thicknesses), as well as maternal anthropometry (body weight, waist circumference and percent body fat). Mothers also completed questionnaires on health and lifestyle behaviors, including infant diet, sleep and temperament. Breastfeeding intensity and duration were assessed via several sources (diaries, telephone interviews, monthly mailings and in-person exams) from birth through the first year of life. Pregnancy course, clinical perinatal and newborn outcomes were obtained from health plan electronic medical records. Infant saliva samples were collected and stored for genetics studies. This large, racially and ethnically diverse cohort of GDM offspring will enable evaluation of the relationship of infant feeding to growth during infancy independent of perinatal characteristics, sociodemographics and other risk factors. The longitudinal design provides the first quantitative measures of breastfeeding intensity and duration among GDM offspring during early life.
Authors: Gunderson EP; Hurston SR; Dewey KG; Faith MS; Charvat-Aguilar N; Khoury VC; Nguyen VT; Quesenberry CP
BMC Pregnancy Childbirth. 2015;15:150. Epub 2015-07-17.
Vascular Factors and Multiple Measures of Early Brain Health: CARDIA Brain MRI Study
To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF). Cross-sectional brain Magnetic Resonance I (MRI) study. Community based cohort in three U.S. sites. A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study. 3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function. Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01). In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of mid-life cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia.
Authors: Launer LJ; Battapady H; Bryan RN; et al.
PLoS ONE. 2015;10(3):e0122138. Epub 2015-03-26.
Blood Pressure and Risk of All-Cause Mortality in Advanced Chronic Kidney Disease and Hemodialysis: The Chronic Renal Insufficiency Cohort Study
Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease, before starting hemodialysis. We determined the association between SBP and mortality at advanced chronic kidney disease and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort participants with advanced chronic kidney disease followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants (1) had an estimated glomerular filtration rate <30 mL/min/1.73 m2 (n=1705), (2) initiated hemodialysis and had dialysis-unit SBP measures (n=403), and (3) initiated hemodialysis and had out-of-dialysis-unit SBP measured at a Chronic Renal Insufficiency Cohort study visit (n=326). Cox models were adjusted for demographics, cardiovascular risk factors, and dialysis parameters. A quadratic term for SBP was included to test for a U-shaped association. At advanced chronic kidney disease, there was no association between SBP and mortality (hazard ratio, 1.02 [95% confidence interval, 0.98-1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (hazard ratio, 1.26 [95% confidence interval, 1.14-1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of-dialysis-unit SBP, which may merit more consideration as a target for clinical management and in interventional trials.
Authors: Bansal N; Go AS; CRIC Study Investigators; et al.
Hypertension. 2015 Jan;65(1):93-100. Epub 2014-10-06.
Impact of drug-eluting stents on the comparative effectiveness of coronary artery bypass surgery and percutaneous coronary intervention
Drug-eluting stents (DES) have largely replaced bare-metal stents (BMS) for percutaneous coronary intervention (PCI). It is uncertain, however, whether introduction of DES had a significant impact on the comparative effectiveness of PCI versus coronary artery bypass graft surgery (CABG) for death and myocardial infarction (MI). We identified Medicare beneficiaries aged ?66 years who underwent multivessel CABG or multivessel PCI and matched PCI and CABG patients on propensity score. We defined the BMS era as January 1999 to April 2003 and the DES era as May 2003 to December 2006. We compared 5-year outcomes of CABG and PCI using Cox proportional hazards models, adjusting for baseline characteristics and year of procedure and tested for a statistically significant interaction (P(int)) of DES era with treatment (CABG or PCI). Five-year survival improved from the BMS era to the DES era by 1.2% for PCI and by 1.1% for CABG, and the CABG:PCI hazard ratio was unchanged (0.90 vs 0.90; P(int) = .96). Five-year MI-free survival improved by 1.4% for PCI and 1.1% for CABG, with no change in the CABG:PCI hazard ratio (0.81 vs 0.82; P(int) = .63). By contrast, survival-free of MI or repeat coronary revascularization improved from the BMS era to the DES era by 5.7% for PCI and 0.9% for CABG, and the CABG:PCI hazard ratio changed significantly (0.50 vs 0.57, P(int) ? .0001). The introduction of DES did not alter the comparative effectiveness of CABG and PCI with respect to hard cardiac outcomes.
Authors: Hlatky MA; Boothroyd DB; Baker LC; Go AS
Am Heart J. 2015 Jan;169(1):149-54. Epub 2014-10-25.
Comparison of Frequency and Outcome of Major Gastrointestinal Hemorrhage in Patients With Atrial Fibrillation on Versus Not Receiving Warfarin Therapy (from the ATRIA and ATRIA-CVRN Cohorts)
To date, there have been few studies evaluating outcomes of patients with atrial fibrillation (AF) who have experienced gastrointestinal (GI) hemorrhages. We examined short- and long-term mortality of major GI hemorrhage in patients with AF on and off warfarin in recent clinical care. We evaluated this association in the large Anticoagulation and Risk Factors in Atrial fibrillation (ATRIA) and ATRIA-Cardiovascular Research Network (CVRN) California community-based cohorts of patients with AF (study years 1996 to 2003 and 2006 to 2009, respectively), where all events were clinician adjudicated. We used proportional hazards regression with propensity score adjustment to estimate the short- (30 days) and long-term (>30 days for 1 year) mortality rate ratio for patients using warfarin compared with those who were not using warfarin at the time of GI hemorrhage. In the 414 ATRIA participants with major GI hemorrhage, 54% were taking warfarin at the time of the hemorrhage; in the 361 ATRIA-CVRN participants with major GI hemorrhage, 58% were taking warfarin. Warfarin use at the time of GI hemorrhage was not associated with 30-day mortality in the ATRIA cohort but was associated with significantly reduced 30-day mortality in the ATRIA-CVRN cohort (adjusted mortality rate ratio [95% confidence interval], ATRIA 0.97 [0.54 to 1.74]; ATRIA-CVRN 0.38 [0.17 to 0.83]). There was a modest suggestion of lower mortality on warfarin after 30 days in both cohorts. In conclusion, our study demonstrates that GI hemorrhages on warfarin are certainly no worse and may be less life threatening than those occurring off warfarin. These findings are in stark contrast to the deleterious effect of warfarin on mortality from intracranial hemorrhage and add another factor favoring anticoagulation in clinical decision making for patients with AF.
Authors: Ashburner JM; Go AS; Reynolds K; Chang Y; Fang MC; Fredman L; Applebaum KM; Singer DE
Am J Cardiol. 2015 Jan 1;115(1):40-6. Epub 2014-10-12.
Challenges of ascertaining national trends in the incidence of coronary heart disease in the United States
Authors: Ford ES; Roger VL; Dunlay SM; Go AS; Rosamond WD
J Am Heart Assoc. 2014 Dec;3(6):e001097. Epub 2014-12-03.
Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms
To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVM), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040). We used data from 338 BAVM cases participating in the University of California, San Francisco (UCSF)-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R(2)>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: 74 BAVM with aneurysm versus 504 controls and 131 BAVM without aneurysm versus 504 controls. We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI 0.99 to 1.53, p=0.064) and rs1333040-T (OR=1.27, 95% CI 1.01 to 1.58, p=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI 1.03 to 2.22, p=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI 0.72 to 1.34, p=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r(2)>0.8) with rs10757278. Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM-associated aneurysms share similar vascular pathology mechanisms with other aneurysm types.
Authors: Bendjilali N; Nelson J; Weinsheimer S; Sidney S; Zaroff JG; Hetts SW; Segal M; Pawlikowska L; McCulloch CE; Young WL; Kim H
J Neurol Neurosurg Psychiatr. 2014 Nov;85(11):1280-3. Epub 2014-04-28.
Defining the role of common variation in the genomic and biological architecture of adult human height
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ?2,000, ?3,700 and ?9,500 SNPs explained ?21%, ?24% and ?29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/?-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Authors: Wood AR; Esko T; Yang J; Vedantam S; Pers TH; Gustafsson S; Chu AY; Estrada K; Luan J; Kutalik Z; Amin N; Buchkovich ML; Croteau-Chonka DC; Day FR; Duan Y; Fall T; Fehrmann R; Ferreira T; Jackson AU; Karjalainen J; Lo KS; Locke AE; Mägi R; Mihailov E; Porcu E; Randall JC; Scherag A; Vinkhuyzen AA; Westra HJ; Winkler TW; Workalemahu T; Zhao JH; Absher D; Albrecht E; Anderson D; Baron J; Beekman M; Demirkan A; Ehret GB; Feenstra B; Feitosa MF; Fischer K; Fraser RM; Goel A; Gong J; Justice AE; Kanoni S; Kleber ME; Kristiansson K; Lim U; Lotay V; Lui JC; Mangino M; Mateo Leach I; Medina-Gomez C; Nalls MA; Nyholt DR; Palmer CD; Pasko D; Pechlivanis S; Prokopenko I; Ried JS; Ripke S; Shungin D; Stancáková A; Strawbridge RJ; Sung YJ; Tanaka T; Teumer A; Trompet S; van der Laan SW; van Setten J; Van Vliet-Ostaptchouk JV; Wang Z; Yengo L; Zhang W; Afzal U; Arnlöv J; Arscott GM; Bandinelli S; Barrett A; Bellis C; Bennett AJ; Berne C; Blüher M; Bolton JL; Böttcher Y; Boyd HA; Bruinenberg M; Buckley BM; Buyske S; Caspersen IH; Chines PS; Clarke R; Claudi-Boehm S; Cooper M; Daw EW; De Jong PA; Deelen J; Delgado G; Denny JC; Dhonukshe-Rutten R; Dimitriou M; Doney AS; Dörr M; Eklund N; Eury E; Folkersen L; Garcia ME; Geller F; Giedraitis V; Go AS; Grallert H; Grammer TB; Gräßler J; Grönberg H; de Groot LC; Groves CJ; Haessler J; Hall P; Haller T; Hallmans G; Hannemann A; Hartman CA; Hassinen M; Hayward C; Heard-Costa NL; Helmer Q; Hemani G; Henders AK; Hillege HL; Hlatky MA; Hoffmann W; Hoffmann P; Holmen O; Houwing-Duistermaat JJ; Illig T; Isaacs A; James AL; Jeff J; Johansen B; Johansson Å; Jolley J; Juliusdottir T; Junttila J; Kho AN; Kinnunen L; Klopp N; Kocher T; Kratzer W; Lichtner P; Lind L; Lindström J; Lobbens S; Lorentzon M; Lu Y; Lyssenko V; Magnusson PK; Mahajan A; Maillard M; McArdle WL; McKenzie CA; McLachlan S; McLaren PJ; Menni C; Merger S; Milani L; Moayyeri A; Monda KL; Morken MA; Müller G; Müller-Nurasyid M; Musk AW; Narisu N; Nauck M; Nolte IM; Nöthen MM; Oozageer L; Pilz S; Rayner NW; Renstrom F; Robertson NR; Rose LM; Roussel R; Sanna S; Scharnagl H; Scholtens S; Schumacher FR; Schunkert H; Scott RA; Sehmi J; Seufferlein T; Shi J; Silventoinen K; Smit JH; Smith AV; Smolonska J; Stanton AV; Stirrups K; Stott DJ; Stringham HM; Sundström J; Swertz MA; Syvänen AC; Tayo BO; Thorleifsson G; Tyrer JP; van Dijk S; van Schoor NM; van der Velde N; van Heemst D; van Oort FV; Vermeulen SH; Verweij N; Vonk JM; Waite LL; Waldenberger M; Wennauer R; Wilkens LR; Willenborg C; Wilsgaard T; Wojczynski MK; Wong A; Wright AF; Zhang Q; Arveiler D; Bakker SJ; Beilby J; Bergman RN; Bergmann S; Biffar R; Blangero J; Boomsma DI; Bornstein SR; Bovet P; Brambilla P; Brown MJ; Campbell H; Caulfield MJ; Chakravarti A; Collins R; Collins FS; Crawford DC; Cupples LA; Danesh J; de Faire U; den Ruijter HM; Erbel R; Erdmann J; Eriksson JG; Farrall M; Ferrannini E; Ferrières J; Ford I; Forouhi NG; Forrester T; Gansevoort RT; Gejman PV; Gieger C; Golay A; Gottesman O; Gudnason V; Gyllensten U; Haas DW; Hall AS; Harris TB; Hattersley AT; Heath AC; Hengstenberg C; Hicks AA; Hindorff LA; Hingorani AD; Hofman A; Hovingh GK; Humphries SE; Hunt SC; Hypponen E; Jacobs KB; Jarvelin MR; Jousilahti P; Jula AM; Kaprio J; Kastelein JJ; Kayser M; Kee F; Keinanen-Kiukaanniemi SM; Kiemeney LA; Kooner JS; Kooperberg C; Koskinen S; Kovacs P; Kraja AT; Kumari M; Kuusisto J; Lakka TA; Langenberg C; Le Marchand L; Lehtimäki T; Lupoli S; Madden PA; Männistö S; Manunta P; Marette A; Matise TC; McKnight B; Meitinger T; Moll FL; Montgomery GW; Morris AD; Morris AP; Murray JC; Nelis M; Ohlsson C; Oldehinkel AJ; Ong KK; Ouwehand WH; Pasterkamp G; Peters A; Pramstaller PP; Price JF; Qi L; Raitakari OT; Rankinen T; Rao DC; Rice TK; Ritchie M; Rudan I; Salomaa V; Samani NJ; Saramies J; Sarzynski MA; Schwarz PE; Sebert S; Sever P; Shuldiner AR; Sinisalo J; Steinthorsdottir V; Stolk RP; Tardif JC; Tönjes A; Tremblay A; Tremoli E; Virtamo J; Vohl MC; Electronic Medical Records and Genomics (eMEMERGEGE) Consortium; MIGen Consortium; PAGEGE Consortium; LifeLines Cohort Study; Amouyel P; Asselbergs FW; Assimes TL; Bochud M; Boehm BO; Boerwinkle E; Bottinger EP; Bouchard C; Cauchi S; Chambers JC; Chanock SJ; Cooper RS; de Bakker PI; Dedoussis G; Ferrucci L; Franks PW; Froguel P; Groop LC; Haiman CA; Hamsten A; Hayes MG; Hui J; Hunter DJ; Hveem K; Jukema JW; Kaplan RC; Kivimaki M; Kuh D; Laakso M; Liu Y; Martin NG; März W; Melbye M; Moebus S; Munroe PB; Njølstad I; Oostra BA; Palmer CN; Pedersen NL; Perola M; Pérusse L; Peters U; Powell JE; Power C; Quertermous T; Rauramaa R; Reinmaa E; Ridker PM; Rivadeneira F; Rotter JI; Saaristo TE; Saleheen D; Schlessinger D; Slagboom PE; Snieder H; Spector TD; Strauch K; Stumvoll M; Tuomilehto J; Uusitupa M; van der Harst P; Völzke H; Walker M; Wareham NJ; Watkins H; Wichmann HE; Wilson JF; Zanen P; Deloukas P; Heid IM; Lindgren CM; Mohlke KL; Speliotes EK; Thorsteinsdottir U; Barroso I; Fox CS; North KE; Strachan DP; Beckmann JS; Berndt SI; Boehnke M; Borecki IB; McCarthy MI; Metspalu A; Stefansson K; Uitterlinden AG; van Duijn CM; Franke L; Willer CJ; Price AL; Lettre G; Loos RJ; Weedon MN; Ingelsson E; O'Connell JR; Abecasis GR; Chasman DI; Goddard ME; Visscher PM; Hirschhorn JN; Frayling TM.
Nat Genet. 2014 Nov;46(11):1173-86. Epub 2014-10-05.
Effect of Statin Use During Hospitalization for Intracerebral Hemorrhage on Mortality and Discharge Disposition
Statin use during hospitalization is associated with improved survival and a better discharge disposition among patients with ischemic stroke. It is unclear whether inpatient statin use has a similar effect among patients with intracerebral hemorrhage (ICH). To determine whether inpatient statin use in ICH is associated with improved outcomes and whether the cessation of statin use is associated with worsened outcomes. Retrospective cohort study of 3481 patients with ICH admitted to any of 20 hospitals in a large integrated health care delivery system over a 10-year period. Detailed electronic medical and pharmacy records were analyzed to explore the association between inpatient statin use and outcomes. The primary outcome measures were survival to 30 days after ICH and discharge to home or inpatient rehabilitation facility. We used multivariable logistic regression, controlling for demographics, comorbidities, initial severity, and code status. In addition, we used instrumental variable modeling to control for confounding by unmeasured covariates at the individual patient level. Among patients hospitalized for ICH, inpatient statin users were more likely than nonusers to be alive 30 days after ICH (odds ratio [OR], 4.25 [95% CI, 3.46-5.23]; P
Authors: Flint AC; Conell C; Rao VA; Klingman JG; Sidney S; Johnston SC; Hemphill JC; Kamel H; Davis SM; Donnan GA
JAMA Neurol. 2014 Nov;71(11):1364-71.
Early and delayed rupture after endovascular abdominal aortic aneurysm repair in a 10-year multicenter registry
Rupture after abdominal endovascular aortic aneurysm repair (EVAR) is a function of graft maintenance of the seal and fixation. We describe our 10-year experience with rupture after EVAR. From 2000 to 2010, 1736 patients with abdominal aortic aneurysm (AAA) from 17 medical centers underwent EVAR in a large, regional integrated health care system. Preoperative demographic and clinical data of interest were collected and stored in our registry. We retrospectively identified patients with postoperative rupture, characterized as “early” and “delayed” rupture (?30 days and >30 days after the initial EVAR, respectively), and identified predictors associated with delayed rupture. The overall follow-up rate was 92%, and the median follow-up was 2.7 years (interquartile range, 1.2-4.4 years) in these 1736 EVAR patients. We identified 20 patients with ruptures; 70% were male, the mean age was 79 years, and mean AAA size at the initial EVAR was 6.3 cm. Six patients underwent initial EVAR for rupture (n = 2) or symptomatic presentation (n = 4). Of the 20 post-EVAR ruptures, 25% (five of 20) were early, all occurring within 2 days after the initial EVAR. Of these five patients, four had intraoperative adverse events leading directly to rupture, with one type I and one type III endoleak. Of the five early ruptures, four patients underwent endovascular repair and one received repair with open surgery, resulting in two perioperative deaths. Among the remaining 15 patients, the median time from initial EVAR to rupture was 31.1 months (interquartile range, 13.8-57.3 months). Most of these delayed ruptures (10 of 15) were preceded by AAA sac increases, including three patients with known endoleaks who underwent reintervention. At the time of delayed rupture, nine of 15 patients had new endoleaks. Among all 20 patients, six patients did not undergo repair (all delayed patients) and died, nine underwent repeated EVAR, and five had open repair. For patients who underwent repair for delayed rupture, mortality at 30 days and 1 year were 44.4% and 66.7%, respectively. Multivariable Cox regression analysis identified age 80 to 89 (hazard ratio, 3.3; 95% confidence interval, 1.1-9.4; P = .03), and symptomatic or ruptured initial indication for EVAR (hazard ratio, 7.4; 95% confidence interval, 2.2-24.8; P < .01) as significant predictors of delayed rupture. Rupture after EVAR is a rare but devastating event, and mortality after repair exceeds 60% at 1 year. Most delayed cases showed late AAA expansion, thereby implicating late loss of seal and increased endoleaks as the cause of rupture in these patients and mandating vigilant surveillance.
Authors: Candell L; Tucker LY; Goodney P; Walker J; Okuhn S; Hill B; Chang R
J Vasc Surg. 2014 Nov;60(5):1146-52. Epub 2014-06-21.
Incident atrial fibrillation and risk of death in adults with chronic kidney disease
Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD); however, the long-term impact of development of AF on the risk of death among patients with CKD is unknown. We studied adults with CKD (glomerular filtration rate <60 mL/min per 1.73 m(2) by the Chronic Kidney Disease Epidemiology Collaboration equation) identified between 2002 and 2010 who were enrolled in Kaiser Permanente Northern California and had no previously documented AF. Incident AF was identified using primary hospital discharge diagnoses or ?2 outpatient visits for AF. Death was comprehensively ascertained from health plan administrative databases, Social Security Administration vital status files, and the California death certificate registry. Covariates included demographics, comorbidity, ambulatory blood pressure, laboratory values (hemoglobin, proteinuria), and longitudinal medication use. Among 81 088 adults with CKD, 6269 (7.7%) developed clinically recognized incident AF during a mean follow-up of 4.8±2.7 years. There were 2388 cases of death that occurred after incident AF (145 per 1000 person-years) compared with 18 865 cases of death during periods without AF (51 per 1000 person-years, P<0.001). After adjustment for potential confounders, incident AF was associated with a 66% increase in relative rate of death (adjusted hazard ratio 1.66, 95% CI 1.57 to 1.77). Incident AF is independently associated with an increased risk of death in adults with CKD. Further study is needed to understand the mechanisms by which CKD is associated with AF and to identify potentially modifiable risk factors to decrease the burden of AF and subsequent risk of death in this high-risk population.
Authors: Bansal N; Fan D; Hsu CY; Ordonez JD; Go AS
J Am Heart Assoc. 2014 Oct;3(5):e001303. Epub 2014-10-20.
CKD and the Risk of Incident Cancer
Previous studies report a higher risk of cancer in patients with ESRD, but the impact of less severe CKD on risk of cancer is uncertain. Our objective was to evaluate the association between level of kidney function and subsequent cancer risk. We performed a retrospective cohort study of 1,190,538 adults who were receiving care within a health care delivery system, had a measurement of kidney function obtained between 2000 and 2008, and had no prior cancer. We examined the association between level of eGFR and the risk of incident cancer; the primary outcome was renal cancer, and secondary outcomes were any cancer and specific cancers (urothelial, prostate, breast, lung, and colorectal). During 6,000,420 person-years of follow-up, we identified 76,809 incident cancers in 72,875 subjects. After adjustment for time-updated confounders, lower eGFR (in milliliters per minute per 1.73 m(2)) was associated with an increased risk of renal cancer (adjusted hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.22 to 1.58 for eGFR=45-59; HR, 1.81; 95% CI, 1.51 to 2.17 for eGFR=30-44; HR, 2.28; 95% CI, 1.78 to 2.92 for eGFR<30). We also observed an increased risk of urothelial cancer at eGFR<30 but no significant associations between eGFR and prostate, breast, lung, colorectal, or any cancer overall. In conclusion, reduced eGFR is associated with an independently higher risk of renal and urothelial cancer but not other cancer types.
Authors: Lowrance WT; Ordoñez J; Udaltsova N; Russo P; Go AS;
J Am Soc Nephrol. 2014 Oct;25(10):2327-34. Epub 2014-05-29.
Epidemiology, pathophysiology, and in-hospital management of pulmonary edema: data from the Romanian Acute Heart Failure Syndromes registry.
AIM: The objective of this study was to evaluate the clinical presentation, inpatient management, and in-hospital outcome of patients hospitalized for acute heart failure syndromes (AHFS) and classified as pulmonary edema (PE).METHODS: The Romanian Acute Heart Failure Syndromes (RO-AHFS) study was a prospective, national, multicenter registry of all consecutive patients admitted with AHFS over a 12-month period. Patients were classified at initial presentation by clinician-investigators into the following clinical profiles: acute decompensated HF, cardiogenic shock, PE, right HF, or hypertensive HF.RESULTS: RO-AHFS enrolled 3224 patients and 28.7% (n = 924) were classified as PE. PE patients were more likely to present with pulmonary congestion, tachypnea, tachycardia, and elevated systolic blood pressure and less likely to have peripheral congestion and body weight increases. Mechanical ventilation was required in 8.8% of PE patients. PE patients received higher doses (i.e. 101.4 ± 27.1 mg) of IV furosemide for a shorter duration (i.e. 69.3 ± 22.3 hours). Vasodilators were given to 73.6% of PE patients. In-hospital all-cause mortality (ACM) in PE patients was 7.4%, and 57% of deaths occurred on day one. Increasing age, concurrent acute coronary syndromes, life-threatening ventricular arrhythmias, elevated BUN, left bundle branch block, inotrope therapy, and requirement for invasive mechanical ventilation were independent risk factors for ACM.CONCLUSIONS: In this national registry, the PE profile was found to be a high-acuity clinical presentation with distinctive treatment patterns and a poor short-term prognosis. Advances in the management of PE may necessitate both the development of novel targeted therapies as well as systems-based strategies to identify high-risk patients early in their course.
Authors: Chioncel, Ovidiu O; Ambrosy, Andrew P AP; Bubenek, Serban S; Filipescu, Daniela D; Vinereanu, Dragos D; Petris, Antoniu A; Christodorescu, Ruxandra R; Macarie, Cezar C; Gheorghiade, Mihai M; Collins, Sean P SP;
Journal of cardiovascular medicine (Hagerstown, Md.). 2016 Feb 01;17(2):92-104. Epub 2014-09-16.
Global perspectives in hospitalized heart failure: regional and ethnic variation in patient characteristics, management, and outcomes.
Heart failure (HF) is a public health problem of global proportions afflicting more than 25 million patients worldwide. Despite stable or declining per capita hospitalization rates in the USA and several European countries, there are over one million hospitalizations for HF annually in the USA, with similar numbers in Europe, accounting for 6.5 million hospital days and the majority of the approximately $40 billion spent each year on HF-related care. Moreover, clinical trial data suggest that post-discharge survival and readmissions have largely remained unchanged. Thus, understanding geographic and ethnic variations in HF is essential to formulating public policy at the local, national, regional, and international levels and setting the agenda for basic, translational, and clinical research endeavors. This paper aims to describe regional and ethnic variations in patient characteristics, management, and outcomes in hospitalized HF.
Authors: Ambrosy, Andrew P AP; Gheorghiade, Mihai M; Chioncel, Ovidiu O; Mentz, Robert J RJ; Butler, Javed J
Current heart failure reports. 2014 Dec 01;11(4):416-27. Epub 2014-09-16.
Relation of serum uric acid levels and outcomes among patients hospitalized for worsening heart failure with reduced ejection fraction (from the efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan trial).
We investigated the clinical profiles associated with serum uric acid (sUA) levels in a large cohort of patients hospitalized for worsening chronic heart failure with ejection fraction (EF) ≤40%, with specific focus on gender, race, and renal function based interactions. In 3,955 of 4,133 patients (96%) with baseline sUA data, clinical characteristics and outcomes were compared across sUA quartiles. The primary end points were all-cause mortality and a composite of cardiovascular mortality or heart failure hospitalization. Interaction analyses were performed for gender, race, and baseline renal function. Median follow-up was 9.9 months. Mean sUA was 9.1 ± 2.8 mg/dl and was higher in men than in women (9.3 ± 2.7 vs 8.7 ± 3.0 mg/dl, p 0.4). Adjusted interaction analyses for gender, race, and admission allopurinol use were not significant. In conclusion, sUA is commonly elevated in patients hospitalized for worsening chronic heart failure and reduced EF, especially in men and blacks. The prognostic use of sUA differs by baseline renal function, suggesting different biologic and pathophysiologic significance of sUA among those with and without significant renal dysfunction.
Authors: Vaduganathan, Muthiah M; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Mentz, Robert J RJ; Subacius, Haris P HP; Chioncel, Ovidiu O; Maggioni, Aldo P AP; Swedberg, Karl K; Zannad, Faiez F; Konstam, Marvin A MA; Senni, Michele M; Givertz, Michael M MM; Butler, Javed J; Gheorghiade, Mihai M;
The American journal of cardiology. 2014 Dec 01;114(11):1713-21. Epub 2014-09-16.
Acute Kidney Injury After CABG Versus PCI: An Observational Study Using 2 Cohorts
Acute kidney injury (AKI) is a known complication after coronary revascularization, but few studies have directly compared the incidence of AKI after coronary artery bypass surgery (CABG) or after percutaneous coronary intervention (PCI) in similar patients. The aim of this study was to investigate whether multivessel CABG compared with PCI as an initial revascularization strategy is associated with a higher risk for AKI. A retrospective analysis of patients undergoing first documented coronary revascularization was conducted using 2 complementary cohorts: 1) Kaiser Permanente Northern California, a diverse, integrated health care delivery system; and 2) Medicare beneficiaries, a large, nationally representative older cohort. AKI was defined in the Kaiser Permanente Northern California cohort by an increase in serum creatinine of ?0.3 mg/dl or ?150% above baseline and in the Medicare cohort by discharge diagnosis codes and the use of dialysis. The incidence of AKI was 20.4% in the Kaiser Permanente Northern California cohort and 6.2% in the Medicare cohort. The incidence of AKI requiring dialysis was <1%. CABG was associated with a 2- to 3-fold significantly higher adjusted odds for developing AKI compared with PCI in both cohorts. AKI is common after multivessel coronary revascularization and is more likely after CABG than after PCI. The risk for AKI should be considered when choosing a coronary revascularization strategy, and ways to prevent AKI after coronary revascularization are needed.
Authors: Chang TI; Leong TK; Boothroyd DB; Hlatky MA; Go AS
J Am Coll Cardiol. 2014 Sep 9;64(10):985-94.
Timing and number of minor infections as risk factors for childhood arterial ischemic stroke
In a population-based case-control study, we examined whether the timing and number of minor infections increased risk of childhood arterial ischemic stroke (AIS). Among 102 children with AIS and 306 age-matched controls identified from a cohort of 2.5 million children in a large integrated health care plan (1993-2007), we abstracted data on all medical visits for minor infection within the 2 years prior to AIS or index date for pairwise age-matched controls. We excluded cases of AIS with severe infection (e.g., sepsis, meningitis). Using conditional logistic regression, we examined the effect of timing and total number of minor infections on stroke risk. After adjusting for known pediatric stroke risk factors, the strongest association between infection and AIS was observed for infectious visits ?3 days prior to stroke (odds ratio [OR] 12.1, 95% confidence interval [CI] 2.5, 57, p = 0.002). Respiratory infections represented 80% of case infections in that time period. Cases had more infectious visits, but not significantly so, for all time periods ?4 days prior to the stroke. A greater cumulative number of infectious visits over 2 years did not increase risk of AIS. Minor infections appear to have a strong but short-lived effect on pediatric stroke risk, while cumulative burden of infection had no effect. Proposed mechanisms for the link between minor infection and stroke in adults include an inflammatory-mediated prothrombotic state and chronic endothelial injury. The transient effect of infection in children may suggest a greater role for a prothrombotic mechanism.
Authors: Hills NK; Sidney S; Fullerton HJ
Neurology. 2014 Sep 2;83(10):890-7. Epub 2014-08-20.
Racial/ethnic differences in hip and diaphyseal femur fractures
Contemporary femur fracture rates were examined in northern California women and compared by race/ethnicity. During 2006-2012, hip fracture rates declined, but diaphyseal fracture rates increased, especially in Asians. Women with diaphyseal fracture were younger and more likely to be bisphosphonate-treated. These disparities in femur fracture should be further examined. The epidemiology of diaphyseal femur fracture differs from proximal femur (hip) fracture, although few studies have examined demographic variations in the current era. This study examines contemporary differences in low-energy femur fracture by race/ethnicity in a large, diverse integrated health-care delivery system. The incidence of hip and diaphyseal fracture in northern California women aged ?50 years old during 2006-2012 was examined. Hip (femoral neck and pertrochanteric) fractures were classified by hospital diagnosis codes, while diaphyseal (subtrochanteric and femoral shaft) fractures were further adjudicated based on radiologic findings. Demographic and clinical data were obtained from health plan databases. Fracture incidence was examined over time and by race/ethnicity. There were 10,648 (97.3 %) hip and 300 (2.7 %) diaphyseal fractures among 10,493 women. The age-adjusted incidence of hip fracture fell from 281 to 240 per 100,000 women and was highest for white women. However, diaphyseal fracture rates increased over time, with a significant upward trend in Asians (9 to 27 per 100,000) who also had the highest rate of diaphyseal fracture. Women with diaphyseal fracture were younger than women with hip fracture, more likely to be of Asian race and to have received bisphosphonate drugs. Women with longer bisphosphonate treatment duration were also more likely to have a diaphyseal fracture, especially younger Asian women. During 2006 to 2012, hip fracture rates declined, but diaphyseal fracture rates increased, particularly among Asian women. The association of diaphyseal fracture and bisphosphonate therapy should be further investigated with examination of fracture pattern.
Authors: Lo JC; Zheng P; Grimsrud CD; Chandra M; Ettinger B; Budayr A; Lau G; Baur MM; Hui RL; Neugebauer R
Osteoporos Int. 2014 Sep;25(9):2313-8. Epub 2014-06-26.
Incidence of malignancy in patients with moderate-to-severe asthma treated with or without omalizumab(?)
The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) assessed the long-term safety of omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment. We sought to evaluate long-term safety in omalizumab-treated and nonomalizumab-treated patients. Primary outcome measures focused on assessment of malignancies. EXCELS was a prospective observational cohort study in patients (?12 years of age) with moderate-to-severe allergic asthma. There were 2 cohorts: omalizumab (taking omalizumab at baseline) and nonomalizumab (no history of omalizumab treatment). Primary outcomes included all confirmed, incident, study-emergent primary malignancies (malignancies), including and excluding nonmelanoma skin cancer (NMSC); all malignancies were externally adjudicated. The omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort (50.0% vs 23.0%). Median follow-up was approximately 5 years for both cohorts. Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts, with a rate ratio of 0.84 (95% CI, 0.62-1.13) for all malignancies and 0.98 (95% CI, 0.71-1.36) for all malignancies excluding NMSC. Kaplan-Meier plots of time to first confirmed study-emergent primary malignancy were similar for the 2 treatment cohorts. Cox proportional hazards modeling, adjusting for confounders and risk factors, resulted in a hazard ratio (omalizumab vs nonomalizumab) of 1.09 (95% CI, 0.87-1.38) for all malignancies and 1.15 (95% CI, 0.83-1.59) for all malignancies excluding NMSC. Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy.
Authors: Long A; Rahmaoui A; Rothman KJ; Guinan E; Eisner M; Bradley MS; Iribarren C; Chen H; Carrigan G; Rosén K; Szefler SJ
J Allergy Clin Immunol. 2014 Sep;134(3):560-567.e4. Epub 2014-03-27.
Short QT in a Cohort of 1.7 Million Persons: Prevalence, Correlates, and Prognosis
Short QT syndrome (QTc ? 300 ms) is a novel hereditary channelopathy linked to syncope, paroxysmal atrial fibrillation, and sudden cardiac death. However, its epidemiological features remain unsettled. (1) To assess the prevalence of short QT in a large population-based sample; (2) to evaluate its demographic and clinical correlates and; (3) to determine its prognosis. A database of 6.4 million electrocardiograms (ECGs) obtained between 1995 and 2008 among 1.7 million persons was used. An internal, population-based method for heart rate correction (QTcreg ) was used and all ECGs with QTcreg ?300 ms were manually validated. Linked health plan databases were used for covariate and survival ascertainment. Of 6,387,070 ECGs, 1086 had an ECG with machine-read QTcreg ?300 ms. Only 4% (45/1086) were validated yielding a prevalence of 0.7 per 100,000 or 1 of 141,935 ECGs. At the person level, the overall prevalence of QTcreg ?300 ms was 2.7 per 100,000 or 1 of 37,335. The factors independently and significantly associated with validated QTcreg ?300 ms were age over 65 years, Black race, prior history of ventricular dysrhythmias, chronic obstructive pulmonary disease, ST-T abnormalities, ischemia, bigeminy pattern, and digitalis effect. After 8.3 years of median follow-up and relative to normal QTcreg , validated QTcreg ?300 ms was associated after multivariate adjustment with a 2.6-fold (95% confidence interval [CI] = 1.9-3.7) increased risk of death. QTcreg ?300 ms was extraordinarily rare and was associated with significant ECG abnormalities and reduced survival.
Authors: Iribarren C; Round AD; Peng JA; Lu M; Klatsky AL; Zaroff JG; Holve TJ; Prasad A; Stang P
Ann Noninvasive Electrocardiol. 2014 Sep;19(5):490-500. Epub 2014-05-14.
Lipid Screening in Children and Adolescents in Community Practice: 2007 to 2010
Integrated guidelines on cardiovascular health and risk reduction in children issued in 2011 newly recommended universal screening for dyslipidemia in children at 9 to 11 years and 17 to 21 years. We determined the frequency and results of lipid testing in 301 080 children and adolescents aged 3 to 19 enrolled in 3 large US health systems in 2007 to 2010 before the 2011 guidelines were issued. Overall, 9.8% of the study population was tested for lipids. The proportion tested varied by body mass index percentile (5.9% of normal weight, 10.8% of overweight, and 26.9% of obese children) and age (8.9% of 9- to 11-year olds and 24.3% of 17- to 19-year olds). In normal weight individuals, 2.8% of 9- to 11-year olds and 22.0% of 17- to 19-year olds were tested. In multivariable models, age and body mass index category remained strongly associated with lipid testing. Sex, race, ethnicity, and blood pressure were weakly associated with testing. Abnormal lipid levels were found in 8.6% for total cholesterol, 22.5% for high-density lipoprotein-cholesterol, 12.0% for non-high-density lipoprotein-cholesterol, 8.0% for low-density lipoprotein-cholesterol, and 21% for triglycerides (age, 10-19 years). There was a strong and graded association of abnormal lipid levels with body mass index, particularly for high-density lipoprotein-cholesterol and triglycerides (2- to 6-fold higher odds ratio in obese when compared with that in normal weight children). Lipid screening was uncommon in 9- to 11-year olds and was performed in a minority of 17- to 19-year olds during 2007 to 2010. These data serve as a benchmark for assessing change in practice patterns after the new recommendations for pediatric lipid screening and management.
Authors: Margolis KL; Lo JC; O'Connor PJ; et al.
Circ Cardiovasc Qual Outcomes. 2014 Sep;7(5):718-26. Epub 2014-08-26.
The Association of Gender to Cardiovascular Outcomes After Coronary Artery Revascularization in Patients With End-Stage Renal Disease
Inadequate recruitment of women and an exclusion of patients with end-stage renal disease (ESRD) in coronary revascularization trials have led to knowledge gaps of gender-based outcomes. Women have equivalent cardiovascular outcomes when compared to men. We conducted a retrospective observational study utilizing Kaiser Permanente Northern California (KPNC) databases and identified 1015 adults with ESRD who underwent coronary revascularization between 1996 and 2008. We ascertained baseline characteristics, primary (mortality at 5 years) and secondary (myocardial infarction [MI] and repeat revascularization) outcomes from KPNC databases, state death certificates, and Social Security Administration files. A multivariable logistic regression was used to determine the association of gender to the prespecified outcomes. Men and women were similar in age (P = 0.23). The mean number of baseline comorbidities was higher in women (2.7, 95% confidence interval [CI]: 2.5-2.9) compared to men (2.3, 95% CI: 2.1-2.4, P = 0.0002). The risk-adjusted odds ratios (OR) of female gender to death at 5 years (OR: 1.12, 95% CI: 0.83-1.52), MI (OR: 1.19, 95% CI: 0.86-1.64), and repeat revascularization (OR: 1.01, 95% CI: 0.70-1.45) were similar to men. Age modified the effect of gender for the primary outcome death (Pinteraction < 0.048), with a trend toward worse outcomes in younger women and improved outcomes in older women. This effect was noted more in patients who underwent coronary artery bypass grafting. Although the overall relative risk of cardiovascular outcomes after coronary revascularization in ESRD was equivalent between men and women, age had a significant interaction with gender on overall mortality.
Authors: Krishnaswami A; Chang TI; Jang JJ; Leong TK; Go AS
Clin Cardiol. 2014 Sep;37(9):546-51. Epub 2014-06-30.
Higher Levels of Cystatin C Are Associated with Worse Cognitive Function in Older Adults with Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort Cognitive Study
To determine the association between cognition and levels of cystatin C in persons with chronic kidney disease (CKD). Prospective observational study. Chronic Renal Insufficiency Cohort Cognitive Study. Individuals with a baseline cognitive assessment completed at the same visit as serum cystatin C measurement (N = 821; mean age 64.9, 50.6% male, 48.6% white). Levels of serum cystatin C were categorized into tertiles; cognitive function was assessed using six neuropsychological tests. Scores on these tests were compared across tertiles of cystatin C using linear regression and logistic regression to examine the association between cystatin C level and cognitive performance (1 standard deviation difference from the mean). After multivariable adjustment for age, race, education, and medical comorbidities in linear models, higher levels of cystatin C were associated with worse cognition on the modified Mini-Mental State Examination, Buschke Delayed Recall, Trail-Making Test Part (Trails) A and Part B, and Boston Naming (P < .05 for all). This association remained statistically significant for Buschke Delayed Recall (P = .01) and Trails A (P = .03) after additional adjustment for estimated glomerular filtration rate (eGFR). The highest tertile of cystatin C was associated with greater likelihood of poor performance on Trails A (odds ratio (OR) = 2.17, 95% confidence interval (CI) = 1.16-4.06), Trails B (OR = 1.89, 95% CI = 1.09-3.27), and Boston Naming (OR = 1.85, 95% CI = 1.07-3.19) than the lowest tertile after multivariate adjustment in logistic models. In individuals with CKD, higher serum cystatin C levels were associated with worse cognition and greater likelihood of poor cognitive performance on attention, executive function, and naming. Cystatin C is a marker of cognitive impairment and may be associated with cognition independent of eGFR.
Authors: Yaffe K; Go AS; CRIC Study Investigators; et al.
J Am Geriatr Soc. 2014 Sep;62(9):1623-9. Epub 2014-08-14.
Maternal gestational weight gain and offspring risk for childhood overweight or obesity
The objective of the study was to evaluate the association between gestational weight gain, per the 2009 Institute of Medicine (IOM) recommendations, and offspring overweight/obesity at 2-5 years of age. This was a prospective cohort study of 4145 women who completed a health survey (2007-2009) and subsequently delivered a singleton at Kaiser Permanente Northern California (2007-2010). Childhood overweight/obesity was defined as a body mass index (BMI) z-score of the 85th percentile or greater of the Centers for Disease Control and Prevention child growth standards. Gestational weight gain was categorized according to the 2009 IOM recommendations. Logistic regression was used; meeting the IOM recommendations was the referent. Exceeding the IOM recommendations was associated with a 46% increase in odds of having an overweight/obese child (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.17-1.83), after adjusting for maternal prepregnancy BMI, race/ethnicity, age at delivery, education, child age, birthweight, gestational age at delivery, gestational diabetes, parity, infant sex, total metabolic equivalents, and dietary pattern. The OR (95% CI) for childhood overweight/obesity among women gaining below the IOM recommendations was 1.23 (0.88-1.71). The associations between gaining outside the IOM recommendations and childhood obesity were stronger among women with a normal prepregnancy BMI (OR, 1.63; 95% CI, 1.03-2.57) (below); OR, 1.79; 95% CI, 1.32-2.43) (exceeded). Gestational weight gain outside the IOM recommendations is associated with increased odds of childhood overweight/obesity, independent of several potential confounders and mediators. Gestational weight gain had a greater impact on childhood overweight/obesity among normal-weight women, suggesting that the effect may be independent of genetic predictors of obesity.
Authors: Sridhar SB; Darbinian J; Ehrlich SF; Markman MA; Gunderson EP; Ferrara A; Hedderson MM
Am J Obstet Gynecol. 2014 Sep;211(3):259.e1-8. Epub 2014-04-13.
Effect of Selective Serotonin Reuptake Inhibitors on Bleeding Risk in Patients With Atrial Fibrillation Taking Warfarin
Selective serotonin reuptake inhibitor (SSRI) medications have been linked to increased bleeding risk; however, the actual association among warfarin, SSRI exposure, and bleeding risk has not been well-established. We studied the AnTicoagulation and Risk factors In Atrial fibrillation cohort of 13,559 adults with atrial fibrillation, restricted to the 9,186 patients contributing follow-up time while taking warfarin. Exposure to SSRIs and tricyclic antidepressants (TCAs) was assessed from pharmacy database dispensing data. The main outcome was hospitalization for major hemorrhage. Results were adjusted for bleeding risk and time in international normalized ratio range >3. We identified 461 major hemorrhages during 32,888 person-years of follow-up, 45 events during SSRI use, 12 during TCA-only use, and 404 without either medication. Hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years, p <0.001) and did not differ between TCA exposure and no antidepressants (1.30 per 100 person-years on TCAs, p = 0.94). After adjustment for underlying bleeding risk and time in international normalized ratio range >3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk 1.41, 95% confidence interval 1.04 to 1.92, p = 0.03), whereas TCA exposure was not (adjusted relative risk 0.82, 95% confidence interval 0.46 to 1.46, p = 0.50). In conclusion, SSRI exposure was associated with higher major hemorrhage risk in patients taking warfarin, and this risk should be considered when selecting antidepressant treatments in those patients.
Authors: Quinn GR; Singer DE; Chang Y; Go AS; Borowsky LH; Udaltsova N; Fang MC
Am J Cardiol. 2014 Aug 15;114(4):583-6. Epub 2014-06-05.
Higher plasma CXCL12 levels predict incident myocardial infarction and death in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort study
Genome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown. We analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13-1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio. In CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.
Authors: Mehta NN; Go A; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators; et al.
Eur Heart J. 2014 Aug 14;35(31):2115-22. Epub 2013-12-04.
Convergent Validity of a Brief Self-reported Physical Activity Questionnaire
The objective of this study is to determine whether summary estimates of a self-report physical activity questionnaire that does not specifically assess frequency or duration (the Coronary Artery Risk Development in Young Adults (CARDIA) physical activity history (PAH)) differs from the summary estimates of one that does (CARDIA Supplemental Questionnaire). After the year 25 examination (2010-2011), 203 CARDIA black and white men and women (age 50.3 ± 3.6 yr) at the Oakland, CA, site participated in this comparison study. The between-questionnaire association and agreement were determined for continuous and categorical estimates on the basis of 1) quartiles and 2) meeting 2008 physical activity guidelines. Differences in participant characteristics by concordance/discordance status were also examined. Finally, receiver operating characteristic curves were computed to determine the accuracy of the PAH compared with the supplemental questionnaire. Reported physical activity levels were high and varied significantly by race and sex (all P < 0.01). Between-questionnaire estimates were significantly correlated (rho = 0.75 to 0.90, all P < 0.001) and had high agreement (? = 0.51 to 0.80) across all race/sex groups. A higher proportion of women than men were classified as concordant by quartile of vigorous intensity (P = 0.001), but no other participant characteristics were associated with concordant/discordant quartile ranking. Participants classified as concordant on the basis of physical activity guidelines had lower body mass index than those classified as discordant (both P < 0.05). The area under the curve was 0.95, suggesting that the PAH has high accuracy for classifying individuals as meeting physical activity guidelines. Although it is inconvenient that the PAH is not expressed in more standard units, these findings support the practice of not directly assessing frequency and duration, which are frequent sources of reporting error.
Authors: Gabriel KP; Sidney S; Jacobs DR; Quesenberry CP; Reis JP; Jiang SF; Sternfeld B
Med Sci Sports Exerc. 2014 Aug;46(8):1570-7.
Left atrial dimension and traditional cardiovascular risk factors predict 20-year clinical cardiovascular events in young healthy adults: the CARDIA study
We investigated whether the addition of left atrial (LA) size determined by echocardiography improves cardiovascular risk prediction in young adults over and above the clinically established Framingham 10-year global CV risk score (FRS). We included white and black CARDIA participants who had echocardiograms in Year-5 examination (1990-91). The combined endpoint after 20 years was incident fatal or non-fatal cardiovascular disease: myocardial infarction, heart failure, cerebrovascular disease, peripheral artery disease, and atrial fibrillation/flutter. Echocardiography-derived M-mode LA diameter (LAD; n = 4082; 149 events) and 2D four-chamber LA area (LAA; n = 2412; 77 events) were then indexed by height or body surface area (BSA). We used Cox regression, areas under the receiver operating characteristic curves (AUC), and net reclassification improvement (NRI) to assess the prediction power of LA size when added to calculated FRS or FRS covariates. The LAD and LAA cohorts had similar characteristics; mean LAD/height was 2.1 ± 0.3 mm/m and LAA/height 9.3 ± 2.0 mm(2)/m. After indexing by height and adjusting for FRS covariates, hazard ratios were 1.31 (95% CI 1.12, 1.60) and 1.43 (95% CI 1.13, 1.80) for LAD and LAA, respectively; AUC was 0.77 for LAD and 0.78 for LAA. When LAD and LAA were indexed to BSA, the results were similar but slightly inferior. Both LAD and LAA showed modest reclassification ability, with non-significant NRIs. LA size measurements independently predict clinical outcomes. However, it only improves discrimination over clinical parameters modestly without altering risk classification. Indexing LA size by height is at least as robust as by BSA. Further research is needed to assess subgroups of young adults who may benefit from LA size information in risk stratification.
Authors: Armstrong AC; Colangelo LA; Lima JA; et al.
Eur Heart J Cardiovasc Imaging. 2014 Aug;15(8):893-9. Epub 2014-02-16.
Outcomes registry for better informed treatment of atrial fibrillation II: Rationale and design of the ORBIT-AF II registry
Recent clinical trials have demonstrated the safety and efficacy of several non-vitamin K oral anticoagulants (NOACs) for the treatment of atrial fibrillation (AF). However, there are limited data on their use and outcomes in routine clinical practice, particularly among patients newly diagnosed as having AF and patients with AF recently transitioned to a NOAC. ORBIT-AF II is a multicenter, national registry of patients with AF that is enrolling up to 15,000 newly diagnosed patients with AF and/or those with AF recently transitioned to a NOAC from 300 US outpatient practices. These patients will be followed for up to 2 years, including clinical status, outcomes (major adverse cardiovascular events, bleeding), and management of anticoagulation surrounding bleeding events. In addition, detailed data regarding the use of these agents in and around cardiac procedures, their complications, and management of such complications will be collected. The ORBIT-AF II registry will provide valuable insights into the safety and effectiveness of NOACs used in AF in community practice settings.
Authors: Steinberg BA; Go AS; ORBIT-AF Steering Committee Investigators; et al.
Am Heart J. 2014 Aug;168(2):160-7. Epub 2014-04-18.
Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease
The effectiveness of beta-blockers for preventing cardiac events has been questioned for patients who have coronary heart disease (CHD) without a prior myocardial infarction (MI). The purpose of this study was to assess the association of beta-blockers with outcomes among patients with new-onset CHD. We studied consecutive patients discharged after the first CHD event (acute coronary syndrome or coronary revascularization) between 2000 and 2008 in an integrated healthcare delivery system who did not use beta-blockers in the year before entry. We used time-varying Cox regression models to determine the hazard ratio (HR) associated with beta-blocker treatment and used treatment-by-covariate interaction tests (p(int)) to determine whether the association differed for patients with or without a recent MI. A total of 26,793 patients were included, 19,843 of whom initiated beta-blocker treatment within 7 days of discharge from their initial CHD event. Over an average of 3.7 years of follow-up, 6,968 patients had an MI or died. Use of beta-blockers was associated with an adjusted HR for mortality of 0.90 (95% confidence limits [CL]: 0.84 to 0.96), and an adjusted HR for death or MI of 0.92 (CL: 0.87 to 0.97). The association between beta-blockers and outcomes differed significantly between patients with and without a recent MI (HR for death: 0.85 vs. 1.02, p(int) = 0.007; and HR for death or MI: 0.87 vs. 1.03, p(int) = 0.005). Use of beta-blockers among patients with new-onset CHD was associated with a lower risk of cardiac events only among patients with a recent MI.
Authors: Andersson C; Shilane D; Go AS; Chang TI; Kazi D; Solomon MD; Boothroyd DB; Hlatky MA
J Am Coll Cardiol. 2014 Jul 22;64(3):247-52.
Lactation intensity and fasting plasma lipids, lipoproteins, non-esterified free fatty acids, leptin and adiponectin in postpartum women with recent gestational diabetes mellitus: The SWIFT cohort
Lactation may influence future progression to type 2 diabetes after gestational diabetes mellitus (GDM). However, biomarkers associated with progression to glucose intolerance have not been examined in relation to lactation intensity among postpartum women with previous GDM. This study investigates whether higher lactation intensity is related to more favorable blood lipids, lipoproteins and adipokines after GDM pregnancy independent of obesity, socio-demographics and insulin resistance. The Study of Women, Infant Feeding, and Type 2 Diabetes (SWIFT) is a prospective cohort study that recruited 1035 women diagnosed with GDM by the 3-h 100g oral glucose tolerance tests (OGTTs) after delivery of a live birth in 2008-2011. Research staff conducted 2-h 75 g OGTTs, and assessed lactation intensity, anthropometry, lifestyle behaviors and socio-demographics at 6-9 weeks postpartum (baseline). We assayed fasting plasma lipids, lipoproteins, non-esterified free fatty acids, leptin and adiponectin from stored samples obtained at 6-9 weeks postpartum in 1007 of the SWIFT participants who were free of diabetes at baseline. Mean biomarker concentrations were compared among lactation intensity groups using multivariable linear regression models. Increasing lactation intensity showed graded monotonic associations with fully adjusted mean biomarkers: 5%-8% higher high-density lipoprotein cholesterol (HDL-cholesterol), 20%-28% lower fasting triglycerides, 15%-21% lower leptin (all trend P-values < 0.01), and with 6% lower adiponectin, but only after adjustment for insulin resistance (trend P-value = 0.04). Higher lactation intensity was associated with more favorable biomarkers for type 2 diabetes, except for lower plasma adiponectin, after GDM delivery. Long-term follow-up studies are needed to assess whether these effects of lactation persist to predict progression to glucose intolerance.
Authors: Gunderson EP; Quesenberry CP; Lo JC; Dewey KG; et al.
Metab Clin Exp. 2014 Jul;63(7):941-50. Epub 2014-04-13.
Healthy Lifestyle Change and Subclinical Atherosclerosis in Young Adults: Coronary Artery Risk Development in Young Adults (CARDIA) Study
The benefits of healthy habits are well established, but it is unclear whether making health behavior changes as an adult can still alter coronary artery disease risk. The Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study (n=3538) assessed 5 healthy lifestyle factors (HLFs) among young adults aged 18 to 30 years (year 0 baseline) and 20 years later (year 20): not overweight/obese, low alcohol intake, healthy diet, physically active, nonsmoker. We tested whether change from year 0 to 20 in a continuous composite HLF score (HLF change; range, -5 to +5) is associated with subclinical atherosclerosis (coronary artery calcification and carotid intima-media thickness) at year 20, after adjustment for demographics, medications, and baseline HLFs. By year 20, 25.3% of the sample improved (HLF change ?+1); 40.4% deteriorated (had fewer HLFs); 34.4% stayed the same; and 19.2% had coronary artery calcification (>0). Each increase in HLFs was associated with reduced odds of detectable coronary artery calcification (odds ratio=0.85; 95% confidence interval, 0.74-0.98) and lower intima-media thickness (carotid bulb ?=-0.024, P=0.001), and each decrease in HLFs was predictive to a similar degree of greater odds of coronary artery calcification (odds ratio=1.17; 95% confidence interval, 1.02-1.33) and greater intima-media thickness (?=+0.020, P<0.01). Healthy lifestyle changes during young adulthood are associated with decreased risk and unhealthy lifestyle changes are associated with increased risk for subclinical atherosclerosis in middle age.
Authors: Spring B; Moller AC; Colangelo LA; Siddique J; Roehrig M; Daviglus ML; Polak JF; Reis JP; Sidney S; Liu K
Circulation. 2014 Jul 1;130(1):10-7. Epub 2014-04-28.
Retinopathy and Progression of CKD: The Chronic Renal Insufficiency Cohort Study
Retinal abnormalities may be associated with changes in the renal vasculature. This study assessed the association between retinopathy and progression of kidney disease in participants of the Chronic Renal Insufficiency Cohort (CRIC) study. This was a prospective study in which patients with CKD enrolled in CRIC had nonmydriatic fundus photographs of both eyes. All CRIC participants in six clinical sites in which fundus cameras were deployed were offered participation. Photographs were reviewed at a reading center. The presence and severity of retinopathy and vessel calibers were assessed using standard protocols by graders masked to clinical information. The associations of retinal features with changes in eGFR and the need for RRT (ESRD) were assessed. Retinal images and renal progression outcomes were obtained from 1852 of the 2605 participants (71.1%) approached. During follow-up (median 2.3 years), 152 participants (8.2%) developed ESRD. Presence and severity of retinopathy at baseline were strongly associated with the risk of subsequent progression to ESRD and reductions in eGFR in unadjusted analyses. For example, participants with retinopathy were 4.4 times (95% confidence interval [95% CI], 3.12 to 6.31) more likely to develop ESRD than those without retinopathy (P<0.001). However, this association was not statistically significant after adjustment for initial eGFR and 24-hour proteinuria. Venular and arteriolar diameter calibers were not associated with ESRD or eGFR decline. The results showed a nonlinear relationship between mean ratio of arteriole/vein calibers and the risk of progression to ESRD; participants within the fourth arteriole/vein ratio quartile were 3.11 times (95% CI, 1.51 to 6.40) more likely to develop ESRD than those in the first quartile (P<0.001). The presence and severity of retinopathy were not associated with ESRD and decline in eGFR after taking into account established risk factors.
Authors: Grunwald JE; Lo JC; Chronic Renal Insufficiency Cohort Study Investigators; et al.
Clin J Am Soc Nephrol. 2014 Jul;9(7):1217-24. Epub 2014-05-08.
Hospital-Level Variation in Use of Cardiovascular Testing for Adults With Incident Heart Failure: Findings from the Cardiovascular Research Network Heart Failure Study
This study aimed to characterize the use of cardiovascular testing for patients with incident heart failure (HF) hospitalization who participated in the National Heart, Lung, and Blood Institute sponsored Cardiovascular Research Network (CVRN) Heart Failure study. HF is a common cause of hospitalization, and testing and treatment patterns may differ substantially between providers. Testing choices have important implications for the cost and quality of care. Crude and adjusted cardiovascular testing rates were calculated for each participating hospital. Cox proportional hazards regression models were used to examine hospital testing rates after adjustment for hospital-level patient case mix. Of the 37,099 patients in the CVRN Heart Failure study, 5,878 patients were hospitalized with incident HF between 2005 and 2008. Of these, evidence of cardiovascular testing was available for 4,650 (79.1%) patients between 14 days before the incident HF admission and ending 6 months after the incident discharge. We compared crude and adjusted cardiovascular testing rates at the hospital level because the majority of testing occurred during the incident HF hospitalization. Of patients who underwent testing, 4,085 (87.9%) had an echocardiogram, 4,345 (93.4%) had a systolic function assessment, and 1,714 (36.9%) had a coronary artery disease assessment. Crude and adjusted testing rates varied markedly across the profiled hospitals, for individual testing modalities (e.g., echocardiography, stress echocardiography, nuclear stress testing, and left heart catheterization) and for specific clinical indications (e.g., systolic function assessment and coronary artery disease assessment). For patients with newly diagnosed HF, we did not observe widespread overuse of cardiovascular testing in the 6 months following incident HF hospitalization relative to existing HF guidelines. Variations in testing were greatest for assessment of ischemia, in which testing guidelines are less certain.
Authors: Farmer SA; Lenzo J; Magid DJ; Gurwitz JH; Smith DH; Hsu G; Sung SH; Go AS
JACC Cardiovasc Imaging. 2014 Jul;7(7):690-700. Epub 2014-06-18.
Comparative Effectiveness of Clopidogrel in Medically Managed Patients with Unstable Angina and non-ST Segment Elevation Myocardial Infarction
This study sought to examine the effectiveness of clopidogrel in real-world, medically managed patients with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI). Although clinical trials have demonstrated the efficacy of clopidogrel to reduce cardiovascular (CV) morbidity and mortality in medically managed patients with UA or NSTEMI, the effectiveness of clopidogrel in actual clinical practice is less certain. A retrospective cohort study was conducted of Kaiser Permanente Northern California members without known coronary artery disease or prior clopidogrel use who presented with UA or NSTEMI between 2003 and 2008 and were medically managed (i.e., no percutaneous coronary intervention or coronary artery bypass grafting during the index hospitalization or within 7 days post-discharge). Over 2 years of follow-up, we measured the association between clopidogrel use and all-cause mortality, hospital stay for MI, and a composite endpoint of death or MI using propensity-matched multivariable Cox analyses. We identified 16,365 patients with incident UA (35%) or NSTEMI (65%); 36% of these patients were prescribed clopidogrel within 7 days of discharge. In 8,562 propensity score-matched patients, clopidogrel users had lower rates of all-cause mortality (8.3% vs. 13.0%; p < 0.01; adjusted hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.54 to 0.72) and the composite of death or MI (13.5% vs. 17.4%; p < 0.01; HR: 0.74, CI: 0.66 to 0.84), but not MI alone (6.7% vs. 7.2%; p = 0.30; HR: 0.93, CI: 0.78 to 1.11), compared with nonusers of clopidogrel. The association between clopidogrel use and the composite of death or MI was significant only among patients presenting with NSTEMI (HR: 0.67; CI: 0.59 to 0.76; pint < 0.01), not among those presenting with UA (HR: 1.25; CI: 0.94 to 1.67). In a large, community-based cohort of patients who were medically managed after UA/NSTEMI, clopidogrel use was associated with a lower risk of death and MI, particularly among patients with NSTEMI.
Authors: Solomon MD; Go AS; Shilane D; Boothroyd DB; Leong TK; Kazi DS; Chang TI; Hlatky MA
J Am Coll Cardiol. 2014 Jun 3;63(21):2249-57. Epub 2014-04-02.
Prevalence of obesity and extreme obesity in children aged 3-5 years
Early childhood adiposity may have significant later health effects. This study examines the prevalence and recognition of obesity and severe obesity among preschool-aged children. The electronic medical record was used to examine body mass index (BMI), height, sex and race/ethnicity in 42,559 children aged 3-5 years between 2007 and 2010. Normal or underweight (BMI?
Authors: Lo JC; Greenspan LC; et al.
Pediatr Obes. 2014 Jun;9(3):167-75. Epub 2013-05-15.
Designing effective drug and device development programs for hospitalized heart failure: a proposal for pretrial registries.
Recent international phase III clinical trials of novel therapies for hospitalized heart failure (HHF) have failed to improve the unacceptably high postdischarge event rate. These large studies have demonstrated notable geographic and site-specific variation in patient profiles and enrollment. Possible contributors to the lack of success in HHF outcome trials include challenges in selecting clinical sites capable of (1) providing adequate numbers of appropriately selected patients and (2) properly executing the study protocol. We propose a "pretrial registry" as a novel tool for improving the efficiency and quality of international HHF trials by focusing on the selection and cultivation of high-quality sites. A pretrial registry may help assess a site’s ability to achieve adequate enrollment of the target patient population, integrate protocol requirements into clinical workflow, and accomplish appropriate follow-up. Although such a process would be associated with additional upfront resource investment, this appropriation may be modest in comparison with the downstream costs associated with maintenance of poorly performing sites, failed clinical trials, and the global health and economic burden of HHF. This review is based on discussions between scientists, clinical trialists, and regulatory representatives regarding methods for improving international HHF trials that took place at the United States Food and Drug Administration on January 12th, 2012.
Authors: Greene, Stephen J SJ; Shah, Ami N AN; Butler, Javed J; Ambrosy, Andrew P AP; Anker, Stefan D SD; Chioncel, Ovidiu O; Collins, Sean P SP; Dinh, Wilfried W; Dunnmon, Preston M PM; Fonarow, Gregg C GC; Lam, Carolyn S P CS; Mentz, Robert J RJ; Pieske, Burkert B; Roessig, Lothar L; Rosano, Giuseppe M C GM; Sato, Naoki N; Vaduganathan, Muthiah M; Gheorghiade, Mihai M
American heart journal. 2014 Aug 01;168(2):142-9. Epub 2014-05-24.
Lack of Concordance between Empirical Scores and Physician Assessments of Stroke and Bleeding Risk in Atrial Fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry
Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians’ estimates is unclear. We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age ?75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS2) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) scores, respectively. Separately, physicians were asked to categorize their patients’ stroke and bleeding risks: low risk (<3%); intermediate risk (3%-6%); and high risk (>6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS2 scores (?2). However, only 16% were assessed as high stroke risk by physicians. Although 17% (n=1749) had high ATRIA bleeding risk (score ?5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes mellitus less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice. There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, the current divergence of anticoagulation treatment decisions from guideline recommendations. https://www.clinicaltrials.gov. Unique identifier: NCT01165710.
Authors: Steinberg BA; Go AS; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators and Patients; et al.
Circulation. 2014 May 20;129(20):2005-12. Epub 2014-03-29.
Lone Atrial Fibrillation: Does It Exist? A “White Paper” of the Journal of the American College of Cardiology
The historical origin of the term “lone atrial fibrillation” (AF) predates by 60 years our current understanding of the pathophysiology of AF, the multitude of known etiologies for AF, and our ability to image and diagnose heart disease. The term was meant to indicate AF in patients for whom subsequent investigations could not demonstrate heart disease, but for many practitioners has become synonymous with “idiopathic AF.” As the list of heart diseases has expanded and diagnostic techniques have improved, the prevalence of lone AF has fallen. The legacy of the intervening years is that definitions of lone AF in the literature are inconsistent so that studies of lone AF are not comparable. Guidelines provide a vague definition of lone AF but do not provide direction about how much or what kind of imaging and other testing are necessary to exclude heart disease. There has been an explosion in the understanding of the pathophysiology of AF in the last 20 years in particular. Nevertheless, there are no apparently unique mechanisms for AF in patients categorized as having lone AF. In addition, the term “lone AF” is not invariably useful in making treatment decisions, and other tools for doing so have been more thoroughly and carefully validated. It is, therefore, recommended that use of the term “lone AF” be avoided.
Authors: Wyse DG; Van Gelder IC; Ellinor PT; Go AS; Kalman JM; Narayan SM; Nattel S; Schotten U; Rienstra M
J Am Coll Cardiol. 2014 May 6;63(17):1715-23. Epub 2014-02-12.
Femur fracture classification in women with a history of breast cancer
Women with breast cancer are at increased risk for femur fracture. Contributing factors include estrogen deficiency, cancer-related therapies, or direct bone involvement. This study examines fracture subtypes in women with prior breast cancer experiencing a femur fracture. Women age ?50 years old with a history of invasive breast cancer who experienced a femur fracture were identified during 2005-2012. Fracture site was classified by hospital diagnosis (for hip) and/or radiologic findings (for femoral diaphysis), with subtype classification as pathologic, atypical or fragility fracture. Clinical characteristics were ascertained using health plan databases and disease registries. There were 802 women with prior breast cancer who experienced a femur fracture. The mean age at fracture was 80.5±9.6 years, with most fractures (93.8%) occurring in the hip and only 6.2% in the femoral diaphysis. However, diaphyseal fractures accounted for 23.6% of fractures in younger women (age ?65 years). Pathologic fractures comprised 9.6% of total fractures (56.0% of diaphyseal fractures) and accounted for half the fractures in younger women. An atypical fracture pattern was seen in 1% of all femur fractures and 16.0% of diaphyseal fractures, with prior bisphosphonate exposure in all atypical fracture cases. Most femur fractures in women with prior breast cancer occurred in the hip. Among younger women and those experiencing diaphyseal fractures, a larger proportion were pathologic and some were found to be atypical. Further studies should examine risk factors for femur fracture in women with breast cancer with specific attention to fracture subtype and pharmacologic exposures.
Authors: Chau S; Chandra M; Grimsrud CD; Gonzalez JR; Hui RL; Lo JC
J Bone Oncol. 2014 May;3(2):49-53. Epub 2014-04-01.
Intersection of cardiovascular disease and kidney disease: atrial fibrillation
Atrial fibrillation is the most common sustained arrhythmia in patients with kidney disease. The purpose of this review is to describe the burden of atrial fibrillation in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), postulate possible mechanisms to explain this burden of disease, understand the clinical consequences of atrial fibrillation and review the treatment options for atrial fibrillation specific to patients with kidney disease. Recent literature has revealed that the clinical multiorgan impact of atrial fibrillation in patients with CKD and ESRD is substantial. Although novel oral anticoagulants to treat atrial fibrillation and prevent associated complications have been tested in large trials in the general population, there is a paucity of data on the efficacy and safety of these agents in patients with advanced CKD and ESRD. Atrial fibrillation is a significant comorbidity in patients with CKD and ESRD with important prognostic implications. More research is needed to understand the mechanisms that contribute to the disproportionate burden of this arrhythmia in patients with kidney disease and in to treatment options specific to this population of high-risk patients.
Authors: Bansal N; Hsu CY; Go AS
Curr Opin Nephrol Hypertens. 2014 May;23(3):275-82.
Increasing Use of Vitamin D Supplementation in the Chronic Renal Insufficiency Cohort Study
This study examined rates and determinants of vitamin D supplementation among Chronic Renal Insufficiency Cohort (CRIC) participants and determined the association between dose and 25-hydroxyvitamin D (25(OH)D) level. The 2010 Institute of Medicine Report noted a significant increase in vitamin D supplementation in the general population, but use in chronic kidney disease (CKD) is unknown. CRIC is a multicenter prospective observational cohort study of 3,939 participants with a median baseline age of 60 and an estimated glomerular filtration rate (eGFR) of 42.1 mL/minute per 1.73 m2. Of the cohort, 54.9% was male, 42.1% were Black, and 48.4% were diabetic. Multivariable logistic generalized estimating equations were used to examine determinants of supplementation use assessed annually between 2003 and 2011. Cross-sectional linear regression models, based on a subset of 1,155 participants, assessed associations between supplement dose and 25(OH)D level, measured by high-performance liquid chromatography coupled with tandem mass spectrometry. The proportion of participants reporting supplement use increased (P < .0001), from 10% at baseline to 44% at 7-year follow-up visits. This was largely due to initiation of products containing only ergocalciferol or cholecalciferol. The odds of supplementation were greater in older, female, non-Black, married participants with greater education and lower body mass index. Among participants taking supplementation, dose was positively associated with 25(OH)D level, adjusted for race, season, diabetes, dietary intake, eGFR, and proteinuria. Only 3.8% of non-Black and 16.5% of Black participants taking a supplement were deficient (<20 ng/mL), whereas 22.7% of non-Black and 62.4% of black participants not reporting supplement use were deficient. Vitamin D supplementation rates rose significantly among CRIC participants over 7 years of follow-up and were associated with greater serum 25(OH)D levels. Studies of vitamin D levels on clinical outcomes in CKD and future vitamin D interventional studies should consider these changes in supplementation practices.
Authors: Mariani LH; Lo JC; CRIC Study Investigators; et al.
J Ren Nutr. 2014 May;24(3):186-93. Epub 2014-03-07.
Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF)
Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF. The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization. Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient-years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age ?75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization. Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients.
Authors: Steinberg BA; Go AS; Piccini JP; et al.
Am Heart J. 2014 May;167(5):735-42.e2. Epub 2014-02-17.
Patterns of intensive care unit admissions in patients hospitalized for heart failure: insights from the RO-AHFS registry.
AIM: The present study aims to describe the epidemiology, baseline clinical characteristics, in-hospital management, and outcome of patients hospitalized for heart failure admitted directly or transferred to the ICU.METHODS AND RESULTS: The Romanian Acute Heart Failure Syndromes (RO-AHFS) registry prospectively enrolled 3224 consecutive patients between January 2008 and May 2009 admitted with a primary diagnosis of heart failure. Participants were classified by ICU admission status (i.e. ICU+/ICU-). Independent clinical predictors of ICU admission and in-hospital mortality were identified using multivariable logistic regression analysis. Overall, 10.7% of patients required ICU level care, 32% as a direct ICU admission, with 68% as an ICU transfer during hospitalization. Patients admitted to the ICU had a mean age of 68.1 ± 11.3 years, 61% were men, 67% had an ischemic cause, and 44% presented with de-novo heart failure. ICU+ patients more frequently presented with low SBP and pulse pressure and abnormal renal function. Mechanical ventilation was required in 32.7% and intravenous inotropes were administered to 56.7% of ICU+ patients. ICU+ patients had higher in-hospital mortality compared to ICU- patients (17.3 vs. 6.5%). Patients admitted directly to the ICU had a 15.3% mortality rate compared to 18.4% in those transferred after admission. Age, serum sodium, SBP below 110 mmHg, and left-ventricular ejection fraction less than 45% were predictive of ICU admission, whereas for ICU+ patients, age, vasopressor, and mechanical ventilation utilization were predictive of mortality.CONCLUSIONS: Patients admitted directly or transferred to the ICU are at a high risk of in-hospital mortality. Clinical variables commonly measured at the time of admission may facilitate disposition decision-making including early triage to the ICU.
Authors: Chioncel, Ovidiu O; Ambrosy, Andrew P AP; Filipescu, Daniela D; Bubenek, Serban S; Vinereanu, Dragos D; Petris, Antoniu A; Collins, Sean P SP; Macarie, Cezar C; Gheorghiade, Mihai M;
Journal of cardiovascular medicine (Hagerstown, Md.). 2015 May 01;16(5):331-40. Epub 2014-04-15.
Clinical profile and prognostic value of anemia at the time of admission and discharge among patients hospitalized for heart failure with reduced ejection fraction: findings from the EVEREST trial.
BACKGROUND: Anemia has been associated with worse outcomes in patients with chronic heart failure (HF). We aimed to characterize the clinical profile and postdischarge outcomes of hospitalized HF patients with anemia at admission or discharge.METHODS AND RESULTS: An analysis was performed on 3731 (90%) of 4133 hospitalized HF patients with ejection fraction ≤40% enrolled in the Efficacy of Vasopressin Antagonist in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial with baseline hemoglobin data, comparing the clinical characteristics and outcomes (all-cause mortality and cardiovascular mortality or HF hospitalization) of patients with and without anemia (hemoglobin 100 days) on adjusted analysis (both P>0.1).CONCLUSIONS: Among hospitalized HF patients with reduced ejection fraction, modest anemia at discharge but not baseline was associated with increased all-cause mortality and short-term cardiovascular mortality plus HF hospitalization.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00071331.
Authors: Mentz, Robert J RJ; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; Subacius, Haris P HP; Swedberg, Karl K; Maggioni, Aldo P AP; Nodari, Savina S; Ponikowski, Piotr P; Anker, Stefan D SD; Butler, Javed J; Gheorghiade, Mihai M
Circulation. Heart failure. 2014 May 01;7(3):401-8. Epub 2014-04-15.
DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC Study
Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD). We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate. The mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m(2) in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.
Authors: Wing MR; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study; et al.
Nephrol Dial Transplant. 2014 Apr;29(4):864-72. Epub 2014-02-09.
An Effective Approach to High Blood Pressure Control: A Science Advisory From the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention
Authors: Go AS; Bauman MA; Coleman King SM; Fonarow GC; Lawrence W; Williams KA; Sanchez E; American Heart Association; American College of Cardiology; Centers for Disease Control and Prevention
Hypertension. 2014 Apr;63(4):878-85. Epub 2013-11-15.
AHA/ACC/CDC Science Advisory: An Effective Approach to High Blood Pressure Control A Science Advisory From the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention
Authors: Go AS; Bauman MA; Coleman King SM; Fonarow GC; Lawrence W; Williams KA; Sanchez E
J Am Coll Cardiol. 2014 Apr 1;63(12):1230-8. Epub 2013-11-15.
Population trends from 2000-2011 in nuclear myocardial perfusion imaging use
Authors: McNulty EJ; Hung YY; Almers LM; Go AS; Yeh RW
JAMA. 2014 Mar 26;311(12):1248-9.
Long-term survival after ischemic stroke in patients with atrial fibrillation
While the short-term impact of atrial fibrillation-related stroke has been well studied, surprisingly little is known about its long-term effect on survival. We followed 13,559 patients with atrial fibrillation for a median of 6 years, identifying ischemic strokes through computerized databases and validating 1,025 events. Stroke severity was determined from hospital records. We compared survival of stroke patients with comparator nonstroke patients (matched for age, sex, race, comorbid conditions, and time of entry into the cohort) using proportional hazard models controlling for warfarin use and compared survival by degree of discharge deficit. Median survival after stroke was 1.8 years compared with 5.7 years for matched nonstroke comparators (hazard ratio [HR] 2.8, 95% confidence interval [CI] 2.5-3.2). This increased risk of all-cause death persisted even after restricting the analysis to the 576 stroke patients who survived 6 months after the initial stroke event (HR 2.0, 95% CI 1.7-2.5, adjusting for warfarin use). Risk of death was strongly associated with stroke severity: HR 2.9 (95% CI 2.3-3.5) for strokes resulting in major deficits and HR 8.3 (95% CI 5.2-13.2) for strokes resulting in severe deficits compared with matched comparators without stroke. Ischemic stroke approximately triples the mortality rate in patients with atrial fibrillation. This effect persists well beyond the immediate period poststroke and is strongly associated with disability after stroke. Stroke prevention by anticoagulation has even greater beneficial effects on survival than usually considered when focusing solely on 30-day mortality rates.
Authors: Fang MC; Go AS; Chang Y; Borowsky LH; Pomernacki NK; Udaltsova N; Singer DE
Neurology. 2014 Mar 25;82(12):1033-7. Epub 2014-02-14.
Framingham score and LV mass predict events in young adults: CARDIA study
Framingham risk score (FRS) underestimates risk in young adults. Left ventricular mass (LVM) relates to cardiovascular disease (CVD), with unclear value in youth. In a young biracial cohort, we investigate how FRS predicts CVD over 20 years and the incremental value of LVM. We also explore the predictive ability of different cut-points for hypertrophy. We assessed FRS and echocardiography-derived LVM (indexed by body surface area or height2.7) from 3980 African-American and white Coronary Artery Risk Development in Young Adults (CARDIA) participants (1990-1991); and followed over 20 years for a combined endpoint: cardiovascular death; nonfatal myocardial infarction, heart failure, cerebrovascular disease, and peripheral artery disease. We assessed the predictive ability of FRS for CVD and also calibration, discrimination, and net reclassification improvement for adding LVM to FRS. Mean age was 30±4 years, 46% males, and 52% white. Event incidence (n=118) across FRS groups was, respectively, 1.3%, 5.4%, and 23.1% (p<0.001); and was 1.4%, 1.3%, 3.7%, and 5.4% (p<0.001) across quartiles of LVM (cut-points 117 g, 144 g, and 176 g). LVM predicted CVD independently of FRS, with the best performance in normal weight participants. Adding LVM to FRS modestly increased discrimination and had a statistically significant reclassification. The 85th percentile (?116 g/m2 for men; ?96 g/m2 for women) showed event prediction more robust than currently recommended cut-points for hypertrophy. In a biracial cohort of young adults, FRS and LVM are helpful independent predictors of CVD. LVM can modestly improve discrimination and reclassify participants beyond FRS. Currently recommended cut-points for hypertrophy may be too high for young adults.
Authors: Armstrong AC; Schreiner PJ; Lima JA; et al.
Int J Cardiol. 2014 Mar 15;172(2):350-5. Epub 2014-01-16.
Lipids, statins, and clinical outcomes in heart failure: rethinking the data.
Lower serum lipid levels are paradoxically predictive of poor clinical outcomes in hospitalized and ambulatory patients with heart failure (HF). In large randomized controlled trials, statins did not demonstrate an overall mortality benefit in chronic HF patients. We currently lack adequate prospective data that aggressive lipid management in HF truly alters disease course and progression. Despite their traditional use as lipid-lowering agents, hypothesis-generating works have suggested that statins may show benefit in specific enriched HF subgroups. Given that patients hospitalized for HF continue to face a high post-discharge event rate and that statins are increasingly inexpensive, widely available, and generally well tolerated, it is imperative that we identify those HF patients most likely to benefit and reconsider testing these agents in specific subpopulations.
Authors: Vaduganathan, Muthiah M; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Gheorghiade, Mihai M
Heart failure reviews. 2014 Nov 13;19(6):695-8. Epub 2014-03-05.
The use of digoxin in patients with worsening chronic heart failure: reconsidering an old drug to reduce hospital admissions.
Digoxin is the oldest cardiac drug still in contemporary use, yet its role in the management of patients with heart failure (HF) remains controversial. A purified cardiac glycoside derived from the foxglove plant, digoxin increases ejection fraction, augments cardiac output, and reduces pulmonary capillary wedge pressure without causing deleterious increases in heart rate or decreases in blood pressure. Moreover, it is also a neurohormonal modulator at low doses. In the pivotal DIG (Digitalis Investigation Group) trial, digoxin therapy was shown to reduce all-cause and HF-specific hospitalizations but had no effect on survival. With the discovery of neurohormonal blockers capable of reducing mortality in HF with reduced ejection fraction, the results of the DIG trial were viewed as neutral, and the use of digoxin declined precipitously. Although modern drug and device-based therapies have dramatically improved the survival of ambulatory patients with HF, outcomes for patients with worsening chronic HF, defined as deteriorating signs and symptoms on standard therapy often leading to unscheduled clinic or emergency department visits or hospitalization, have largely remained unchanged over the past 2 decades. The available data suggest that a therapeutic trial of digoxin may be appropriate in patients with worsening chronic heart failure who remain symptomatic.
Authors: Ambrosy, Andrew P AP; Butler, Javed J; Ahmed, Ali A; Vaduganathan, Muthiah M; van Veldhuisen, Dirk J DJ; Colucci, Wilson S WS; Gheorghiade, Mihai M
Journal of the American College of Cardiology. 2014 May 13;63(18):1823-32. Epub 2014-03-05.
The predictive value of transaminases at admission in patients hospitalized for heart failure: findings from the RO-AHFS registry.
BACKGROUND: Transaminases are commonly elevated in both the inpatient and ambulatory settings in heart failure (HF).AIMS: To determine the prevalence and degree of elevated transaminase levels at admission and to evaluate the association between transaminase levels and in-hospital morbidity and mortality.METHODS: Over a 12-month period, the Romanian Acute Heart Failure Syndromes (RO-AHFS) registry enrolled consecutive patients hospitalized for HF at 13 medical centres. A post-hoc analysis of the 489 patients (15.2%) with alanine transaminase (ALT) and aspartate transaminase (AST) (upper limits of normal 31 IU/l and 32 IU/l, respectively) measured at baseline was performed. In-hospital mortality was compared across quartiles using multivariable Cox regression models.RESULTS: The prevalences of elevated ALT and AST were 28% and 24% and the medians (interquartile range) were 22 (16-47) and 23 (16-37 IU/L). Patients with elevated transaminases more commonly had right HF, cardiogenic shock, or an ejection fraction CONCLUSIONS: In patients hospitalized for HF, there is a graded relationship between admission transaminase levels and surrogates for in-hospital morbidity, while more pronounced elevations of ALT predict in-hospital mortality independent of known prognostic indicators.
Authors: Ambrosy, Andrew P AP; Gheorghiade, Mihai M; Bubenek, Serban S; Vinereanu, Dragos D; Vaduganathan, Muthiah M; Macarie, Cezar C; Chioncel, Ovidiu O;
European heart journal. Acute cardiovascular care. 2013 Jun 01;2(2):99-108. Epub 2014-02-05.
The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries.
Heart failure is a global pandemic affecting an estimated 26 million people worldwide and resulting in more than 1 million hospitalizations annually in both the United States and Europe. Although the outcomes for ambulatory HF patients with a reduced ejection fraction (EF) have improved with the discovery of multiple evidence-based drug and device therapies, hospitalized heart failure (HHF) patients continue to experience unacceptably high post-discharge mortality and readmission rates that have not changed in the last 2 decades. In addition, the proportion of HHF patients classified as having a preserved EF continues to grow and may overtake HF with a reduced EF in the near future. However, the prognosis for HF with a preserved EF is similar and there are currently no available disease-modifying therapies. HHF registries have significantly improved our understanding of this clinical entity and remain an important source of data shaping both public policy and research efforts. The authors review global HHF registries to describe the patient characteristics, management, outcomes and their predictors, quality improvement initiatives, regional differences, and limitations of the available data. Moreover, based on the lessons learned, they also propose a roadmap for the design and conduct of future HHF registries.
Authors: Ambrosy, Andrew P AP; Fonarow, Gregg C GC; Butler, Javed J; Chioncel, Ovidiu O; Greene, Stephen J SJ; Vaduganathan, Muthiah M; Nodari, Savina S; Lam, Carolyn S P CSP; Sato, Naoki N; Shah, Ami N AN; Gheorghiade, Mihai M
Journal of the American College of Cardiology. 2014 Apr 01;63(12):1123-1133. Epub 2014-02-05.
Sedentary Screen Time and Left Ventricular Structure and Function: the CARDIA Study
Sedentary screen time (watching TV or using a computer) predicts cardiovascular outcomes independently from moderate and vigorous physical activity and could affect left ventricular structure and function through the adverse consequences of sedentary behavior. This study aimed to determine whether sedentary screen time is associated with measures of left ventricular structure and function. The Coronary Artery Risk Development in Young Adults Study measured screen time by questionnaire and left ventricular structure and function by echocardiography in 2854 black and white participants, age 43-55 yr, in 2010-2011. Generalized linear models evaluated cross-sectional trends for echocardiography measures across higher categories of screen time and adjusting for demographics, smoking, alcohol, and physical activity. Further models adjusted for potential intermediate factors (blood pressure, antihypertensive medication use, diabetes, and body mass index). The relationship between screen time and left ventricular mass (LVM) differed in blacks versus whites. Among whites, higher screen time was associated with larger LVM (P < 0.001), after adjustment for height, demographics, and lifestyle variables. Associations between screen time and LVM persisted when adjusting for blood pressure, antihypertensive medication use, and diabetes (P = 0.008) but not with additional adjustment for body mass index (P = 0.503). Similar relationships were observed for screen time with LVM indexed to height, relative wall thickness, and mass-to-volume ratio. Screen time was not associated with left ventricular structure among blacks or left ventricular function in either race group. Sedentary screen time is associated with greater LVM in white adults, and this relationship was largely explained by higher overall adiposity. The lack of association in blacks supports a potential qualitative difference in the cardiovascular consequences of sedentary screen-based behavior.
Authors: Gibbs BB; Reis JP; Schelbert EB; Craft LL; Sidney S; Lima J; Lewis CE
Med Sci Sports Exerc. 2014 Feb;46(2):276-83.
Impact of breastfeeding on maternal metabolism: implications for women with gestational diabetes
Lactating compared with nonlactating women display more favorable metabolic parameters, including less atherogenic blood lipids, lower fasting and postprandial blood glucose as well as insulin, and greater insulin sensitivity in the first 4 months postpartum. However, direct evidence demonstrating that these metabolic changes persist from delivery to postweaning is much less available. Studies have reported that longer lactation duration may reduce long-term risk of cardiometabolic disease, including type 2 diabetes, but findings from most studies are limited by self-report of disease outcomes, absence of longitudinal biochemical data, or no assessment of maternal lifestyle behaviors. Studies of women with a history gestational diabetes mellitus (GDM) also reported associations between lactation duration and lower the incidence of type 2 diabetes and the metabolic syndrome. The mechanisms are not understood, but hormonal regulation of pancreatic ?-cell proliferation and function or other metabolic pathways may mediate the lactation association with cardiometabolic disease in women.
Authors: Gunderson EP
Curr Diab Rep. 2014 Feb;14(2):460.
Association of kidney disease outcomes with risk factors for CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) study
Various indicators of progression of chronic kidney disease (CKD) have been used as outcomes in clinical research studies. The effect of using varying measures on the association of risk factors with CKD progression has not been well characterized. Prospective cohort study. The Chronic Renal Insufficiency Cohort (CRIC) Study (N=3,939) enrolled men and women with mild to moderate CKD, 48% of whom had diabetes and 42% were self-reported black race. Age, race, sex, diabetes, baseline estimated glomerular filtration rate (eGFR), proteinuria, and other established CKD risk factors. Death, end-stage renal disease (ESRD), and eGFR events, including: (1) eGFR halving, (2) eGFR<15mL/min/1.73m(2), (3) eGFR halving and <15mL/min/1.73m(2), (4) eGFR decrease of 20mL/min/1.73m(2), (5) eGFR halving or decrease of 20mL/min/1.73m(2), and (6) eGFR decrease of 25% and change in CKD stage. Mean entry eGFR was 44.9mL/min/1.73m(2). Annual rates of death, ESRD, and eGFR halving were 2.5%, 4.0%, and 6.1%, respectively, during an average follow-up of 5.4 years. Associations between risk factors and ESRD and eGFR events were similar across different definitions. However, these associations were substantially different from those with death. HRs for ESRD, eGFR halving, and death in the highest compared to the lowest proteinuria category were 11.83 (95% CI, 8.40-16.65), 11.19 (95% CI, 8.53-14.68), and 1.47 (95% CI, 1.10-1.96), respectively. Participants may not be representative of the entire CKD population. Using ESRD or eGFR events, but not death, in the definition of kidney disease outcomes is appropriate in follow-up studies to identify risk factors for CKD progression.
Authors: Yang W; Teal V; CRIC Study Investigators; et al.
Am J Kidney Dis. 2014 Feb;63(2):236-43. Epub 2013-10-30.
Fibroblast Growth Factor-23 and Cardiovascular Events in CKD
An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.
Authors: Scialla JJ; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators; et al.
J Am Soc Nephrol. 2014 Feb;25(2):349-60. Epub 2013-10-24.
Perceived weight discrimination in the CARDIA study: Differences by race, sex, and weight status
To examine self-reported weight discrimination and differences based on race, sex, and BMI in a biracial cohort of community-based middle-aged adults. Participants (3,466, mean age = 50 years, mean BMI = 30 kg/m²) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study who completed the 25-year examination of this epidemiological investigation in 2010-2011 were reported. The sample included normal weight, overweight, and obese participants. CARDIA participants are distributed into four race-sex groups, with about half being African-American and half White. Participants completed a self-reported measure of weight discrimination. Among overweight/obese participants, weight discrimination was lowest for White men (12.0%) and highest for White women (30.2%). The adjusted odds ratio (95% CI) for weight discrimination in those with class 2/3 obesity (BMI ≥ 35 kg/m²) versus the normal-weight was most pronounced: African American men, 4.59 (1.71-12.34); African American women, 7.82 (3.57-17.13); White men, 6.99 (2.27-21.49); and White women, 18.60 (8.97-38.54). Being overweight (BMI = 25-29.9 kg/m²) vs. normal weight was associated with increased discrimination in White women only: 2.10 (1.11-3.96). Novel evidence for a race-sex interaction on perceived weight discrimination, with White women more likely to report discrimination at all levels of overweight and obesity was provided. Pychosocial mechanisms responsible for these differences deserve exploration.
Authors: Dutton GR; Lewis TT; Durant N; Halanych J; Kiefe CI; Sidney S; Kim Y; Lewis CE
Obesity (Silver Spring). 2014 Feb;22(2):530-6. Epub 2013-06-13.
Heart Disease and Stroke Statistics–2014 Update: A Report From the American Heart Association
Authors: Go AS; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2014 Jan 21;129(3):e28-e292. Epub 2013-12-18.
Executive summary: heart disease and stroke statistics–2014 update: a report from the american heart association
Authors: Go AS; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2014 Jan 21;129(3):399-410.
Relation of Left Ventricular Mass at Age 23 to 35 Years to Global Left Ventricular Systolic Function 20 Years Later (from the Coronary Artery Risk Development in Young Adults Study)
Left ventricular (LV) mass and the LV ejection fraction (LVEF) are major independent predictors of future cardiovascular disease. The association of LV mass with the future LVEF in younger populations has not been studied. The aim of this study was to investigate the relation of LV mass index (LVMI) at ages 23 to 35 years to LV function after 20 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) study. CARDIA is a longitudinal study that enrolled young adults in 1985 and 1986. In this study, participants with echocardiographic examinations at years 5 and 25 were included. LVMI and the LVEF were assessed using M-mode echocardiography at year 5 and using M-mode and 2-dimensional imaging at year 25. Statistical analytic models assessed the correlation between LVMI and LV functional parameters cross-sectionally and longitudinally. A total of 2,339 participants were included. The mean LVEF at year 25 was 62%. Although there was no cross-sectional correlation between LVMI and the LVEF at year 5, there was a small but statistically significant negative correlation between LVMI at year 5 and the LVEF 20 years later (r = -0.10, p <0.0001); this inverse association persisted for LVMI in the multivariate model. High LVMI was an independent predictor of systolic dysfunction (LVEF <50%) 20 years later (odds ratio 1.46, p = 0.0018). In conclusion, LVMI in young adulthood in association with chronic risk exposure affects systolic function in middle age; the antecedents of heart failure may occur at younger ages than previously thought.
Authors: Kishi S; Armstrong AC; Gidding SS; Jacobs DR; Sidney S; Lewis CE; Schreiner PJ; Liu K; Lima JA
Am J Cardiol. 2014 Jan 15;113(2):377-83. Epub 2013-10-04.
Adoption and Effectiveness of Internal Mammary Artery Grafting in Coronary Artery Bypass Surgery Among Medicare Beneficiaries
The aim of this study was to assess the pattern of the adoption of internal mammary artery (IMA) grafting in the United States, test its association with clinical outcomes, and assess whether its effectiveness differs in key clinical subgroups. The effect of IMA grafting on major clinical outcomes has never been tested in a large randomized trial, yet it is now a quality standard for coronary artery bypass graft (CABG) surgery. We identified Medicare beneficiaries ?66 years of age who underwent isolated multivessel CABG between 1988 and 2008, and we documented patterns of IMA use over time. We used a multivariable propensity score to match patients with and without an IMA and compared rates of death, myocardial infarction (MI), and repeat revascularization. We tested for variations in IMA effectiveness with treatment × covariate interaction tests. The IMA use in CABG rose slowly from 31% in 1988 to 91% in 2008, with persistent wide geographic variations. Among 60,896 propensity score-matched patients over a median 6.8-year follow-up, IMA use was associated with lower all-cause mortality (adjusted hazard ratio: 0.77, p < 0.001), lower death or MI (adjusted hazard ratio: 0.77, p < 0.001), and fewer repeat revascularizations over 5 years (8% vs. 9%, p < 0.001). The association between IMA use and lower mortality was significantly weaker (p ? 0.008) for older patients, women, and patients with diabetes or peripheral arterial disease. Internal mammary artery grafting was adopted slowly and still shows substantial geographic variation. IMA use is associated with lower rates of death, MI, and repeat coronary revascularization.
Authors: Hlatky MA; Boothroyd DB; Reitz BA; Shilane DA; Baker LC; Go AS
J Am Coll Cardiol. 2014 Jan 7-14;63(1):33-9. Epub 2013-09-27.
HIV/HCV coinfection ameliorates the atherogenic lipoprotein abnormalities of HIV infection
Higher levels of small low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) subclasses have been associated with increased risk of cardiovascular disease. The extent to which HIV infection and HIV/hepatitis C virus (HCV) coinfection are associated with abnormalities of lipoprotein subclasses is unknown. Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy in plasma samples from 569 HIV-infected and 5948 control participants in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM), Coronary Artery Risk Development in Young Adults (CARDIA), and Multi-Ethnic Study of Atherosclerosis (MESA) studies. Multivariable regression was used to estimate the association of HIV and HIV/HCV coinfection with lipoprotein measures with adjustment for demographics, lifestyle factors, and waist-to-hip ratio. Relative to controls, small LDL levels were higher in HIV-monoinfected persons (+381?nmol/l, P?<0.0001), with no increase seen in HIV/HCV coinfection (-16.6?nmol/l). Levels of large LDL levels were lower (-196?nmol/l, P?<0.0001) and small HDL were higher (+8.2??mol/l, P?
Authors: Wheeler AL; Scherzer R; Lee D; Delaney JA; Bacchetti P; Shlipak MG; Sidney S; Grunfeld C; Tien PC; Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM)
AIDS. 2014 Jan 2;28(1):49-58.
A pragmatic cluster randomized clinical trial of diabetes prevention strategies for women with gestational diabetes: design and rationale of the Gestational Diabetes’ Effects on Moms (GEM) study
Women with gestational diabetes (GDM) are at high risk of developing diabetes later in life. After a GDM diagnosis, women receive prenatal care to control their blood glucose levels via diet, physical activity and medications. Continuing such lifestyle skills into early motherhood may reduce the risk of diabetes in this high risk population. In the Gestational Diabetes’ Effects on Moms (GEM) study, we are evaluating the comparative effectiveness of diabetes prevention strategies for weight management designed for pregnant/postpartum women with GDM and delivered at the health system level. The GEM study is a pragmatic cluster randomized clinical trial of 44 medical facilities at Kaiser Permanente Northern California randomly assigned to either the intervention or usual care conditions, that includes 2,320 women with a GDM diagnosis between March 27, 2011 and March 30, 2012. A Diabetes Prevention Program-derived print/telephone lifestyle intervention of 13 telephonic sessions tailored to pregnant/postpartum women was developed. The effectiveness of this intervention added to usual care is to be compared to usual care practices alone, which includes two pages of printed lifestyle recommendations sent to postpartum women via mail. Primary outcomes include the proportion of women who reach a postpartum weight goal and total weight change. Secondary outcomes include postpartum glycemia, blood pressure, depression, percent of calories from fat, total caloric intake and physical activity levels. Data were collected through electronic medical records and surveys at baseline (soon after GDM diagnosis), 6 weeks (range 2 to 11 weeks), 6 months (range 12 to 34 weeks) and 12 months postpartum (range 35 to 64 weeks). There is a need for evidence regarding the effectiveness of lifestyle modification for the prevention of diabetes in women with GDM, as well as confirmation that a diabetes prevention program delivered at the health system level is able to successfully reach this population. Given the use of a telephonic case management model, our Diabetes Prevention Program-derived print/telephone intervention has the potential to be adopted in other settings and to inform policies to promote the prevention of diabetes among women with GDM.
Authors: Ferrara A; Hedderson MM; Brown SD; Ehrlich SF; Caan BJ; Sternfeld B; Gordon NP; Schmittdiel JA; Gunderson EP; Quesenberry CP; et al.
BMC Pregnancy Childbirth. 2014;14:21. Epub 2014-01-15.
Association Between Chronic Kidney Disease Progression and Cardiovascular Disease: Results from the CRIC Study
There is limited information on the risk of progression of chronic kidney disease (CKD) among individuals with CVD (cardiovascular disease). We studied the association between prevalent CVD and the risk of progression of CKD among persons enrolled in a long-term observational study. A prospective cohort study of 3,939 women and men with CKD enrolled in the chronic renal insufficiency cohort (CRIC) study between June 2003 and June 2008. Prevalent cardiovascular disease (myocardial infarction/revascularization, heart failure, stroke, and peripheral vascular disease) was determined by self-report at baseline. The primary outcome was a composite of either end-stage renal disease or a 50% decline in estimated glomerular filtration rate (eGFR) from baseline. One-third (1,316 of 3,939, 33.4%) of the study participants reported a history of any cardiovascular disease, and 9.6% (n = 382) a history of heart failure at baseline. After a median follow up of 6.63 years, 1,028 patients experienced the primary outcome. The composite of any CVD at baseline was not independently associated with the primary outcome (Hazard Ratio 1.04 95% CI (0.91, 1.19)). However, a history of heart failure was independently associated with a 29% higher risk of the primary outcome (Hazard Ratio 1.29 95% CI (1.06, 1.57)). The relationship between heart failure and risk of CKD progression was consistent in subgroups defined by age, race, gender, baseline eGFR, and diabetes. Neither the composite measure of any CVD or heart failure was associated with the rate of decline in eGFR. Self-reported heart failure was an independent risk factor for the development of the endpoint of ESRD or 50% decline in GFR in a cohort of patients with chronic kidney disease.
Authors: Rahman M; Go AS; CRIC Study Investigators; et al.
Am J Nephrol. 2014;40(5):399-407. Epub 2014-11-11.
Prepregnancy SHBG Concentrations and Risk for Subsequently Developing Gestational Diabetes Mellitus
Lower levels of sex hormone-binding globulin (SHBG) have been associated with increased risk of diabetes among postmenopausal women; however, it is unclear whether they are associated with glucose intolerance in younger women. We examined whether SHBG concentrations, measured before pregnancy, are associated with risk of gestational diabetes mellitus (GDM). This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up examination (1984-1996) and had a subsequent pregnancy (1984-2009). Eligible women were free of recognized diabetes. Case patients were 256 women in whom GDM developed. Two control subjects were selected for each case patient and were matched for year of blood draw, age at examination, age at pregnancy, and number of intervening pregnancies. Compared with the highest quartile of SHBG concentrations, the odds of GDM increased with decreasing quartile (odds ratio 1.06 [95% CI 0.44-2.52]; 2.33 [1.07-5.09]; 4.06 [1.90-8.65]; P for trend < 0.001), after adjusting for family history of diabetes, prepregnancy BMI, race/ethnicity, alcohol use, prepregnancy weight changes, and homeostasis model assessment of insulin resistance. Having SHBG levels below the median (<64.5 nmol/L) and a BMI ?25.0 kg/m(2) was associated with fivefold increased odds of GDM compared with normal-weight women with SHBG levels at or above the median (5.34 [3.00-9.49]). Low prepregnancy SHBG concentrations were associated with increased risk of GDM and might be useful in identifying women at risk for GDM for early prevention strategies.
Authors: Hedderson MM; Xu F; Darbinian JA; Quesenberry CP; Sridhar S; Kim C; Gunderson EP; Ferrara A
Diabetes Care. 2014;37(5):1296-303. Epub 2014-02-21.
Bone health history in breast cancer patients on aromatase inhibitors
A cross-sectional study was performed to assess bone health history among aromatase inhibitor (AI) users before breast cancer (BC) diagnosis, which may impact fracture risk after AI therapy and choice of initial hormonal therapy. A total of 2,157 invasive BC patients initially treated with an AI were identified from a prospective cohort study at Kaiser Permanente Northern California (KPNC). Data on demographic and lifestyle factors were obtained from in-person interviews, and bone health history and clinical data from KPNC clinical databases. The prevalence of osteoporosis and fractures in postmenopausal AI users was assessed, compared with 325 postmenopausal TAM users. The associations of bone health history with demographic and lifestyle factors in AI users were also examined. Among all initial AI users, 11.2% had a prior history of osteoporosis, 16.3% had a prior history of any fracture, and 4.6% had a prior history of major fracture. Postmenopausal women who were taking TAM as their initial hormonal therapy had significantly higher prevalence of prior osteoporosis than postmenopausal AI users (21.5% vs. 11.8%, p<0.0001). Among initial AI users, the associations of history of osteoporosis and fracture in BC patients with demographic and lifestyle factors were, in general, consistent with those known in healthy older women. This study is one of the first to characterize AI users and risk factors for bone morbidity before BC diagnosis. In the future, this study will examine lifestyle, molecular, and genetic risk factors for AI-induced fractures.
Authors: Kwan ML; Lo JC; Quesenberry CP; Kushi LH; Yao S; et al.
PLoS ONE. 2014;9(10):e111477. Epub 2014-10-29.
Temporal trends in mortality after coronary artery revascularization in patients with end-stage renal disease
Recent studies that have assessed the comparative effectiveness between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with end-stage renal disease (ESRD) that have included analyses of temporal trends in mortality have noted mixed results. We conducted an observational longitudinal cohort study of all adults with ESRD undergoing CABG or PCI within Kaiser Permanente Northern California. The primary predictor, index period of revascularization, was categorized into 3 periods: 1996-1999 (reference), 2000-2003, and 2004-2008, with the primary outcome being 3-year all-cause mortality. A multivariable Cox regression model with the assumption of independent censoring was used to determine the adjusted relative risk of the primary predictor. Among 1015 ESRD patients, 3-year mortality showed no significant change in the 2000-2003 period but was lower during the 2004-2008 period with an adjusted hazard ratio of 0.66 (95% confidence interval: 0.49-0.88; trend test p = 0.01). No change in 30-day mortality was noted. Further adjustment for receipt of medications at baseline and after revascularization did not materially affect risk estimates. No significant interactions were observed between the type of revascularization (CABG or PCI) and the period of the index revascularization. Among a high-risk cohort of patients with ESRD and coronary artery disease within Kaiser Permanente Northern California who were referred for coronary revascularization by either CABG or PCI, the relative risk of mortality in the 2004-2008 period decreased by 34% compared with the 1996-1999 period, with the benefit primarily in the decrease in late mortality.
Authors: Krishnaswami A; Leong TK; Hlatky MA; Chang TI; Go AS
Perm J. 2014 Summer;18(3):11-6.
Association of early adult modifiable cardiovascular risk factors with left atrial size over a 20-year follow-up period: the CARDIA study
We investigate how early adult and 20-year changes in modifiable cardiovascular risk factors (MRF) predict left atrial dimension (LAD) at age 43-55 years. The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled black and white adults (1985-1986). We included 2903 participants with echocardiography and MRF assessment in follow-up years 5 and 25. At years 5 and 25, LAD was assessed by M-mode echocardiography, then indexed to body surface area (BSA) or height. Blood pressure (BP), body mass index (BMI), heart rate (HR), smoking, alcohol use, diabetes and physical activity were defined as MRF. Associations of MRF with LAD were assessed using multivariable regression adjusted for age, ethnicity, gender and year-5 left atrial (LA) size. The participants were 30±4 years; 55% white; 44% men. LAD and LAD/height were modest but significantly higher over the follow-up period, but LAD/BSA decreased slightly. Increased baseline and 20-year changes in BP were related to enlargement of LAD and indices. Higher baseline and changes in BMI were also related to higher LAD and LAD/height, but the opposite direction was found for LAD/BSA. Increase in baseline HR was related to lower LAD but not LAD indices, when only baseline covariates were included in the model. However, baseline and 20-year changes in HR were significantly associated to LA size. In a biracial cohort of young adults, the most robust predictors for LA enlargement over a 20-year follow-up period were higher BP and BMI. However, an inverse direction was found for the relationship between BMI and LAD/BSA. HR showed an inverse relation to LA size.
Authors: Armstrong AC; Gidding SS; Colangelo LA; Kishi S; Liu K; Sidney S; Konety S; Lewis CE; Correia LC; Lima JA
BMJ Open. 2014;4(1):e004001. Epub 2014-01-02.
History of Gestational Diabetes Mellitus and Future Risk of Atherosclerosis in Mid-life: The Coronary Artery Risk Development in Young Adults Study
History of gestational diabetes mellitus (GDM) increases lifetime risk of type 2 diabetes (DM) and the metabolic syndrome (MetS), which increase risk of cardiovascular disease. It is unclear, however, whether GDM increases risk of early atherosclerosis independent of pre-pregnancy obesity and subsequent metabolic disease. Of 2787 women (18 to 30 years) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we studied 898 (47% black) who were free of DM and heart disease at baseline (1985-1986), delivered ?1 post-baseline births, reported GDM history, and had common carotid intima media thickness (ccIMT, mm) measured in 2005-2006. We used multivariable linear regression to assess associations between GDM and ccIMT adjusted for race, age, parity, and pre-pregnancy cardiometabolic risk factors. We assessed mediators (weight gain, insulin resistance, blood pressure), and effect modification by incident DM or MetS during the 20-year period. Of the 898 women, 119 (13%) reported GDM (7.6 per 100 deliveries). Average age was 31 at last birth and 44 at ccIMT measurement for GDM and non-GDM groups. Unadjusted mean ccIMT was 0.023 mm higher for GDM than non-GDM groups (P=0.029), but pre-pregnancy BMI attenuated the difference to 0.016 mm (P=0.109). In 777 women without subsequent DM or the MetS, mean ccIMT was 0.023 mm higher for GDM versus non-GDM groups controlling for race, age, parity, and pre-pregnancy BMI (0.784 versus 0.761, P=0.039). Addition of pre-pregnancy insulin resistance index had minimal impact on adjusted mean net ccIMT difference (0.22 mm). Mean ccIMT did not differ by GDM status among 121 women who developed DM or the MetS (P=0.58). History of GDM may be a marker for early atherosclerosis independent of pre-pregnancy obesity among women who have not developed type 2 diabetes or the metabolic syndrome.
Authors: Gunderson EP; Chiang V; Pletcher MJ; Jacobs DR; Quesenberry CP; Sidney S; Lewis CE
J Am Heart Assoc. 2014;3(2):e000490. Epub 2014-03-12.
Hostility Modifies the Association between TV Viewing and Cardiometabolic Risk
It was hypothesized that television viewing is predictive of cardiometabolic risk. Moreover, people with hostile personality type may be more susceptible to TV-induced negative emotions and harmful health habits which increase occurrence of cardiometabolic risk. The prospective association of TV viewing on cardiometabolic risk was examined along with whether hostile personality trait was a modifier. A total of 3,269 Black and White participants in the coronary artery risk development in young adults (CARDIA) study were assessed from age 23 to age 35. A cross-lagged panel model at exam years 5, 10, 15, and 20, covering 15 years, was used to test whether hours of daily TV viewing predicted cardiometabolic risk, controlling confounding variables. Multiple group analysis of additional cross-lagged panel models stratified by high and low levels of hostility was used to evaluate whether the association was modified by the hostile personality trait. The cross-lagged association of TV viewing at years 5 and 15 on clustered cardiometabolic risk score at years 10 and 20 was significant (B = 0.058 and 0.051), but not at 10 to 15 years. This association was significant for those with high hostility (B = 0.068 for exam years 5 to 10 and 0.057 for exam years 15 to 20) but not low hostility. These findings indicate that TV viewing is positively associated with cardiometabolic risk. Further, they indicate that hostility might be a modifier for the association between TV viewing and cardiometabolic risk.
Authors: Fabio A; Chen CY; Kim KH; Erickson D; Jacobs DR; Zgibor JC; Chung T; Matthews KA; Sidney S; Iribarren C; Pereira MA
J Obes. 2014;2014:784594. Epub 2014-06-23.
Incremental prognostic information from kidney function in patients with new onset coronary heart disease
Prognostic factors are usually evaluated by their statistical significance rather than by their clinical utility. Risk reclassification measures the extent to which a novel marker adds useful information to a prognostic model. The extent to which estimated glomerular filtration rate (eGFR) adds information about prognosis among patients with coronary heart disease is uncertain. We studied patients in an integrated health care delivery system with newly diagnosed coronary heart disease. We developed a model of the risk of death over 2 years of follow-up and then added eGFR to the model and measured changes in C-index, net reclassification improvement, and integrated discrimination improvement. Almost half of the 31,533 study patients had reduced eGFR (<60 mL/min per 1.73 m(2)). Mortality was significantly higher among patients who had lower levels of eGFR, even after adjustment for baseline characteristics (P < .0001). The addition of eGFR to the prognostic model increased the C-index from 0.837 to 0.843, the net reclassification improvement by 3.2% (P < .0001), and integrated discrimination improvement by 1.3% (P = .007). Estimated glomerular filtration rate is an informative prognostic factor among patients with incident coronary heart disease, independent of other clinical characteristics.
Authors: Hlatky MA; Shilane D; Chang TI; Boothroyd D; Go AS
Am Heart J. 2014 Jan;167(1):86-92. Epub 2013-10-23.
Maternal prepregnancy obesity and insulin treatment during pregnancy are independently associated with delayed lactogenesis in women with recent gestational diabetes mellitus
The timely onset of stage II lactogenesis (OL) is important for successful breastfeeding and newborn health. Several risk factors for delayed OL are common in women with a history of gestational diabetes mellitus (GDM), which may affect their chances for successful breastfeeding outcomes. We investigated the prevalence and risk factors associated with delayed OL in a racially and ethnically diverse cohort of postpartum women with recent GDM. We analyzed data collected in the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy (SWIFT), which is a prospective cohort of women diagnosed with GDM who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. At 6-9 wk postpartum, delayed OL was assessed by maternal report of breast fullness and defined as occurring after 72 h postpartum. We obtained data on prenatal course and postdelivery infant feeding practices from electronic medical records and in-person surveys. We used multivariable logistic regression models to estimate associations of delayed OL with prenatal, delivery, and postnatal characteristics. The analysis included 883 SWIFT participants who initiated breastfeeding and did not have diabetes at 6-9 wk postpartum. Delayed OL was reported by 33% of women and was associated with prepregnancy obesity (OR: 1.56; 95% CI: 1.07, 2.29), older maternal age (OR: 1.05; 95% CI: 1.01, 1.08), insulin GDM treatment (OR: 3.11; 95% CI: 1.37, 7.05), and suboptimal in-hospital breastfeeding (OR: 1.65; 95% CI: 1.20, 2.26). A higher gestational age was associated with decreased odds of delayed OL but only in multiparous mothers (OR: 0.79; 95% CI: 0.67, 0.94). One-third of women with recent GDM experienced delayed OL. Maternal obesity, insulin treatment, and suboptimal in-hospital breastfeeding were key risk factors for delayed OL. Early breastfeeding support for GDM women with these risk factors may be needed to ensure successful lactation. This trial was registered at clinicaltrials.gov as NCT01967030.
Authors: Matias SL; Dewey KG; Quesenberry CP; Gunderson EP
Am J Clin Nutr. 2014 Jan;99(1):115-21. Epub 2013-11-06.
Severe obesity in children: prevalence, persistence and relation to hypertension
Newer approaches for classifying gradations of pediatric obesity by level of body mass index (BMI) percentage above the 95th percentile have recently been recommended in the management and tracking of obese children. Examining the prevalence and persistence of severe obesity using such methods along with the associations with other cardiovascular risk factors such as hypertension is important for characterizing the clinical significance of severe obesity classification methods. This retrospective study was conducted in an integrated healthcare delivery system to characterize obesity and obesity severity in children and adolescents by level of body mass index (BMI) percentage above the 95th BMI percentile, to examine tracking of obesity status over 2-3 years, and to examine associations with blood pressure. Moderate obesity was defined by BMI 100-119% of the 95th percentile and severe obesity by BMI ?120%?×?95th percentile. Hypertension was defined by 3 consecutive blood pressures ?95th percentile (for age, sex and height) on separate days and was examined in association with obesity severity. Among 117,618 children aged 6-17 years with measured blood pressure and BMI at a well-child visit during 2007-2010, the prevalence of obesity was 17.9% overall and was highest among Hispanics (28.9%) and blacks (20.5%) for boys, and blacks (23.3%) and Hispanics (21.5%) for girls. Severe obesity prevalence was 5.6% overall and was highest in 12-17 year old Hispanic boys (10.6%) and black girls (9.5%). Subsequent BMI obtained 2-3 years later also demonstrated strong tracking of severe obesity. Stratification of BMI by percentage above the 95th BMI percentile was associated with a graded increase in the risk of hypertension, with severe obesity contributing to a 2.7-fold greater odds of hypertension compared to moderate obesity. Severe obesity was found in 5.6% of this community-based pediatric population, varied by gender and race/ethnicity (highest among Hispanics and blacks) and showed strong evidence for persistence over several years. Increasing gradation of obesity was associated with higher risk for hypertension, with a nearly three-fold increased risk when comparing severe to moderate obesity, underscoring the heightened health risk associated with severe obesity in children and adolescents.
Authors: Lo JC; Greenspan LC; et al.
Int J Pediatr Endocrinol. 2014;2014(1):3. Epub 2014-03-03.
Determinants of the creatinine clearance to glomerular filtration rate ratio in patients with chronic kidney disease: a cross-sectional study
Creatinine secretion, as quantified by the ratio of creatinine clearance (CrCl) to glomerular filtration rate (GFR), may introduce another source of error when using serum creatinine concentration to estimate GFR. Few studies have examined determinants of the CrCl/GFR ratio. We sought to study whether higher levels of albuminuria would be associated with higher, and being non-Hispanic black with lower, CrCl/GFR ratio. We did a cross-sectional analysis of 1342 patients with chronic kidney disease from the Chronic Renal Insufficiency Cohort (CRIC) who had baseline measure of iothalamate GFR (iGFR) and 24-hour urine collections. Our predictors included urine albumin as determined from 24-hour urine collections (categorized as: <30, 30-299, 300-2999 and ?3000 mg), and race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic). Our outcome was CrCl/iGFR ratio, a measure of creatinine secretion. Mean iGFR was 48.0 ± 19.9 mL/min/1.73 m², median albuminuria was 84 mg per day, and 36.8% of the study participants were non-Hispanic black. Mean CrCl/iGFR ratio was 1.19 ± 0.48. There was no association between the CrCl/iGFR ratio and urine albumin (coefficient 0.11 [95% CI-0.01-0.22] for higest verus lowest levels of albuminuria, p = 0.07). Also, there was no association between race/ethnicity and CrCl/iGFR ratio (coefficient for non-Hispanic blacks was-0.03 [95% CI-0.09-0.03] compared with whites, p = 0.38). Contrary to what had been suggested by prior smaller studies, CrCl/GFR ratio does not vary with degree of proteinuria or race/ethnicity. The ratio is also closer to 1.0 than reported by several frequently cited reports in the literature.||After the publication of our paper Lin et al. "Determinants of the creatinine clearance to glomerular filtration rate ratio in patients with chronic kidney disease: a cross-sectional study" BMC Nephrology 2013, 14:268, we became aware of errors in the manuscript arising from to a misunderstanding of serum creatinine calibration in the released Chronic Renal Insufficiency Cohort (CRIC) study data obtained from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Data Repository. Specifically further multiplication by 0.95 was actually not necessary to arrive at the standardized creatinine values.Here we present the revised results of the re-analyses along with revisions of the relevant tables. Mean CrCl/iGFR ratio should be 1.13?±?0.46 instead of 1.19?±?0.48. The main conclusion of the paper remain unchanged: "Contrary to what had been suggested by prior smaller studies, CrCl/GFR ratio does not vary with degree of proteinuria or race/ethnicity. The ratio is also closer to 1.0 than reported by several frequently cited reports in the literature."
Authors: Lin YC; Bansal N; Vittinghoff E; Go AS; Hsu CY
BMC Nephrol. 2013;14:268. Epub 2013-12-05.
Indirect effect of financial strain on daily cortisol output through daily negative to positive affect index in the Coronary Artery Risk Development in Young Adults Study
Daily affect is important to health and has been linked to cortisol. The combination of high negative affect and low positive affect may have a bigger impact on increasing HPA axis activity than either positive or negative affect alone. Financial strain may both dampen positive affect as well as increase negative affect, and thus provides an excellent context for understanding the associations between daily affect and cortisol. Using random effects mixed modeling with maximum likelihood estimation, we examined the relationship between self-reported financial strain and estimated mean daily cortisol level (latent cortisol variable), based on six salivary cortisol assessments throughout the day, and whether this relationship was mediated by greater daily negative to positive affect index measured concurrently in a sample of 776 Coronary Artery Risk Development in Young Adults (CARDIA) Study participants. The analysis revealed that while no total direct effect existed for financial strain on cortisol, there was a significant indirect effect of high negative affect to low positive affect, linking financial strain to elevated cortisol. In this sample, the effects of financial strain on cortisol through either positive affect or negative affect alone were not significant. A combined affect index may be a more sensitive and powerful measure than either negative or positive affect alone, tapping the burden of chronic financial strain, and its effects on biology.
Authors: Puterman E; Haritatos J; Adler NE; Sidney S; Schwartz JE; Epel ES
Psychoneuroendocrinology. 2013 Dec;38(12):2883-9. Epub 2013-08-20.
The Role of Lactation in GDM Women
Lactating women exhibit more favorable blood glucose and insulin profiles, as well as increased insulin sensitivity than nonlactating women. Yet, much less is known about whether these favorable effects on metabolic risk factors persist long-term among women with gestational diabetes mellitus (GDM). The evidence that lactation reduces incident type 2 diabetes after GDM pregnancy is limited and inconsistent. Well-controlled, prospective studies that measure lactation intensity and duration, and comprehensively screen for postpartum glucose tolerance are needed to conclusively determine whether lactation can lead to reduced risk of type 2 diabetes after GDM pregnancy.
Authors: Gunderson EP
Clin Obstet Gynecol. 2013 Dec;56(4):844-52.
Common variants associated with plasma triglycerides and risk for coronary artery disease
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Authors: Do R; Iribarren C; Kathiresan S; et al.
Nat Genet. 2013 Nov;45(11):1345-52. Epub 2013-10-06.
Effectiveness and Safety of Spironolactone for Systolic Heart Failure
Aldosterone receptor antagonists have been shown in randomized trials to reduce morbidity and mortality in adults with symptomatic systolic heart failure. We studied the effectiveness and safety of spironolactone in adults with newly diagnosed systolic heart failure in clinical practice. We identified all adults with newly diagnosed heart failure, left ventricular ejection fraction of <40%, and no previous spironolactone use from 2006 to 2008 in Kaiser Permanente Northern California. We excluded patients with baseline serum creatinine level of >2.5 mg/dl or a serum potassium level of >5.0 mEq/L. We used Cox regression with time-varying covariates to evaluate the independent association between spironolactone use and death, hospitalization, severe hyperkalemia, and acute kidney injury. Among 2,538 eligible patients with a median follow-up of 2.5 years, 521 patients (22%) initiated spironolactone, which was not associated with risk of hospitalization (adjusted hazard ratio 0.91, 95% confidence interval 0.77 to 1.08) or death (adjusted hazard ratio 0.93, confidence interval 0.60 to 1.44). Crude rates of severe hyperkalemia and acute kidney injury during spironolactone use were similar to that seen in clinical trials. Spironolactone was independently associated with a 3.5-fold increased risk of hyperkalemia but not with acute kidney injury. Within a diverse community-based cohort with incident systolic heart failure, use of spironolactone was not independently associated with risks of hospitalization or death. Our findings suggest that the benefits of spironolactone in clinical practice may be reduced compared with other guideline-recommended medications.
Authors: Lee KK; Shilane D; Hlatky MA; Yang J; Steimle AE; Go AS
Am J Cardiol. 2013 Nov;112(9):1427-32.
Validation of a population-based method to assess drug-induced alterations in the QT interval: a self-controlled crossover study
The purpose of this study was to ascertain, in the context of an integrated health care delivery system, the association between a comprehensive list of drugs known to have potential QT liability and QT prolongation or shortening. By using a self-controlled crossover study with 59?467 subjects, we ascertained intra-individual change in log-linear regression-corrected QT (QTcreg ) during the period between 1995 and mid-2008 for 90 drugs while adjusting for age, gender, race/ethnicity, comorbid conditions, number of electrocardiograms (ECGs), and time between pre-ECG and post-ECG. The proportion of users of each drug-developing incident long QT was also estimated. Two drugs (nicardipine and levalbuterol) had no statistically significant intra-individual QTcreg shortening effects, 10 drugs had no statistically significant prolonging effect, and 78 (87%) of the drugs had statistically significant intra-individual mean QTcreg lengthening effects, ranging from 7.6?ms for aripiprazole to 25.2?ms for amiodarone. Three drugs were associated with mean QTcreg prolongation of 20?ms or greater: amiodarone (antiarrhythmic), terfenadine (antihistaminic), and quinidine (antiarrhythmic); whereas 11 drugs were associated with mean QTcreg prolongation of 15?ms or greater but less than 20?ms: trimipramine (tricyclic antidepressant), clomipramine (tricyclic antidepressant), disopyramide (antiarrhythmic), chlorpromazine (antipsychotic), sotalol (beta blocker), itraconazole (antifungal), phenylpropanolamine (decongestant/anorectic), fenfluramine (appetite suppressant), midodrine (antihypotensive), digoxin (cardiac glycoside/antiarrhythmic), and procainamide (antiarrhythmic). QT prolonging effects were common and varied in strength. Our results lend support to past Food and Drug Administration regulatory actions and support the role for ongoing surveillance of drug-induced QT prolongation.
Authors: Iribarren C; Round AD; Peng JA; Lu M; Zaroff JG; Holve TJ; Prasad A; Stang P
Pharmacoepidemiol Drug Saf. 2013 Nov;22(11):1222-32. Epub 2013-07-16.
Subclinical atherosclerotic calcification and cognitive functioning in middle-aged adults: The CARDIA study
Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults. This cross-sectional study included 2510 black and white adults (age: 43-55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010-11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory). A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p < 0.05). In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging.
Authors: Reis JP; Launer LJ; Terry JG; Loria CM; Zeki Al Hazzouri A; Sidney S; Yaffe K; Jacobs DR; Whitlow CT; Zhu N; Carr JJ
Atherosclerosis. 2013 Nov;231(1):72-7. Epub 2013-09-10.
Discovery and refinement of loci associated with lipid levels
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
Authors: Global Lipids Genetics Consortium; Iribarren C; Abecasis GR; et al.
Nat Genet. 2013 Nov;45(11):1274-83. Epub 2013-10-06.
Relation of serum magnesium levels and postdischarge outcomes in patients hospitalized for heart failure (from the EVEREST Trial).
Serum magnesium levels may be impacted by neurohormonal activation, renal function, and diuretics. The clinical profile and prognostic significance of serum magnesium level concentration in patients hospitalized for heart failure (HF) with reduced ejection fraction is unclear. In this retrospective analysis of the placebo group of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, we evaluated 1,982 patients hospitalized for worsening HF with ejection fractions ≤40%. Baseline magnesium levels were measured within 48 hours of admission and analyzed as a continuous variable and in quartiles. The primary end points of all-cause mortality (ACM) and cardiovascular mortality or HF rehospitalization were analyzed using Cox regression models. Mean baseline magnesium level was 2.1 ± 0.3 mg/dl. Compared with the lowest quartile, patients in the highest magnesium level quartile were more likely to be older, men, have lower heart rates and blood pressures, have ischemic HF origin, and have higher creatinine and natriuretic peptide levels (all p
Authors: Vaduganathan, Muthiah M; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Mentz, Robert J RJ; Fonarow, Gregg C GC; Zannad, Faiez F; Maggioni, Aldo P AP; Konstam, Marvin A MA; Subacius, Haris P HP; Nodari, Savina S; Butler, Javed J; Gheorghiade, Mihai M;
The American journal of cardiology. 2013 Dec 01;112(11):1763-9. Epub 2013-10-04.
Associations between use of the hospitalist model and quality of care and outcomes of older patients hospitalized for heart failure
This study sought to examine the associations of hospitalist and cardiologist care of patients with heart failure with outcomes and adherence to quality measures. The hospitalist model of inpatient care has grown nationally, but its associations with quality of care and outcomes of patients hospitalized with heart failure are not known. We analyzed data from the Get With the Guidelines-Heart Failure registry linked to Medicare claims for 2005 through 2008. For each hospital, we calculated the percentage of heart failure hospitalizations for which a hospitalist was the attending physician. We examined outcomes and care quality for patients stratified by rates of hospitalist use. Using multivariable models, we estimated associations between hospital-level use of hospitalists and cardiologists and 30-day risk-adjusted outcomes and adherence to measures of quality care. The analysis included 31,505 Medicare beneficiaries in 166 hospitals. Across hospitals, the use of hospitalists varied from 0% to 83%. After multivariable adjustment, a 10% increase in the use of hospitalists was associated with a slight increase in mortality (risk ratio: 1.03; 95% confidence interval [CI]: 1.00 to 1.06) and decrease in length of stay (0.09 days; 95% CI: 0.02 to 0.16). There was no association with 30-day readmission. Increased use of hospitalists in hospitals with high use of cardiologists was associated with improved defect-free adherence to a composite of heart failure performance measures (risk ratio: 1.03; 95% CI: 1.01 to 1.06). Hospitalist care varied significantly across hospitals for heart failure admissions and was not associated with improved 30-day outcomes. Comanagement by hospitalists and cardiologists may help to improve adherence to some quality measures, but it remains unclear what care model improves 30-day clinical outcomes.
Authors: Kociol RD; Hammill BG; Fonarow GC; Heidenreich PA; Go AS; Peterson ED; Curtis LH; Hernandez AF
JACC Heart Fail. 2013 Oct;1(5):445-53. Epub 2013-09-11.
A cross sectional association between bone mineral density and parathyroid hormone and other biomarkers in community-dwelling young adults: the CARDIA Study
Most association studies of bone-related biomarkers (BBMs) with bone mineral density (BMD) have been conducted in postmenopausal women. We tested whether the following BBMs were cross-sectionally associated with BMD among young adults: serum 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25OHD), PTH, osteocalcin, bone-specific alkaline phosphatase (BAP), and urinary pyridinoline/urinary creatinine. We studied 319 individuals (134 women, 149 black, 24-36 years) recruited during 1992 through 1993 in Oakland, California. BMD was assessed with dual-energy x-ray absorptiometry. Linear regression models estimated the association between BMD and each BBM. 1,25(OH)2D was inversely associated with all BMDs. 25OHD was positively, and PTH inversely, associated with lumbar spine, total hip, and whole-body BMD. BAP was inversely associated with left arm, right arm, and whole-body BMD but not with spine or hip BMD. Neither osteocalcin nor urinary pyridinoline/urinary creatinine was associated with BMD. When we placed all BBMs (including 1,25(OH)2D) in one model, the pattern and magnitude of association was similar except for PTH, which was attenuated. The association of BMD and BBMs did not differ significantly by race or sex. In this cross-sectional study of healthy young men and women who had PTH levels considered normal in clinical practice, higher PTH was associated with lower BMD, particularly in weight-bearing sites (ie, spine and hip). The inverse association of 1,25(OH)2D, together with the attenuation of PTH, suggests that the observed association of PTH is mediated by 1,25(OH)2D. BAP was inversely associated with arm BMD. BBMs can be important markers of skeletal activity in young adults, but their clinical role on bone health among this population is yet to be fully determined.
Authors: Fujiyoshi A; Polgreen LE; Hurley DL; Gross MD; Sidney S; Jacobs DR
J Clin Endocrinol Metab. 2013 Oct;98(10):4038-46.
Posttraumatic Stress Disorder (PTSD) and Coronary Heart Disease
Authors: Sidney S
J Am Coll Cardiol. 2013 Sep 10;62(11):979-80. Epub 2013 Jun 27.
Response to Letter Regarding Article, ‘Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation: Validation of the R2CHADS2 Index in the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study Cohorts’
Authors: Piccini JP; Go AS; ROCKET AF Steering Committee and Investigators; et al.
Circulation. 2013 Sep 10;128(11):e172-3.
African American race but not genome-wide ancestry is negatively associated with atrial fibrillation among postmenopausal women in the Women’s Health Initiative
Atrial fibrillation (AF) is the most common arrhythmia in women and is associated with higher rates of stroke and death. Rates of AF are lower in African American subjects compared with European Americans, suggesting European ancestry could contribute to AF risk. The Women’s Health Initiative (WHI) Observational Study (OS) followed up 93,676 women since the mid 1990s for various cardiovascular outcomes including AF. Multivariate Cox hazard regression analysis was used to measure the association between African American race and incident AF. A total of 8,119 African American women from the WHI randomized clinical trials and OS were genotyped on the Affymetrix Human SNP Array 6.0. Genome-wide ancestry and previously reported single nucleotide polymorphisms associated with AF in European cohorts were tested for association with AF using multivariate logistic regression analyses. Self-reported African American race was associated with lower rates of AF (hazard ratio 0.43, 95% CI 0.32-0.60) in the OS, independent of demographic and clinical risk factors. In the genotyped cohort, there were 558 women with AF. By contrast, genome-wide European ancestry was not associated with AF. None of the single nucleotide polymorphisms previously associated with AF in European populations, including rs2200733, were associated with AF in the WHI African American cohort. African American race is significantly and inversely correlated with AF in postmenopausal women. The etiology of this association remains unclear and may be related to unidentified environmental differences. Larger studies are necessary to identify genetic determinants of AF in African Americans.
Authors: Perez MV; Hoffmann TJ; Tang H; Thornton T; Stefanick ML; Larson JC; Kooperberg C; Reiner AP; Caan B; Iribarren C; Risch N
Am Heart J. 2013 Sep;166(3):566-72.
White blood cell count in young adulthood and coronary artery calcification in early middle age: coronary artery risk development in young adults (CARDIA) study
White blood cell (WBC) count is associated with incident coronary heart disease (CHD). Data are sparse regarding its association in young adults with future coronary artery calcification (CAC). Our study was conducted among coronary artery risk development in young adults (CARDIA) participants (n=3,094). We examined the association between baseline (Y0) WBC counts and CHD risk factors using linear regression models. We further assessed prospective associations between Y0 WBC and inflammatory biomarkers during the follow-up, and the presence of CAC 15 and 20 years later. In total, 272 and 566 subjects had CAC scores>0 at year (Y) 15 and Y20, respectively. Baseline total WBC counts were cross-sectionally associated with SBP, BMI, and smoking, or HDL-cholesterol (p?0.01) at Y0, and prospectively associated with C-reactive protein at Y7, Y15, and Y20, and fibrinogen at Y5 and Y20 (p<0.01). After adjustment for potential confounding factors, baseline neutrophil count was borderline associated with CAC presence 15 years later (OR=1.18 per unit, 95% CI 1.00-1.44) and total WBC (OR=1.07, 95% CI 0.96-1.19) or eosinophil (OR=1.12, 95%CI 1.00-1.25) was borderline associated with CAC presence at Y20. Baseline total WBC counts in young adults was associated prospectively with CAC presence 20 years later after adjusting for age, sex, and race. Results are attenuated when other risk factors are accounted for. Our results suggest the possible early involvement of WBC, particularly eosinophils, in the early stages of atherosclerosis.
Authors: Hou L; Carr JJ; Liu K; et al.
Eur J Epidemiol. 2013 Sep;28(9):735-42.
Effectiveness and safety of digoxin among contemporary adults with incident systolic heart failure
Clinical guidelines recommend digoxin for patients with symptomatic systolic heart failure (HF) receiving optimal medical therapy, but this recommendation is based on limited, older trial data. We evaluated the effectiveness and safety of digoxin in a contemporary cohort of patients with incident systolic HF. We identified adults with incident systolic HF between 2006 and 2008 within Kaiser Permanente Northern California who had no prior digoxin use. We used multivariable extended Cox regression to examine the association between new digoxin use and risks of death and HF hospitalization, controlling for medical history, laboratory results, medications, HF disease severity, and the propensity for digoxin use. We also conducted analyses stratified by sex and concurrent ?-blocker use. Among 2891 newly diagnosed patients with systolic HF, 529 (18%) received digoxin. During a median 2.5 years of follow-up, incident digoxin use was associated with higher rates of death (14.2 versus 11.3 per 100 person-years) and HF hospitalization (28.2 versus 24.4 per 100 person-years). In multivariable analysis, incident digoxin use was associated with higher mortality (hazard ratio, 1.72; 95% confidence interval, 1.25-2.36) but no significant difference in the risk of HF hospitalization (hazard ratio, 1.05; 95% confidence interval, 0.82-1.34). Results were similar in analyses stratified by sex and ?-blocker use. Digoxin use in patients with incident systolic HF was independently associated with a higher risk of death but no difference in HF hospitalization.
Authors: Freeman JV; Yang J; Sung SH; Hlatky MA; Go AS
Circ Cardiovasc Qual Outcomes. 2013 Sep 1;6(5):525-33. Epub 2013-09-10.
Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study
OBJECTIVES: This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study ( approximately 2,100 genes; approximately 50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). RESULTS: Of 268 SNPs reaching p < 5 x 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
Authors: Ferguson JF; Go AS; CRIC Study Principal Investigators; et al.
J Am Coll Cardiol. 2013 Aug 27;62(9):789-98. Epub 2013 May 30.
Improved blood pressure control associated with a large-scale hypertension program
IMPORTANCE: Hypertension control for large populations remains a major challenge. OBJECTIVE: To describe a large-scale hypertension program in Northern California and to compare rates of hypertension control in that program with statewide and national estimates. DESIGN, SETTING, AND PATIENTS: The Kaiser Permanente Northern California (KPNC) hypertension program included a multifaceted approach to blood pressure control. Patients identified as having hypertension within an integrated health care delivery system in Northern California from 2001-2009 were included. The comparison group comprised insured patients in California between 2006-2009 who were included in the Healthcare Effectiveness Data and Information Set (HEDIS) commercial measurement by California health insurance plans participating in the National Committee for Quality Assurance (NCQA) quality measure reporting process. A secondary comparison group was included to obtain the reported national mean NCQA HEDIS commercial rates of hypertension control between 2001-2009 from health plans that participated in the NCQA HEDIS quality measure reporting process. MAIN OUTCOMES AND MEASURES: Hypertension control as defined by NCQA HEDIS. RESULTS: The KPNC hypertension registry included 349,937 patients when established in 2001 and increased to 652,763 by 2009. The NCQA HEDIS commercial measurement for hypertension control within KPNC increased from 43.6% (95% CI, 39.4%-48.6%) to 80.4% (95% CI, 75.6%-84.4%) during the study period (P < .001 for trend). In contrast, the national mean NCQA HEDIS commercial measurement increased from 55.4% to 64.1%. California mean NCQA HEDIS commercial rates of hypertension were similar to those reported nationally from 2006-2009 (63.4% to 69.4%). CONCLUSIONS AND RELEVANCE: Among adults diagnosed with hypertension, implementation of a large-scale hypertension program was associated with a significant increase in hypertension control compared with state and national control rates. Key elements of the program included a comprehensive hypertension registry, development and sharing of performance metrics, evidence-based guidelines, medical assistant visits for blood pressure measurement, and single-pill combination pharmacotherapy.
Authors: Jaffe MG; Lee GA; Young JD; Sidney S; Go AS
JAMA. 2013 Aug 21;310(7):699-705.
Risk of Coronary Disease in South Asian Americans
Authors: Hajra A; Li Y; Siu S; Udaltsova N; Armstrong MA; Friedman GD; Klatsky AL
J Am Coll Cardiol. 2013 Aug 13;62(7):644-5. Epub 2013 Jun 13.
Role of trauma and infection in childhood hemorrhagic stroke due to vascular lesions
OBJECTIVE: Trauma and infection have been postulated as ‘triggers’ for hemorrhage from underlying brain vascular lesions (arteriovenous malformations, cavernous malformations, and aneurysms) in pediatric hemorrhagic stroke. We decided to perform an association study examining these environmental risk factors. METHODS: In this case-control study nested within the cohort of 2.3 million children enrolled in a Northern California integrated health plan (1993-2004), we identified childhood hemorrhagic stroke cases through electronic searches of diagnostic and radiology databases, confirmed through chart review. Three age- and facility-matched controls per case were randomly selected from the study population. Exposure variables were measured using medical records documented before stroke diagnosis. Main outcome measure was hemorrhagic stroke. RESULTS: Of 132 childhood, non-neonatal hemorrhagic stroke cases, 65 had underlying vascular lesions: 34 arteriovenous malformations, 16 cavernous malformations, and 15 aneurysms. A documented exposure to head and neck trauma in the prior 12 weeks was present in 3 cases (4.6%) with underlying vascular lesions, compared with no controls (p < 0.015). However, all 3 vascular lesions were aneurysms, and traumatic pseudoaneurysms were possible. Recent minor infection (prior 4 weeks) was present in 5 cases (7.7%) and 9 controls (4.6%) (p = 0.34). CONCLUSIONS: Our observed association between trauma and hemorrhagic stroke with a vascular lesion may be explained by traumatic pseudoaneurysms. Neither recent head or neck trauma nor infection appeared to be a 'trigger' for pediatric hemorrhagic stroke due to underlying vascular malformations.
Authors: Singhal NS; Hills NK; Sidney S; Fullerton HJ
Neurology. 2013 Aug 6;81(6):581-4. Epub 2013 Jul 3.
Forecasting the Future of Stroke in the United States: A Policy Statement From the American Heart Association and American Stroke Association
BACKGROUND AND PURPOSE: Stroke is a leading cause of disability, cognitive impairment, and death in the United States and accounts for 1.7% of national health expenditures. Because the population is aging and the risk of stroke more than doubles for each successive decade after the age of 55 years, these costs are anticipated to rise dramatically. The objective of this report was to project future annual costs of care for stroke from 2012 to 2030 and discuss potential cost reduction strategies. METHODS AND RESULTS: The American Heart Association/American Stroke Association developed methodology to project the future costs of stroke-related care. Estimates excluded costs associated with other cardiovascular diseases (hypertension, coronary heart disease, and congestive heart failure). By 2030, 3.88% of the US population>18 years of age is projected to have had a stroke. Between 2012 and 2030, real (2010$) total direct annual stroke-related medical costs are expected to increase from $71.55 billion to $183.13 billion. Real indirect annual costs (attributable to lost productivity) are projected to rise from $33.65 billion to $56.54 billion over the same period. Overall, total annual costs of stroke are projected to increase to $240.67 billion by 2030, an increase of 129%. CONCLUSIONS: These projections suggest that the annual costs of stroke will increase substantially over the next 2 decades. Greater emphasis on implementing effective preventive, acute care, and rehabilitative services will have both medical and societal benefits.
Authors: Ovbiagele B; Khavjou OA; American Heart Association Advocacy Coordinating Committee and Stroke Council; et al.
Stroke. 2013 Aug;44(8):2361-75. Epub 2013 May 22.
Ten-year results of endovascular abdominal aortic aneurysm repair from a large multicenter registry
OBJECTIVE: To assess outcomes after endovascular abdominal aortic aneurysm repair (EVAR) in an integrated health care system. METHODS: Between 2000 and 2010, 1736 patients underwent EVAR at 17 centers. Demographic data, comorbidities, and outcomes of interest were collected. EVAR in patients presenting with ruptured or symptomatic aneurysms was categorized as urgent; otherwise, it was considered elective. Primary outcomes were mortality and aneurysm-related mortality (ARM). Secondary outcomes were change in aneurysm sac size, endoleak status, major adverse events, and reintervention. RESULTS: Overall, the median age was 76 years (interquartile range, 70-81 years), 86% were male, and 82% were Caucasian. Most cases (93.8%) were elective, but urgent use of EVAR increased from 4% in the first 5 years to 7.3% in the last 5 years of the study period. Mean aneurysm size was 5.8 cm. Patients were followed for an average of 3 years (range, 1-11 years); 8% were lost to follow-up. Intraoperatively, 4.5% of patients required adjunctive maneuvers for endoleak, fixation, or flow-limiting issues. The 30-day mortality rate was 1.2%, and the perioperative morbidity rate was 6.6%. Intraoperative type I and II endoleaks were uncommon (2.3% and 9.3%, respectively). Life-table analysis at 5 years demonstrated excellent overall survival (66%) and freedom from ARM (97%). Postoperative endoleak was seen in 30% of patients and was associated with an increase in sac size over time. Finally, the total reintervention rate was 15%, including 91 instances (5%) of revisional EVAR. The overall major adverse event rate was 7.9% and decreased significantly from 12.3% in the first 5 years to 5.6% in the second 5 years of the study period (P < .001). Overall ARM was worse in patients with postoperative endoleak (4.1% vs 1.8%; P < .01) or in those who underwent reintervention (7.6% vs 1.6%; P < .001). CONCLUSIONS: Results from a contemporary EVAR registry in an integrated health care system demonstrate favorable perioperative outcomes and excellent clinical efficacy. However, postoperative endoleak and the need for reintervention continue to be challenging problems for patients after EVAR.
Authors: Chang RW; Goodney P; Tucker LY; Okuhn S; Hua H; Rhoades A; Sivamurthy N; Hill B
J Vasc Surg. 2013 Aug;58(2):324-32. Epub 2013 May 14.
Patterns of care and persistence after incident elevated blood pressure
BACKGROUND AND OBJECTIVE: Screening for hypertension in children occurs during routine care. When blood pressure (BP) is elevated in the hypertensive range, a repeat measurement within 1 to 2 weeks is recommended. The objective was to assess patterns of care after an incident elevated BP, including timing of repeat BP measurement and likelihood of persistently elevated BP. METHODS: This retrospective study was conducted in 3 health care organizations. All children aged 3 through 17 years with an incident elevated BP at an outpatient visit during 2007 through 2010 were identified. Within this group, we assessed the proportion who had a repeat BP measured within 1 month of their incident elevated BP and the proportion who subsequently met the definition of hypertension. Multivariate analyses were used to identify factors associated with follow-up BP within 1 month of initial elevated BP. RESULTS: Among 72,625 children and adolescents in the population, 6108 (8.4%) had an incident elevated BP during the study period. Among 6108 with an incident elevated BP, 20.9% had a repeat BP measured within 1 month. In multivariate analyses, having a follow-up BP within 1 month was not significantly more likely among individuals with obesity or stage 2 systolic elevation. Among 6108 individuals with an incident elevated BP, 84 (1.4%) had a second and third consecutive elevated BP within 12 months. CONCLUSIONS: Whereas >8% of children and adolescents had an incident elevated BP, the great majority of BPs were not repeated within 1 month. However, relatively few individuals subsequently met the definition of hypertension.
Authors: Daley MF; Lo JC; Magid DJ; et al.
Pediatrics. 2013 Aug;132(2):e349-55. Epub 2013 Jul 1.
Risk Adjustment for Health Care Financing in Chronic Disease: What Are We Missing By Failing to Account for Disease Severity?
BACKGROUND: Adjustment for differing risks among patients is usually incorporated into newer payment approaches, and current risk models rely on age, sex, and diagnosis codes. It is unknown the extent to which controlling additionally for disease severity improves cost prediction. Failure to adjust for within-disease variation may create incentives to avoid sicker patients. We address this issue among patients with chronic obstructive pulmonary disease (COPD). METHODS: Cost and clinical data were collected prospectively from 1202 COPD patients at Kaiser Permanente. Baseline analysis included age, sex, and diagnosis codes (using the Diagnostic Cost Group Relative Risk Score) in a general linear model predicting total medical costs in the following year. We determined whether adding COPD severity measures-forced expiratory volume in 1 second, 6-Minute Walk Test, dyspnea score, body mass index, and BODE Index (composite of the other 4 measures)-improved predictions. Separately, we examined household income as a cost predictor. RESULTS: Mean costs were $12,334/y. Controlling for Relative Risk Score, each (1/2) SD worsening in COPD severity factor was associated with $629 to $1135 in increased annual costs (all P<0.01). The lowest stratum of forced expiratory volume in 1 second (<30% normal) predicted $4098 (95% confidence interval, $576-$8773) additional costs. Household income predicted excess costs when added to the baseline model (P=0.038), but this became nonsignificant when also incorporating the BODE Index. CONCLUSIONS: Disease severity measures explain significant cost variations beyond current risk models, and adding them to such models appears important to fairly compensate organizations that accept responsibility for sicker COPD patients. Appropriately controlling for disease severity also accounts for costs otherwise associated with lower socioeconomic status.
Authors: Omachi TA; Gregorich SE; Eisner MD; Penaloza RA; Tolstykh IV; Yelin EH; Iribarren C; Dudley RA; Blanc PD
Med Care. 2013 Aug;51(8):740-7.
Acute seizures predict epilepsy after childhood stroke
To determine incidence rates and predictors of epilepsy after childhood stroke and compare these to published estimates of 3 to 5% cumulative epilepsy incidence by 5 years poststroke in adults. In a retrospective population-based study of children with stroke (29 days-19 years) in an integrated health care system (1993-2007), poststroke seizures were identified through electronic searches and confirmed by chart review. Stroke and seizure characteristics were abstracted from medical records. Survival analysis was used to determine rates and predictors of remote seizures and active epilepsy (anticonvulsant treatment for remote seizure within prior 6 months) at last follow-up. From a population of 2.5 million children, we identified 305 stroke cases. Over a median follow-up of 4.1 years (interquartile range?=?1.8-6.8), 49 children had a first unprovoked remote seizure. The average annual incidence rate of first remote seizure was 4.4% (95% confidence interval [CI]?=?3.3-5.8) with a cumulative risk of 16% (95% CI?=?12-21) at 5 years and 33% (95% CI?=?23-46) at 10 years poststroke. The cumulative risk of active epilepsy was 13% (95% CI?=?9-18) at 5 years and 30% (95% CI?=?20-44) at 10 years. Acute seizures at the time of stroke predicted development of active epilepsy (hazard ratio?=?4.2, 95% CI?=?2.2-8.1). At last follow-up, ? of the children with active epilepsy had a recent breakthrough seizure despite anticonvulsant usage. Unlike adults, children are uniquely vulnerable to epilepsy after stroke. Children with acute seizures at the time of stroke are at particularly high risk.
Authors: Fox CK; Glass HC; Sidney S; Lowenstein DH; Fullerton HJ
Ann Neurol. 2013 Aug;74(2):249-56.
Haemoconcentration, renal function, and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial.
AIMS: Haemoconcentration has been studied as a marker of decongestion in patients with hospitalization for heart failure (HHF). We describe the relationship between haemoconcentration, worsening renal function, post-discharge outcomes, and clinical and laboratory markers of congestion in a large multinational cohort of patients with HHF.METHODS AND RESULTS: In 1684 patients with HHF with ejection fraction (EF) ≤40% assigned to the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, absolute in-hospital haematocrit change was calculated as the change between baseline and discharge or day 7 (whichever occurred first). Patient characteristics, changes in renal function, and outcomes over a median follow-up of 9.9 months were compared by in-hospital haematocrit change. Overall, 26% of patients had evidence of haemoconcentration (i.e., ≥3% absolute increase in haematocrit). Patients with greater increases in haematocrit tended to have better baseline renal function. Haemoconcentration correlated with greater risk of in-hospital worsening renal function, but renal parameters generally returned to baseline within 4 weeks post-discharge. Patients with haemoconcentration were less likely to have clinical congestion at discharge, and experienced greater in-hospital decreases in body weight and natriuretic peptide levels. After adjustment for baseline clinical risk factors, every 5% increase of in-hospital haematocrit change was associated with a decreased risk of all-cause death [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.95]. Haematocrit change was also associated with decreased cardiovascular mortality or heart failure (HF) hospitalization at ≤100 days post-randomization (HR 0.73, 95% CI 0.71-0.76).CONCLUSION: In this large cohort of patients with HHF with reduced EF, haemoconcentration was associated with greater improvements in congestion and decreased mortality and HF re-hospitalization despite an increased risk of in-hospital worsening renal function.
Authors: Greene, Stephen J SJ; Gheorghiade, Mihai M; Vaduganathan, Muthiah M; Ambrosy, Andrew P AP; Mentz, Robert J RJ; Subacius, Haris H; Maggioni, Aldo P AP; Nodari, Savina S; Konstam, Marvin A MA; Butler, Javed J; Filippatos, Gerasimos G;
European journal of heart failure. 2013 Dec 01;15(12):1401-11. Epub 2013-07-11.
Not time to RELAX in acute heart failure.
Authors: Ambrosy, Andrew P AP; Witteles, Ronald M RM
Lancet (London, England). 2013 May 25;381(9880):1813. Epub 2013-07-11.
Geographic variation in cardiovascular procedure use among Medicare fee-for-service vs Medicare Advantage beneficiaries
IMPORTANCE: Little is known about how different financial incentives between Medicare Advantage and Medicare fee-for-service (FFS) reimbursement structures influence use of cardiovascular procedures. OBJECTIVE: To compare regional cardiovascular procedure rates between Medicare Advantage and Medicare FFS beneficiaries. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of Medicare beneficiaries older than 65 years between 2003-2007 comparing rates of coronary angiography, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) surgery across 32 hospital referral regions in 12 states. MAIN OUTCOMES AND MEASURES: Rates of coronary angiography, PCI, and CABG surgery. RESULTS: We evaluated a total of 878,339 Medicare Advantage patients and 5,013,650 Medicare FFS patients. Compared with Medicare FFS patients, Medicare Advantage patients had lower age-, sex-, race-, and income-adjusted procedure rates per 1000 person-years for angiography (16.5 [95% CI, 14.8-18.2] vs 25.9 [95% CI, 24.0-27.9]; P < .001) and PCI (6.8 [95% CI, 6.0-7.6] vs 9.8 [95% CI, 9.0-10.6]; P < .001) but similar rates for CABG surgery (3.1 [95% CI, 2.8-3.5] vs 3.4 [95% CI, 3.1-3.7]; P = .33). There were no significant differences between Medicare Advantage and Medicare FFS patients in the rates per 1000 person-years of urgent angiography (3.9 [95% CI, 3.6-4.2] vs 4.3 [95% CI, 4.0-4.6]; P = .24) or PCI (2.4 [95% CI, 2.2-2.7] vs 2.7 [95% CI, 2.5-2.9]; P = .16). Procedure rates varied widely across hospital referral regions among Medicare Advantage and Medicare FFS patients. For angiography, the rates per 1000 person-years ranged from 9.8 to 40.6 for Medicare Advantage beneficiaries and from 15.7 to 44.3 for Medicare FFS beneficiaries. For PCI, the rates ranged from 3.5 to 16.8 for Medicare Advantage and from 4.7 to 16.1 for Medicare FFS. The rates for CABG surgery ranged from 1.5 to 6.1 for Medicare Advantage and from 2.5 to 6.0 for Medicare FFS. Across regions, we found no statistically significant correlation between Medicare Advantage and Medicare FFS beneficiary utilization for angiography (Spearman r = 0.19, P = .29) and modest correlations for PCI (Spearman r = 0.33, P = .06) and CABG surgery (Spearman r = 0.35, P = .05). Among Medicare Advantage beneficiaries, adjustment for additional cardiac risk factors had little influence on procedure rates. CONCLUSIONS AND RELEVANCE: Although Medicare beneficiaries enrolled in capitated Medicare Advantage programs had lower angiography and PCI procedure rates than those enrolled in Medicare FFS, the degree of geographic variation in procedure rates was substantial among Medicare Advantage beneficiaries and was similar in magnitude to that observed among Medicare FFS beneficiaries.
Authors: Matlock DD; Go AS; Magid DJ; et al.
JAMA. 2013 Jul 10;310(2):155-62.
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack
Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone. In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect. Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group. Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage. (Funded by the Ministry of Science and Technology of the People's Republic of China; CHANCE ClinicalTrials.gov number, NCT00979589.).
Authors: Wang Y; Zhao X; CHANCE Investigators; et al.
N Engl J Med. 2013 Jul 4;369(1):11-9. Epub 2013-06-26.
Risk Factors for Adverse Outcomes by Left Ventricular Ejection Fraction in a Contemporary Heart Failure Population
BACKGROUND: Although heart failure (HF) is a syndrome with important differences in response to therapy by left ventricular ejection fraction (LVEF), existing risk stratification models typically group all HF patients together. The relative importance of common predictor variables for important clinical outcomes across strata of LVEF is relatively unknown. METHODS AND RESULTS: We identified all members with HF between 2005 and 2008 from 4 integrated healthcare systems in the Cardiovascular Research Network. LVEF was categorized as preserved (LVEF >/= 50% or normal), borderline (41%-49% or mildly reduced), and reduced (
Authors: Allen LA; Magid DJ; Gurwitz JH; Smith DH; Goldberg RJ; Saczynski J; Thorp ML; Hsu G; Sung SH; Go AS
Circ Heart Fail. 2013 Jul;6(4):635-46. Epub 2013 May 24.
Risks and Benefits of Anticoagulation in Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry
Patients with atrial fibrillation (AF) at the highest stroke risk derive the largest benefit from oral anticoagulation (OAC). Those with the highest stroke risk have been paradoxically less likely to receive OAC. This study assessed the association between stroke and bleeding risk on rates of OAC. We analyzed OAC use among 10,098 patients with AF from 174 community-based outpatient practices enrolled in 2010-2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). OAC was defined as warfarin or dabigatran use at study enrollment. Stroke and bleeding risk were calculated using congestive heart failure, hypertension, age, diabetes mellitus, prior stroke (CHADS?), and anticoagulation and risk factors in AF (ATRIA) scores, respectively. The mean subject age was 73 years; 58% were men. Overall, 76% of patients received OAC (71% warfarin and 5% dabigatran). The use of OAC increased among those with higher CHADS? scores, from 53% for CHADS?=0 to 80% for CHADS??2 (P<0.001). OAC use fell slightly with increasing ATRIA bleeding risk score, from 81% for ATRIA=3 to 73% for ATRIA?5 (P<0.001). A significant interaction existed between ATRIA and CHADS? scores (P=0.021). Among those with low bleeding risk, use of OAC increased significantly with increasing stroke risk. Among those with high bleeding risk, CHADS? stroke risk had a smaller impact on use of OAC. In community-based outpatients with AF, use of OAC was high and driven by not only predominantly stroke but also bleeding risk. Stroke risk significantly affects OAC use among those with low bleeding risk, whereas those with high bleeding risk demonstrate consistently lower use of OAC regardless of stroke risk.
Authors: Cullen MW; Go AS; ORBIT-AF Investigators; et al.
Circ Cardiovasc Qual Outcomes. 2013 Jul;6(4):461-9. Epub 2013-06-11.
Oral Contraceptive Use and the ECG: Evidence of an Adverse QT Effect on Corrected QT Interval
A prolonged corrected QT (QTc) interval is a marker for an increased risk of sudden cardiac death. We evaluated the relationship between oral contraceptive (OC) use, type of OC, and QTc interval. We identified 410,782 ECGs performed at Northern California Kaiser Permanente on female patients between 15 and 53 years from January, 1995 to June, 2008. QT was corrected for heart rate using log-linear regression. OC generation (first, second and third) was classified by increasing progestin androgenic potency, while the fourth generation was classified as antiandrogenic. Among 410,782 women, 8.4% were on OC. In multivariate analysis after correction for comorbidities, there was an independent shortening effect of OCs overall (slope = -0.5 ms; SE = 0.12, P < 0.0002). Users of first and second generation progestins had a significantly shorter QTc than nonusers (P < 0.0001), while users of fourth generation had a significantly longer QTc than nonusers (slope = 3.6 ms, SE = 0.35, P < 0.0001). Overall, OC use has a shortening effect on the QTc. Shorter QTc is seen with first and second generation OC while fourth generation OC use has a lengthening effect on the QTc. Careful examination of adverse event rates in fourth generation OC users is needed.
Authors: Sedlak T; Shufelt C; Iribarren C; Lyon LL; Bairey Merz CN
Ann Noninvasive Electrocardiol. 2013 Jul;18(4):389-98. Epub 2013-05-03.
Changes in weight and health behaviors after pregnancies complicated by gestational diabetes mellitus: The CARDIA study
Prepregnancy to postpregnancy change in weight, body mass index (BMI), waist circumference, diet, and physical activity in women with and without gestational diabetes mellitus (GDM) were compared. Using the Coronary Artery Risk Development in Young Adults study, women with at least one pregnancy during 20 years of follow-up (n = 1,488 with 3,125 pregnancies) was identified. Linear regression with generalized estimating equations to compare prepregnancy to postpregnancy changes in health behaviors and anthropometric measurements between 137 GDM pregnancies and 1,637 non-GDM pregnancies, adjusted for parity, age at delivery, outcome measure at the prepregnancy exam, race, education, mode of delivery, and interval between delivery and postpregnancy examination were used. When compared with women without GDM in pregnancy, women with GDM had higher prepregnancy mean weight (158.3 vs. 149.6 lb, P = 0.011) and BMI (26.7 vs. 25.1 kg/m(2) , P = 0.002), but nonsignificantly lower total daily caloric intake and similar levels of physical activity. Both GDM and non-GDM groups had higher average postpartum weight of 7-8 lbs and decreased physical activity on average 1.4 years after pregnancy. Both groups similarly increased total caloric intake but reduced fast food frequency. Prepregnancy to postpregnancy changes in body weight, BMI, waist circumference, physical activity, and diet did not differ between women with and without GDM in pregnancy. Following pregnancy, women with and without GDM increased caloric intake, BMI, and weight and decreased physical activity, but reduced their frequency of eating fast food. Given these trends, postpartum lifestyle interventions, particularly for women with GDM, are needed to reduce obesity and diabetes risk.
Authors: Bennett WL; Liu SH; Yeh HC; Nicholson WK; Gunderson EP; Lewis CE; Clark JM
Obesity (Silver Spring). 2013 Jun;21(6):1269-75. Epub 2013-05-13.
Housing Instability and Incident Hypertension in the CARDIA Cohort
Housing instability, a growing public health problem, may be an independent environmental risk factor for hypertension, but limited prospective data exist. We sought to determine the independent association of housing instability in early adulthood (year 5, 1990-1991) and incident hypertension over the subsequent 15 years of follow-up (years 7, 10, 15, and 20) in the Coronary Artery Risk Development in Young Adults (CARDIA) study (N = 5,115). Because causes of inadequate housing and its effects on health are thought to vary by race and sex, we hypothesized that housing instability would exert a differential effect on incident hypertension by race and sex. At year 5, all CARDIA participants were asked about housing and those free of hypertension were analyzed (N = 4,342). We defined housing instability as living in overcrowded housing, moving frequently, or living doubled up. Of the 4,342 participants, 8.5 % were living in unstable housing. Across all participants, housing instability was not associated with incident hypertension (incidence rate ratio (IRR), 1.1; 95 % CI, 0.9-1.5) after adjusting for demographics, socioeconomic status, substance use, social factors, body mass index, and study site. However, the association varied by race and sex (p value for interaction, <0.001). Unstably housed white women had a hypertension incidence rate 4.7 times (IRR, 4.7; 95 % CI, 2.4-9.2) that of stably housed white women in adjusted analysis. There was no association among white men, black women, or black men. These findings suggest that housing instability may be a more important risk factor among white women, and may act independently or as a marker for other psychosocial stressors (e.g., stress from intimate partner violence) leading to development of hypertension. Studies that examine the role of these psychosocial stressors in development of hypertension risk among unstably housed white women are needed.
Authors: Vijayaraghavan M; Kushel MB; Vittinghoff E; Kertesz S; Jacobs D; Lewis CE; Sidney S; Bibbins-Domingo K
J Urban Health. 2013 Jun;90(3):427-41.
Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5x10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Authors: Randall JC; Iribarren C; Schlessinger D; et al.
PLoS Genet. 2013 Jun;9(6):e1003500. Epub 2013 Jun 6.
A New Risk Scheme to Predict Ischemic Stroke and Other Thromboembolism in Atrial Fibrillation: The ATRIA Study Stroke Risk Score
More accurate and reliable stroke risk prediction tools are needed to optimize anticoagulation decision making in patients with atrial fibrillation (AF). We developed a new AF stroke prediction model using the original Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) AF cohort and externally validated the score in a separate, contemporary, community-based inception AF cohort, ATRIA-Cardiovascular Research Network (CVRN) cohort. The derivation ATRIA cohort consisted of 10 927 patients with nonvalvular AF contributing 32 609 person-years off warfarin and 685 thromboembolic events (TEs). The external validation ATRIA-CVRN cohort included 25 306 AF patients contributing 26 263 person-years off warfarin and 496 TEs. Cox models identified 8 variables, age, prior stroke, female sex, diabetes mellitus, heart failure, hypertension, proteinuria, and eGFR<45 mL/min per 1.73 m(2) or end-stage renal disease, plus an age×prior stroke interaction term for the final model. Point scores were assigned proportional to model coefficients. The c-index in the ATRIA cohort was 0.73 (95% CI, 0.71 to 0.75), increasing to 0.76 (95% CI, 0.74 to 0.79) when only severe events were considered. In the ATRIA-CVRN, c-indexes were 0.70 (95% CI, 0.67 to 0.72) and 0.75 (95% CI, 0.72 to 0.78) for all events and severe events, respectively. The C-index was greater and net reclassification improvement positive comparing the ATRIA score with the CHADS2 or CHA2DS2-VASc scores. The ATRIA stroke risk score performed better than existing risk scores, was validated successfully, and showed improvement in predicting severe events, which is of greatest concern. The ATRIA score should improve the antithrombotic decision for patients with AF and should provide a secure foundation for the addition of biomarkers in future prognostic models.
Authors: Singer DE; Chang Y; Borowsky LH; Fang MC; Pomernacki NK; Udaltsova N; Reynolds K; Go AS
J Am Heart Assoc. 2013 Jun;2(3):e000250.
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
Authors: den Hoed M; Eijgelsheim M; Esko T; Brundel BJ; Peal DS; Evans DM; Nolte IM; Segre AV; Holm H; Handsaker RE; Westra HJ; Johnson T; Isaacs A; Yang J; Lundby A; Zhao JH; Kim YJ; Go MJ; Almgren P; Bochud M; Boucher G; Cornelis MC; Gudbjartsson D; Hadley D; van der Harst P; Hayward C; den Heijer M; Igl W; Jackson AU; Kutalik Z; Luan J; Kemp JP; Kristiansson K; Ladenvall C; Lorentzon M; Montasser ME; Njajou OT; O'Reilly PF; Padmanabhan S; St Pourcain B; Rankinen T; Salo P; Tanaka T; Timpson NJ; Vitart V; Waite L; Wheeler W; Zhang W; Draisma HH; Feitosa MF; Kerr KF; Lind PA; Mihailov E; Onland-Moret NC; Song C; Weedon MN; Xie W; Yengo L; Absher D; Albert CM; Alonso A; Arking DE; de Bakker PI; Balkau B; Barlassina C; Benaglio P; Bis JC; Bouatia-Naji N; Brage S; Chanock SJ; Chines PS; Chung M; Darbar D; Dina C; Dorr M; Elliott P; Felix SB; Fischer K; Fuchsberger C; de Geus EJ; Goyette P; Gudnason V; Harris TB; Hartikainen AL; Havulinna AS; Heckbert SR; Hicks AA; Hofman A; Holewijn S; Hoogstra-Berends F; Hottenga JJ; Jensen MK; Johansson A; Junttila J; Kaab S; Kanon B; Ketkar S; Khaw KT; Knowles JW; Kooner AS; Kors JA; Kumari M; Milani L; Laiho P; Lakatta EG; Langenberg C; Leusink M; Liu Y; Luben RN; Lunetta KL; Lynch SN; Markus MR; Marques-Vidal P; Mateo Leach I; McArdle WL; McCarroll SA; Medland SE; Miller KA; Montgomery GW; Morrison AC; Muller-Nurasyid M; Navarro P; Nelis M; O'Connell JR; O'Donnell CJ; Ong KK; Newman AB; Peters A; Polasek O; Pouta A; Pramstaller PP; Psaty BM; Rao DC; Ring SM; Rossin EJ; Rudan D; Sanna S; Scott RA; Sehmi JS; Sharp S; Shin JT; Singleton AB; Smith AV; Soranzo N; Spector TD; Stewart C; Stringham HM; Tarasov KV; Uitterlinden AG; Vandenput L; Hwang SJ; Whitfield JB; Wijmenga C; Wild SH; Willemsen G; Wilson JF; Witteman JC; Wong A; Wong Q; Jamshidi Y; Zitting P; Boer JM; Boomsma DI; Borecki IB; van Duijn CM; Ekelund U; Forouhi NG; Froguel P; Hingorani A; Ingelsson E; Kivimaki M; Kronmal RA; Kuh D; Lind L; Martin NG; Oostra BA; Pedersen NL; Quertermous T; Rotter JI; van der Schouw YT; Verschuren WM; Walker M; Albanes D; Arnar DO; Assimes TL; Bandinelli S; Boehnke M; de Boer RA; Bouchard C; Caulfield WL; Chambers JC; Curhan G; Cusi D; Eriksson J; Ferrucci L; van Gilst WH; Glorioso N; de Graaf J; Groop L; Gyllensten U; Hsueh WC; Hu FB; Huikuri HV; Hunter DJ; Iribarren C; Isomaa B; Jarvelin MR; Jula A; Kahonen M; Kiemeney LA; Van der Klauw MM; Kooner JS; Kraft P; Iacoviello L; Lehtimaki T; Lokki ML; Mitchell BD; Navis G; Nieminen MS; Ohlsson C; Poulter NR; Qi L; Raitakari OT; Rimm EB; Rioux JD; Rizzi F; Rudan I; Salomaa V; Sever PS; Shields DC; Shuldiner AR; Sinisalo J; Stanton AV; Stolk RP; Strachan DP; Tardif JC; Thorsteinsdottir U; Tuomilehto J; van Veldhuisen DJ; Virtamo J; Viikari J; Vollenweider P; Waeber G; Widen E; Cho YS; Olsen JV; Visscher PM; Willer C; Franke L; Global BPgen Consortium; CARDIoGRAM Consortium; Erdmann J; Thompson JR; PR GWAS Consortium; Pfeufer A
Nat Genet. 2013 Jun;45(6):621-31. Epub 2013 Apr 14.
Association of single- vs dual-chamber ICDs with mortality, readmissions, and complications among patients receiving an ICD for primary prevention
IMPORTANCE: Randomized trials of implantable cardioverter-defibrillators (ICDs) for primary prevention predominantly used single-chamber devices. In clinical practice, patients often receive dual-chamber ICDs, even without clear indications for pacing. The outcomes of dual- vs single-chamber devices are uncertain. OBJECTIVE: To compare outcomes of single- and dual-chamber ICDs for primary prevention of sudden cardiac death. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of admissions in the National Cardiovascular Data Registry’s (NCDR) ICD registry from 2006-2009 that could be linked to Centers for Medicare & Medicaid Services fee-for-service Medicare claims data. Patients were included if they received an ICD for primary prevention and did not have a documented indication for pacing. MAIN OUTCOMES AND MEASURES: Adjusted risks of 1-year mortality, all-cause readmission, heart failure readmission, and device-related complications within 90 days were estimated with propensity-score matching based on patient, clinician, and hospital factors. RESULTS: Among 32,034 patients, 12,246 (38%) received a single-chamber device and 19,788 (62%) received a dual-chamber device. In a propensity-matched cohort, rates of complications were lower for single-chamber devices (3.51% vs 4.72%; P < .001; risk difference, -1.20 [95% CI, -1.72 to -0.69]), but device type was not significantly associated with 1-year mortality (unadjusted rate, 9.85% vs 9.77%; hazard ratio [HR], 0.99 [95% CI, 0.91 to 1.07]; P = .79), 1-year all-cause hospitalization (unadjusted rate, 43.86% vs 44.83%; HR, 1.00 [95% CI, 0.97-1.04]; P = .82), or hospitalization for heart failure (unadjusted rate, 14.73% vs 15.38%; HR, 1.05 [95% CI, 0.99-1.12]; P = .19). CONCLUSIONS AND RELEVANCE: Among patients receiving an ICD for primary prevention without indications for pacing, the use of a dual-chamber device compared with a single-chamber device was associated with a higher risk of device-related complications and similar 1-year mortality and hospitalization outcomes. Reasons for preferentially using dual-chamber ICDs in this setting remains unclear.
Authors: Peterson PN; Varosy PD; Heidenreich PA; Wang Y; Dewland TA; Curtis JP; Go AS; Greenlee RT; Magid DJ; Normand SL; Masoudi FA
JAMA. 2013 May 15;309(19):2025-34.
Chronic Kidney Disease and Outcomes in Heart Failure With Preserved Versus Reduced Ejection Fraction: The Cardiovascular Research Network PRESERVE Study
There is scant evidence on the effect that chronic kidney disease (CKD) confers on clinically meaningful outcomes among patients with heart failure with preserved left ventricular ejection fraction (HF-PEF). We identified a community-based cohort of patients with HF. Electronic medical record data were used to divide into HF-PEF and reduced left ventricular EF on the basis of quantitative and qualitative estimates. Level of CKD was assessed by estimated glomerular filtration rate (eGFR) and by dipstick proteinuria. We followed patients for a median of 22.1 months for outcomes of death and hospitalization (HF-specific and all-cause). Multivariable Cox regression estimated the adjusted relative-risk of outcomes by level of CKD, separately for HF-PEF and HF with reduced left ventricular EF. We identified 14 579 patients with HF-PEF and 9762 with HF with reduced left ventricular EF. When compared with patients with eGFR between 60 and 89 mL/min per 1.73 m(2), lower eGFR was associated with an independent graded increased risk of death and hospitalization. For example, among patients with HF-PEF, the risk of death was nearly double for eGFR 15 to 29 mL/min per 1.73 m(2) and 7× higher for eGFR<15 mL/min per 1.73 m(2), with similar findings in those with HF with reduced left ventricular EF. CKD is common and an important independent predictor of death and hospitalization in adults with HF across the spectrum of left ventricular systolic function. Our study highlights the need to develop new and effective interventions for the growing number of patients with HF complicated by CKD.
Authors: Smith DH; Thorp ML; Gurwitz JH; McManus DD; Goldberg RJ; Allen LA; Hsu G; Sung SH; Magid DJ; Go AS
Circ Cardiovasc Qual Outcomes. 2013 May;6(3):333-42.
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Authors: Berndt SI; Iribarren C; Ingelsson E; et al.
Nat Genet. 2013 May;45(5):501-12. Epub 2013 Apr 7.
Comparative effectiveness of coronary artery bypass grafting and percutaneous coronary intervention for multivessel coronary disease in a community-based population with chronic kidney disease
BACKGROUND: Randomized clinical trials comparing coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) have largely excluded patients with chronic kidney disease (CKD), leading to uncertainty about the optimal coronary revascularization strategy. We sought to test the hypothesis that an initial strategy of CABG would be associated with lower risks of long-term mortality and cardiovascular morbidity compared with PCI for the treatment of multivessel coronary heart disease in the setting of CKD. METHODS: We created a propensity score-matched cohort of patients aged >/=30 years with no prior dialysis or renal transplant who received multivessel coronary revascularization between 1996 and 2008 within a large integrated health care delivery system in northern California. We used extended Cox regression to examine death from any cause, acute coronary syndrome, and repeat revascularization. RESULTS: Coronary artery bypass grafting was associated with a significantly lower adjusted rate of death than PCI across all strata of estimated glomerular filtration rate (eGFR) (in mL/min per 1.73 m(2)): the adjusted hazard ratio (HR) was 0.81, 95% CI 0.68 to 1.00 for patients with eGFR >/=60; HR 0.73 (CI 0.56-0.95) for eGFR of 45 to 59; and HR 0.87 (CI 0.67-1.14) for eGFR <45. Coronary artery bypass grafting was also associated with significantly lower rates of acute coronary syndrome and repeat revascularization at all levels of eGFR compared with PCI. CONCLUSIONS: Among adults with and without CKD, multivessel CABG was associated with lower risks of death and coronary events compared with multivessel PCI.
Authors: Chang TI; Leong TK; Kazi DS; Lee HS; Hlatky MA; Go AS
Am Heart J. 2013 May;165(5):800-8, 808.e1-2. Epub 2013 Apr 2.
Contemporary Prevalence and Correlates of Incident Heart Failure with Preserved Ejection Fraction
BACKGROUND: We assessed the prevalence of preserved left ventricular ejection fraction in patients with incident heart failure and differences in the demographic and clinical characteristics that may differentiate patients presenting with heart failure with preserved versus reduced left ventricular ejection fraction. METHODS: We identified all patients with newly diagnosed heart failure between 2005 and 2008 from 4 sites in the Cardiovascular Research Network on the basis of hospital discharge and ambulatory visit diagnoses, and assigned a category of preserved, borderline, or reduced left ventricular ejection fraction using data from electronic databases and chart review. RESULTS: We identified 11,994 patients with incident heart failure; of these, 6210 (51.8%) had preserved left ventricular ejection fraction, 1870 (15.6%) had borderline systolic dysfunction, and 3914 (32.6%) had reduced left ventricular ejection fraction. For those with heart failure with preserved left ventricular ejection fraction, the mean age was 74.7 years and 57.1% were women; for those with borderline systolic dysfunction, the mean age was 71.6 years and 38.4% were women; and for those with reduced left ventricular ejection fraction, the mean age was 69.1 years and 32.6% were women. Compared with white patients, black patients were less likely to have heart failure with preserved systolic function. Those with a history of coronary artery bypass surgery, mitral or aortic valvular disease, atrial fibrillation or flutter, or a diagnosis of hypertension were more likely to have heart failure with preserved systolic function, as were those with a diverse range of noncardiac comorbid conditions, including chronic lung disease, chronic liver disease, a history of a hospitalized bleed, a history of a mechanical fall, a diagnosis of depression, and a diagnosis of dementia. Patients with a history of acute myocardial infarction and a history of ventricular fibrillation or ventricular tachycardia were less likely to have heart failure with preserved left ventricular ejection fraction. Patients with higher systolic blood pressures at baseline and lower low-density lipoprotein levels were more likely to have heart failure with preserved left ventricular ejection fraction, as were those with lower hemoglobin levels and the lowest glomerular filtration rates. CONCLUSIONS: Heart failure with preserved left ventricular ejection fraction is the most common form of the heart failure syndrome among patients newly presenting with this condition, and women and older adults are especially affected. Evidence-based treatment strategies apply to less than one third of patients with newly diagnosed heart failure.
Authors: Gurwitz JH; Magid DJ; Smith DH; Goldberg RJ; McManus DD; Allen LA; Saczynski JS; Thorp ML; Hsu G; Sung SH; Go AS
Am J Med. 2013 May;126(5):393-400. Epub 2013 Mar 14.
Comparison of Medication Practices in Patients With Heart Failure and Preserved Versus Those With Reduced Ejection Fraction (from the Cardiovascular Research Network [CVRN])
Limited data exist describing the differences in the medical treatment of patients with heart failure with preserved ejection fraction (HF-PEF) from those with heart failure with reduced ejection fraction (HF-REF) in more generalizable population-based cohorts. We studied patients with incident HF diagnosed from 2005 to 2008 from 4 sites participating in the Cardiovascular Research Network. These patients, their medication profile, and left ventricular systolic function status were identified from the hospital discharge and ambulatory visit diagnoses, pharmacy dispensing information, and imaging reports found in the health plan electronic databases and through chart review. The study population consisted of 6,210 patients with newly diagnosed HF-PEF and 3,914 patients with newly diagnosed HF-REF. The mean age of our study population was 73 years, 48% were women, and 74% were white. The patients with HF-REF were less likely to have been treated with various cardiac and HF-related medications before their index HF event; however, they were significantly more likely to have been treated with new cardiac medications and HF therapies after the diagnosis of HF than were the patients with HF-PEF. After controlling for several potentially confounding factors, the patients with HF-PEF were significantly less likely to have been treated with multiple cardiac drug regimens (adjusted odds ratio 0.69, 95% confidence interval 0.59 to 0.81) and multiple HF-related therapies (adjusted odds ratio 0.40, 95% confidence interval 0.38 to 0.42) than were patients with HF-REF. In conclusion, the present results from a large, population-based sample suggest considerable variation in the previous and new use of different cardiac medication classes of drugs in patients with HF-PEF versus HF-REF.
Authors: Goldberg RJ; Gurwitz JH; Saczynski JS; Hsu G; McManus DD; Magid DJ; Smith DH; Go AS; CVRN PRESERVE HF Investigators
Am J Cardiol. 2013 May 1;111(9):1324-9. Epub 2013 Feb 1.
Association of Cardiac Troponin T With Left Ventricular Structure and Function in CKD
BACKGROUND: Serum cardiac troponin T (cTnT) is associated with increased risk of heart failure and cardiovascular death in several population settings. We evaluated associations of cTnT levels with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease (CKD) without heart failure. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort (CRIC; N=3,243). PREDICTOR: The primary predictor was cTnT level. Secondary predictors included demographic and clinical characteristics, hemoglobin level, high-sensitivity C-reactive protein level, and estimated glomerular filtration rate using cystatin C. OUTCOMES: Echocardiography was used to determine left ventricular (LV) mass and LV systolic and diastolic function. MEASUREMENTS: Circulating cTnT was measured in stored sera using the highly sensitive assay. Logistic and linear regression models were used to examine associations of cTnT level with each echocardiographic outcome. RESULTS: cTnT was detectable in 2,735 (84%) persons; median level was 13.3 (IQR, 7.7-23.8) pg/mL. Compared with undetectable cTnT (<3.0 pg/mL), the highest quartile (23.9-738.7 pg/mL) was approximately 2 times as likely to have LV hypertrophy (OR, 2.43; 95% CI, 1.44-4.09) in the fully adjusted model. cTnT level had a more modest association with LV systolic dysfunction; as a log-linear variable, a significant association was present in the fully adjusted model (OR of 1.4 [95% CI, 1.2-1.7] per 1-log unit; P < 0.001). There was no significant independent association between cTnT level and LV diastolic dysfunction. When evaluated as a screening test, cTnT level functioned only modestly for LV hypertrophy and concentric hypertrophy detection (area under the curve, 0.64 for both), with weaker areas under the curve for the other outcomes. LIMITATIONS: The presence of coronary artery disease was not formally assessed using either noninvasive or angiographic techniques in this study. CONCLUSIONS: In this large CKD cohort without heart failure, detectable cTnT had a strong association with LV hypertrophy, a more modest association with LV systolic dysfunction, and no association with diastolic dysfunction. These findings indicate that circulating cTnT levels in patients with CKD are predominantly an indicator of pathologic LV hypertrophy.
Authors: Mishra RK; Li Y; DeFilippi C; Fischer MJ; Yang W; Keane M; Chen J; He J; Kallem R; Horwitz EJ; Rafey M; Raj DS; Go AS; Shlipak MG; CRIC Study Investigators
Am J Kidney Dis. 2013 May;61(5):701-9. Epub 2013 Jan 4.
Impact of Gestational Diabetes Mellitus on Pubertal Changes in Adiposity and Metabolic Profiles in Latino Offspring
OBJECTIVE: To examine the impact of maternal gestational diabetes mellitus (GDM) status on longitudinal changes in adiposity and metabolic variables in overweight Latino offspring (from age 8-20 years) across puberty. STUDY DESIGN: This longitudinal cohort of 210 overweight Latino children was measured annually for a period of 3 +/- 1 years for Tanner stage through physical examination, adiposity by dual-energy X-ray absorptiometry and magnetic resonance imaging, lipids, and glucose and insulin action via the oral glucose tolerance test and frequently sampled intravenous glucose tolerance test. Linear mixed-effects modeling estimated the impact of maternal GDM status on baseline and changes in adiposity and metabolic variables across puberty. RESULTS: In our cohort, 22% of offspring were from GDM pregnancies. At baseline, the GDM offspring were heavier at birth, more likely to have a family history of type 2 diabetes, and less likely to have been breastfed (for any duration). Compared with the non-GDM offspring, the GDM offspring had greater increases in total body fat (+6.5% vs +4.5%; P = .03) and steeper declines in acute insulin response (-39% vs -17%; P < .001) and disposition index (-57% vs -35%; P < .001) across Tanner stages, independent of ethnicity, sex, breastfeeding status, family history of diabetes, and baseline and changes in body composition. CONCLUSION: These findings confirm the elevated risk for excess adiposity and type 2 diabetes in GDM offspring, and further underscore the need for interventions targeting Latino GDM and their offspring.
Authors: Davis JN; Gunderson EP; Gyllenhammer LE; Goran MI
J Pediatr. 2013 Apr;162(4):741-5. Epub 2012 Nov 10.
Response to the letter from Dr. Szarewski
Authors: Sidney S
Contraception. 2013 Apr;87(4):506-7. Epub 2012 Dec 13.
Peripartum cardiomyopathy: population-based birth prevalence and 7-year mortality
Authors: Walton DL; Gunderson EP; Go AS
Obstet Gynecol. 2013 Apr;121(4):879-80.
Breast Arterial Calcification: a New Marker of Cardiovascular Risk?
Mammographically-detected breast arterial calcifications (BAC) are considered to be an incidental finding without clinical importance since they are not associated with increased risk of breast cancer. The goal of this article is to review existing evidence that the presence of BAC on mammography correlates with several (but not all) traditional cardiovascular disease (CVD) risk factors and with prevalent and incident CVD. Thus, BAC detected during routine mammography is a noteworthy finding that could be valuable in identifying asymptomatic women at increased future CVD risk that may be candidates for more aggressive management. In addition, there are notable differences in measures of subclinical atherosclerosis burden in women (ie, coronary artery calcification) by race/ethnic background, and the same appears to be true for BAC, although data are very limited. Another noteworthy limitation of prior research on BAC is the reliance on absence vs presence of BAC; no study to date has determined gradation of BAC. Further research is thus required to elucidate the role of BAC gradation in the prediction of CVD outcomes and to determine whether adding BAC gradation to prediction models based on traditional risk factors improves classification of CVD risk.
Authors: Iribarren C; Molloi S
Curr Cardiovasc Risk Rep. 2013 Apr;7(2):126-135. Epub 2013-02-03.
Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden: A Collaborative Meta-Analysis
OBJECTIVES: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
Authors: Chan K; Go AS; Ye S; et al.
J Am Coll Cardiol. 2013 Mar 5;61(9):957-70. Epub 2013 Jan 23.
Effectiveness of beta-Blockers in Heart Failure With Left Ventricular Systolic Dysfunction and Chronic Kidney Disease
Establishing medication effectiveness outside of a randomized trial requires careful study design to mitigate selection bias. Previous observational studies of ?-blockers in patients with chronic kidney disease and heart failure have had methodologic limitations that may have introduced bias. We examined whether initiation of ?-blocker therapy was associated with better outcomes among patients with chronic kidney disease and newly diagnosed heart failure with left ventricular systolic dysfunction. We identified 668 adults in the Kaiser Permanente Northern California system from 2006 to 2008 with chronic kidney disease, incident heart failure, left ventricular systolic dysfunction, and no previous ?-blocker use. We defined chronic kidney disease as estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2) or proteinuria, and we excluded patients receiving dialysis. We used extended Cox regression to assess the association of treatment with death and the combined end point of death or heart failure hospitalization. Initiation of ?-blocker therapy was associated with a significantly lower crude risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.35-0.63), but this association was attenuated and no longer significant after multivariable adjustment (HR 0.75, CI 0.51-1.12). ?-Blocker therapy was significantly associated with a lower risk of death or heart failure hospitalization even after adjustment for potential confounders (HR 0.67, CI 0.51-0.88). ?-Blocker therapy is associated with lower risk of death or heart failure hospitalization among patients with chronic kidney disease, incident heart failure, and left ventricular systolic dysfunction.
Authors: Chang TI; Yang J; Freeman JV; Hlatky MA; Go AS
J Card Fail. 2013 Mar;19(3):176-82.
Association of Electrocardiographically Determined Left Ventricular Mass With Incident Diabetes, 1985-1986 to 2010-2011: Coronary Artery Risk Development in Young Adults (CARDIA) study
OBJECTIVE: Electrocardiographic indices reflecting left ventricular hypertrophy are associated with incident diabetes in clinical populations at risk for coronary heart disease. We tested whether electrocardiographically determined left ventricular mass was positively associated with incident diabetes in a population sample. RESEARCH DESIGN AND METHODS: Coronary Artery Risk Development in Young Adults (CARDIA) study participants (n = 4,739) were followed from 1985-1986 to 2010-2011 for incident diabetes. Validated sex- and race-specific formulas were applied to standard electrocardiograms to determine left ventricular mass. RESULTS: Over 25 years, 444 participants developed diabetes (9.4%). After adjustment for demographic, behavioral, and clinical covariates, participants in the highest quartile of left ventricular mass index (LVMI) were twice as likely to develop diabetes than participants in the lower three quartiles (hazard ratio 2.61 [95% CI 2.16-3.17]). Neither Cornell voltage nor Cornell voltage product was associated with incident diabetes in fully adjusted models. CONCLUSIONS: Electrocardiographically determined LVMI may be a useful noninvasive marker for identifying adults at risk for diabetes.
Authors: Carnethon MR; Ning H; Soliman EZ; Lewis CE; Schreiner PJ; Sidney S; Lloyd-Jones DM
Diabetes Care. 2013 Mar;36(3):645-7. Epub 2012 Nov 16.
A Longitudinal Study of Left Ventricular Function and Structure from CKD to ESRD: The CRIC Study
BACKGROUND AND OBJECTIVES: Abnormal left ventricular structure and function are associated with increased risk of adverse outcomes among patients with CKD and ESRD. A better understanding of changes in left ventricular mass and ejection fraction during the transition from CKD to ESRD may provide important insights to opportunities to improve cardiac outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a longitudinal study of a subset of participants of the Chronic Renal Insufficiency Cohort who were enrolled from 2003 to 2007 and followed through January of 2011. Participants were included if they had serial echocardiograms performed at advanced CKD (defined as estimated GFR<20 ml/min per 1.73 m(2)) and again after ESRD (defined as need for hemodialysis or peritoneal dialysis). RESULTS: A total of 190 participants (44% female, 66% black) had echocardiograms during advanced CKD and after ESRD. Mean (SD) estimated GFR at advanced CKD was 16.9 (3.5) ml/min per 1.73 m(2). Mean (SD) time between the advanced CKD echocardiogram and ESRD echocardiogram was 2.0 (1.0) years. There was no significant change in left ventricular mass index (62.3-59.5 g/m(2.7), P=0.10) between advanced CKD and ESRD; however, ejection fraction significantly decreased (53%-50%, P=0.002). Interactions for age, race, dialysis modality, and diabetes status were not significant (P>0.05). CONCLUSIONS: Mean left ventricular mass index did not change significantly from advanced CKD to ESRD; however, ejection fraction declined during this transition period. Although left ventricular mass index is fixed by advanced stages of CKD, ejection fraction decline during more advanced stages of CKD may be an important contributor to cardiovascular disease and mortality after dialysis.
Authors: Bansal N; Go AS; CRIC Study Investigators; et al.
Clin J Am Soc Nephrol. 2013 Mar;8(3):355-62. Epub 2013 Feb 14.
Preterm Birth and Future Maternal Blood Pressure, Inflammation, and Intimal-medial Thickness: The CARDIA Study
Preterm birth (PTB, <37 weeks) may be a marker of endothelial dysfunction and a proinflammatory phenotype; both are risk factors for cardiovascular disease. We studied 916 women (46% black) with 1181 live births between enrollment in the Coronary Artery Risk Development in Young Adults study (age 18-30 years) and 20 years later. C-reactive protein was measured at years 7, 15, and 20. Interleukin-6 and carotid intima-media thickness, which incorporated the common carotid arteries, bifurcations, and internal carotid arteries, were measured at year 20. Blood pressure, lipids, anthropometrics, and pregnancy events were assessed at all visits. Change in risk factors and differences in inflammatory markers and intima-media thickness according to PTB were evaluated. Women with PTBs (n=226) had higher mean systolic blood pressures before pregnancy (106 versus 105 mm Hg, respectively; P=0.03). Systolic and diastolic blood pressure increased more rapidly over 20 years compared with women with term births (P<0.01 time interaction), even after removing women with self-reported hypertension in pregnancy. Women with PTB versus term births had similar mean intima-media thickness adjusted for age, body mass index, race, lifestyle, and cardiovascular risk factors. C-reactive protein and interleukin-6 did not differ according to PTB. Women with PTB, regardless of hypertension during pregnancy, had higher blood pressure after pregnancy compared with women with term births. In the United States, where rates of PTB are high and race disparities persist, PTB may identify women with higher blood pressure in the years after pregnancy.
Authors: Catov JM; Lewis CE; Lee M; Wellons MF; Gunderson EP
Hypertension. 2013 Mar;61(3):641-6. Epub 2013 Jan 14.
Hepatic abscess with biliary communication following transarterial chemoembolization of hepatocellular carcinoma.
Authors: Huang, Robert J RJ; Ambrosy, Andrew P AP; Triadafilopoulos, George G
Digestive diseases and sciences. 2013 Sep 25;58(9):2463-5. Epub 2013-02-20.
Incident Atrial Fibrillation and Risk of End-Stage Renal Disease in Adults with Chronic Kidney Disease
BACKGROUND: Atrial fibrillation (AF) frequently occurs in patients with chronic kidney disease (CKD). However, the long-term impact of development of AF on the risk of adverse renal outcomes in patients with CKD is unknown. In this study, we determined the association between incident AF and risk of end-stage renal disease (ESRD) among adults with CKD. METHODS AND RESULTS: We studied adults with CKD (defined as estimated glomerular filtration rate eGFR <60 mL/min per 1.73 m(2) by the Chronic Kidney Disease Epidemiology Collaboration equation) enrolled in Kaiser Permanente Northern California who were identified between 2002 and 2010 and who did not have previous ESRD or previously documented AF. Incident AF was identified by using primary hospital discharge diagnoses or 2 or more outpatient visits for AF. Incident ESRD was ascertained from a comprehensive health plan registry for dialysis and renal transplant. Among 206 229 adults with CKD, 16 463 developed incident AF. During a mean follow-up of 5.1+/-2.5 years, there were 345 cases of ESRD that occurred after development of incident AF (74 per 1000 person-years) in comparison with 6505 cases of ESRD during periods without AF (64 per 1000 person-years, P<0.001). After adjustment for potential confounders, incident AF was associated with a 67% increase in the rate of ESRD (hazard ratio, 1.67; 95% confidence interval, 1.46-1.91). CONCLUSIONS: Incident AF is independently associated with increased risk of developing ESRD in adults with CKD. Further study is needed to identify potentially modifiable pathways through which AF leads to a higher risk of progression to ESRD.
Authors: Bansal N; Fan D; Hsu CY; Ordonez JD; Marcus GM; Go AS
Circulation. 2013 Feb 5;127(5):569-74. Epub 2012 Dec 28.
Retinopathy and Cognitive Impairment in Adults With CKD
BACKGROUND: Retinal microvascular abnormalities have been associated with cognitive impairment, possibly serving as a marker of cerebral small-vessel disease. This relationship has not been evaluated in persons with chronic kidney disease (CKD), a condition associated with increased risk of both retinal pathology and cognitive impairment. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 588 participants 52 years or older with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTOR: Retinopathy graded using the Early Treatment Diabetic Retinopathy Study severity scale and diameters of retinal vessels. OUTCOMES: Neuropsychological battery of 6 cognitive tests. MEASUREMENTS: Logistic regression models were used to evaluate the association of retinopathy, individual retinopathy features, and retinal vessel diameters with cognitive impairment (
Authors: Yaffe K; Go AS; CRIC Study Investigators; et al.
Am J Kidney Dis. 2013 Feb;61(2):219-27. Epub 2012 Dec 1.
Daily Treatment Time and Functional Gains of Stroke Patients During Inpatient Rehabilitation
OBJECTIVE: To study the effects of daily treatment time on functional gain of patients who have had a stroke. DESIGN: A retrospective cohort study. SETTING: An inpatient rehabilitation hospital (IRH) in northern California. PARTICIPANTS: Three hundred sixty patients who had a stroke and were discharged from the IRH in 2007. INTERVENTIONS: Average minutes of rehabilitation therapy per day, including physical therapy, occupation therapy, speech and language therapy, and total treatment. MAIN OUTCOME MEASURES: Functional gain measured by the Functional Independence Measure, including activities of daily living, mobility, cognition, and the total of the Functional Independence Measure (FIM) scores. RESULTS: The study sample had a mean age of 64.8 years; 57.4% were men and 61.4% were white. The mean total daily therapy time was 190.3 minutes, and the mean total functional gain was 26.0. A longer daily therapeutic duration was significantly associated with total functional gain (r = .23, P = .0094). Patients who received a total therapy time of <3.0 hours per day had significantly lower total functional gain than did those treated >/=3.0 hours. No significant difference in total functional gain was found between patients treated >/=3.0 but <3.5 hours and >/=3.5 hours per day. The daily treatment time of physical therapy, occupational therapy, and speech and language therapy also was significantly associated with corresponding subscale functional gains. In addition, hemorrhagic stroke, left brain injury, earlier IRH admission, and a longer IRH stay were associated with total functional improvement. CONCLUSIONS: The study demonstrated a significant relationship between daily therapeutic duration and functional gain during IRH stay and showed treatment time thresholds for optimal functional outcomes for patients in inpatient rehabilitation who had a stroke.
Authors: Wang H; Camicia M; Terdiman J; Mannava MK; Sidney S; Sandel ME
PM R. 2013 Feb;5(2):122-8. Epub 2012 Nov 2.
Atrial fibrillation and outcomes in heart failure with preserved versus reduced left ventricular ejection fraction
BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) are 2 of the most common cardiovascular conditions nationally and AF frequently complicates HF. We examined how AF has impacts on adverse outcomes in HF-PEF versus HF-REF within a large, contemporary cohort. METHODS AND RESULTS: We identified all adults diagnosed with HF-PEF or HF-REF based on hospital discharge and ambulatory visit diagnoses and relevant imaging results for 2005-2008 from 4 health plans in the Cardiovascular Research Network. Data on demographic features, diagnoses, procedures, outpatient pharmacy use, and laboratory results were ascertained from health plan databases. Hospitalizations for HF, stroke, and any reason were identified from hospital discharge and billing claims databases. Deaths were ascertained from health plan and state death files. Among 23 644 patients with HF, 11 429 (48.3%) had documented AF (9081 preexisting, 2348 incident). Compared with patients who did not have AF, patients with AF had higher adjusted rates of ischemic stroke (hazard ratio [HR] 2.47 for incident AF; HR 1.57 for preexisting AF), hospitalization for HF (HR 2.00 for incident AF; HR 1.22 for preexisting AF), all-cause hospitalization (HR 1.45 for incident AF; HR 1.15 for preexisting AF), and death (incident AF HR 1.67; preexisting AF HR 1.13). The associations of AF with these outcomes were similar for HF-PEF and HF-REF, with the exception of ischemic stroke. CONCLUSIONS: AF is a potent risk factor for adverse outcomes in patients with HF-PEF or HF-REF. Effective interventions are needed to improve the prognosis of these high-risk patients.
Authors: McManus DD; Hsu G; Sung SH; Saczynski JS; Smith DH; Magid DJ; Gurwitz JH; Goldberg RJ; Go AS; Cardiovascular Research Network PRESERVE Study
J Am Heart Assoc. 2013 Feb 1;2(1):e005694.
Sex differences in cardiovascular outcomes in patients with incident hypertension
BACKGROUND:: The time of initial hypertension diagnosis represents an opportunity to assess subsequent risk of adverse cardiovascular outcomes. The extent to which women and men with newly identified hypertension are at a similar risk for adverse cardiovascular events, including chronic kidney disease (CKD), is not well known. METHODS:: Among women and men with incident hypertension from 2001 to 2006 enrolled in the Cardiovascular Research Network (CVRN) Hypertension Registry, we compared incident events including all-cause death; hospitalization for myocardial infarction (MI), heart failure or stroke; and the development of CKD. Multivariable models were adjusted for patient demographic and clinical characteristics. RESULTS:: Among 177 521 patients with incident hypertension, 55% were women. Compared with men, women were older, more likely white and had more kidney disease at baseline. Over median 3.2 years (interquartile range 1.6-4.8) of follow-up, after adjustment, women were equally likely to be hospitalized for heart failure [hazard ratio 0.90, 95% confidence interval (CI) 0.76-1.07] and were significantly less likely to die of any cause (hazard ratio 0.85, 95% CI 0.80-0.90) or be hospitalized for MI (hazard ratio 0.44, 95% CI 0.39-0.50) or stroke (hazard ratio 0.68, 95% CI 0.60-0.77) compared with men. Women were significantly more likely to develop CKD (9.60 vs. 7.15%; adjusted hazard ratio 1.17, 95% CI 1.12-1.22) than men. CONCLUSION:: In this cohort with incident hypertension, women were more likely to develop CKD and less likely to develop other cardiovascular outcomes compared with men. Future studies should investigate the potential reasons for these sex differences.
Authors: Daugherty SL; Masoudi FA; Zeng C; Ho PM; Margolis KL; O'Connor PJ; Go AS; Magid DJ
J Hypertens. 2013 Feb;31(2):271-7.
Cardiovascular health through young adulthood and cognitive functioning in midlife
OBJECTIVE: A study was undertaken to examine the association between overall cardiovascular health as recently defined by the American Heart Association in young adulthood to middle age and cognitive function in midlife. Overall ideal cardiovascular health incorporates 7 metrics, including the avoidance of overweight or obesity, a healthful diet, nonsmoking, and physical activity, total cholesterol, blood pressure, and fasting glucose at goal levels. METHODS: This analysis of the Coronary Artery Risk Development in Young Adults study, a multicenter community-based study with 25 years of follow-up, included 2,932 participants aged 18 to 30 years at baseline (year 0) who attended follow-up examinations at years 7 and 25. Cardiovascular health metrics were measured at each examination. The Digit Symbol Substitution Test (DSST), modified Stroop test, and Rey Auditory Verbal Learning Test (RAVLT) were completed at year 25. RESULTS: A greater number of ideal cardiovascular metrics in young adulthood and middle age were independently associated with better cognitive function in midlife (p for trend < 0.01, for all). Specifically, each additional ideal metric was associated with 1.32 more symbols on the DSST (95% confidence interval [CI] = 0.93 - 1.71), a 0.77-point lower interference score on the Stroop test (95% CI=-1.03 to -0.45), and 0.12 more words on the RAVLT (95% CI = 0.04 to 0.20). Participants who had >/=5 ideal metrics at a greater number of the 3 examinations over the 25-year period exhibited better performance on each cognitive test in middle age (p for trend < 0.01, for all). INTERPRETATION: Ideal cardiovascular health in young adulthood and its maintenance to middle age is associated with better psychomotor speed, executive function, and verbal memory in midlife.
Authors: Reis JP; Loria CM; Launer LJ; Sidney S; Liu K; Jacobs DR Jr; Zhu N; Lloyd-Jones DM; He K; Yaffe K
Ann Neurol. 2013 Feb;73(2):170-9. Epub 2013 Feb 26.
Association of N-terminal Pro-B-type Natriuretic Peptide With Left Ventricular Structure and Function in Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort [CRIC])
We evaluated the cross-sectional associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease without clinical heart failure, the Chronic Renal Insufficiency Cohort (n = 3,232). The associations of NT-proBNP with echocardiographically determined left ventricular (LV) mass and LV systolic and diastolic function were evaluated using multivariate logistic and linear regression models. Reclassification of participants’ predicted risk of LV hypertrophy (LVH), systolic and diastolic dysfunction was performed using a category-free net reclassification improvement index that compared a clinical model with and without NT-proBNP. The median NT-proBNP was 126.6 pg/ml (interquartile range 55.5 to 303.7). The greatest quartile of NT-proBNP was associated with a nearly threefold odds of LVH (odds ratio 2.7, 95% confidence interval [CI] 1.8 to 4.0) and LV systolic dysfunction (odds ratio 2.7, 95% CI 1.7 to 4.5) and a twofold odds of diastolic dysfunction (odds ratio 2.0, 95% CI 1.3 to 2.9) in the fully adjusted models. When evaluated alone as a screening test, NT-proBNP functioned modestly for the detection of LVH (area under the curve 0.66) and LV systolic dysfunction (area under the curve 0.62) and poorly for the detection of diastolic dysfunction (area under the curve 0.51). However, when added to the clinical model, NT-proBNP significantly reclassified participants’ likelihood of having LVH (net reclassification improvement 0.14, 95% CI 0.13-0.15; p <0.001) and LV systolic dysfunction (net reclassification improvement 0.28, 95% CI 0.27 to 0.30; p <0.001) but not diastolic dysfunction (net reclassification improvement 0.10, 95% CI 0.10 to 0.11; p = 0.07). In conclusion, in this large chronic kidney disease cohort without heart failure, NT-proBNP had strong associations with prevalent LVH and LV systolic dysfunction.
Authors: Mishra RK; Shlipak MG; Chronic Renal Insufficiency Cohort Investigators; et al.
Am J Cardiol. 2013 Feb 1;111(3):432-8. Epub 2012 Nov 22.
Prehypertension and Hypertension in Community-Based Pediatric Practice
OBJECTIVE: To examine the prevalence of prehypertension and hypertension among children receiving well-child care in community-based practices. METHODS: Children aged 3 to 17 years with measurements of height, weight, and blood pressure (BP) obtained at an initial (index) well-child visit between July 2007 and December 2009 were included in this retrospective cohort study across 3 large, integrated health care delivery systems. Index BP classification was based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents: normal BP, <90th percentile; prehypertension, 90th to 94th percentile; hypertension, 3 BP measurements >/=95th percentile (index and 2 subsequent consecutive visits). RESULTS: The cohort included 199 513 children (24.3% aged 3-5 years, 34.5% aged 6-11 years, and 41.2% aged 12-17 years) with substantial racial/ethnic diversity (35.9% white, 7.8% black, 17.6% Hispanic, 11.7% Asian/Pacific Islander, and 27.0% other/unknown race). At the index visit, 81.9% of participants were normotensive, 12.7% had prehypertension, and 5.4% had a BP in the hypertension range (>/=95th percentile). Of the 10 848 children with an index hypertensive BP level, 3.8% of those with a follow-up BP measurement had confirmed hypertension (estimated 0.3% prevalence). Increasing age and BMI were significantly associated with prehypertension and confirmed hypertension (P < .001 for trend). Among racial/ethnic groups, blacks and Asians had the highest prevalence of hypertension. CONCLUSIONS: The prevalence of hypertension in this community-based study is lower than previously reported from school-based studies. With the size and diversity of this cohort, these results suggest the prevalence of hypertension in children may actually be lower than previously reported.
Authors: Lo JC; O'Connor PJ; et al.
Pediatrics. 2013 Feb;131(2):e415-24. Epub 2013 Jan 28.
Use of Medications for Secondary Prevention After Coronary Bypass Surgery Compared With Percutaneous Coronary Intervention
OBJECTIVES: This study sought to compare use of evidence-based secondary preventive medications after coronary bypass surgery (CABG) and percutaneous coronary intervention (PCI). BACKGROUND: Use of cardioprotective medication after coronary revascularization has been inconsistent and relatively low in older studies. METHODS: We studied patients in a large integrated healthcare delivery system who underwent CABG or PCI for new onset coronary disease. We used data from health plan databases about prescriptions dispensed during the first year after initial coronary revascularization to identify patients who never filled a prescription and to calculate the medication possession ratio among patients who filled at least 1 prescription. We focused on angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs), beta-blockers, and statins. RESULTS: Between 2000 and 2007, 8,837 patients with new onset coronary disease underwent initial CABG, and 14,516 underwent initial PCI. Patients receiving CABG were more likely than patients receiving PCI to not fill a prescription for a statin (7.1% vs. 4.8%, p < 0.0001) or for an ACEI/ARB (29.1% vs. 22.4%, p < 0.0001), but similar proportions never filled a prescription for a beta-blocker (6.4% vs. 6.1%). Among those who filled at least 1 prescription post-revascularization, patients receiving CABG had lower medication possession ratios than patients receiving PCI for ACEI/ARBs (69.4% vs. 77.8%, p < 0.0001), beta-blockers (76.1% vs. 80.6%, p < 0.0001), and statins (82.7% vs. 84.2%, p < 0.001). CONCLUSIONS: Patients who received CABG were generally less likely than patients who received PCI to fill prescriptions for secondary preventive medications and to use those medications consistently in the first year after the procedure.
Authors: Hlatky MA; Solomon MD; Shilane D; Leong TK; Brindis R; Go AS
J Am Coll Cardiol. 2013 Jan 22;61(3):295-301. Epub 2012 Dec 12.
Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation: Validation of the R2CHADS2 Index in the ROCKET AF and ATRIA Study Cohorts
BACKGROUND: We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial. METHODS AND RESULTS: In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance >/=30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R(2)CHADS(2)) improved net reclassification index by 6.2% compared with CHA(2)DS(2)VASc (C statistic=0.578) and by 8.2% compared with CHADS(2) (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R(2)CHADS(2) in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS(2). CONCLUSIONS: In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function. CLINICAL TRIAL REGISTRATION: URL: https://www.ClinicalTrials.gov. Unique identifier: NCT00403767.
Authors: Piccini JP; Go AS; ROCKET AF Steering Committee and Investigators; et al.
Circulation. 2013 Jan 15;127(2):224-32. Epub 2012 Dec 3.
The disconnect between phase II and phase III trials of drugs for heart failure.
Hospitalization for heart failure (HF) is a clinical entity associated with high postdischarge morbidity and mortality, yet few therapies are available to improve outcomes in patients with this condition. In the past decade, large phase III studies of HF treatments have failed to demonstrate drug efficacy, safety, or both, despite encouraging results from preceding phase II trials. This Review is focused on this disconnect between the results of phase II and phase III trials of drugs for HF and discusses findings from five drug-development programs (for levosimendan, tezosentan, tolvaptan, rolofylline, and nesiritide) to shed light on common themes in clinical trials conducted in patients hospitalized for HF. In particular, the importance of selecting the ‘right’ patient population, drug, and clinical end points to optimize the trial design is discussed. Areas that require further investigation are highlighted and we suggest possible directions that will help to guide future clinical trials in these patients. Large, expensive phase III trials should not be initiated without adequate phase II evidence or on the basis of overly optimistic interpretation of phase II data. Additionally, drug development programs should be targeted not only to change short-term symptoms, but also to improve the postdischarge event rate.
Authors: Vaduganathan, Muthiah M; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Gheorghiade, Mihai M; Butler, Javed J
Nature reviews. Cardiology. 2013 Feb 25;10(2):85-97. Epub 2013-01-08.
Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial.
AIMS: Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized.METHODS AND RESULTS: A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median ~24 h) for worsening HF with an EF ≤ 40% and two or more signs or symptoms of fluid overload [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.9 months. Clinician-investigators assessed patients daily for dyspnoea, orthopnoea, fatigue, rales, pedal oedema, and JVD and rated signs and symptoms on a standardized 4-point scale ranging from 0 to 3. A modified composite congestion score (CCS) was calculated by summing the individual scores for orthopnoea, JVD, and pedal oedema. Endpoints were HHF, all-cause mortality (ACM), and ACM + HHF. Multivariable Cox regression models were used to evaluate the risk of CCS at discharge on outcomes at 30 days and for the entire follow-up period. The mean CCS obtained after initial therapy decreased from the mean ± SD of 4.07 ± 1.84 and the median (25th, 75th) of 4 (3, 5) at baseline to 1.11 ± 1.42 and 1 (0, 2) at discharge. At discharge, nearly three-quarters of study participants had a CCS of 0 or 1 and fewer than 10% of patients had a CCS >3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at discharge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints at 30 days (HHF: 1.06, 0.95-1.19; ACM: 1.34, 1.14-1.58; and ACM + HHF: 1.13, 1.03-1.25) and all outcomes for the overall study period (HHF: 1.07, 1.01-1.14; ACM: 1.16, 1.09-1.24; and ACM + HHF 1.11, 1.06-1.17). Patients with a CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up. CONCLUSION: Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs and symptoms at discharge still experienced a high mortality and readmission rate.
Authors: Ambrosy, Andrew P AP; Pang, Peter S PS; Khan, Sadiya S; Konstam, Marvin A MA; Fonarow, Gregg C GC; Traver, Brian B; Maggioni, Aldo P AP; Cook, Thomas T; Swedberg, Karl K; Burnett, John C JC; Grinfeld, Liliana L; Udelson, James E JE; Zannad, Faiez F; Gheorghiade, Mihai M;
European heart journal. 2013 Mar 25;34(11):835-43. Epub 2013-01-04.
Heart Disease and Stroke Statistics–2013 Update A Report From the American Heart Association
Authors: Go AS; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2013 Jan 1;127(1):e6-e245. Epub 2012 Dec 12.
A Multisite Study of Long-term Remission and Relapse of Type 2 Diabetes Mellitus Following Gastric Bypass
BACKGROUND: Gastric bypass has profound effects on glycemic control in adults with type 2 diabetes mellitus. The goal of this study was to examine the long-term rates and clinical predictors of diabetes remission and relapse among patients undergoing gastric bypass. METHODS: We conducted a retrospective cohort study of adults with uncontrolled or medication-controlled type 2 diabetes who underwent gastric bypass from 1995 to 2008 in three integrated health care delivery systems in the USA. Remission and relapse events were defined by diabetes medication use and clinical laboratory measures of glycemic control. We identified 4,434 adults with uncontrolled or medication-controlled type 2 diabetes who had gastric bypass. RESULTS: Overall, 68.2 % (95 % confidence interval [CI], 66 and 70 %) experienced an initial complete diabetes remission within 5 years after surgery. Among these, 35.1 % (95 % CI, 32 and 38 %) redeveloped diabetes within 5 years. The median duration of remission was 8.3 years. Significant predictors of complete remission and relapse were poor preoperative glycemic control, insulin use, and longer diabetes duration. Weight trajectories after surgery were significantly different for never remitters, relapsers, and durable remitters (p = 0.03). CONCLUSIONS: Gastric bypass surgery is associated with durable remission of type 2 diabetes in many but not all severely obese diabetic adults, and about one third experience a relapse within 5 years of initial remission. More research is needed to understand the mechanisms of diabetes relapse, the optimal timing of surgery in effecting a durable remission, and the relationship between remission duration and incident microvascular and macrovascular events.
Authors: Arterburn DE; Bogart A; Sherwood NE; Sidney S; Coleman KJ; Haneuse S; O'Connor PJ; Theis MK; Campos GM; McCulloch D; Selby J
Obes Surg. 2013 Jan;23(1):93-102.
Executive Summary: Heart Disease and Stroke Statistics–2013 Update: A Report From the American Heart Association
Authors: Go AS; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2013 Jan 1;127(1):143-52.
Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users
BACKGROUND: Combined hormonal contraceptives (CHCs) place women at increased risk of venous thromboembolic events (VTEs) and arterial thrombotic events (ATEs), including acute myocardial infarction and ischemic stroke. There is concern that three recent CHC preparations [drospirenone-containing pills (DRSPs), the norelgestromin-containing transdermal patch (NGMN) and the etonogestrel vaginal ring (ETON)] may place women at even higher risk of thrombosis than other older low-dose CHCs with a known safety profile. STUDY DESIGN: All VTEs and all hospitalized ATEs were identified in women, ages 10-55 years, from two integrated health care programs and two state Medicaid programs during the time period covering their new use of DRSP, NGMN, ETON or one of four low-dose estrogen comparator CHCs. The relative risk of thrombotic and thromboembolic outcomes associated with the newer CHCs in relation to the comparators was assessed with Cox proportional hazards regression models adjusting for age, site and year of entry into the study. RESULTS: The hazards ratio for DRSP in relation to low-dose estrogen comparators among new users was 1.77 (95% confidence interval 1.33-2.35) for VTE and 2.01 (1.06-3.81) for ATE. The increased risk of DRSP was limited to the 10-34-year age group for VTE and the 35-55-year group for ATE. Use of the NGMN patch and ETON vaginal ring was not associated with increased risk of either thromboembolic or thrombotic outcomes. CONCLUSIONS: In new users, DRSP was associated with higher risk of thrombotic events (VTE and ATE) relative to low-dose estrogen comparator CHCs, while the use of the NGMN patch and ETON vaginal ring was not.
Authors: Sidney S; Cheetham TC; Connell FA; Ouellet-Hellstrom R; Graham DJ; Davis D; Sorel M; Quesenberry CP Jr; Cooper WO
Contraception. 2013 Jan;87(1):93-100. Epub 2012 Oct 19.
Both Pulmonary and Extra-Pulmonary Factors Predict the Development of Disability in Chronic Obstructive Pulmonary Disease
BACKGROUND: Although chronic obstructive pulmonary disease (COPD) is a major cause of disability worldwide, its determinants remain poorly defined. OBJECTIVE: We hypothesized that both pulmonary and extra-pulmonary factors would predict prospective disablement across a hierarchy of activities in persons with COPD. METHODS: Six hundred and nine participants were studied at baseline (T0) and 2.5 years later (T1). The Valued Life Activities (VLA) scale quantified disability (10-point scale: 0 = no difficulty and 10 = unable to perform), defining disability as any activity newly rated ‘unable to perform’ at T1. Predictors included pulmonary (lung function, 6-minute walk distance and COPD severity score) and extra-pulmonary (quadriceps strength and lower extremity function) factors. Prospective disability risk was tested by separate logistic regression models for each predictor (baseline value and its change, T0-T1; odds ratios were scaled at 1 standard deviation per factor. Incident disability across a hierarchy of obligatory, committed and discretionary VLA subscales was compared. RESULTS: Subjects manifested a 40% or greater increased odds of developing disability for each predictor (baseline and change over time). Disability in discretionary activities developed at a rate 2.2-times higher than observed in committed activities, which was in turn 2.5-times higher than the rate observed in obligatory activities (p < 0.05 for each level). CONCLUSIONS: Disability is common in COPD. Both pulmonary and extra-pulmonary factors are important in predicting its development.
Authors: Singer JP; Katz PP; Iribarren C; Omachi TA; Sanchez G; Yelin EH; Cisternas MG; Blanc PD
Respiration. 2013;85(5):375-83. Epub 2012 Jun 9.
Predictors of high sensitivity cardiac troponin T in chronic kidney disease patients: a cross-sectional study in the chronic renal insufficiency cohort (CRIC)
Cardiac troponin T is independently associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). Serum levels of high sensitivity cardiac troponin T (hs-TnT) reflect subclinical myocardial injury in ambulatory patients. We sought to determine the distribution and predictors of hs-TnT in CKD patients without overt cardiovascular disease (CVD). We studied 2464 participants within the multi-ethnic Chronic Renal Insufficiency Cohort (CRIC) who did not have self-reported CVD. We considered renal and non-renal factors as potential determinants of hs-TnT, including demographics, comorbidities, left ventricular (LV) mass, serologic factors, estimated glomerular filtration rate (eGFR) and albumin to creatinine ratio. Hs-TnT was detectable in 81% of subjects, and the median (IQR) hs-TnT was 9.4 pg/ml (4.3-18.3). Analysis was performed using Tobit regression, adjusting for renal and non-renal factors. After adjustment, lower eGFR was associated with higher expected hs-TnT; participants with eGFR < 30 ml/min/1.73 m(2) had 3-fold higher expected hs-TnT compared to subjects with eGFR > 60. Older age, male gender, black race, LV mass, diabetes and higher blood pressure all had strong, independent associations with higher expected hs-TnT. Knowledge of the determinants of hs-TnT in this cohort may guide further research on the pathology of heart disease in patients with CKD and help to stratify sub-groups of CKD patients at higher cardiovascular risk.
Authors: Dubin RF; Go AS; CRIC Study Investigators; et al.
BMC Nephrol. 2013;14:229. Epub 2013-10-22.
Patterns of Comorbidity in Older Adults with Heart Failure: The Cardiovascular Research Network PRESERVE Study
OBJECTIVES: To examine whether the total burden of comorbidity and pattern of co-occurring conditions varies in individuals with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HF-P) or HF with reduced LVEF (HF-R). DESIGN: Cross-sectional cohort study. SETTING: Four participating health plans within the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Research Network. PARTICIPANTS: All members aged 65 and older with HF based on hospital discharge and ambulatory visit diagnoses. MEASUREMENTS: Participants with a LVEF of 50% or greater were classified as having HF-P. Presence of cardiac and noncardiac comorbidities was obtained from health plan administrative databases. RESULTS: Of 23,435 individuals identified with HF and LVEF information, 53% (12,407) had confirmed HF-P (mean age 79.6; 60% female). More than three-quarters of the sample had three or more co-occurring conditions in addition to HF, and half had five or more cooccurring conditions. Participants with HF-P had a slightly higher burden of comorbidity than those with HF-R (mean 4.5 vs 4.4, P = .002). Patterns of how specific conditions co-occurred did not vary in participants with preserved or reduced systolic function. CONCLUSION: There is a high degree of comorbidity and multiple morbidity in individuals with HF. The burden and pattern of comorbidity varies only slightly in individuals with preserved or reduced LVEF.
Authors: Saczynski JS; Go AS; Magid DJ; Smith DH; McManus DD; Allen L; Ogarek J; Goldberg RJ; Gurwitz JH
J Am Geriatr Soc. 2013 Jan;61(1):26-33.
The 2013 Heart Disease and Stroke Statistical Update and theNeed for a National Cardiovascular Surveillance System
Authors: Sidney S; Rosamond WD; Howard VJ; Luepker RV; National Forum for Heart Disease and Stroke Prevention
Circulation. 2013 Jan 1;127(1):21-3. Epub 2012 Dec 13.
Physical performance and frailty in chronic kidney disease
Poor physical performance and frailty are associated with elevated risks of death and disability. Chronic kidney disease (CKD) is also strongly associated with these outcomes. The risks of poor physical performance and frailty among CKD patients, however, are not well established. We measured the Short Physical Performance Battery (SPPB; a summary test of gait speed, chair raises and balance; range 0-12) and the five elements of frailty among 1,111 Chronic Renal Insufficiency Cohort participants. Adjusting for demographics and multiple comorbidities, we fit a linear regression model for the outcome of SPPB score and an ordinal logistic regression model for frailty status. Median (interquartile range, IQR) age was 65 (57-71) years, median estimated glomerular filtration rate (eGFR) for non-dialysis patients was 49 (36-62) ml/min/1.73 m(2), and median SPPB score was 9 (7-10). Seven percent of participants were frail and 43% were pre-frail. Compared with the SPPB score for eGFR >60 ml/min/1.73 m(2), the SPPB was 0.51 points lower for eGFR 30-59; 0.61 points lower for eGFR 15-29, and 1.75 points lower for eGFR <15 (p < 0.01 for all comparisons). eGFR 30-59 (odds ratio, OR 1.45; p = 0.024), eGFR 15-29 (OR 2.02; p = 0.002) and eGFR <15 (OR 4.83; p < 0.001) were associated with worse frailty status compared with eGFR >60 ml/min/1.73 m(2). CKD severity was associated with poor physical performance and frailty in a graded fashion. Future trials should determine if outcomes for CKD patients with frailty and poor physical performance are improved by targeted interventions.
Authors: Reese PP; Lo JC; Go AS; CRIC Study Investigators; et al.
Am J Nephrol. 2013;38(4):307-15. Epub 2013-10-04.
A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation
Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGF?) signaling pathway. To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM. A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P?=?2.2×10(-9)); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR?=?0.81, P?=?0.8). Rare CNV analysis did not identify genes significantly associated with BAVM. We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.
Authors: Bendjilali N; Zaroff JG; Pawlikowska L; et al.
PLoS ONE. 2013;8(10):e71434. Epub 2013-10-03.
Large-scale association analysis identifies new risk loci for coronary artery disease
Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Authors: CARDIoGRAMplusC4D Consortium; Deloukas P; Kanoni S; Willenborg C; Farrall M; Assimes TL; Thompson JR; Ingelsson E; Saleheen D; Erdmann J; Goldstein BA; Stirrups K; Konig IR; Cazier JB; Johansson A; Hall AS; Lee JY; Willer CJ; Chambers JC; Esko T; Folkersen L; Goel A; Grundberg E; Havulinna AS; Ho WK; Hopewell JC; Eriksson N; Kleber ME; Kristiansson K; Lundmark P; Lyytikainen LP; Rafelt S; Shungin D; Strawbridge RJ; Thorleifsson G; Tikkanen E; Van Zuydam N; Voight BF; Waite LL; Zhang W; Ziegler A; Absher D; Altshuler D; Balmforth AJ; Barroso I; Braund PS; Burgdorf C; Claudi-Boehm S; Cox D; Dimitriou M; Do R; DIAGRAM Consortium; CARDIOGENICS Consortium; Doney AS; El Mokhtari N; Eriksson P; Fischer K; Fontanillas P; Franco-Cereceda A; Gigante B; Groop L; Gustafsson S; Hager J; Hallmans G; Han BG; Hunt SE; Kang HM; Illig T; Kessler T; Knowles JW; Kolovou G; Kuusisto J; Langenberg C; Langford C; Leander K; Lokki ML; Lundmark A; McCarthy MI; Meisinger C; Melander O; Mihailov E; Maouche S; Morris AD; Muller-Nurasyid M; MuTHER Consortium; Nikus K; Peden JF; Rayner NW; Rasheed A; Rosinger S; Rubin D; Rumpf MP; Schafer A; Sivananthan M; Song C; Stewart AF; Tan ST; Thorgeirsson G; van der Schoot CE; Wagner PJ; Wellcome Trust Case Control Consortium; Wells GA; Wild PS; Yang TP; Amouyel P; Arveiler D; Basart H; Boehnke M; Boerwinkle E; Brambilla P; Cambien F; Cupples AL; de Faire U; Dehghan A; Diemert P; Epstein SE; Evans A; Ferrario MM; Ferrieres J; Gauguier D; Go AS; Goodall AH; Gudnason V; Hazen SL; Holm H; Iribarren C; Jang Y; Kahonen M; Kee F; Kim HS; Klopp N; Koenig W; Kratzer W; Kuulasmaa K; Laakso M; Laaksonen R; Lee JY; Lind L; Ouwehand WH; Parish S; Park JE; Pedersen NL; Peters A; Quertermous T; Rader DJ; Salomaa V; Schadt E; Shah SH; Sinisalo J; Stark K; Stefansson K; Tregouet DA; Virtamo J; Wallentin L; Wareham N; Zimmermann ME; Nieminen MS; Hengstenberg C; Sandhu MS; Pastinen T; Syvanen AC; Hovingh GK; Dedoussis G; Franks PW; Lehtimaki T; Metspalu A; Zalloua PA; Siegbahn A; Schreiber S; Ripatti S; Blankenberg SS; Perola M; Clarke R; Boehm BO; O'Donnell C; Reilly MP; Marz W; Collins R; Kathiresan S; Hamsten A; Kooner JS; Thorsteinsdottir U; Danesh J; Palmer CN; Roberts R; Watkins H; Schunkert H; Samani NJ
Nat Genet. 2013 Jan;45(1):25-33. Epub 2012 Dec 2.
Validation of the Kidney Disease Quality of Life Short Form 36 (KDQOL-36) US Spanish and English versions in a cohort of Hispanics with chronic kidney disease
OBJECTIVE: Evaluate the reliability and validity of the Kidney Disease Quality of Life Short Form 36 (KDQOL-36) in Hispanics with mild-to-moderate chronic kidney disease (CKD). DESIGN: Cross-sectional SETTING: Chronic Renal Insufficiency Cohort Study PARTICIPANTS: 420 Hispanic (150 English- and 270 Spanish-speakers), and 409 non-Hispanic White individuals, matched by age (mean 57 years), sex (60% male), kidney function (mean estimated glomerular filtration rate 36ml/min/1.73m2), and diabetes (70%). METHODS: To measure construct validity, we selected instruments, comorbidities, and laboratory tests related to at least one KDQOL-36 subscale. Reliability was determined by calculating Cronbach’s alpha. RESULTS: Reliability of each KDQOL-36 subscale [SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS), Symptoms/Problems, Burden of Kidney Disease and Effects of Kidney Disease] was very good (Cronbach’s alpha >0.8). Construct validity was supported by expected negative correlation between MCS scores and the Beck Depression Inventory in all three subgroups (r=-0.56 to -0.61, P<.0001). There was inverse correlation between the Symptoms/ Problems subscale and the Patient Symptom Form (r= -0.70 to -0.77, P<.0001). We also found significant, positive correlation between the PCS score and a physical activity survey (r=+0.29 to +0.38, P< or =.003); and between the PCS and MCS scores and the Kansas City Questionnaire (r= +0.31 to +0.64, P<.0001). Reliability and validity were similar across all racial/ethnic groups analyzed separately. CONCLUSION: Our findings support the use of the KDQOL-36 as a measure of HRQOL in this cohort of US Hispanics with CKD.
Authors: Ricardo AC; Go A; CRIC Investigators; et al.
Ethn Dis. 2013 Spring;23(2):202-9.
Intakes of long-chain omega-3 (n-3) PUFAs and fish in relation to incidence of asthma among American young adults: the CARDIA study
BACKGROUND: Although long-chain omega-3 (n-3) PUFAs (LComega3PUFAs) have been linked to the prevention of some inflammatory disorders, little is known about the association between these fatty acids and incidence of asthma. OBJECTIVE: The objective was to prospectively investigate the association between LComega3PUFAs and fish intake and incidence of asthma among American young adults. DESIGN: A 20-y follow-up longitudinal analysis was conducted in a biracial cohort of 4162 Americans, aged 18-30 y, with a history of asthma at baseline in 1985. Diet was assessed by a validated interviewer-administered quantitative food-frequency questionnaire at the examinations in 1985, 1992, and 2005. Incident self-reported asthma was defined as having a physician diagnosis of asthma and/or the use of asthma medications between 1985 and 2005. RESULTS: During the 20-y follow-up, 446 incident cases of asthma were identified. LComega3PUFA intake was significantly inversely associated with incidence of asthma after adjustment for sociodemographic, major lifestyle, and dietary confounders. The multivariable-adjusted HR for the highest quintile of LComega3PUFA intake as compared with the lowest quintile was 0.46 (95% CI: 0.33, 0.64; P-trend < 0.01). However, a higher frequency of nonfried fish consumption was not significantly associated with the risk of asthma. DHA showed a greater inverse association than did EPA. The association between LComega3PUFAs and incident asthma was not appreciably modified by sex, race, BMI, smoking status, or atopic status. CONCLUSION: This study showed that intakes of LComega3PUFAs are inversely longitudinally associated with the incidence of asthma in American young adults.
Authors: Li J; Xun P; Zamora D; Sood A; Liu K; Daviglus M; Iribarren C; Jacobs D Jr; Shikany JM; He K
Am J Clin Nutr. 2013 Jan;97(1):173-8. Epub 2012 Nov 28.
Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial.
BACKGROUND: Systolic blood pressure (SBP) is related to the pathophysiologic development and progression of heart failure (HF) and is inversely associated with adverse outcomes during hospitalization for HF (HHF). The prognostic value of SBP after initiating inhospital therapy and the mode of death and etiology of cardiovascular readmissions based on SBP have not been well characterized in HHF.METHODS: A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 hours of admission for worsening HF with an ejection fraction (EF) ≤40% and an SBP ≥90 mm Hg, for a median follow-up of 9.9 months. Systolic blood pressure was measured at baseline, daily during hospitalization, and at discharge/day 7. Patients were divided into the following quartiles by SBP at baseline: ≤105, 106 to 119, 120 to 130, and ≥131 mm Hg. Outcomes were all-cause mortality (ACM) and the composite of cardiovascular mortality or HHF (CVM + HHF). The associations between baseline, discharge, and inhospital change in SBP and ACM and CVM + HHF were assessed using multivariable Cox proportional hazards regression models adjusted for known covariates.RESULTS: Median (25th, 75th) SBP at baseline was 120 (105, 130) mm Hg and ranged from 82 to 202 mm Hg. Patients with a lower SBP were younger and more likely to be male; had a higher prevalence of prior revascularization and ventricular arrhythmias; had a lower EF, worse renal function, higher natriuretic peptide concentrations, and wider QRS durations; and were more likely to require intravenous inotropes during hospitalization. Lower SBP was associated with increased mortality, driven by HF and sudden cardiac death, and cardiovascular hospitalization, primarily caused by HHF. After adjusting for potential confounders, SBP was inversely associated with risk of the coprimary end points both at baseline (ACM: hazard ratio [HR]/10-mm Hg decrease 1.15, 95% CI1.08-1.22; CVM + HHF: HR 1.09/10-mm Hg decrease, 95% CI 1.04-1.14) and at the time of discharge/day 7 (ACM: HR 1.15/10-mm Hg decrease, 95% CI 1.08-1.22; CVM + HHF: HR 1.07/10-mm Hg decrease, 95% CI 1.02-1.13), but the association with inhospital SBP change was not significant.CONCLUSION: Systolic blood pressure is an independent clinical predictor of morbidity and mortality after initial therapy during HHF with reduced EF.
Authors: Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; Mentz, Robert J RJ; Greene, Stephen J SJ; Subačius, Haris H; Konstam, Marvin A MA; Maggioni, Aldo P AP; Swedberg, Karl K; Gheorghiade, Mihai M
American heart journal. 2013 Feb 25;165(2):216-25. Epub 2012-12-29.
Risk Factors for Coronary Artery Calcium Among Patients With Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort Study)
Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). We examined the cross-sectional association between novel risk factors and coronary artery calcium (CAC) measured using electron beam computed tomography or multidetector computed tomography among 2,018 patients with CKD. Using the total Agatston scores, the participants were classified as having no (0), moderate (>0-100), or high (>100) CAC. After adjustment for age, gender, race, study sites, cigarette smoking, previous cardiovascular disease, hypertension, and diabetes, the use of lipid-lowering drugs, body mass index, waist circumference, and cystatin C, several novel risk factors were significantly associated with high CAC. For example, the odds ratios of high CAC associated with 1 SD greater level of risk factors were 1.20 (95% confidence interval 1.04 to 1.38) for serum calcium, 1.21 (95% confidence interval 1.04 to 1.41) for serum phosphate, 0.83 (95% confidence interval 0.71 to 0.97) for log (total parathyroid hormone), 1.21 (95% confidence interval 1.03 to 1.43) for log (homeostasis model assessment-insulin resistance), and 1.23 (95% confidence interval 1.04 to 1.45) for hemoglobin A1c. Additionally, the multivariate-adjusted odds ratio for 1 SD greater level of cystatin C was 1.31 (95% confidence interval 1.14 to 1.50). Serum high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and homocysteine were not statistically significantly associated with high CAC. In conclusion, these data indicate that abnormal calcium and phosphate metabolism, insulin resistance, and declining kidney function are associated with the prevalence of high CAC, independent of the traditional risk factors in patients with CKD. Additional studies are warranted to examine the causal effect of these risk factors on CAC in patients with CKD.
Authors: He J; Go AS; CRIC Investigators; et al.
Am J Cardiol. 2012 Dec 15;110(12):1735-41. Epub 2012 Sep 14.
Association of arginine vasopressin levels with outcomes and the effect of V2 blockade in patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial.
BACKGROUND: Arginine vasopressin (AVP) levels are elevated in proportion to heart failure severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening heart failure with reduced ejection fraction is unclear.METHODS AND RESULTS: The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial investigated the effects of tolvaptan in patients with worsening heart failure and ejection fraction ≤40%. The present analysis examined baseline and follow-up AVP levels in 3196 EVEREST patients with valid AVP measurements. Coprimary end points included all-cause mortality, and the composite of cardiovascular mortality or heart failure hospitalization. Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased all-cause mortality (hazard ratio, 1.33; 95% confidence interval, 1.13-1.55) and cardiovascular mortality or heart failure hospitalization (hazard ratio, 1.23; 95% confidence interval, 1.08-1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival (P=0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP (PCONCLUSIONS: Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.
Authors: Lanfear, David E DE; Sabbah, Hani N HN; Goldsmith, Steven R SR; Greene, Stephen J SJ; Ambrosy, Andrew P AP; Fought, Angela J AJ; Kwasny, Mary J MJ; Swedberg, Karl K; Yancy, Clyde W CW; Konstam, Marvin A MA; Maggioni, Aldo P AP; Zannad, Faiez F; Gheorghiade, Mihai M;
Circulation. Heart failure. 2013 Jan 05;6(1):47-52. Epub 2012-12-12.
Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: insights from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial.
OBJECTIVES: The study investigated whether the number of participants enrolled per site in an acute heart failure trial is associated with participant characteristics and outcomes.BACKGROUND: Whether and how site enrollment volume affects clinical trials is not known.METHODS: A total of 4,133 participants enrolled among 359 sites were grouped on the basis of total enrollment into 1 to 10, 11 to 30, and >30 participants per site and were compared for outcomes (cardiovascular mortality or heart failure hospitalization).RESULTS: Per-site enrollment ranged from 0 to 75 (median 6; 77 sites had no enrollment). Regional differences in enrollment were noted between North and South America, and Western and Eastern Europe (p < 0.001). Participants from sites with fewer enrollments were more likely to be older and male, have lower ejection fraction and blood pressure as well as worse comorbidity and laboratory profile, and were less likely to be on angiotensin-converting enzyme inhibitors or aldosterone antagonists. During a median follow-up of 9.9 months, 1,700 (41%) participants had an outcome event. Compared to event rate at sites with >30 participants (32%), those with 1 to 10 (51%, hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.56 to 2.02) and 11 to 30 (42%, HR: 1.44, 95% CI: 1.28 to 1.62) participants per site groups had worse outcomes. This relationship was comparable across regions (p = 0.43). After adjustment for risk factors, participants enrolled at sites with fewer enrollees were at higher risk for adverse outcomes (HR: 1.26, 95% CI: 1.08 to 1.46 for 1 to 10; HR: 1.22, 95% CI: 1.07 to 1.38 for 11 to 30 vs. >30 participant sites). Higher proportion of participants from site with >30 participants completed the protocol (45.5% for 30 participants; p < 0.001).CONCLUSIONS: Baseline characteristics, protocol completion, and outcomes differed significantly among higher versus lower enrolling sites. These data imply that the number of participant enrolled per site may influence trials beyond logistics.
Authors: Butler, Javed J; Subacius, Haris H; Vaduganathan, Muthiah M; Fonarow, Gregg C GC; Ambrosy, Andrew P AP; Konstam, Marvin A MA; Maggioni, Aldo A; Mentz, Robert J RJ; Swedberg, Karl K; Zannad, Faiez F; Gheorghiade, Mihai M;
Journal of the American College of Cardiology. 2013 Feb 05;61(5):571-9. Epub 2012-12-12.
Prognostic significance of serum total cholesterol and triglyceride levels in patients hospitalized for heart failure with reduced ejection fraction (from the EVEREST Trial).
Lower cholesterol levels are associated with worse outcomes in patients with chronic heart failure (HF) and have been shown to predict in-hospital mortality. The relation between lipid profile and postdischarge outcomes in patients hospitalized for worsening HF is less clear. In this post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), 3,957 patients hospitalized for worsening HF with ejection fractions ≤40% were examined. Baseline total cholesterol and triglyceride levels were measured
Authors: Greene, Stephen J SJ; Vaduganathan, Muthiah M; Lupi, Laura L; Ambrosy, Andrew P AP; Mentz, Robert J RJ; Konstam, Marvin A MA; Nodari, Savina S; Subacius, Haris P HP; Fonarow, Gregg C GC; Bonow, Robert O RO; Gheorghiade, Mihai M;
The American journal of cardiology. 2013 Feb 15;111(4):574-81. Epub 2012-12-01.
Cardiovascular Predictors of Long-Term Outcomes After Non-Traumatic Subarachnoid Hemorrhage
BACKGROUND AND PURPOSE: Cardiac injury is common after subarachnoid hemorrhage (SAH) and is associated with adverse early outcomes, but long-term effects are unknown. The first aim of this study was to compare the long-term rates of death, stroke, and cardiac events in SAH survivors versus a matched population without SAH. The second aim was to quantify the effects of cardiac injury on the outcome rates. METHODS: This was a retrospective cohort study of patients with and without non-traumatic SAH. For aim #1, the predictor variable was SAH and the outcome variables were all-cause and cerebrovascular mortality, stroke, cardiac mortality, acute coronary syndrome (ACS), and heart failure (HF) admission. A multivariable Cox proportional hazards analysis was performed. For aim #2, the predictor variables were cardiac injury (elevated serum cardiac enzymes or a diagnosis code for ACS) and dysfunction (pulmonary edema on X-Ray or a diagnosis code for HF). RESULTS: Compared with 4,695 members without SAH, the 910 SAH patients had higher rates of all-cause mortality (hazard ratio [HR 2.6], 95% confidence intervals [CI] 2.0-3.4), cerebrovascular mortality (HR 30.6, CI 13.5-69.4), and stroke (HR 10.2, CI 7.5-13.8). Compared with the non-SAH group, the SAH patients with cardiac injury had increased rates of all-cause mortality (HR 5.3, CI 3.0-9.3), cardiac mortality (HR 7.3, CI 1.7-31.6), and heart failure (HR 4.3, CI 1.53-11.88). CONCLUSIONS: SAH survivors have increased long-term mortality and stroke rates compared with a matched non-SAH population. SAH-induced cardiac injury is associated with an increased risk of death and heart failure hospitalization.
Authors: Zaroff JG; Leong J; Kim H; Young WL; Cullen SP; Rao VA; Sorel M; Quesenberry CP Jr; Sidney S
Neurocrit Care. 2012 Dec;17(3):374-81.
Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts
Asthma has been associated with increased cardiovascular disease (CVD) risk. The authors ascertained the association of asthma with CVD and the roles that sex, concurrent allergy, and asthma medications may play in this association. They assembled a cohort of 203,595 Northern California adults with asthma and a parallel asthma-free referent cohort (matched 1:1 on age, sex, and race/ethnicity); both cohorts were followed for incident nonfatal or fatal CVD and all-cause mortality from January 1, 1996, through December 31, 2008. Each cohort was 66% female and 47% white. After adjustment for age, sex, race/ethnicity, cardiac risk factors, and comorbid allergy, asthma was associated with a 1.40-fold (95% confidence interval (CI): 1.35, 1.45) increased hazard of coronary heart disease, a 1.20-fold (95% CI: 1.15, 1.25) hazard of cerebrovascular disease, a 2.14-fold (95% CI: 2.06, 2.22) hazard of heart failure, and a 3.28-fold (95% CI: 3.15, 3.41) hazard of all-cause mortality. Stronger associations were noted among women. Comorbid allergy predicted CVD but did not synergistically increase the CVD risk associated with asthma. Only asthma patients using asthma medications (particularly those on oral corticosteroids alone or in combination) were at enhanced risk of CVD. In conclusion, asthma was prospectively associated with increased risk of major CVD. Modifying effects were noted for sex and asthma medication use but not for comorbid allergy.
Authors: Iribarren C; Tolstykh IV; Miller MK; Sobel E; Eisner MD
Am J Epidemiol. 2012 Dec 1;176(11):1014-24. Epub 2012 Nov 8.
G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation
Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic CNS angiogenesis; thus we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using ?(2) analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of 3 GPR124 SNPs adjacent to exon 2 and localized to a 16 kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P=0.001; rs7823249 T, P=0.014; rs12676965 C, P=0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P=0.033). Haplotype analysis revealed a significant overall association (?(2)=12.55, 4 df, P=0.014); 2 haplotypes (ATCC, P=0.006 and GGCT, P=0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2, however genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel indel polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.
Authors: Weinsheimer S; Zaroff JG; Kim H; et al.
Transl Stroke Res. 2012 Dec;3(4):418-27. Epub 2012-08-14.
Recent trauma and acute infection as risk factors for childhood arterial ischemic stroke
OBJECTIVE: Trauma and acute infection have been associated with stroke in adults, and are prevalent exposures in children. We hypothesized that these environmental factors are independently associated with childhood arterial ischemic stroke (AIS). METHODS: In a case-control study nested within a cohort of 2.5 million children (
Authors: Hills NK; Johnston SC; Sidney S; Zielinski BA; Fullerton HJ
Ann Neurol. 2012 Dec;72(6):850-8.
Clinical characteristics, bone mineral density and non-vertebral osteoporotic fracture outcomes among post-menopausal U.S. South Asian Women
PURPOSE: There is limited data pertaining to osteoporotic fractures among North American women of South Asian (SA) descent. This study examines fracture incidence and risk factors among post-menopausal SA, Chinese and White women undergoing mineral density (BMD) testing within a large healthcare organization in Northern California. METHODS: Using data from a retrospective study of women aged 50-85 years with femoral neck BMD measured between 1997 and 2003, we identified a subset of women of SA race and an age-matched subgroup of Chinese (1:5) and White (1:10) women and examined rates of incident wrist, humerus and hip fractures up to 10 years following BMD. Clinical and demographic risk factors were identified using health plan databases. Multivariable Cox regression analyses were conducted to examine predictors of incident fractures. RESULTS: The study cohort included 449 SA, 2245 Chinese and 4490 White women, with an average age of 58.4 +/- 6.1 years. The prevalence of femoral neck osteoporosis was higher among SA (8.9%) compared to White (6.5%) women and tended to be lower than Chinese (11.9%) women. More SA (7.1%) and White (9.6%) women had prior fracture compared to Chinese women (4.5%) and racial differences in smoking, rheumatoid arthritis, glucocorticoid use and hormone replacement therapy were seen. During a median of 8.4 years follow-up, wrist fracture incidence was similar among SA and White women (286 and 303 per 100,000 person-years, respectively) but significantly lower among Chinese women (130 per 100,000 person-years). In multivariable analyses, lower BMD, prior fracture and White and SA race (compared to Chinese race), were associated with a higher relative rate of wrist fracture. Lower BMD, prior fracture, older age and White but not SA race were also associated with a higher relative rate of non-vertebral (wrist, humerus or hip) fractures. CONCLUSIONS: Post-menopausal South Asian women differed from Chinese and White women with respect to prevalence of femoral neck osteoporosis, certain risk factors and site of osteoporotic fracture. These findings support the need for more studies examining fracture risk and outcomes specific to SA women residing in the U.S. to inform clinical decisions relevant to fracture risk.
Authors: Khandelwal S; Chandra M; Lo JC
Bone. 2012 Dec;51(6):1025-8. Epub 2012 Aug 19.
Longitudinal study of implantable cardioverter-defibrillators: methods and clinical characteristics of patients receiving implantable cardioverter-defibrillators for primary prevention in contemporary practice
BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are increasingly used for primary prevention after randomized, controlled trials demonstrating that they reduce the risk of death in patients with left ventricular systolic dysfunction. The extent to which the clinical characteristics and long-term outcomes of unselected, community-based patients with left ventricular systolic dysfunction undergoing primary prevention ICD implantation in a real-world setting compare with those enrolled in the randomized, controlled trials is not well characterized. This study is being conducted to address these questions. METHODS AND RESULTS: The study cohort includes consecutive patients undergoing primary prevention ICD placement between January 1, 2006 and December 31, 2009 in 7 health plans. Baseline clinical characteristics were acquired from the National Cardiovascular Data Registry ICD Registry. Longitudinal data collection is underway, and will include hospitalization, mortality, and resource use from standardized health plan data archives. Data regarding ICD therapies will be obtained through chart abstraction and adjudicated by a panel of experts in device therapy. Compared with the populations of primary prevention ICD therapy randomized, controlled trials, the cohort (n=2621) is on average significantly older (by 2.5-6.5 years), more often female, more often from racial and ethnic minority groups, and has a higher burden of coexisting conditions. The cohort is similar, however, to a national population undergoing primary prevention ICD placement. CONCLUSIONS: Patients undergoing primary prevention ICD implantation in this study differ from those enrolled in the randomized, controlled trials that established the efficacy of ICDs. Understanding a broad range of health outcomes, including ICD therapies, will provide patients, clinicians, and policy makers with contemporary data to inform decision-making.
Authors: Masoudi FA; Go AS; Greenlee RT; et al.
Circ Cardiovasc Qual Outcomes. 2012 Nov;5(6):e78-85.
Bone resorption and fracture across the menopausal transition: the Study of Women’s Health Across the Nation
OBJECTIVE: Bone turnover markers (BTMs) predict fracture in older women, whereas data on younger women are lacking. To test the hypothesis that BTMs measured before and after menopause predict fracture risk, we performed a cohort study of 2,305 women. METHODS: Women attended up to nine clinic visits for an average of 7.6 +/- 1.6 years; all were aged 42 to 52 years and were premenopausal or early perimenopausal at baseline. Incident fractures were self-reported. Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen (NTX) were measured at baseline. NTX was measured at each annual follow-up. Interval-censored survival models or generalized estimating equations were used to test whether baseline BTMs and changes in NTX, respectively, were associated with fracture risk. Hazard ratios (HRs) or odds ratios were calculated with 95% CIs. RESULTS: Women who experienced fractures (n = 184) had about a 10% higher baseline median NTX (34.4 vs 31.5 nanomoles of bone collagen equivalents per liter per nanomole of creatinine per liter; P = 0.001), but there was no difference in osteocalcin. A 1-SD decrease in lumbar spine bone mineral density (BMD) measured premenopausally was associated with a higher fracture risk during menopause (HR, 1.50; 95% CI, 1.28-1.68). Women with a baseline NTX greater than the median had a 45% higher risk of fracture, multivariable-adjusted (HR, 1.46; 95% CI, 1.05-2.26). The HR of fracture among women with both the lowest spine BMD (quartile 1) and the highest NTX (quartile 4) at baseline was 2.87 (95% CI, 1.61-6.01), compared with women with lower NTX and higher BMD. Women whose NTX increased more than the median had a higher risk of fracture (odds ratio, 1.51; 95% CI, 1.08-2.10). Women who had baseline NTX greater than the median experienced greater loss of spine and hip BMD. CONCLUSIONS: A higher urinary NTX excretion measured before menopause and across menopause is associated with a higher risk of fracture. Our results are consistent with the pathophysiology of transmenopausal changes in bone strength.
Authors: Cauley JA; Lo JC; Sowers MR; et al.
Menopause. 2012 Nov;19(11):1200-7.
Detection of Atrial Fibrillation After Stroke and the Risk of Recurrent Stroke
Failure to expeditiously diagnose atrial fibrillation (AF) as the cause of ischemic stroke has unclear consequences. We studied the association between detection of AF after discharge and the risk of recurrent stroke. We followed a prospectively assembled cohort of patients hospitalized for stroke for 1 year for new diagnoses of AF and recurrent stroke. We compared rates of recurrent stroke in patients with a new diagnosis of AF and those without a new diagnosis of AF after discharge using Kaplan-Meier survival statistics. We conducted Cox proportional hazards analysis of the diagnosis and timing of AF and recurrent stroke after adjustment for age, sex, race, preexisting AF, hypertension, dyslipidemia, diabetes, previous stroke, and use of antithrombotic and statin medications. Among 5575 patients with stroke, 113 (2.0%) received a new diagnosis of AF after discharge, and 221 (4.0%) had recurrent stroke. At 1 year, the KaplanMeier rate of recurrent stroke was 18.9% in those with a new diagnosis of AF and 4.5% in others, including those with AF diagnosed before or during the index hospitalization (P = .001). The association between a new diagnosis of AF and stroke recurrence persisted after adjustment for potential confounders (hazard ratio, 5.6; 95% confidence interval, 3.4-9.1). A new diagnosis of AF after discharge for stroke is associated with an increased risk of recurrent stroke, even compared with patients with known AF. These findings identify a subset of patients at high risk for recurrent stroke and highlight the importance of timely detection of AF in patients with stroke.
Authors: Kamel H; Johnson DR; Hegde M; Go AS; Sidney S; Sorel M; Hills NK; Johnston SC
J Stroke Cerebrovasc Dis. 2012 Nov;21(8):726-31. Epub 2011 May 5.
Recruitment of Hispanics into an Observational Study of Chronic Kidney Disease: The Hispanic Chronic Renal Insufficiency Cohort Study Experience
Despite the large burden of chronic kidney disease (CKD) in Hispanics, this population has been underrepresented in research studies. We describe the recruitment strategies employed by the Hispanic Chronic Renal Insufficiency Cohort Study, which led to the successful enrollment of a large population of Hispanic adults with CKD into a prospective observational cohort study. Recruitment efforts by bilingual staff focused on community clinics with Hispanic providers in high-density Hispanic neighborhoods in Chicago, academic medical centers, and private nephrology practices. Methods of publicizing the study included church meetings, local Hispanic print media, Spanish television and radio stations, and local health fairs. From October 2005 to July 2008, we recruited 327 Hispanics aged 21-74 years with mild-to-moderate CKD as determined by age-specific estimated glomerular filtration rate (eGFR). Of 716 individuals completing a screening visit, 49% did not meet eGFR inclusion criteria and 46% completed a baseline visit. The mean age at enrollment was 57.1 and 67.1% of participants were male. Approximately 75% of enrolled individuals were Mexican American, 15% Puerto Rican, and 10% had other Latin American ancestry. Eighty two percent of participants were Spanish-speakers. Community-based and academic primary care clinics yielded the highest percentage of participants screened (45.9% and 22.4%) and enrolled (38.2% and 24.5%). However, academic and community-based specialty clinics achieved the highest enrollment yield from individuals screened (61.9% to 71.4%). A strategy focused on primary care and nephrology clinics and the use of bilingual recruiters allowed us to overcome barriers to the recruitment of Hispanics with CKD.
Authors: Lora CM; Ricardo AC; Brecklin CS; Fischer MJ; Rosman RT; Carmona E; Lopez A; Balaram M; Nessel L; Tao KK; Xie D; Kusek JW; Go AS; Lash JP
Contemp Clin Trials. 2012 Nov;33(6):1238-44. Epub 2012 Jul 27.
Atrial fibrillation or flutter on initial electrocardiogram is associated with worse outcomes in patients admitted for worsening heart failure with reduced ejection fraction: findings from the EVEREST Trial.
BACKGROUND: Heart failure (HF) complicated by atrial fibrillation/flutter (AF/AFL) is associated with worse outcomes. However, the clinical profile and outcomes of patients following hospitalization for HF with AF/AFL on initial electrocardiogram (ECG) has not been well studied.METHODS: EVEREST was a randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with HF with ejection fraction ≤40%. A post hoc analysis was performed comparing the clinical characteristics and outcomes [all-cause mortality and cardiovascular mortality/HF hospitalization] of patients with AF/AFL versus sinus rhythm (SR) on baseline ECG, which were centrally analyzed. Times to events were compared using log-rank tests and Cox regression models.RESULTS: Of the 4133 patients, 1195 (29%) were classified with AF/AFL and 2071(50%) with SR. The remaining patients (21%) were excluded because ECGs were unavailable (n = 106), rhythm was paced (n = 727), or junctional/other supraventricular (n = 34). AF/AFL patients were older, with increased weight, faster heart rate, higher blood urea nitrogen, and natriuretic peptide levels compared to SR patients. Anticoagulation was prescribed in 67% of AF/AFL patients on discharge. AF/AFL patients were less likely to receive β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (all P < .05). After risk adjustment, AF/AFL was associated with increased mortality (hazard ratio 1.23; 95% CI, 1.04-1.46) and cardiovascular mortality/HF hospitalization (hazard ratio 1.26; 95% CI, 1.07-1.47).CONCLUSION: AF/AFL on initial ECG in patients hospitalized with HF with reduced ejection fraction is associated with lower use of evidence-based therapies and increased mortality and rehospitalization compared to patients in SR.
Authors: Mentz, Robert J RJ; Chung, Matthew J MJ; Gheorghiade, Mihai M; Pang, Peter S PS; Kwasny, Mary J MJ; Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; O'Connor, Christopher M CM; Swedberg, Karl K; Zannad, Faiez F; Konstam, Marvin A MA; Maggioni, Aldo P AP
American heart journal. 2012 Dec 15;164(6):884-92.e2. Epub 2012-10-29.
FTO genotype is associated with phenotypic variability of body mass index
There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using approximately 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of approximately 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
Authors: Yang J; Iribarren C; Zillikens MC; et al.
Nature. 2012 Oct 11;490(7419):267-72. Epub 2012 Sep 16.
Predictive value of low relative lymphocyte count in patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial.
BACKGROUND: Low lymphocyte count has been shown to be an independent prognostic marker in heart failure (HF) in the outpatient setting. Limited data exist regarding whether relative lymphocyte count correlates with postdischarge outcomes in patients hospitalized for HF.METHODS AND RESULTS: We performed a post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, which randomized 4133 patients hospitalized for worsening HF with an ejection fraction ≤40% within 48 hours of admission to tolvaptan or placebo for a median follow-up of 9.9 months. The primary end points of all-cause mortality and cardiovascular mortality or HF hospitalization were analyzed in patients with available baseline complete blood counts (n=3717). Lymphocyte percentage was analyzed as a continuous variable. Times to events were compared using log-rank tests and multivariable Cox regression models. Patients with low lymphocyte percentage tended to be older and had higher rates of comorbid disease (diabetes mellitus, atrial fibrillation, and renal insufficiency). Low lymphocyte counts were associated with wide QRS duration, high natriuretic peptides, and low ejection fraction, blood pressure, and serum sodium. These patients were less likely to receive evidence-based HF medications. After adjusting for 22 known clinical risk factors, a 10% decrease in lymphocytes was associated with an increased hazard of all-cause mortality (adjusted hazard ratio 1.31 [95% CI: 1.14-1.150], PCONCLUSIONS: Low relative lymphocyte count during hospitalization for HF is an independent predictor of poor outcomes in the early postdischarge period, beyond traditional prognostic indicators.
Authors: Vaduganathan, Muthiah M; Ambrosy, Andrew P AP; Greene, Stephen J SJ; Mentz, Robert J RJ; Subacius, Haris P HP; Maggioni, Aldo P AP; Swedberg, Karl K; Nodari, Savina S; Zannad, Faiez F; Konstam, Marvin A MA; Butler, Javed J; Gheorghiade, Mihai M;
Circulation. Heart failure. 2012 Nov 15;5(6):750-8. Epub 2012-10-09.
Ethnic variability in bone geometry as assessed by hip structure analysis: Findings from the hip strength across the menopausal transition study
Racial/ethnic origin plays an important role in fracture risk. Racial/ethnic differences in fracture rates cannot be fully explained by bone mineral density (BMD). Studies examining the influence of bone geometry and strength on fracture risk have focused primarily on older adults and have not included people from diverse racial/ethnic backgrounds. Our goal was to explore racial/ethnic differences in hip geometry and strength in a large sample of midlife women. We performed Hip Structure Analysis (HSA) on hip DXA scans from 1942 pre- and early peri-menopausal women. The sample included Caucasian (50%), African American (27%), Chinese (11%) and Japanese (12%) women, age 42-52 years. HSA was performed using software developed at John’s Hopkins University. African American women had higher conventional (8.4-9.7%) and HSA BMD (5.4-19.8%) than other groups with the exception being Japanese women who had the highest HSA BMD (9.7-31.4%). HSA indices associated with more favorable geometry and greater strength and resistance to fracture were more prevalent in African American and Japanese women. Femurs of African American women had a smaller outer diameter, a larger cross-sectional area and section modulus, and a lower buckling ratio. Japanese women presented a different pattern with a higher section modulus and lower buckling ratio, similar to African American women, but a wider outer diameter; this was offset by a greater cross-sectional area and a more centrally located centroid. Chinese women had similar conventional BMD as Caucasian women but a smaller neck region area and HSA BMD at both regions. They also had a smaller cross-sectional area and section modulus, a more medially located centroid, and a higher buckling ratio than Caucasian women. The observed biomechanical differences may help explain racial/ethnic variability in fracture rates. Future research should explore the contribution of hip geometry to fracture risk across all race/ethnicities. (c) 2012 American Society for Bone and Mineral Research.
Authors: Danielson ME; Beck TJ; Lian Y; Karlamangla AS; Greendale GA; Ruppert K; Lo J; Greenspan S; Vuga M; Cauley JA
J Bone Miner Res. 2012 Oct 8.
Associations between Kidney Function and Subclinical Cardiac Abnormalities in CKD
Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR (eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories >/=60, 45-59, 30-44, and <30 ml/min per 1.73 m(2), respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of <30 ml/min per 1.73 m(2) had twofold higher odds of LVH (OR=2.20, 95% CI=1.40-3.40; P<0.001) relative to subjects with eGFR>/=60 ml/min per 1.73 m(2). This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30-44 ml/min per 1.73 m(2) also significantly associated with LVH and abnormal LV geometry compared with eGFR>/=60 ml/min per 1.73 m(2). In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables.
Authors: Park M; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Group; et al.
J Am Soc Nephrol. 2012 Oct;23(10):1725-34. Epub 2012 Aug 30.
Application of new method for evaluating performance of fracture risk tool
Authors: Sobel EM; Ettinger B; Lo JC; Pressman AR
Am J Manag Care. 2012 Oct;18(10):e398.
Detection of Paroxysmal Atrial Fibrillation by 30-Day Event Monitoring in Cryptogenic Ischemic Stroke: The Stroke and Monitoring for PAF in Real Time (SMART) Registry
BACKGROUND AND PURPOSE: Patients with cryptogenic ischemic stroke may have undetected paroxysmal atrial fibrillation (PAF). We established the Stroke and Monitoring for PAF in Real Time (SMART) Registry to determine the yield of 30-day outpatient PAF monitoring in cryptogenic ischemic stroke. METHODS: The SMART Registry was a 3-year, prospective multicenter registry of 239 patients with cryptogenic ischemic stroke undergoing 30-day outpatient autotriggered PAF detection in Kaiser Permanente Northern California. RESULTS: In intention-to-monitor analysis, PAF was detected in 29 of 239 patients (12.1%; 95% CI, 8.6%-16.9%). After retrospective chart review was performed, a new diagnosis of PAF was confirmed in 26 of 236 patients (11.0%; 95% CI, 7.6%-15.7%). The majority of detected PAF events were asymptomatic; only 6 of 98 recorded PAF events (6.1%) were patient-triggered or associated with symptoms. CONCLUSIONS: -Approximately 1 in every 9 patients with cryptogenic ischemic stroke was found to have new PAF within 30 days. Routine monitoring in this population should be strongly considered.
Authors: Flint AC; Banki NM; Ren X; Rao VA; Go AS
Stroke. 2012 Oct;43(10):2788-90. Epub 2012 Aug 7.
Influence of documented history of coronary artery disease on outcomes in patients admitted for worsening heart failure with reduced ejection fraction in the EVEREST trial.
AIMS: Data on the prognosis of heart failure (HF) patients with coronary artery disease (CAD) have been conflicting. We describe the clinical characteristics and mode-specific outcomes of HF patients with reduced ejection fraction (EF) and documented CAD in a large randomized trial.METHODS AND RESULTS: EVEREST was a prospective, randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with worsening HF and reduced EF. Patients were classified as having CAD based on patient-reported myocardial infarction (MI) or coronary revascularization. We analysed the characteristics and outcomes [all-cause mortality and cardiovascular (CV) mortality/HF hospitalization] of patients with and without documented CAD. All events were centrally adjudicated. Documented CAD was present in 2353 patients (57%). Patients with CAD were older and had more co-morbidities compared with those without CAD. Patients with CAD were more likely to receive a beta-blocker, but less likely to receive an angiotensin-converting enzyme (ACE) inhibitor or aldosterone antagonist (P < 0.01). After risk adjustment, patients with documented CAD had similar mortality [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.97-1.30], but were at an increased risk for CV mortality/HF hospitalization (HR 1.25, 95% CI 1.12-1.41) due to an increased risk for HF hospitalization (HR 1.26, 95% CI 1.10-1.44). Patients with CAD had increased HF- and MI-related events, but similar rates of sudden cardiac death.CONCLUSION: Documented CAD in patients hospitalized for worsening HF with reduced EF was associated with a higher burden of co-morbidities, lower use of HF therapies (except beta-blockers), and increased HF hospitalization, while all-cause mortality was similar.
Authors: Mentz, Robert J RJ; Allen, Bradley D BD; Kwasny, Mary J MJ; Konstam, Marvin A MA; Udelson, James E JE; Ambrosy, Andrew P AP; Fought, Angela J AJ; Vaduganathan, Muthiah M; O'Connor, Christopher M CM; Zannad, Faiez F; Maggioni, Aldo P AP; Swedberg, Karl K; Bonow, Robert O RO; Gheorghiade, Mihai M
European journal of heart failure. 2013 Jan 15;15(1):61-8. Epub 2012-09-11.
Retinopathy and Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort (CRIC) Study
OBJECTIVE: To investigate the association between retinopathy and chronic kidney disease. METHODS: In this observational, cross-sectional study, 2605 patients of the Chronic Renal Insufficiency Cohort (CRIC) study, a multicenter study of chronic kidney disease, were offered participation. Nonmydriatic fundus photographs of the disc and macula in both eyes were obtained in 1936 of these subjects. The photographs were reviewed in a masked fashion at a central photograph reading center using standard protocols. Presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed by trained graders and a retinal specialist using protocols developed for large epidemiologic studies. Kidney function measurements and information on traditional and nontraditional risk factors for decreased kidney function were obtained from the CRIC study. RESULTS: Greater severity of retinopathy was associated with lower estimated glomerular filtration rate after adjustment for traditional and nontraditional risk factors. The presence of vascular abnormalities usually associated with hypertension was also associated with lower estimated glomerular filtration rate. We found no strong direct relationship between estimated glomerular filtration rate and average arteriolar or venular calibers. CONCLUSIONS: Our findings show a strong association between severity of retinopathy and its features and level of kidney function after adjustment for traditional and nontraditional risk factors for chronic kidney disease, suggesting that retinovascular pathology reflects renal disease.
Authors: Grunwald JE; Lo JC; Go A; for the CRIC Study Group; et al.
Arch Ophthalmol. 2012 Sep 1;130(9):1136-44.
Atypical Femur Fractures Among Breast Cancer and Multiple Myeloma Patients Receiving Intravenous Bisphosphonate Therapy: A Case Series
PURPOSE: Atypical femur fractures represent a potential complication of chronic oral bisphosphonate therapy in women with osteoporosis, but the risk of atypical femur fractures among cancer patients receiving intravenous bisphosphonates at higher cumulative doses remains unclear. We examined femur fractures occurring in cancer patients treated with intravenous bisphosphonates (IVBP) to determine whether a subset may be atypical fractures. METHODS: Between 2005 and 2010, we identified patients with known IVBP therapy for multiple myeloma or metastatic breast cancer, who subsequently sustained a femur fracture based on hospitalization, oncology, pharmacy and chemotherapy visit records. Radiographs were examined by an orthopedic surgeon to determine anatomic fracture site and pattern. An atypical fracture was defined as a transverse or short oblique fracture occurring below the lesser trochanter with evidence of focal hypertrophy of the lateral cortex and absence of biopsy-proven malignancy or radiation therapy at the fracture site. RESULTS: A total of 62 patients with breast cancer (N=39) or multiple myeloma (N=23) with femur fracture and prior IVBP treatment for bone malignancy were identified. There were 30 proximal hip, 18 subtrochanteric and 14 femoral shaft fractures. Intraoperative bone samples were sent in 29 of 58 fracture cases undergoing operative repair, with 76% positive for malignancy. Six cases (4 breast cancer, 2 multiple myeloma) of atypical femur fracture were identified, two with negative intraoperative pathology and four with no bone biopsy samples sent. Five of the six patients with atypical fracture had bilateral femur findings, including two with transverse fracture in the contralateral femur and three with focal hypertrophy of the contralateral cortex. Two atypical fracture cases also experienced osteonecrosis of the jaw compared to 3 in the remaining cohort (33% vs. 5%, p=0.07). Patients with atypical fracture received more IVBP (median 55 vs. 15 doses) and zoledronic acid (32 vs. 12 doses) and had longer treatment duration (median 5.9 vs. 1.6 years) compared to patients without atypical fracture (all p
Authors: Chang ST; Tenforde AS; Grimsrud CD; Gonzalez JR; Baer DM; Chandra M; Lo JC; O'Ryan FS
Bone. 2012 Sep;51(3):524-7. Epub 2012 May 23.
Pharmacotherapy in Medicare Beneficiaries With Atrial Fibrillation
BACKGROUND: There are limited data regarding national patterns of pharmacotherapy for atrial fibrillation (AF) among older patients. Drug exposure data are now captured for Medicare beneficiaries enrolled in prescription drug plans. OBJECTIVE: To describe pharmacotherapy for AF among Medicare beneficiaries. METHODS: By using a 5% national sample of Medicare claims data, we compared demographic characteristics, comorbidity, and treatment patterns according to Medicare Part D status among patients with prevalent AF in 2006 and 2007. RESULTS: In 2006, 27,174 patients (29.3%) with prevalent AF were enrolled in Medicare Part D. In 2007, enrollment increased to 45,711 (49.1%). Most enrollees were taking rate-control agents (74.0% in 2007). beta-Blocker use was higher in those with concomitant AF and heart failure and increased with higher CHADS(2) scores (P <.001). Antiarrhythmic use was 18.7% in 2006 and 19.1% in 2007, with amiodarone accounting for more than 50%. Class Ic drugs were used in 3.2% of the patients in 2007. Warfarin use was <60% and declined with increasing stroke risk (P <.001). CONCLUSION: Pharmacotherapy for AF varied according to comorbidity and underlying risk. Amiodarone was the most commonly prescribed antiarrhythmic agent. Postmarketing surveillance using Medicare Part D claims data linked to clinical data may help inform comparative safety, effectiveness, and net clinical benefit of drug therapy for AF in older patients in real-world settings.
Authors: Piccini JP; Mi X; DeWald TA; Go AS; Hernandez AF; Curtis LH
Heart Rhythm. 2012 Sep;9(9):1403-8. Epub 2012 Apr 24.
Treatment of vitamin d deficiency within a large integrated health care delivery system
BACKGROUND: In the past decade, increasing attention has focused on identification and treatment of vitamin D deficiency although repletion outcomes of pharmacologic vitamin D therapy have not been examined at a population level. OBJECTIVE: To investigate population trends and outcomes of pharmacologic treatment of vitamin D deficiency. METHODS: We conducted a retrospective cohort study using data from an integrated health system with approximately 3.2 million members. Automated laboratory and pharmacy databases were used to identify patients aged 18 years or older with hypovitaminosis D (defined as a 25-hydroxy-vitamin D [25(OH)D] serum level < 20 nanograms [ng] per mL) who newly initiated pharmacologic ergocalciferol (50,000 international units [IU] per week) during 2007-2010 and did not have a prescription for ergocalciferol in the prior 12 months. Patients were required to be continuously enrolled for 12 months before and 6 months after ergocalciferol initiation. Age, gender, race/ethnicity, body mass index, and 25(OH)D levels were obtained from health plan electronic medical records and administrative, laboratory, and pharmacy databases. Outcome and predictors of repletion among the subset who received 12 weekly doses of 50,000 IU ergocalciferol (total dose 600,000 IU) were examined using multivariable logistic regression. RESULTS: There were 72,093 vitamin D-deficient patients who newly initiated pharmacologic ergocalciferol. During the study period, the use of ergocalciferol increased nearly 8-fold from 161 per 100,000 adult members in 2007 to 1,241 per 100,000 adult members in 2010. One-fifth (n = 14,727) had severe vitamin D deficiency (25[OH]D level < 10 ng per mL). Among 23,322 patients receiving 50,000 IU ergocalciferol for 12 weeks in whom subsequent 25(OH)D levels were measured between 90 and 365 days after the index ergocalciferol prescription date, 74.0% achieved 25(OH)D of at least 20 ng per mL, and 35.8% achieved 25(OH)D of at least 30 ng per mL. Increasing age (adjusted odds ratio [OR] 1.02, 95% CI 1.02-1.02) and higher baseline 25(OH)D level (OR 1.11, 95% CI 1.10-1.12) were associated with greater odds of successful repletion. Asian race (OR 0.80, 95% CI 0.73-0.88), Hispanic ethnicity (OR 0.71, 95% CI 0.65-0.77), and increasing overweight/obesity (OR 0.78, 95% CI 0.72-0.85 for body mass index [BMI], 25.0-29.9 kg/m(2); OR 0.66, 95% CI 0.60-0.71 for BMI 30.0-39.9 kg/m(2); OR 0.53, 95% CI 0.48-0.60 for BMI >/= 40 kg/m(2)) were associated with lower odds of repletion compared with BMI 18.5-24.9 kg/m(2). CONCLUSIONS: There is increasing recognition and treatment of vitamin D deficiency within the health care setting. Patients of younger age, Asian and Hispanic race/ethnicity, and those who are obese or with more severe vitamin D deficiency may be at greater risk for incomplete repletion using standard regimens and may require additional treatment to achieve optimal levels.
Authors: Stratton-Loeffler MJ; Lo JC; Hui RL; Coates A; Minkoff JR; Budayr A
J Manag Care Pharm. 2012 Sep;18(7):497-505.
Prevalence of cervical insufficiency in polycystic ovarian syndrome
BACKGROUND: Pregnant women with polycystic ovarian syndrome (PCOS) experience a greater rate of adverse obstetrical outcomes compared with non-PCOS women. We examined the prevalence and incidence of cervical insufficiency (CI) in a community cohort of pregnant women with and without PCOS. METHODS: A retrospective cohort study was conducted within a large integrated health care delivery system among non-diabetic PCOS women with second or third trimester delivery during 2002-2005 (singleton or twin gestation). PCOS was defined by Rotterdam criteria. A non-PCOS comparison group matched for delivery year and hospital facility was used to estimate the background rate of CI. Women were designated as having new CI diagnosed in the index pregnancy (based on cervical dilation and/or cervical shortening) and prior CI based on prior diagnosis of CI with prophylactic cerclage placed in the subsequent pregnancy. RESULTS: We identified 999 PCOS women, of whom 29 (2.9%) had CI. There were 18 patients with new CI and 11 with prior CI having prophylactic cerclage placement; four CI patients had twin gestation. In contrast, only five (0.5%) non-PCOS women had CI: two with new CI and three with prior CI. The proportion of newly diagnosed incident CI (1.8 versus 0.2%) or prevalent CI (2.9 versus 0.5%) was significantly greater for PCOS compared with non-PCOS pregnant women (both P < 0.01). Among PCOS women, CI prevalence was particularly high among South Asians (7.8%) and Blacks (17.5%) compared with Whites (1%) and significantly associated with gonadotropin use (including in vitro fertilization). Overall, the PCOS status was associated with an increased odds of prevalent CI pregnancy (adjusted odds ratio 4.8, 95% confidence interval 1.5-15.4), even after adjusting for maternal age, nulliparity, race/ethnicity, body mass index and fertility treatment. CONCLUSION: In this large and ethnically diverse PCOS cohort, we found that CI occurred with a higher than expected frequency in PCOS women, particularly among South Asian and Black women. PCOS women with CI were also more likely to have received gonadotropin therapy. Future studies should examine whether natural and hormone-altered PCOS is a risk factor for CI, the role of race/ethnicity, fertility drugs and consideration for heightened mid-trimester surveillance in higher risk subgroups of pregnant women with PCOS.
Authors: Feigenbaum SL; Crites Y; Hararah MK; Yamamoto MP; Yang J; Lo JC
Hum Reprod. 2012 Sep;27(9):2837-42. Epub 2012 Jun 14.
Sex Hormones and the QT Interval: A Review
A prolonged QT interval is a marker for an increased risk of ventricular tachyarrhythmias. Both endogenous and exogenous sex hormones have been shown to affect the QT interval. Endogenous testosterone and progesterone shorten the action potential, and estrogen lengthens the QT interval. During a single menstrual cycle, progesterone levels, but not estrogen levels, have the dominant effect on ventricular repolarization in women. Studies of menopausal hormone therapy (MHT) in the form of estrogen-alone therapy (ET) and estrogen plus progesterone therapy (EPT) have suggested a counterbalancing effect of exogenous estrogen and progesterone on the QT. Specifically, ET lengthens the QT, whereas EPT has no effect. To date, there are no studies on oral contraception (OC) and the QT interval, and future research is needed. This review outlines the current literature on sex hormones and QT interval, including the endogenous effects of estrogen, progesterone, and testosterone and the exogenous effects of estrogen and progesterone therapy in the forms of MHT and hormone contraception. Further, we review the potential mechanisms and pathophysiology of sex hormones on the QT interval.
Authors: Sedlak T; Shufelt C; Iribarren C; Merz CN
J Womens Health (Larchmt). 2012 Sep;21(9):933-41. Epub 2012 Jun 4.
Capecitabine-induced chest pain relieved by diltiazem.
Five patients with primary colorectal adenocarcinoma or anal squamous cell carcinoma were started on a 2-weeks-on, 1-week-off capecitabine dosing regimen in addition to other chemotherapeutic agents and/or radiation. Within the first few doses, patients experienced chest pain and/or dyspnea at rest or with exertion. Acute electrocardiographic findings suggestive of ischemia were found in some cases at initial presentation, and 1 patient had troponin elevation consistent with an acute ST-segment elevation myocardial infarction. Subsequent ischemia evaluations were not suggestive of clinically significant coronary artery disease. All patients experienced immediate and sustained relief from chest pain after discontinuation of capecitabine and were able to successfully tolerate retreatment using a novel management strategy based on secondary prophylaxis with diltiazem. In conclusion, guidelines for the evaluation of and therapy for capecitabine-induced chest pain are proposed.
Authors: Ambrosy, Andrew P AP; Kunz, Pamela L PL; Fisher, George A GA; Witteles, Ronald M RM
The American journal of cardiology. 2012 Dec 01;110(11):1623-6. Epub 2012-08-31.
Bisphosphonate-Related Osteonecrosis of the Jaw in Patients With Oral Bisphosphonate Exposure: Clinical Course and Outcomes
PURPOSE: To characterize the spectrum and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) occurring with oral bisphosphonate therapy. MATERIALS AND METHODS: We assembled a retrospective cohort of patients who had developed oral BRONJ according to the 2009 American Association of Oral and Maxillofacial Surgeons criteria and received care within Kaiser Permanente, Northern California, during 2004 to 2011. Patients with intravenous bisphosphonate exposure were excluded. The demographic factors, comorbidities, pharmacologic exposure, maxillofacial findings, and outcomes were ascertained from the clinical and radiologic records. RESULTS: We identified 30 cases of oral BRONJ (median age 77 years, 87% women). All had received oral bisphosphonate for osteoporosis/osteopenia (median duration 4.4 years, interquartile range 1.9 to 6.6). More than one half (57%) had comorbidities or relevant drug exposure, including rheumatoid arthritis, diabetes, glucocorticoid therapy, and disease-modifying antirheumatic medications. Extractions preceded BRONJ in 17 patients and trauma in 3; 10 developed BRONJ spontaneously. Overall, 83% had healed within 3 to 52 months, although the relative rate of healing varied by antecedent factor and/or the presence of comorbid conditions/exposures. Nearly all patients with trauma-related and spontaneous BRONJ healed within 1 year (median 7.0 and 7.5 months, respectively) compared with those developing BRONJ after extraction, in whom the median time to healing was 18 months (P < .0001). Patients with relevant comorbidities had a lower probability of healing (P = .0002) and a longer median time to healing (20 months) than patients without comorbidities (7.5 months). CONCLUSIONS: We found that postextraction patients and those with comorbid conditions/exposures showed refractory BRONJ with prolonged healing times. Practitioners should be aware that the BRONJ clinical course and outcome varies depending on the antecedent factor and comorbidity status.
Authors: O'Ryan FS; Lo JC
J Oral Maxillofac Surg. 2012 Aug;70(8):1844-53. Epub 2012 May 16.
High critical care usage due to pediatric stroke: Results of a population-based study
OBJECTIVES: To measure intensive care unit (ICU) admission, intubation, decompressive craniotomy, and outcomes at discharge in a large population-based study of children with ischemic and hemorrhagic stroke. METHODS: In a retrospective study of all children enrolled in a Northern Californian integrated health care plan (1993-2003), we identified cases of symptomatic childhood stroke (age >28 days through 19 years) from inpatient and outpatient electronic diagnoses and radiology reports, and confirmed them through chart review. Data regarding stroke evaluation, management, and outcomes at discharge were abstracted. Intensive care unit (ICU) admission, intubation, and decompressive neurosurgery rates were measured, and multivariate logistic regression was used to identify predictors of critical care usage and outcomes at discharge. RESULTS: Of 256 cases (132 hemorrhagic and 124 ischemic), 61% were admitted to the ICU, 32% were intubated, and 11% were treated with a decompressive neurosurgery. Rates were particularly high among children with hemorrhagic stroke (73% admitted to the ICU, 42% intubated, and 19% received a decompressive neurosurgery). Altered mental status at presentation was the most robust predictor for all 3 measures of critical care utilization. Neurologic deficits at discharge were documented in 57%, and were less common after hemorrhagic than ischemic stroke: 48% vs 66% (odds ratio 0.5, 95% confidence interval 0.3-0.8). Case fatality was 4% overall, 7% among children admitted to the ICU, and was similar between ischemic and hemorrhagic stroke. CONCLUSIONS: ICU admission is frequent after childhood stroke and appears to be justified by high rates of intubation and surgical decompression.
Authors: Fox CK; Johnston SC; Sidney S; Fullerton HJ
Neurology. 2012 Jul 31;79(5):420-7. Epub 2012 Jun 27.
Association Between Retinopathy and Cardiovascular Disease in Patients With Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort [CRIC] Study)
Patients with chronic kidney disease experience co-morbid illnesses, including cardiovascular disease (CVD) and retinopathy. The purpose of the present study was to assess the association between retinopathy and self-reported CVD in a subgroup of the participants in the Chronic Renal Insufficiency Cohort study. For this observational, ancillary investigation, 2,605 Chronic Renal Insufficiency Cohort participants were invited to participate in the present study, and nonmydriatic fundus photographs in both eyes were obtained for 1,936 subjects. The photographs were reviewed in a masked fashion at a central photograph reading center. The presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed using standard protocols by trained graders who were masked to the information about the study participants. A history of self-reported CVD was obtained using a medical history questionnaire. Kidney function measurements and traditional and nontraditional risk factors for CVD were obtained from the Chronic Renal Insufficiency Cohort study. A greater severity of retinopathy was associated with a greater prevalence of any CVD, and this association persisted after adjustment for the traditional risk factors for CVD. The presence of vascular abnormalities usually associated with hypertension was also associated with increased prevalence of CVD. We found a direct relation between CVD prevalence and mean venular caliber. In conclusion, the presence of retinopathy was associated with CVD, suggesting that retinovascular pathology might indicate macrovascular disease, even after adjustment for renal dysfunction and traditional CVD risk factors. This would make the assessment of retinal morphology a valuable tool in CKD studies of CVD outcomes.
Authors: Grunwald JE; Lo JC; the Chronic Renal Insufficiency Cohort (CRIC) Study Group; et al.
Am J Cardiol. 2012 Jul 15;110(2):246-53. Epub 2012 Apr 18.
Influence of breastfeeding during the postpartum oral glucose tolerance test on plasma glucose and insulin
OBJECTIVE: To examine the effect of breastfeeding during the postpartum oral glucose tolerance test (OGTT) on maternal blood glucose and insulin among women with recent gestational diabetes mellitus. METHODS: Participants were enrolled in the Study of Women, Infant Feeding, and Type 2 Diabetes, a prospective observational cohort study of 1,035 Kaiser Permanente Northern California members who had been diagnosed with GDM and subsequently underwent a 2-hour 75-g OGTT at 6-9 weeks postpartum for the study enrollment examinations from 2008 to 2011. For this analysis, we selected 835 study participants who reported any intensity of lactation and were observed either breastfeeding their infants (ie, putting the infant to the breast) or not breastfeeding during the OGTT. RESULTS: Of 835 lactating women, 205 (25%) breastfed their infants during the 2-hour 75-g OGTT at 6-9 weeks postpartum. Mean (standard deviation) duration of breastfeeding during the OGTT was 15.3 (8.1) minutes. Compared with not having breastfed during the OGTT, having breastfed during the test was associated with lower adjusted mean (95% confidence interval) 2-hour glucose (mg/dL) by -6.2 (-11.5 to -1.0; P=.02), 2-hour insulin (microunits/mL) by -15.1 (-26.8 to -3.5; P=.01), and natural log 2-hour insulin by -0.15 (-0.25 to -0.06; P<.01), and with higher insulin sensitivity index0,120 by 0.08 (0.02-0.15; P=.02), but no differences in plasma fasting glucose or insulin concentrations. CONCLUSION: Among postpartum women with recent gestational diabetes mellitus, breastfeeding an infant during the 2-hour 75-g OGTT may modestly lower plasma 2-hour glucose (5% lower on average) as well as insulin concentrations in response to ingestion of glucose.
Authors: Gunderson EP; Hedderson MM; Quesenberry CP; Lo JC; Ferrara A; Sternfeld B; et al.
Obstet Gynecol. 2012 Jul;120(1):136-43.
Fasting Insulin Level Is Positively Associated With Incidence of Hypertension Among American Young Adults: A 20-year follow-up study
OBJECTIVE: Although hyperinsulinemia, a surrogate of insulin resistance, may play a role in the pathogenesis of hypertension (HTN), the longitudinal association between fasting insulin level and HTN development is still controversial. We examined the relation between fasting insulin and incidence of HTN in a large prospective cohort. RESEARCH DESIGN AND METHODS: A prospective cohort of 3,413 Americans, aged 18-30 years, without HTN in 1985 (baseline) were enrolled. Six follow-ups were conducted in 1987, 1990, 1992, 1995, 2000, and 2005. Fasting insulin and glucose levels were assessed by a radioimmunoassay and hexokinase method, respectively. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs of incident HTN (defined as the initiation of antihypertensive medication, systolic blood pressure >/=140 mmHg, or diastolic blood pressure >/=90 mmHg). RESULTS: During the 20-year follow-up, 796 incident cases were identified. After adjustment for potential confounders, participants in the highest quartile of insulin levels had a significantly higher incidence of HTN (HR 1.85 [95% CI 1.42-2.40]; P(trend) < 0.001) compared with those in the lowest quartile. The positive association persisted in each sex/ethnicity/weight status subgroup. A similar dose-response relation was observed when insulin-to-glucose ratio or homeostatic model assessment of insulin resistance was used as exposure. CONCLUSIONS: Fasting serum insulin levels or hyperinsulinemia in young adulthood was positively associated with incidence of HTN later in life for both men and women, African Americans and Caucasians, and those with normal weight and overweight. Our findings suggested that fasting insulin ascertainment may help clinicians identify those at high risk of HTN.
Authors: Xun P; Liu K; Cao W; Sidney S; Williams OD; He K
Diabetes Care. 2012 Jul;35(7):1532-7. Epub 2012 Apr 17.
Clinical correlates of atypical femoral fracture
BACKGROUND: Reports of atypical femur fracture in bisphosphonate-exposed women have prompted interest in characterizing the clinical profiles of these patients. METHODS: Among women age >/=60 years with hip or femur fracture during 2007-2008, we identified 79 with low-trauma subtrochanteric or femoral shaft fracture. Radiographic images were reviewed to assign fracture pattern and distinguish atypical femur fracture from non-atypical femur fracture. Differences in clinical characteristics and pharmacologic exposures were compared. RESULTS: Among 79 women (38 subtrochanteric and 41 femoral shaft fracture), 38 had an atypical femur fracture. Compared to those with a non-atypical femur fracture, women with atypical femur fracture were significantly younger (74.0 vs 81.0 years), more likely to be Asian (50.0 vs 2.4%) and to have received bisphosphonate therapy (97.4 vs 41.5%). Similarly, the contralateral femur showed a stress or complete fracture in 39.5% of atypical femur fractures vs 2.4% non-atypical femur fracture, and focal cortical hypertrophy of the contralateral femur in an additional 21.1% of atypical cases. CONCLUSIONS: Women suffering atypical femur fractures have a markedly different clinical profile from those sustaining typical fractures. Women with atypical femur fracture tend to be younger, Asian, and bisphosphonate-exposed. The high frequency of contralateral femur findings suggests a generalized process.
Authors: Lo JC; Huang SY; Lee GA; Khandewal S; Provus J; Ettinger B; Gonzalez JR; Hui RL; Grimsrud CD
Bone. 2012 Jul;51(1):181-4. Epub 2012 Mar 4.
Thirty-Day Mortality After Ischemic Stroke and Intracranial Hemorrhage in Patients With Atrial Fibrillation On and Off Anticoagulants
BACKGROUND AND PURPOSE: Prescribing warfarin for atrial fibrillation depends in large part on the expected reduction in ischemic stroke risk versus the expected increased risk of intracranial hemorrhage (ICH). However, the anticoagulation decision also depends on the relative severity of such events. We assessed the impact of anticoagulation on 30-day mortality from ischemic stroke versus ICH in a large community-based cohort of patients with atrial fibrillation. METHODS: We followed 13 559 patients with atrial fibrillation enrolled in an integrated healthcare delivery system for a median 6 years. Incident ischemic strokes and ICHs were identified from computerized databases and validated through medical record review. The association of warfarin and international normalized ratio at presentation with 30-day mortality was modeled using multivariable logistic regression adjusting for clinical factors. RESULTS: We identified 1025 incident ischemic strokes and 299 ICHs during follow-up. Compared with no antithrombotic therapy, warfarin was associated with reduced Rankin score and lower 30-day mortality from ischemic stroke (adjusted OR, 0.64; 95% CI, 0.45-0.91) but a higher mortality from ICH (OR, 1.62; 95% CI, 0.88-2.98). Therapeutic international normalized ratios (2-3) were associated with an especially low ischemic stroke mortality (OR, 0.38; 95% CI, 0.20-0.70), whereas international normalized ratios >3 increased the odds of dying of ICH by 2.66-fold (95% CI, 1.21-5.86). CONCLUSIONS: Warfarin reduces 30-day mortality from ischemic stroke but increases ICH-related mortality. Both effects on event severity as well as on event rates need to be incorporated into rational decision-making about anticoagulants for atrial fibrillation.
Authors: Fang MC; Go AS; Chang Y; Borowsky LH; Pomernacki NK; Udaltsova N; Singer DE
Stroke. 2012 Jul;43(7):1795-9. Epub 2012 Apr 26.
Combining SERCA2a activation and Na-K ATPase inhibition: a promising new approach to managing acute heart failure syndromes with low cardiac output.
Heart failure (HF) patients are a medically complex and heterogeneous population with multiple cardiac and non-cardiac comorbidities. Although there are a multitude of etiologic substrates and initiating and amplifying mechanisms contributing to disease progression, these pathophysiologic processes ultimately all lead to impaired myocardial function. The myocardium must both pump oxygenated, nutrient-rich blood throughout the body (systolic function) and receive deoxygenated, nutrient-poor blood returning from the periphery (diastolic function). At the molecular level, it is well-established that Ca2+ plays a central role in excitation-contracting coupling with action potentials stimulating the opening of L-type Ca2+ in the plasma membrane and ryanodine receptor 2 (RyR2) in the sarcoplasmic reticulum (SR) membrane during systole and the Na-Ca2+ exchanger and SERCA2a returning Ca2+ to the extracellular space and SR, respectively, during diastole. However, there is increasing recognition that impaired Ca2+ cycling may contribute to myocardial dysfunction. Preclinical studies and clinical trials indicate that combining SERCA2a activation and Na-K ATPase inhibition may increase contractility (inotropy) and facilitate active relaxation (lusitropy), improving both systolic and diastolic functions. Istaroxime, a novel luso-inotrope that activates SERCA2a and inhibits the Na-K ATPase, is currently in phase II clinical development and has been shown to improve systolic and diastolic functions and central hemodynamics, increase systolic but not diastolic blood pressure, and decrease substantially heart rate. Irrespective of its clinical utility, the development of istaroxime has evolved our understanding of the clinical importance of inhibiting the Na-K ATPase in order to obtain a clinically significant effect from SERCA2a activation in the setting of myocardial failure.
Authors: Gheorghiade, Mihai M; Ambrosy, Andrew P AP; Ferrandi, Mara M; Ferrari, Patrizia P
Discovery medicine. 2011 Aug 01;12(63):141-51. Epub 2012-06-04.
A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90 days: analysis from the EVEREST trial.
Hospitalization for worsening chronic heart failure results in high post-discharge mortality, morbidity, and cost. However, thorough characterization, soon after discharge of patients with early post-discharge events has not been previously performed. The objectives of this study were to describe the baseline, in-hospital, and post-discharge clinical, laboratory, and neurohormonal profiles of patients hospitalized for worsening heart failure with reduced ejection fraction (EF) who die or are re-admitted for cardiovascular (CV) causes within 90 days of initial hospitalization. Retrospective analysis of 4,133 patients hospitalized for worsening heart failure with EF ≤40% in the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which randomized patients to tolvaptan or placebo, both in addition to standard therapy. Clinical and laboratory parameters were obtained within 48 h of admission, during hospitalization, and post-discharge weeks 1, 4, 8, and every 8 weeks thereafter for a median of 9.9 months. Patients with events within 90 days were compared with those with later/no events. All-cause mortality (ACM) and CV re-hospitalization were independently adjudicated. Within 90 days of admission, 395 patients (9.6%) died and 801 patients (19.4%) were re-hospitalized for CV causes. Significant baseline and longitudinal differences were seen between groups with early versus later (>90 days) or no events at 12 months post-randomization. Post-discharge outcomes were similar in the tolvaptan and placebo groups. Patients with early post-discharge events experienced clinically significant worsening in signs and symptoms, laboratory values, and neurohormonal parameters soon after discharge. Identifying these abnormalities may facilitate efforts to reduce post-discharge mortality and re-hospitalization.
Authors: Gheorghiade, Mihai M; Pang, Peter S PS; Ambrosy, Andrew P AP; Lan, Gloria G; Schmidt, Philip P; Filippatos, Gerasimos G; Konstam, Marvin M; Swedberg, Karl K; Cook, Thomas T; Traver, Brian B; Maggioni, Aldo A; Burnett, John J; Grinfeld, Liliana L; Udelson, James J; Zannad, Faiez F
Heart failure reviews. 2012 May 01;17(3):485-509. Epub 2012-06-04.
Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial.
AIMS: Abnormal liver function tests (LFTs) are common in ambulatory heart failure (HF). The aim of this study was to characterize abnormal LFTs during index hospitalization.METHODS AND RESULTS: A post-hoc analysis was carried out of the placebo group of the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial, which enrolled patients hospitalized for HF with an ejection fraction (EF) ≤40% and no history of primary significant liver disease or acute hepatic failure. LFTs (abbreviation, cut-offs for abnormal values) including serum albumin (ALB, 34 IU/L), alanine transaminase (ALT, >34 IU/L), alkaline phosphatase (AP, >123 IU/L),γ-glutamyl transferase (GGT, >50 IU/L), and total bilirubin (T Bili, >1.2 mg/dL) were measured at baseline, discharge/day 7, and post-discharge. Co-primary endpoints were all-cause mortality (ACM) and cardiovascular mortality or first HF hospitalization (CVM + HFH). Study participants had a mean age of 65.6 ±12.0 years, were mostly male, reported high prevalences of medical co-morbidities, and were well treated with evidence-based therapies. Baseline LFT abnormalities were common (ALB 17%, AST 21%, ALT 21%, AP 23%, GGT 62%, and T Bili 26%). Abnormal T Bili was the only marker to decrease substantially from baseline (26%) to discharge/day 7 (19%). All LFTs, except AP, improved post-discharge. Lower baseline ALB and elevated T Bili were associated with higher rates of ACM, and in-hospital decreases in ALB and increases in T Bili were associated with higher rates of both ACM and CVM + HFH.CONCLUSION: LFT abnormalities are common during hospitalization for HF in patients with reduced EF and were persistent at discharge. Baseline and in-hospital changes in ALB and T Bili provide additional prognostic value.
Authors: Ambrosy, Andrew P AP; Vaduganathan, Muthiah M; Huffman, Mark D MD; Khan, Sadiya S; Kwasny, Mary J MJ; Fought, Angela J AJ; Maggioni, Aldo P AP; Swedberg, Karl K; Konstam, Marvin A MA; Zannad, Faiez F; Gheorghiade, Mihai M;
European journal of heart failure. 2012 Mar 01;14(3):302-11. Epub 2012-06-04.
B-type natriuretic peptide assessment in ambulatory heart failure patients: insights from IMPROVE HF.
BACKGROUND: B-type natriuretic peptide (BNP) levels provide diagnostic and prognostic information in heart failure. This study determined the frequency of BNP assessment and analyzed demographic characteristics, clinical variables and the utilization of guideline-recommended heart failure therapies by BNP level in outpatients with reduced left ventricular ejection fraction (LVEF).METHODS AND RESULTS: The IMPROVE HF registry (The Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting) is a prospective cohort study of patients at least 18 years of age with a LVEF 35% or less and chronic heart failure or previous myocardial infarction (MI) presenting to cardiology and multispecialty practices. The medical records of 15,381 patients were reviewed. BNP was measured in 4213 (27.4%) patients and the median plasma BNP level was 384 pg/ml (interquartile range 158-877 pg/ml). Patients were stratified by plasma BNP measurements into the following tertiles: 219 pg/ml or less, more than 219 to 649 pg/ml, and more than 649 pg/ml. Jugular venous distension, pedal edema, rales and systolic murmur on physical examination and elevated renal function parameters were associated with higher BNP levels. BNP assessment and elevated BNP levels were not associated with greater use of any of the quality of care measures. However, patients with a BNP in the top tertile were less likely to be treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or aldosterone antagonists compared with patients with a BNP in the bottom tertile.CONCLUSION: Among practices participating in IMPROVE HF, BNP was not measured in most outpatients with reduced LVEF and chronic heart failure or previous MI. BNP assessment or the BNP level in patients with recorded measurements, with few exceptions, did not impact the utilization of guideline-recommended therapies.
Authors: Ambrosy, Andrew P AP; Fonarow, Gregg C GC; Albert, Nancy M NM; Curtis, Anne B AB; Heywood, J Thomas JT; Mehra, Mandeep R MR; O'Connor, Christopher M CM; Reynolds, Dwight D; Walsh, Mary N MN; Yancy, Clyde W CW; Gheorghiade, Mihai M
Journal of cardiovascular medicine (Hagerstown, Md.). 2012 Jun 01;13(6):360-7. Epub 2012-06-04.
Current management and future directions for the treatment of patients hospitalized for heart failure with low blood pressure.
Although patients hospitalized with heart failure have relatively low in-hospital mortality, the post-discharge rehospitalization and mortality rates remain high despite advances in treatment. Most patients admitted for heart failure have normal or high blood pressure, but 15-25 % have low systolic blood pressure with or without signs and/or symptoms of hypoperfusion. All pharmacological agents known to improve the prognosis of patients with heart failure also reduce blood pressure, and this limits their use in patients with heart failure and low blood pressure (HF-LBP). However, patients with HF-LBP have much higher in-hospital and post-discharge mortality. In these patients, a conceptually important therapeutic target is to improve cardiac output in order to alleviate signs of hypoperfusion. Accordingly, the majority of these patients will require an inotrope as cardiac dysfunction is the cause of their low cardiac output. However, the short-term use of currently available inotropes has been associated with further decreases in blood pressure and increases in heart rate, myocardial oxygen consumption and arrhythmias. Agents that improve cardiac contractility without this undesirable effects should be developed. To the best of our knowledge, the epidemiology, pathophysiology and therapy of patients with HF-LBP have not been addressed thoroughly. In June 2010, a workshop that included scientists and clinicians was held in Rome, Italy. The objectives of this meeting were to (1) develop a working definition for HF-LBP, (2) describe its clinical characteristics and pathophysiology, (3) review current therapies and their limitations, (4) discuss novel agents in development and (5) create a framework for the design and conduct of future clinical trials.
Authors: Gheorghiade, Mihai M; Vaduganathan, Muthiah M; Ambrosy, Andrew A; Böhm, Michael M; Campia, Umberto U; Cleland, John G F JG; Fedele, Francesco F; Fonarow, Gregg C GC; Maggioni, Aldo P AP; Mebazaa, Alexandre A; Mehra, Mandeep M; Metra, Marco M; Nodari, Savina S; Pang, Peter S PS; Ponikowski, Piotr P; Sabbah, Hani N HN; Komajda, Michel M; Butler, Javed J
Heart failure reviews. 2013 Mar 01;18(2):107-22. Epub 2012-06-04.
The impact of chronic obstructive pulmonary disease in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST Trial.
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is prevalent in heart failure (HF) patients, yet these patients are poorly characterized. We aimed to describe the characteristics and outcomes of patients with systolic dysfunction and COPD in a contemporary HF randomized trial.METHODS AND RESULTS: EVEREST investigated 4,133 patients hospitalized with worsening HF and an ejection fraction (EF) ≤40%. We analyzed the characteristics and outcomes (all-cause mortality and cardiovascular mortality/HF hospitalization) of patients according to baseline COPD status. COPD was present in 10% (n = 416) of patients. Patients with COPD had a higher prevalence of comorbidities and were less likely to receive a β-blocker, angiotensin-converting enzyme inhibitor, or aldosterone antagonist. On univariate analysis, COPD was associated with increased all-cause mortality (HR 1.41, 95% CI 1.18-1.67) and cardiovascular mortality/HF hospitalization (HR 1.29, 95% CI 1.11-1.49). After adjusting for potential confounders, the risk associated with COPD remained increased, but was not statistically significant.CONCLUSION: The presence of COPD in HF patients is associated with an increased burden of comorbidities, lower use of HF therapies, and a trend toward worse outcomes. These findings provide a starting point for prospective investigations of the treatment of HF comorbidities to reduce the high postdischarge event rates.
Authors: Mentz, Robert J RJ; Schmidt, Philip H PH; Kwasny, Mary J MJ; Ambrosy, Andrew P AP; O'Connor, Christopher M CM; Konstam, Marvin A MA; Zannad, Faiez F; Maggioni, Aldo P AP; Swedberg, Karl K; Gheorghiade, Mihai M
Journal of cardiac failure. 2012 Jul 01;18(7):515-23. Epub 2012-06-04.
Practice variation in neuroimaging to evaluate dizziness in the ED
BACKGROUND: The appropriate role of neuroimaging to evaluate emergency department (ED) patients with dizziness is not established by guidelines or evidence. METHODS: We identified all adults with a triage complaint of dizziness who were evaluated at 20 EDs of a large Northern California integrated health care program in 2008. Using comprehensive medical records, we captured all head computed tomographies (CTs) or brain magnetic resonance images (MRIs) completed at presentation or within 2 days and all stroke diagnoses within 1 week. We assessed variation in neuroimaging use by site using a random-effects logistic model to account for differences in patient- (demographic and vascular risk factors) and site-level factors (volume, % patients with dizziness, and % patients with dizziness admitted) and linear regression to assess the relationship between neuroimaging rates and stroke diagnosis rates by site. RESULTS: Of 378 992 patients seen in 2008, 20 795 (5.5%) had at least one ED visit for dizziness. Overall, 5585 patients (26.9%) had a head CT and 652 (3.1%) had a brain MRI. Between 21.8% and 32.8% of ED patients with dizziness at each site had a head CT (P < .001). For brain MRI, the range was 0.8% to 6.2%-a nearly 8-fold variation (P < .001) that persisted after adjustment for patient- and site-level factors. Higher neuroimaging rates did not translate into higher stroke diagnoses rates, with 0.7% to 2.5% of patients with dizziness diagnosed with stroke by site. CONCLUSION: The use of neuroimaging for ED patients with dizziness varies substantially without an associated improvement in stroke diagnosis, which is identified only rarely.
Authors: Kim AS; Sidney S; Klingman JG; Johnston SC
Am J Emerg Med. 2012 Jun;30(5):665-72. Epub 2011 May 12.
Relationship of obesity with respiratory symptoms and decreased functional capacity in adults without established COPD
BACKGROUND: Obesity contributes to respiratory symptoms and exercise limitation, but the relationships between obesity, airflow obstruction (AO), respiratory symptoms and functional limitation are complex. AIMS: To determine the relationship of obesity with airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD). METHODS: We analysed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilisation attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, six-minute walk test (SMWT), and the Short Performance Physical Battery (SPPB). Multiple regression analyses were used to test the associations of obesity (body mass index >30kg/m2) and smoking with AO (forced expiratory volume in 1s/forced vital capacity ratio <0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO. RESULTS: Of 371 subjects (aged 40-65 years), 69 (19%) had AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI 1.04 to 1.49) while obesity was negatively associated with AO (OR 0.54; 95% CI 0.30 to 0.98). Obesity was associated with increased odds of reporting dyspnoea on exertion (OR 3.6; 95% CI 2.0 to 6.4), productive cough (OR 2.5; 95% CI 1.1 to 6.0), and with decrements in SMWT distance (67+/-9m; 95% CI 50 to 84m) and SPPB score (OR 1.9; 95% CI 1.1 to 3.5). None of these outcomes was associated with AO. CONCLUSIONS: Although AO and obesity are both common among adults without an established COPD diagnosis, obesity (but not AO) is linked to a higher risk of reporting dyspnoea on exertion, productive cough, and poorer functional capacity.
Authors: Zutler M; Singer JP; Omachi TA; Eisner M; Iribarren C; Katz P; Blanc PD
Prim Care Respir J. 2012 Jun;21(2):194-201.
Inpatient statin use predicts improved ischemic stroke discharge disposition
OBJECTIVE: To determine whether statin use is associated with improved discharge disposition after ischemic stroke. METHODS: We used generalized ordinal logistic regression to analyze discharge disposition among 12,689 patients with ischemic stroke over a 7-year period at 17 hospitals in an integrated care delivery system. We also analyzed treatment patterns by hospital to control for the possibility of confounding at the individual patient level. RESULTS: Statin users before and during stroke hospitalization were more likely to have a good discharge outcome (odds ratio [OR] for discharge to home = 1.38, 95% confidence interval [CI] 1.25-1.52, p < 0.001; OR for discharge to home or institution = 2.08, 95% CI 1.72-2.51, p < 0.001). Patients who underwent statin withdrawal were less likely to have a good discharge outcome (OR for discharge to home = 0.77, 95% CI 0.63-0.94, p = 0.012; OR for discharge to home or institution = 0.43, 95% CI 0.33-0.55, p < 0.001). In grouped-treatment analysis, an instrumental variable method using treatment patterns by hospital, higher probability of inpatient statin use predicted a higher likelihood of discharge to home (OR = 2.56, 95% CI 1.71-3.85, p < 0.001). In last prior treatment analysis, a novel instrumental variable method, patients with a higher probability of statin use were more likely to have a good discharge outcome (OR for each better level of ordinal discharge outcome = 1.19, 95% CI 1.09-1.30, p = 0.001). CONCLUSIONS: Statin use is strongly associated with improved discharge disposition after ischemic stroke.
Authors: Flint AC; Nguyen-Huynh M; Johnston SC; et al.
Neurology. 2012 May 22;78(21):1678-83.
Design of Clinical Trials in Acute Kidney Injury: A Report from an NIDDK Workshop–Prevention Trials
AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the ‘Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers’ workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI.
Authors: Okusa MD; Go AS; Star RA; et al.
Clin J Am Soc Nephrol. 2012 May;7(5):851-5. Epub 2012 Mar 22.
Design of Clinical Trials in AKI: A Report from an NIDDK Workshop. Trials of Patients with Sepsis and in Selected Hospital Settings
AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, ‘Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers,’ in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients.
Authors: Molitoris BA; Go AS; Star RA; et al.
Clin J Am Soc Nephrol. 2012 May;7(5):856-60. Epub 2012 Mar 22.
Design of Clinical Trials in Acute Kidney Injury: Report from an NIDDK Workshop on Trial Methodology
Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients’ health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled ‘Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers’ in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.
Authors: Palevsky PM; Go AS; Star RA; et al.
Clin J Am Soc Nephrol. 2012 May;7(5):844-50. Epub 2012 Mar 22.
Folate intake and incidence of hypertension among American young adults: a 20-y follow-up study
BACKGROUND: Laboratory studies suggest that folate intake may decrease blood pressure (BP) through increasing nitric oxide synthesis in endothelial cells and/or reducing plasma homocysteine concentrations. However, human studies, particularly longitudinal data, are limited. OBJECTIVE: Our objective was to investigate whether dietary folate intake is associated with the 20-y incidence of hypertension. DESIGN: We prospectively followed 4400 men and women (African Americans and whites aged 18-30 y) without hypertension at baseline (1985) in the Coronary Artery Risk Development in Young Adults study 6 times, in 1987, 1990, 1992, 1995, 2000, and 2005. Diet was assessed by dietary-history questionnaire at baseline and in 1992 and 2005. Incident hypertension was defined as the first occurrence at any follow-up examination of systolic BP >/=140 mm Hg, diastolic BP >/=90 mm Hg, or use of antihypertensive medication. RESULTS: A total of 989 incident cases were identified during the 20-y follow-up. After adjustment for potential confounders, participants in the highest quintile of total folate intake had a significantly lower incidence of hypertension (HR: 0.48; 95% CI: 0.38, 0.62; P-trend < 0.01) than did those in the lowest quintile. The multivariable HRs for the same comparison were 0.33 (95% CI: 0.22, 0.51; P-trend < 0.01) in whites and 0.54 (95% CI: 0.40, 0.75; P-trend < 0.01) in African Americans (P-interaction = 0.047). The inverse associations were confirmed in a subset of the cohort (n = 1445) with serum folate measured at baseline and in 1992 and 2000. CONCLUSIONS: Higher folate intake in young adulthood was longitudinally associated with a lower incidence of hypertension later in life. This inverse association was more pronounced in whites. Additional studies are warranted to establish the causal inference.
Authors: Xun P; Liu K; Loria CM; Bujnowski D; Shikany JM; Schreiner PJ; Sidney S; He K
Am J Clin Nutr. 2012 May;95(5):1023-30. Epub 2012 Apr 4.
A new era in stroke prevention for atrial fibrillation: comment on ‘current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation
Authors: Singer DE; Go AS
Arch Intern Med. 2012 Apr 23;172(8):631-3.
Pregnancy during adolescence has lasting adverse effects on blood lipids: A 10-year longitudinal study of black and white females
BACKGROUND: Primiparity has been associated with 3 to 4 mg/dL lower high-density lipoprotein cholesterol concentrations in black and white adult women that persist several years after delivery. OBJECTIVE: To examine the lasting effects of adolescent pregnancy on blood lipids, an early risk factor for future cardiometabolic diseases. DESIGN: The National Heart Lung and Blood Institute’s Growth and Health Study is a multicenter prospective cohort that measured fasting blood lipids for 1013 (513 black, 500 white) participants at baseline (1987-1988) ages 9-10, and again at follow-up (1996-1997) ages 18-19. METHODS: Change in fasting plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, defined as the difference between baseline and follow-up measurements, was compared among 186 (145 black, 41 white) primi- or multiparas, 106 (55 black, 51 white) nulliparous, gravidas versus 721 (313 black, 408 white) nulligravidas. Fully adjusted multiple linear regression models estimated blood lipid changes among these pregnancy groups adjusted for race, age at menarche, baseline lipids, physical inactivity, body mass index, and family sociodemographics. RESULTS: In the 10-year study period, adolescent paras compared with nulligravidas had greater decrements in high-density lipoprotein cholesterol (mg/dL; fully adjusted mean [95% confidence interval] group differences in black -4.3 [-6.7, -2.0]; P < .001 and white: -4.5 [-8.2, -0.7]; P = .016) and greater increments in fasting triglycerides (mg/dL; adjusted mean [95% confidence interval] group differences in black: 10.4 [3.9, 16.8]; P < .001, and white: 11.6 [-3.6, 26.8]; P = .167). CONCLUSION: Adolescent pregnancy contributes to pro-atherogenic lipid profiles that persist after delivery. Further research is needed to assess whether adolescent pregnancy has implications for future cardiovascular disease risk in young women.
Authors: Gunderson EP; Schreiber G; Striegel-Moore R; Hudes M; Daniels S; Biro FM; Crawford PB
J Clin Lipidol. 2012 Mar-Apr;6(2):139-49. Epub 2011 Dec 23.
Age-related somatic structural changes in the nuclear genome of human blood cells
Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects >/=60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were
Authors: Forsberg LA; Iribarren C; Dumanski JP; et al.
Am J Hum Genet. 2012 Feb 10;90(2):217-28. Epub 2012 Feb 2.
Antithrombotic Therapy for Atrial Fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
BACKGROUND: The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. METHODS: We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. RESULTS: For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS(2) [congestive heart failure, hypertension, age >/= 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS(2) score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS(2) score of >/= 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy. CONCLUSIONS: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS(2) score of >/= 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach.
Authors: You JJ; Go AS; American College of Chest Physicians; et al.
Chest. 2012 Feb;141(2 Suppl):e531S-75S.
The impact of subtrochanteric fracture criteria on hip fracture classification
SUMMARY: Hospital diagnosis codes are useful for assessing hip fracture rates in large populations. However, these codes do not reliably differentiate hip fractures that occur in the subtrochanteric region. Identification of subtrochanteric fractures requires review of radiographic images to distinguish these fractures from the more commonly occurring trochanteric fractures. PURPOSE: This study examines the accuracy of coded hospital diagnoses for hip fracture compared to fracture site verification based on operative and radiologic data. The variability in subtrochanteric fracture assignment was also examined using different anatomic criteria. METHODS: This retrospective study includes female members of Kaiser Permanente Northern California age 60 years and older with nontraumatic hip fracture during 2007-2008. Anatomic site was verified by operative and radiologic records, including radiographic image review for fractures occurring in the subtrochanteric region. Two different criteria were compared for subtrochanteric fracture. RESULTS: We identified 2,824 women with incident hip fracture during the 2-year period. The average age was 82.9 +/- 8.2 years and 15% were non-White. International Classification of Diseases, Ninth Revision (ICD-9) coding was accurate for femoral neck and trochanteric fractures (>90% confirmed by operative/radiologic reports), compared to only 26% for subtrochanteric fractures using the Orthopedic Trauma Association (OTA) criteria for subtrochanteric fracture. Using OTA classification, 1.3% of hip fractures were assigned as subtrochanteric compared to 4.2% when the criteria were broadened to include the lesser trochanter. Both femoral neck and pertrochanteric fracture rates increased exponentially with age, while age-related rates in subtrochanteric fracture differed by diagnostic classification method; the broader criteria including the lesser trochanter produced age-related trends that mirrored femoral neck and pertrochanteric fractures. CONCLUSION: Unlike femoral neck and pertrochanteric fractures, epidemiologic studies of subtrochanteric fractures cannot rely on ICD-9 codes alone. Review of radiologic images using OTA criteria is required for identification of subtrochanteric fractures occurring below the lesser trochanter.
Authors: Huang SY; Grimsrud CD; Provus J; Hararah M; Chandra M; Ettinger B; Lo JC
Osteoporos Int. 2012 Feb;23(2):743-50. Epub 2011 May 12.
Correlates of Heart Rate Recovery Over 20 Years in a Healthy Population Sample
INTRODUCTION: Slow HR recovery (HRR) from a graded exercise treadmill test (GXT) is a marker of impaired parasympathetic reactivation that is associated with elevated mortality. Our objective was to test whether demographic, behavioral, or CHD risk factors during young adulthood were associated with the development of slow HRR. METHODS: Participants from the Coronary Artery Risk Development in Young Adults study underwent symptom-limited maximal GXT using a modified Balke protocol at baseline (1985-1986) and 20-yr follow-up (2005-2006) examinations. HRR was calculated as the difference between peak HR and HR 2 min after cessation of the GXT. Slow HRR was defined as 2-min HRR <22 beats.min(-1). RESULTS: In 2730 participants who did not have slow HRR at baseline, mean +/- SD HRR was 44 +/- 11 beats.min(-1) at baseline and declined to 40 +/- 12 beats.min(-1) in 2005-2006; slow HRR developed in 5% (n = 135) of the sample by 2005-2006. Female sex, black race, fewer years of education, obesity, cigarette smoking, higher depressive symptoms, higher fasting glucose, hypertension, metabolic syndrome, and physical inactivity and low fitness were each associated with incident slow HRR. In a multivariable model, higher body mass index, larger waist, low education, fasting glucose, and current smoking remained significantly associated with incident slow HRR. Increasing body mass index (per SD higher) during follow-up and incident hypertension, diabetes, and metabolic syndrome (in the subsets of participants who were free from those conditions at baseline) were each associated with significantly elevated odds of incident slow HRR. CONCLUSIONS: On average, HRR declines with aging; however, the odds of having slow HRR in early middle age is significantly associated with traditional CHD risk factors.
Authors: Carnethon MR; Sternfeld B; Liu K; Jacobs DR Jr; Schreiner PJ; Williams OD; Lewis CE; Sidney S
Med Sci Sports Exerc. 2012 Feb;44(2):273-9.
Association between marijuana exposure and pulmonary function over 20 years
CONTEXT: Marijuana smoke contains many of the same constituents as tobacco smoke, but whether it has similar adverse effects on pulmonary function is unclear. OBJECTIVE: To analyze associations between marijuana (both current and lifetime exposure) and pulmonary function. DESIGN, SETTING, AND PARTICIPANTS: The Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal study collecting repeated measurements of pulmonary function and smoking over 20 years (March 26, 1985-August 19, 2006) in a cohort of 5115 men and women in 4 US cities. Mixed linear modeling was used to account for individual age-based trajectories of pulmonary function and other covariates including tobacco use, which was analyzed in parallel as a positive control. Lifetime exposure to marijuana joints was expressed in joint-years, with 1 joint-year of exposure equivalent to smoking 365 joints or filled pipe bowls. MAIN OUTCOME MEASURES: Forced expiratory volume in the first second of expiration (FEV(1)) and forced vital capacity (FVC). RESULTS: Marijuana exposure was nearly as common as tobacco exposure but was mostly light (median, 2-3 episodes per month). Tobacco exposure, both current and lifetime, was linearly associated with lower FEV(1) and FVC. In contrast, the association between marijuana exposure and pulmonary function was nonlinear (P < .001): at low levels of exposure, FEV(1) increased by 13 mL/joint-year (95% CI, 6.4 to 20; P < .001) and FVC by 20 mL/joint-year (95% CI, 12 to 27; P < .001), but at higher levels of exposure, these associations leveled or even reversed. The slope for FEV(1) was -2.2 mL/joint-year (95% CI, -4.6 to 0.3; P = .08) at more than 10 joint-years and -3.2 mL per marijuana smoking episode/mo (95% CI, -5.8 to -0.6; P = .02) at more than 20 episodes/mo. With very heavy marijuana use, the net association with FEV(1) was not significantly different from baseline, and the net association with FVC remained significantly greater than baseline (eg, at 20 joint-years, 76 mL [95% CI, 34 to 117]; P < .001). CONCLUSION: Occasional and low cumulative marijuana use was not associated with adverse effects on pulmonary function.
Authors: Pletcher MJ; Vittinghoff E; Kalhan R; Richman J; Safford M; Sidney S; Lin F; Kertesz S
JAMA. 2012 Jan 11;307(2):173-81.
Procedural complications, rehospitalizations, and repeat procedures after catheter ablation for atrial fibrillation
OBJECTIVES: The purpose of this study was to estimate rates and identify predictors of inpatient complications and 30-day readmissions, as well as repeat hospitalization rates for arrhythmia recurrence following atrial fibrillation (AF) ablation. BACKGROUND: AF is the most common clinically significant arrhythmia and is associated with increased morbidity and mortality. Radiofrequency or cryotherapy ablation of AF is a relatively new treatment option, and data on post-procedural outcomes in large general populations are limited. METHODS: Using data from the California State Inpatient Database, we identified all adult patients who underwent their first AF ablation from 2005 to 2008. We used multivariable logistic regression to identify predictors of complications and/or 30-day readmissions and Kaplan-Meier analyses to estimate rates of all-cause and arrhythmia readmissions. RESULTS: Among 4,156 patients who underwent an initial AF ablation, 5% had periprocedural complications, most commonly vascular, and 9% were readmitted within 30 days. Older age, female, prior AF hospitalizations, and less hospital experience with AF ablation were associated with higher adjusted risk of complications and/or 30-day readmissions. The rate of all-cause hospitalization was 38.5% by 1 year. The rate of readmission for recurrent AF, atrial flutter, and/or repeat ablation was 21.7% by 1 year and 29.6% by 2 years. CONCLUSIONS: Periprocedural complications occurred in 1 of 20 patients undergoing AF ablation, and all-cause and arrhythmia-related rehospitalizations were common. Older age, female sex, prior AF hospitalizations, and recent hospital procedure experience were associated with a higher risk of complications and/or 30-day readmission after AF ablation.
Authors: Shah RU; Freeman JV; Shilane D; Wang PJ; Go AS; Hlatky MA
J Am Coll Cardiol. 2012 Jan 10;59(2):143-9.
Heart Disease and Stroke Statistics–2012 Update: A Report From the American Heart Association
Authors: Roger VL; Go AS; on behalf of the American Heart Association Statistics Committee and Stroke; et al.
Circulation. 2012 Jan 3;125(1):e2-e220. Epub 2011 Dec 15.
Executive Summary: Heart Disease and Stroke Statistics–2012 Update: A Report From the American Heart Association
Authors: Roger VL; Go AS; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2012 Jan 3;125(1):188-97.
Lactation Intensity and Postpartum Maternal Glucose Tolerance and Insulin Resistance in Women With Recent GDM: The SWIFT cohort
OBJECTIVE: To examine the association between breastfeeding intensity in relation to maternal blood glucose and insulin and glucose intolerance based on the postpartum 2-h 75-g oral glucose tolerance test (OGTT) results at 6-9 weeks after a pregnancy with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: We selected 522 participants enrolled into the Study of Women, Infant Feeding, and Type 2 Diabetes (SWIFT), a prospective observational cohort study of Kaiser Permanente Northern California members diagnosed with GDM using the 3-h 100-g OGTT by the Carpenter and Coustan criteria. Women were classified as normal, prediabetes, or diabetes according to American Diabetes Association criteria based on the postpartum 2-h 75-g OGTT results. RESULTS: Compared with exclusive or mostly formula feeding (>17 oz formula per 24 h), exclusive breastfeeding and mostly breastfeeding (
Authors: Gunderson EP; Hedderson MM; Quesenberry CP; Lo JC; Sternfeld B; Ferrara A; Selby JV; et al.
Diabetes Care. 2012 Jan;35(1):50-6. Epub 2011 Oct 19.
A protocol for active surveillance of acute myocardial infarction in association with the use of a new antidiabetic pharmaceutical agent
PURPOSE: To describe a protocol for active surveillance of acute myocardial infarction (AMI) in users of a recently approved oral antidiabetic medication, saxagliptin, and to provide the rationale for decisions made in drafting the protocol. METHODS: A new-user cohort design is planned for evaluating data from at least four Mini-Sentinel data partners from 1 August 2009 (following US Food and Drug Administration’s approval of saxagliptin) through mid-2013. New users of saxagliptin will be compared in separate analyses with new users of sitagliptin, pioglitazone, long-acting insulins, and second-generation sulfonylureas. Two approaches to controlling for confounding will be evaluated: matching by exposure propensity score and stratification by AMI risk score. The primary analyses will use Cox regression models specified in a way that does not require pooling of patient-level data from the data partners. The Cox models are fit to summarized data on risk sets composed of saxagliptin users and similar comparator users at the time of an AMI. Secondary analyses will use alternative methods including Poisson regression and will explore whether further adjustment for covariates available only at some data partners (e.g., blood pressure) modifies results. RESULTS: The results of this study are pending. CONCLUSIONS: The proposed protocol describes a design for surveillance to evaluate the safety of a newly marketed agent as postmarket experience accrues. It uses data from multiple partner organizations without requiring sharing of patient-level data and compares alternative approaches to controlling for confounding. It is hoped that this initial active surveillance project of the Mini-Sentinel will provide insights that inform future population-based surveillance of medical product safety. Copyright (c) 2012 John Wiley & Sons, Ltd.
Authors: Fireman B; Toh S; Butler MG; Go AS; Joffe HV; Graham DJ; Nelson JC; Daniel GW; Selby JV
Pharmacoepidemiol Drug Saf. 2012 Jan;21 Suppl 1:282-90.
Statin Use During Ischemic Stroke Hospitalization Is Strongly Associated With Improved Poststroke Survival
BACKGROUND AND PURPOSE: Statins reduce infarct size in animal models of stroke and have been hypothesized to improve clinical outcomes after ischemic stroke. We examined the relationship between statin use before and during stroke hospitalization and poststroke survival. METHODS: We analyzed records from 12 689 patients admitted with ischemic stroke to any of 17 hospitals in a large integrated healthcare delivery system between January 2000 and December 2007. We used multivariable survival analysis and grouped-treatment analysis, an instrumental variable method that uses treatment differences between facilities to avoid individual patient-level confounding. RESULTS: Statin use before ischemic stroke hospitalization was associated with improved survival (hazard ratio, 0.85; 95% CI, 0.79-0.93; P<0.001), and use before and during hospitalization was associated with better rates of survival (hazard ratio, 0.59; 95% CI, 0.53-0.65; P<0.001). Patients taking a statin before their stroke who underwent statin withdrawal in the hospital had a substantially greater risk of death (hazard ratio, 2.5; 95% CI, 2.1-2.9; P<0.001). The benefit was greater for high-dose (>60 mg/day) statin use (hazard ratio, 0.43; 95% CI, 0.34-0.53; P<0.001) than for lower dose (<60 mg/day) statin use (hazard ratio, 0.60; 95% CI, 0.54-0.67; P<0.001; test for trend P<0.001), and earlier treatment in-hospital further improved survival. Grouped-treatment analysis showed that the association between statin use and survival cannot be explained by patient-level confounding. CONCLUSIONS: Statin use early in stroke hospitalization is strongly associated with improved poststroke survival, and statin withdrawal in the hospital, even for a brief period, is associated with worsened survival.
Authors: Flint AC; Johnston SC; et al.
Stroke. 2012 Jan;43(1):147-54. Epub 2011 Oct 20.
Targeted maximum likelihood estimation for prediction calibration
Estimators of the conditional expectation, i.e., prediction, function involve a global bias-variance trade off. In some cases, an estimator that yields unbiased estimates of the conditional expectation for a particular partitioning of the data may be desirable. Such estimators are calibrated with respect to the partitioning. We identify the conditional expectation given a particular partitioning as a smooth parameter of the distribution of the data, where the partitioning may be defined on the covariate space or on the prediction space of the estimator. We propose a targeted maximum likelihood estimation (TMLE) procedure that updates an initial prediction estimator such that the updated estimator yields an unbiased and efficient estimator of this smooth parameter in the nonparametric statistical model. When the partitioning is defined on the prediction space of the estimator, our TMLE involves enforcing an implicit constraint on the estimator itself. We show that our resulting estimator of the smooth parameter is equal to the empirical estimator, which is also known to be unbiased and efficient in the nonparametric statistical model. We derive the TMLE for single time-point prediction and also time-dependent prediction in a counting process framework.
Authors: Brooks J; van der Laan MJ; Go AS
Int J Biostat. 2012 Oct 31;8(1):30.
ADHD medications and risk of serious cardiovascular events in young and middle-aged adults
CONTEXT: More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention-deficit/hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure, raising concerns about their cardiovascular safety. OBJECTIVE: To examine whether current use of medications prescribed primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, population-based cohort study using electronic health care records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at 1 site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data. Participants were adults aged 25 through 64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n = 150,359) was matched to 2 nonusers on study site, birth year, sex, and calendar year (443,198 total users and nonusers). MAIN OUTCOME MEASURES: Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke, with comparison between current or new users and remote users to account for potential healthy-user bias. RESULTS: During 806,182 person-years of follow-up (median, 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person-years of current use (median, 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14-1.57) for MI, 0.30 (95% CI, 0.20-0.42) for SCD, and 0.56 (95% CI, 0.43-0.72) for stroke. The multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current use vs nonuse of ADHD medications was 0.83 (95% CI, 0.72-0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI, 0.63-0.94). The adjusted RR for current use vs remote use was 1.03 (95% CI, 0.86-1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI, 0.82-1.28); the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years at ages 25-44 years and 0.77 events per 1000 person-years at ages 45-64 years. CONCLUSIONS: Among young and middle-aged adults, current or new use of ADHD medications, compared with nonuse or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy-user bias.
Authors: Habel LA; Fireman BH; Go AS; Nguyen-Huynh MN; Selby JV; et al.
JAMA. 2011 Dec 28;306(24):2673-83. Epub 2011 Dec 12.
Association between second-generation antipsychotics and newly diagnosed treated diabetes mellitus: does the effect differ by dose?
BACKGROUND: The benefits of some second-generation antipsychotics (SGAs) must be weighed against the increased risk for diabetes mellitus. This study examines whether the association between SGAs and diabetes differs by dose. METHODS: Patients were >/=18 years of age from three US healthcare systems and exposed to an SGA for >/=45 days between November 1, 2002 and March 31, 2005. Patients had no evidence of diabetes before index date and no previous antipsychotic prescription filled within 3 months before index date.49,946 patients were exposed to SGAs during the study period. Person-time exposed to antipsychotic dose (categorized by tertiles for each drug) was calculated. Newly treated diabetes was identified using pharmacy data to determine patients exposed to anti-diabetic therapies. Adjusted hazard ratios for diabetes across dose tertiles of SGA were calculated using the lowest dose tertile as reference. RESULTS: Olanzapine exhibited a dose-dependent relationship for risk for diabetes, with elevated and progressive risk across intermediate (diabetes rate per 100 person-years = 1.9; adjusted Hazard Ratio (HR), 1.7, 95% confidence interval (CI), 1.0-3.1) and top tertile doses (diabetes rate per 100 person-years = 2.7; adjusted HR, 2.5, 95% CI, 1.4-4.5). Quetiapine and risperidone exhibited elevated risk at top dose tertile with no evidence of increased risk at intermediate dose tertile. Unlike olanzapine, quetiapine, and risperidone, neither aripiprazole nor ziprasidone were associated with risk of diabetes at any dose tertile. CONCLUSIONS: In this large multi-site epidemiologic study, within each drug-specific stratum, the risk of diabetes for persons exposed to olanzapine, risperidone, and quetiapine was dose-dependent and elevated at therapeutic doses. In contrast, in aripiprazole-specific and ziprasidone-specific stratum, these newer agents were not associated with an increased risk of diabetes and dose-dependent relationships were not apparent. Although, these estimates should be interpreted with caution as they are imprecise due to small numbers.
Authors: Ulcickas Yood M; Quesenberry CP Jr; Oliveria SA; Tsai AL; Kim E; Cziraky MJ; McQuade RD; Newcomer JW; L'italien GJ; DeLorenze GN
BMC Psychiatry. 2011 Dec 15;11:197.
The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system
BACKGROUND: Preventing fetal exposure to isotretinoin is widely acknowledged as an important safety issue. The iPLEDGE program is the latest in a series of Food and Drug Administration-mandated risk management programs designed to prevent pregnancies in female patients of childbearing potential (FCBP) taking isotretinoin. OBJECTIVE: We sought to evaluate the effect of iPLEDGE relative to the prior risk management program (system to manage Accutane-related teratogenicity [SMART]) on the risk of isotretinoin fetal exposure in FCBP in a managed care setting. METHODS: All FCBP at Kaiser Permanente Southern and Northern California who filled at least one prescription for isotretinoin during a 4-year period (March 1, 2004, to February 29, 2008) were included in this retrospective cohort study (n = 8344). Chart review was performed to confirm fetal exposures and outcomes. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence intervals. RESULTS: There were a total of 29 fetal exposures and 9912 isotretinoin treatment courses. After iPLEDGE was implemented, the unadjusted rate of fetal exposure decreased from 3.11 to 2.67 per 1000 treatment courses (P = .69). The hazard ratio = 0.76 (95% confidence interval 0.36-1.61) for fetal exposures to isotretinoin during treatment courses filled after iPLEDGE implementation compared with SMART. LIMITATIONS: Limitations include limited generalizability of results, small sample size (n = 29 total documented fetal exposures), and potential uncontrolled confounders. CONCLUSION: Evaluating the impact of iPLEDGE on isotretinoin fetal exposures is important in understanding the full risks and benefits of isotretinoin treatment. We found no evidence that iPLEDGE significantly decreased the risk of fetal exposure in FCBP compared to the SMART program.
Authors: Shin J; Cheetham TC; Wong L; Niu F; Kass E; Yoshinaga MA; Sorel M; McCombs JS; Sidney S
J Am Acad Dermatol. 2011 Dec;65(6):1117-25. Epub 2011 May 11.
Antipsychotic Medication Use Among Children and Risk of Diabetes Mellitus
OBJECTIVE: To assess whether the risk of incident diabetes was increased with the use of second-generation antipsychotics (SGAs) in a large diverse cohort of children. METHODS: A retrospective study was conducted by using the administrative databases of 3 health plans participating in the Health Maintenance Organization Research Network. Children 5 to 18 years of age who initiated SGA therapy between January 2001 and December 2008 and 2 comparison groups, namely, nonusers of psychotropic drugs and users of antidepressant medications, were identified. Diagnoses from inpatient and outpatient records, pharmacy dispensings, and outpatient laboratory results were used to identify incident cases of diabetes. RESULTS: The crude incidence rate of diabetes for the SGA-exposed cohort was 3.23 cases per 1000 person-years (95% confidence interval [CI]: 1.67-5.65), compared with 0.76 cases per 1000 person-years (95% CI: 0.49-1.12) among nonusers of psychotropic medications and 1.86 cases per 1000 person-years (95% CI: 1.12-2.90) among antidepressant users. The risk of incident diabetes was significantly increased among SGA users (unadjusted incidence rate ratio: 4.24 [95% CI: 1.95-8.72]) in comparison with nonusers of psychotropic medications but was not significantly increased in comparison with antidepressant medication users (unadjusted incidence rate ratio: 1.74 [95% CI: 0.77-3.78]). CONCLUSIONS: Although we found a potentially fourfold increased rate of diabetes among children exposed to SGAs, the findings were inconsistent and depended on the comparison group and the outcome definition.
Authors: Andrade SE; Lo JC; Roblin D; Fouayzi H; Connor DF; Penfold RB; Chandra M; Reed G; Gurwitz JH
Pediatrics. 2011 Dec;128(6):1135-41. Epub 2011 Nov 21.
Validation of the Stroke Prognostic Instrument-II in a Large, Modern, Community-Based Cohort of Ischemic Stroke Survivors
BACKGROUND AND PURPOSE: The risk of recurrent stroke in the modern era of secondary stroke prevention is not well defined. Several prediction models, including the Stroke Prognostic Instrument-II (SPI-II), have been created to identify patients at highest risk, but their performance in modern populations has been infrequently tested. We aimed to assess the 1-year risk of recurrence after hospital discharge in a recent, large, community-based cohort of patients with ischemic stroke and to validate the SPI-II prediction model in this cohort. METHODS: From 2004 through 2006, 5575 patients with acute ischemic stroke were prospectively identified and followed for recurrent events. Kaplan-Meier statistics were used to analyze the cumulative incidence of recurrent ischemic stroke. Harrell c-statistic was calculated to determine the performance of SPI-II in predicting stroke or death at 1 year, and the log-rank test was used to compare the differences among low-, middle-, and high-risk groups. RESULTS: Among 5575 patients with ischemic stroke, recurrence was observed in 221 during the subsequent year. Kaplan-Meier estimates of cumulative rates of recurrent stroke were 2.5%, 3.6%, and 4.8% at 3, 6, and 12 months, respectively. Rates of stroke or death for SPI-II in the low-, middle-, and high-risk groups were 8.2%, 24.5%, and 35.6%, respectively (trend, P=0.001). The c-statistic for SPI-II was 0.62 (95% CI, 0.61-0.64). CONCLUSIONS: The modern 1-year rate of recurrent stroke after hospital discharge is low but still substantial at 4.8%. SPI-II is a modestly effective tool in identifying patients with ischemic stroke at highest risk of developing recurrence or death.
Authors: Navi BB; Kamel H; Sidney S; Klingman JG; Nguyen-Huynh MN; Johnston SC
Stroke. 2011 Dec;42(12):3392-6. Epub 2011 Sep 29.
Lower Extremity Fat Mass Is Associated With Insulin Resistance in Overweight and Obese Individuals: The CARDIA Study
Lower extremity fat mass (LEFM) has been shown to be favorably associated with glucose metabolism. However, it is not clear whether this relationship is similar across varying levels of obesity. We hypothesized that lower amounts of LEFM is associated with higher insulin resistance (IR) and this association may vary according to weight status. Participants with available measures were examined from the Coronary Artery Risk Development in Young Adults study (CARDIA), a multi-center longitudinal study of the etiology of atherosclerosis in black and white men and women aged 38-50 years old in 2005-2006 (n = 1,579). The homeostasis model assessment of IR (HOMA(IR)) was calculated to estimate IR, regional adiposity was measured using dual energy X-ray absorptiometry (DXA), and weight status was defined according to BMI categories. Obese and overweight participants exhibited higher IR, total fat mass (FM), trunk FM (TFM), and LEFM compared to normal weight participants. After controlling for age, height, race, study center, education, smoking, and cardiorespiratory fitness (CRF), greater LEFM was significantly associated with higher IR only in normal weight men and women. Further adjustment for TFM revealed that lower LEFM was significantly associated with higher IR in overweight and obese men and women and the positive association in normal weight individuals was attenuated. These results suggest that excess adiposity in the lower extremities may attenuate the metabolic risk observed at a given level of abdominal adiposity in overweight and obese individuals. Weight status presents additional complexity since the metabolic influence of adipose tissue may not be homogenous across anatomic regions or level of obesity.
Authors: Shay CM; Carnethon MR; Church TR; Hankinson AL; Chan C; Jacobs Jr DR; Lewis CE; Schreiner PJ; Sternfeld B; Sidney S
Obesity (Silver Spring). 2011 Nov;19(11):2248-53. Epub 2011 May 26.
FGF23 induces left ventricular hypertrophy
Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
Authors: Faul C; Amaral AP; Oskouei B; Hu MC; Sloan A; Isakova T; Gutierrez OM; Aguillon-Prada R; Lincoln J; Hare JM; Mundel P; Morales A; Scialla J; Fischer M; Soliman EZ; Chen J; Go AS; Rosas SE; Nessel L; Townsend RR; Feldman HI; St John Sutton M; Ojo A; Gadegbeku C; Di Marco GS; Reuter S; Kentrup D; Tiemann K; Brand M; Hill JA; Moe OW; Kuro-O M; Kusek JW; Keane MG; Wolf M
J Clin Invest. 2011 Nov;121(11):4393-408. Epub 2011 Oct 10.
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>/=140 mm Hg systolic blood pressure or >/=90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure; which used a multi-stage design in 200;000 individuals of European descent; identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3; NPR3-C5orf23; ADM; FURIN-FES; GOSR2; GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension; left ventricular wall thickness; stroke and coronary artery disease; but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian; South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure; and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Authors: International Consortium for Blood Pressure Genome-Wide Association Studies; Galan P; Guarrera S; Rice KM; Bergman R; et al.
Nature. 2011 Sep 11;478(7367):103-9.
Chronic kidney disease and risk for presenting with acute myocardial infarction versus stable exertional angina in adults with coronary heart disease
OBJECTIVES: The aim of this study was to examine whether kidney dysfunction is associated with the type of clinical presentation of coronary heart disease (CHD). BACKGROUND: Reduced kidney function increases the risk for developing CHD, but it is not known whether it also influences the acuity of clinical presentation, which has important prognostic implications. METHODS: A case-control study was conducted of subjects whose first clinical presentation of CHD was either acute myocardial infarction or stable exertional angina between October 2001 and December 2003. Estimated glomerular filtration rate (eGFR) before the incident event was calculated using calibrated serum creatinine and the abbreviated MDRD (Modification of Diet in Renal Disease) equation. Patient characteristics and use of medications were ascertained from self-report and health plan databases. Multivariable logistic regression was used to examine the association of reduced eGFR and CHD presentation. RESULTS: A total of 803 adults with incident acute myocardial infarctions and 419 adults with incident stable exertional angina who had baseline eGFRs
Authors: Go AS; Bansal N; Chandra M; Lathon PV; Fortmann SP; Iribarren C; Hsu CY; Hlatky MA; ADVANCE Study Investigators
J Am Coll Cardiol. 2011 Oct 4;58(15):1600-7.
Methods for Assessing Fracture Risk Prediction Models: Experience With FRAX in a Large Integrated Health Care Delivery System
Area under the receiver operating characteristics (AUROC) curve is often used to evaluate risk models. However, reclassification tests provide an alternative assessment of model performance. We performed both evaluations on results from FRAX (World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK), a fracture risk tool, using Kaiser Permanente Northern California women older than 50yr with bone mineral density (BMD) measured during 1997-2003. We compared FRAX performance with and without BMD in the model. Among 94,489 women with mean follow-up of 6.6yr, 1579 (1.7%) sustained a hip fracture. Overall, AUROCs were 0.83 and 0.84 for FRAX without and with BMD, suggesting that BMD did not contribute to model performance. AUROC decreased with increasing age, and BMD contributed significantly to higher AUROC among those aged 70yr and older. Using an 81% sensitivity threshold (optimum level from receiver operating characteristic curve, corresponding to 1.2% cutoff), 35% of those categorized above were reassigned below when BMD was added. In contrast, only 10% of those categorized below were reassigned to the higher risk category when BMD was added. The net reclassification improvement was 5.5% (p<0.01). Two versions of this risk tool have similar AUROCs, but alternative assessments indicate that addition of BMD improves performance. Multiple methods should be used to evaluate risk tool performance with less reliance on AUROC alone.
Authors: Pressman AR; Lo JC; Chandra M; Ettinger B
J Clin Densitom. 2011 Oct-Dec;14(4):407-15. Epub 2011 Oct 1.
Outcomes registry for better informed treatment of atrial fibrillation: Rationale and design of ORBIT-AF
BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of stroke, heart failure, and death. Data on contemporary treatment patterns and outcomes associated with AF in clinical practice are limited. METHODS/DESIGN: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation is a multicenter, prospective, ambulatory-based registry of incident and prevalent AF. The registry will be a nationwide collaboration of health care providers, including internists, primary care physicians, cardiologists, and electrophysiologists. Initial target enrollment is approximately 10,000 patients to be recruited from approximately 200 US outpatient practices. Enrolled patients will be observed for >/=2 years. A patient-reported outcomes substudy in >/=1,500 patients will provide serial quality-of-life assessments. The goal is to characterize treatment and outcomes of patients with AF, thereby promoting better quality of AF care and improved patient outcomes. CONCLUSION: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation will provide insights into ‘real-world’ treatment including rate and rhythm control, stroke prevention, transitions to new therapies, and clinical and patient-centered outcomes among patients with AF in community practice settings (ClinicalTrials.gov NCT01165710).
Authors: Piccini JP; Go AS; Peterson ED; et al.
Am Heart J. 2011 Oct;162(4):606-612.e1.
Cardiovascular disease among hispanics and non-hispanics in the chronic renal insufficiency cohort (CRIC) study
BACKGROUND AND OBJECTIVES: Hispanics are the largest minority group in the United States. The leading cause of death in patients with chronic kidney disease (CKD) is cardiovascular disease (CVD), yet little is known about its prevalence among Hispanics with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted cross-sectional analyses of prevalent self-reported clinical and subclinical measures of CVD among 497 Hispanics, 1638 non-Hispanic Caucasians, and 1650 non-Hispanic African Americans, aged 21 to 74 years, with mild-to-moderate CKD at enrollment in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic CRIC (HCRIC) studies. Measures of subclinical CVD included left ventricular hypertrophy (LVH), coronary artery calcification (CAC), and ankle-brachial index. RESULTS: Self-reported coronary heart disease (CHD) was lower in Hispanics compared with non-Hispanic Caucasians (18% versus 23%, P = 0.02). Compared with non-Hispanic Caucasians, Hispanics had a lower prevalence of CAC >100 (41% versus 34%, P = 0.03) and CAC >400 (26% versus 19%, P = 0.02). However, after adjusting for sociodemographic factors, these differences were no longer significant. In adjusted analyses, Hispanics had a higher odds of LVH compared with non-Hispanic Caucasians (odds ratio 1.97, 95% confidence interval, 1.22 to 3.17, P = 0.005), and a higher odds of CAC >400 compared with non-Hispanic African Americans (odds ratio, 2.49, 95% confidence interval, 1.11 to 5.58, P = 0.03). Hispanic ethnicity was not independently associated with any other CVD measures. CONCLUSIONS: Prevalent LVH was more common among Hispanics than non-Hispanic Caucasians, and elevated CAC score was more common among Hispanics than non-Hispanic African Americans. Understanding reasons for these racial/ethnic differences and their association with long-term clinical outcomes is needed.
Authors: Ricardo AC; Go AS; CRIC and HCRIC Investigators; et al.
Clin J Am Soc Nephrol. 2011 Sep;6(9):2121-31.
Comparison of Hemoglobin A1c With Fasting Plasma Glucose and 2-h Postchallenge Glucose for Risk Stratification Among Women With Recent Gestational Diabetes Mellitus
OBJECTIVE: Postpartum testing with a 75-g 2-h oral glucose tolerance test or fasting plasma glucose (FPG) alone is often not performed among women with histories of gestational diabetes mellitus (GDM). Use of hemoglobin A(1c) (A1C) might increase testing. The association between A1C and glucose has not been examined in women with histories of GDM. RESEARCH DESIGN AND METHODS: We assessed the association of A1C >/=5.7% with FPG >/=100 mg/dL and 2-h glucose >/=140 mg/dL among 54 women with histories of GDM between 6 weeks and 36 months postpartum. RESULTS: A1C >/=5.7% had 65% sensitivity and 68% specificity for identifying elevated FPG or 2-h glucose and 75% sensitivity and 62% specificity for elevated FPG alone. The area under the receiver operating characteristic curve for A1C was 0.76 for elevated FPG or 2-h glucose and 0.77 for elevated FPG alone. CONCLUSIONS: The agreement between A1C and glucose levels is fair for detection of abnormal glucose tolerance among women with histories of GDM.
Authors: Kim C; Herman WH; Cheung NW; Gunderson EP; Richardson C
Diabetes Care. 2011 Sep;34(9):1949-51. Epub 2011 Jul 12.
Bone and the perimenopause
Loss of ovarian function has a profound impact on female skeletal health. Bone mineral density findings from the Study of Women’s Health Across the Nation demonstrate an accelerated rate of bone loss during the menopausal transition. The greatest reduction occurs in the year before the final menstrual period and the first 2 years thereafter. Clinical management includes maintenance of adequate dietary calcium and vitamin D intake, attention to modifiable risk factors, and osteoporosis screening. Indications, benefits, and risks of pharmacologic osteoporosis therapy should be assessed individually; there are currently no established guidelines addressing the treatment and prevention of osteoporosis in perimenopausal women.
Authors: Lo JC; Burnett-Bowie SA; Finkelstein JS
Obstet Gynecol Clin North Am. 2011 Sep;38(3):503-17.
Mental illness and warfarin use in atrial fibrillation
OBJECTIVES: To determine whether atrial fibrillation (AF) patients with mental health conditions (MHCs) were less likely than AF patients without MHCs to be prescribed warfarin and, if receiving warfarin, to maintain an International Normalized Ratio (INR) within the therapeutic range. STUDY DESIGN: Detailed chart review of AF patients using a Veterans Health Administration (VHA) facility in 2003. METHODS: For a random sample of 296 AF patients, records identified clinician-diagnosed MHCs (independent variable) and AF-related care in 2003 (dependent variables), receipt of warfarin, INR values below/above key thresholds, and time spent within the therapeutic range (2.0-3.0) or highly out of range. Differences between the MHC and comparison groups were examined using X2 tests and logistic regression controlling for age and comorbidity. RESULTS: Among warfarin-eligible AF patients (n = 246), 48.5% of those with MHCs versus 28.9% of those without MHCs were not treated with warfarin (P = .004). Among those receiving warfarin and monitored in VHA, highly supratherapeutic INRs were more common in the MHC group; for example, 27.3% versus 1.6% had any INR >5.0 (P <.001). Differences persisted after adjusting for age and comorbidity. CONCLUSIONS: MHC patients with AF were less likely than those without MHC to have adequate management of their AF care. Interventions directed at AF patients with MHC may help to optimize their outcomes.
Authors: Walker GA; Heidenreich PA; Phibbs CS; Go AS; Chiu VY; Schmitt SK; Ananth L; Frayne SM
Am J Manag Care. 2011 Sep;17(9):617-24.
Epidemiology of peripartum cardiomyopathy: incidence, predictors, and outcomes
OBJECTIVES: To estimate the incidence, describe the mortality, and identify independent predictors of peripartum cardiomyopathy, a very serious cardiovascular complication of pregnancy associated with maternal morbidity and mortality among otherwise healthy women without prior heart disease. METHODS: We identified all cases of diagnosed heart failure that occurred among women within 1 month before to 5 months after delivery of a liveborn neonate in Kaiser Permanente Northern California delivery hospitals between 1995 and 2004. Incident peripartum cardiomyopathy was confirmed from medical records documenting dilated cardiomyopathy with reduced left ventricular systolic function after excluding women with prior heart failure or valvular disease. Data sources included medical records, electronic clinical databases, and state birth and death files. RESULTS: Among 227,224 eligible women, we confirmed 110 recognized peripartum cardiomyopathy cases (incidence: 4.84 per 10,000 live births, 95% confidence interval 3.98-5.83). Independent predictors included maternal age of 25 years or older, non-Hispanic African American and Filipino groups, parity of 4 or greater, multiple gestation, severe anemia, pre-existing and pregnancy-related hypertensive disorders, and hemolysis, elevated liver enzymes, low platelets syndrome. Maternal death rate (per 1,000 person-years) was higher among cases (6.12) than noncases (0.23; P<.001). Neonates whose mothers developed peripartum cardiomyopathy experienced poorer clinical outcomes. CONCLUSION: Within a large, diverse northern California population, 1 of every 2,066 women delivering a liveborn neonate had recognized, confirmed peripartum cardiomyopathy, which was associated with higher maternal and neonatal death rates and worse neonatal outcomes. Several readily available patient characteristics can be used to identify women at risk for this severe pregnancy complication. LEVEL OF EVIDENCE: II.
Authors: Gunderson EP; Croen LA; Chiang V; Yoshida CK; Walton D; Go AS
Obstet Gynecol. 2011 Sep;118(3):583-91.
Slowing demand for total joint arthroplasty in a population of 3.2 million
Accurate projections of future demand require constant updates of current data. This article reviews the most recent usage data for primary total joint arthroplasty (TJA) in a community-based hospital system with 3.2 million members. We used administrative databases to determine plan membership, surgical volume, and age-adjusted incidence rates for TJA from 1996 through 2009. The annual growth rate in surgical volume peaked in 2002 at 18% and decreased to 3% by 2009. The annual growth rate for age-adjusted incidence rates peaked in 2002 at 13% and declined to 2% in 2009. In our population, the incidence of TJA continues to rise but at a much slower pace than in recent years.
Authors: Bini SA; Sidney S; Sorel M
J Arthroplasty. 2011 Sep;26(6 Suppl):124-8.
CKD in Hispanics: Baseline characteristics from the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic-CRIC Studies
BACKGROUND: Little is known regarding chronic kidney disease (CKD) in Hispanics. We compared baseline characteristics of Hispanic participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies with non-Hispanic CRIC participants. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Participants were aged 21-74 years with CKD using age-based estimated glomerular filtration rate (eGFR) at enrollment into the CRIC/H-CRIC Studies. H-CRIC included Hispanics recruited at the University of Illinois in 2005-2008, whereas CRIC included Hispanics and non-Hispanics recruited at 7 clinical centers in 2003-2007. FACTOR: Race/ethnicity. OUTCOMES: Blood pressure, angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor blocker (ARB) use, and CKD-associated complications. MEASUREMENTS: Demographic characteristics, laboratory data, blood pressure, and medications were assessed using standard techniques and protocols. RESULTS: Of H-CRIC/CRIC participants, 497 were Hispanic, 1,650 were non-Hispanic black, and 1,638 were non-Hispanic white. Low income and educational attainment were nearly twice as prevalent in Hispanics compared with non-Hispanics (P < 0.01). Hispanics had self-reported diabetes (67%) more frequently than non-Hispanic blacks (51%) and whites (40%; P < 0.01). Blood pressure >130/80 mm Hg was more common in Hispanics (62%) than blacks (57%) and whites (35%; P < 0.05), and abnormalities in hematologic, metabolic, and bone metabolism parameters were more prevalent in Hispanics (P < 0.05), even after stratifying by entry eGFR. Hispanics had the lowest use of ACE inhibitors/ARBs among the high-risk subgroups, including participants with diabetes, proteinuria, and blood pressure >130/80 mm Hg. Mean eGFR was lower in Hispanics (39.6 mL/min/1.73 m(2)) than in blacks (43.7 mL/min/1.73 m(2)) and whites (46.2 mL/min/1.73 m(2)), whereas median proteinuria was higher in Hispanics (protein excretion, 0.72 g/d) than in blacks (0.24 g/d) and whites (0.12 g/d; P < 0.01). LIMITATIONS: Generalizability; observed associations limited by residual bias and confounding. CONCLUSIONS: Hispanics with CKD in the CRIC/H-CRIC Studies are disproportionately burdened with lower socioeconomic status, more frequent diabetes mellitus, less ACE-inhibitor/ARB use, worse blood pressure control, and more severe CKD and associated complications than their non-Hispanic counterparts.
Authors: Fischer MJ; Go AS; CRIC and H-CRIC Study Groups; et al.
Am J Kidney Dis. 2011 Aug;58(2):214-27. Epub 2011 Jun 25.
Postacute care and ischemic stroke mortality: findings from an integrated health care system in northern california
OBJECTIVE: To study the association of postacute care (PAC) settings and mortality outcome of patients who sustained an ischemic stroke. DESIGN: A retrospective cohort study. SETTING: An integrated health care system in northern California. PARTICIPANTS: Patients who sustained an acute ischemic stroke between 1996 and 2004, survived the initial acute care hospital stay, and received PAC services within 14 days of discharge (n = 16,538) and 61 days of discharge (n = 16,468). INTERVENTIONS: PAC rehabilitation ranked by resource level, that is, inpatient rehabilitation hospital (IRH), skilled nursing facility (SNF), home health (HH), and outpatient (OP) rehabilitation. MAIN OUTCOME MEASUREMENTS: One-year mortality after acute care hospital discharge. RESULTS: The highest level of PAC services received within 14 days of acute care discharge was IRH for 5.6% of patients, SNF for 48.3% of patients, HH for 18.9% of patients, and OP for 27.3% of patients. The highest level of PAC services received within 61 days of acute care discharge was IRH for 10.9% of patients, SNF for 40.4% of patients, HH for 19.1% of patients, and OP for 29.6% of patients. Cox proportional hazard models showed that patients whose highest level of PAC service was provided by an IRH, through HH, or OP had a significantly better 1-year survival than did those admitted to an SNF. The following factors were associated with a higher risk of 1-year mortality: older age, male gender, African American ethnicity, history of previous stroke, higher Deyo-Charlson comorbidity scores, a longer acute care hospital stay, and hospitalization in one remotely located health service area. CONCLUSIONS: In the year after a stroke occurred, the rate of patient survival varied based on PAC rehabilitation services. Age, gender, race or ethnicity, history of a previous stroke, comorbid conditions, and service area also were significantly associated with 1-year mortality after acute care discharge. Further investigation of the differences in mortality among PAC settings is indicated.
Authors: Wang H; Sandel ME; Terdiman J; Armstrong MA; Klatsky A; Camicia M; Sidney S
PM R. 2011 Aug;3(8):686-94.
Fat mass modifies the association of fat-free mass with symptom-limited treadmill duration in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
BACKGROUND: The assessment of fat mass and fat-free mass in relation to the symptom-limited maximal exercise duration (Max(dur)) of a treadmill test allows for insight into the association of body composition with treadmill performance potential. OBJECTIVE: We investigated the complex associations between fat mass and fat-free mass and Max(dur) in a population setting. DESIGN: The Max(dur) of a graded exercise treadmill test and body composition by dual-energy X-ray absorptiometry were estimated in 2413 black and white men and women aged 38-50 y from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. RESULTS: The mean Max(dur) was approximately 7.5 s shorter per kilogram of fat mass in both men and women and independent of fat-free mass, height, race, television watching, physical activity, systolic blood pressure, lung function, and education. Fat mass modified the association of fat-free mass with the Max(dur) (2-way interaction P < 0.001), and the interaction was stronger in women than in men. In men in the lowest fat-mass quartile, the Max(dur) was 1.3 s longer per kilogram of fat-free mass and was 0.5 s shorter per kilogram of fat-free mass in the highest fat-mass quartile. In contrast, in women with the least fat mass, the Max(dur) was 2.7 s longer per kilogram of fat-free mass and was 2.8 s shorter per kilogram of fat-free mass in the highest fat-mass quartile. CONCLUSIONS: The Max(dur) was negatively related to fat mass. Fat-free mass in obese people contributed little to the treadmill performance potential as assessed by the Max(dur), although the contribution of fat-free mass was positive in thinner people.
Authors: Zhu N; Jacobs DR Jr; Sidney S; Sternfeld B; Carnethon M; Lewis CE; Shay CM; Sood A; Bouchard C
Am J Clin Nutr. 2011 Aug;94(2):385-91. Epub 2011 Jun 8.
Fish oil, selenium and mercury in relation to incidence of hypertension: a 20-year follow-up study
Abstract. Xun P, Hou N, Daviglus M, Liu K, Morris JS, Shikany JM, Sidney S, Jacobs DR, He K (Department of Nutrition, Gillings School of Global Public Health and School of Medicine and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL; Research Reactor Center, University of Missouri-Columbia, Columbia, MO; Division of Preventive Medicine, School of medicine, University of Alabama at Birmingham, Birmingham, AL; Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN; and Department of Nutrition, University of Oslo, Oslo, Norway). Fish oil, selenium and mercury in relation to incidence of hypertension: a 20-year follow-up study. J Intern Med 2011; doi: 10.1111/j.1365-2796.2010.02338.x. Objectives. Long-chain omega-3 polyunsaturated fatty acids (LComega3PUFAs), selenium (Se) and mercury (Hg) are three important components in fish. The cardioprotective effect of LComega3PUFA intake has been recognized; however, the hypothesis that this benefit may be greatest with high Se and low Hg levels has not been investigated. Design. A cohort of 4508 American adults aged 18-30, without hypertension at baseline in 1985, were enrolled. Six follow-ups were conducted at examinations in 1987, 1990, 1992, 1995, 2000 and 2005. Diet was assessed by a validated interviewer-administered quantitative food frequency questionnaire at exams in 1985, 1992 and 2005. Incident hypertension was defined as first occurrence at any follow-up examination of systolic blood pressure (BP) >/= 140 mmHg, diastolic BP >/= 90 mmHg or taking antihypertensive medication. Toenail clippings were collected in 1987, and Se and Hg levels were quantified by instrumental neutron-activation analysis. Result. Participants in the highest LComega3PUFA intake quartile had a significantly lower incidence of hypertension (hazard ratio: 0.65; 95% CI: 0.53-0.79; P(trend) < 0.01) compared to those in the lowest quartile after adjustment for potential confounders. Docosahexaenoic acid showed a greater inverse association than eicosapentaenoic acid. The inverse association of LComega3PUFA intake with hypertension appeared more pronounced at higher Se and lower Hg levels, although interaction tests were statistically nonsignificant. Conclusions. Our findings indicated that LComega3PUFA intake was inversely associated with incidence of hypertension. The prior hypothesis that the potential antihypertensive effect of LComega3PUFA intake varies depending on joint levels of Se and Hg received modest support and cannot be ruled out.
Authors: Xun P; Hou N; Daviglus M; Liu K; Morris JS; Shikany JM; Sidney S; He K; Jacobs DR Jr
J Intern Med. 2011 Aug;270(2):175-86. Epub 2011 Jan 9.
Ethnicity and risk of hospitalization for asthma and chronic obstructive pulmonary disease
PURPOSE: To identify ethnic differences for risk of hospitalization for asthma and chronic obstructive pulmonary disease (COPD). METHODS: We undertook a cohort study with 126,019 participants: 55% whites, 27% blacks, 11% Asians, and 4% Hispanics. To estimate asthma and COPD risk, we used Cox proportional hazards models adjusted for age, sex, body mass index, education, smoking, and alcohol intake. End points were hospitalizations for asthma or COPD. RESULTS: Compared with whites, relative risks (RR) with 95% confidence intervals (95% CI) for asthma among other groups were: blacks, 1.7 (1.4-2.0); Hispanics, 0.9 (0.6-1.4); and Asians, 1.6 (1.2-2.1). Among Asians, increased risk was concentrated in Filipino men and women and South Asian men. For COPD, whites were at highest risk; RR of blacks was 0.9 (0.7-1.0); Hispanics, 0.6 (0.3- 0.9); and Asians, 0.4 (0.3-0.6). COPD risk among Asians was lowest in Chinese with RR of 0.3 (0.1-0.5). CONCLUSIONS: Ethnic disparities in risk of asthma and COPD as well as between both diseases exist, especially for Asian Americans, who have high asthma risk and low COPD risk. While residual confounding for smoking or other environmental factors could be partially responsible, genetic factors in Asians may be involved in decreased COPD risk.
Authors: Tran HN; Siu S; Iribarren C; Udaltsova N; Klatsky AL
Ann Epidemiol. 2011 Aug;21(8):615-22. Epub 2011 Mar 17.
Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial.
AIM: To provide an in-depth clinical characterization and analysis of outcomes of the patients hospitalized for heart failure (HF) who subsequently develop worsening renal function (WRF) during hospitalization or soon after discharge.METHODS AND RESULTS: Of the 4133 patients hospitalized with worsening HF and reduced left ventricular ejection fraction (LVEF) (≤40%) in the EVEREST trial, 2072 were randomized to tolvaptan, a selective vasopressin-2 receptor antagonist, and 2061 were randomized to placebo, both in addition to standard therapy. This analysis included the 2021 (98%) patients in the placebo group with a complete set of renal function parameters. Renal function parameters and clinical variables were measured prospectively during hospitalization and after discharge. Worsening renal function was defined as an increase in sCr ≥0.3 mg/dL during the in-hospital (randomization to discharge or Day 7) and post-discharge (discharge or Day 7 to 4 weeks post-discharge) periods. Blood pressure (BP), body weight (BW), natriuretic peptides (NPs), and congestion score were correlated with WRF. The prognostic value of baseline renal function at admission and WRF during hospitalization and post-discharge on long-term outcomes were assessed using a Cox proportional hazards model adjusted for other baseline covariates. At randomization, 53.2% of patients had moderately or severely reduced estimated glomerular filtration rate (eGFR) (CONCLUSION: The prevalence of renal dysfunction is high in patients hospitalized for HF with reduced LVEF. Worsening renal function may occur not only during hospitalization, but also in the early post-discharge period. Since worsening renal function during hospitalization is associated with a significant decrease in signs and symptoms of congestion, body weight and natriuretic peptides, which are good prognostic indicators, worsening renal function during hospitalization as an endpoint in clinical trials should be re-evaluated.
Authors: Blair, John E A JE; Pang, Peter S PS; Schrier, Robert W RW; Metra, Marco M; Traver, Brian B; Cook, Thomas T; Campia, Umberto U; Ambrosy, Andrew A; Burnett, John C JC; Grinfeld, Liliana L; Maggioni, Aldo P AP; Swedberg, Karl K; Udelson, James E JE; Zannad, Faiez F; Konstam, Marvin A MA; Gheorghiade, Mihai M;
European heart journal. 2011 Oct 01;32(20):2563-72. Epub 2011-07-23.
American Heart Association atrial fibrillation research summit: a conference report from the American Heart Association
Authors: Estes NA 3rd; Go AS; Benjamin EJ; et al.
Circulation. 2011 Jul 19;124(3):363-72. Epub 2011 Jun 27.
A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study
OBJECTIVES: The purpose of this study was to develop a risk stratification score to predict warfarin-associated hemorrhage. BACKGROUND: Optimal decision making regarding warfarin use for atrial fibrillation requires estimation of hemorrhage risk. METHODS: We followed up 9,186 patients with atrial fibrillation contributing 32,888 person-years of follow-up on warfarin, obtaining data from clinical databases and validating hemorrhage events using medical record review. We used Cox regression models to develop a hemorrhage risk stratification score, selecting candidate variables using bootstrapping approaches. The final model was internally validated by split-sample testing and compared with 6 published hemorrhage risk schemes. RESULTS: We observed 461 first major hemorrhages during follow-up (1.4% annually). Five independent variables were included in the final model and weighted by regression coefficients: anemia (3 points), severe renal disease (e.g., glomerular filtration rate <30 ml/min or dialysis-dependent, 3 points), age >/=75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Major hemorrhage rates ranged from 0.4% (0 points) to 17.3% per year (10 points). Collapsed into a 3-category risk score, major hemorrhage rates were 0.8% for low risk (0 to 3 points), 2.6% for intermediate risk (4 points), and 5.8% for high risk (5 to 10 points). The c-index for the continuous risk score was 0.74 and 0.69 for the 3-category score, higher than in the other risk schemes. There was net reclassification improvement versus all 6 comparators (from 27% to 56%). CONCLUSIONS: A simple 5-variable risk score was effective in quantifying the risk of warfarin-associated hemorrhage in a large community-based cohort of patients with atrial fibrillation.
Authors: Fang MC; Go AS; Chang Y; Borowsky LH; Pomernacki NK; Udaltsova N; Singer DE
J Am Coll Cardiol. 2011 Jul 19;58(4):395-401.
Urgent neurology consultation from the ED for transient ischemic attack
OBJECTIVE: The objective of this study was to evaluate the association between urgent neurology consultation and outcomes for patients with transient ischemic attack (TIA). METHODS: In a secondary analysis of data from 1707 emergency department patients with transient ischemic attack from March 1997 to May 1998, we compared presentation, management, and outcomes by neurology consultation status using generalized estimating equations to adjust for ABCD(2) score and clustering by facility and survival analysis for outcomes. RESULTS: Consultation was obtained f28% of patients. Median ABCD(2) scores were comparable, but consultation was associated with hospital admission (odds ratio, 1.35 [1.02-1.78], P = .04) and use of antithrombotics (odds ratio, 1.88 [1.20-2.93], P = .005). The cumulative stroke risk was significantly lower within 1 week (5.3% versus 7.5%, P = .02) but not at 90 days (9.9% versus 11.0%, P = .21). CONCLUSIONS: Consultation was not targeted to high-risk patients but was associated with some quality of care measures and improved early outcomes; however, improvement in 90-day outcomes was not established.
Authors: Kim AS; Sidney S; Bernstein AL; Douglas VC; Johnston SC
Am J Emerg Med. 2011 Jul;29(6):601-8. Epub 2010 Apr 24.
Coronary multidetector computed tomographic angiography to evaluate coronary artery disease in liver transplant candidates: methods, feasibility and initial experience.
AIMS: In patients undergoing orthotopic liver transplantation (OLT), coronary artery disease (CAD), obstructive and nonobstructive, is associated with high morbidity and mortality. In OLT candidates, stress testing for detecting ischemia is often inaccurate, and this patient population often has relative contraindications for cardiac catheterization. The objective of this study was to describe the methods, assess the feasibility and determine the extent and severity of CAD in OLT candidates without a prior history of CAD using coronary multidetector computer tomographic angiography (MDCTA).METHODS: Sixty-five OLT candidates without known CAD underwent coronary MDCTA with dual source cardiac computed tomography (Siemens Definition). Coronary arteries were divided into 17 segments based on American Heart Association guidelines and evaluated independently by two blinded reviewers. Image quality of coronary MDCTA was assessed on a four-point Likert scale (0 = poor, 1 = fair, 2 = good, and 3 = excellent). Atherosclerotic lesions were evaluated for severity [mild (0-50%), moderate (51-70%), and severe (71-100%)], morphology, extent, location and consistency.RESULTS: Image quality was graded as good or excellent in 73.8%. In this cohort of OLT candidates without known CAD, 9% had normal coronary arteries, 58% had mild CAD and 34% had moderate to severe CAD. Plaque severity and burden scores were high.CONCLUSION: The prevalence of asymptomatic CAD is high in OLT candidates. Coronary MDCTA is feasible in OLT candidates and appears to be a useful technique to diagnose occult CAD in this patient population.
Authors: Keeling, Aoife N AN; Flaherty, James D JD; Davarpanah, Amir H AH; Ambrosy, Andrew A; Farrelly, Cormac T CT; Harinstein, Matthew E ME; Flamm, Steven L SL; Abecassis, Michael I MI; Skaro, Anton I AI; Carr, James C JC; Gheorghiade, Mihai M
Journal of cardiovascular medicine (Hagerstown, Md.). 2011 Jul 01;12(7):460-8. Epub 2011-06-15.
The Romanian Acute Heart Failure Syndromes (RO-AHFS) registry.
AIMS: The objective of the RO-AHFS registry was to evaluate the epidemiology, clinical presentation, inpatient management, and hospital course in a population hospitalized for acute heart failure syndromes.METHODS: During a 12-month period, 13 Romanian medical centers enrolled all consecutive patients hospitalized with a primary diagnosis of AHFS. Patients were classified into the following 5 clinical profiles at admission: acute decompensated heart failure, cardiogenic shock, pulmonary edema, right heart failure, and hypertensive heart failure. Statistical significance was assessed using Fisher exact test or the χ(2) test for categorical variables and a 1-way analysis of variance for continuous variables. Independent predictors of in-hospital all-cause mortality (ACM) were identified using a multivariate logistic regression model.RESULTS: A total of 3,224 consecutive patients hospitalized with AHFS were enrolled. The cohort had a mean age of 69.2 ± 11.8 years and 56% were men. The mean left ventricular ejection fraction was 37.7% ± 12.5%. The percentage of patients treated with evidence-based heart failure therapies increased from admission to discharge, but even at discharge, only 56%, 66%, and 54% of patients were on a β-blocker, an angiotensin-converting enzyme inhibitors or an angiotensin receptor blocker, and a mineralocorticoid receptor antagonist, respectively. In-hospital ACM was 7.7% with substantial variation between sites (4.1%-11.0%). Increasing age, inotrope therapy, the presence of life-threatening ventricular arrhythmias, and elevated baseline blood urea nitrogen were all found to be independent risk factors for in-hospital ACM, whereas elevated systolic blood pressure and baseline treatment with a β-blocker had a protective effect.CONCLUSIONS: The RO-AHFS study found substantial variation both among sites and between Romania and other European countries. National and regional registries have important clinical implications for patient care and the design and conduct of global clinical trials.
Authors: Chioncel, Ovidiu O; Vinereanu, Dragos D; Datcu, Mihai M; Ionescu, Dan Dominic DD; Capalneanu, Radu R; Brukner, Ioan I; Dorobantu, Maria M; Ambrosy, Andrew A; Macarie, Cezar C; Gheorghiade, Mihai M
American heart journal. 2011 Jul 01;162(1):142-53.e1. Epub 2011-06-15.
Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease
CONTEXT: A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. OBJECTIVE: To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS: A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. MAIN OUTCOME MEASURES: All-cause mortality and end-stage renal disease. RESULTS: At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). CONCLUSION: Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.
Authors: Isakova T; Lo J; Chronic Renal Insufficiency Cohort (CRIC) Study Group; et al.
JAMA. 2011 Jun 15;305(23):2432-9.
Physical activity in older subjects is associated with increased coronary vasodilation: the ADVANCE study
OBJECTIVES: We investigated the association between physical activity and coronary vasodilation to nitroglycerin (NTG) in the ADVANCE (Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology) cohort of older healthy subjects. BACKGROUND: Physical activity may exert its beneficial effects by augmenting coronary responsiveness to nitric oxide. The relationship between physical activity and coronary vasodilatory response to NTG, an exogenous nitric oxide donor, has not been studied in a community-based population with typical activity levels. METHODS: In 212 older adults (ages 60 to 72 years) without cardiovascular disease, we measured the coronary vasodilatory response to NTG using magnetic resonance angiography and physical activity using the Stanford Seven-Day Physical Activity Recall Questionnaire. The primary predictor measure was total physical activity (kcal/kg/day). The primary outcome measure was coronary vasodilatory response (percent increase of cross-sectional area post-NTG). RESULTS: Coronary vasodilation was 27.6% in more active subjects (>35 kcal/kg/day, e.g., 1 h of walking per day) compared to 18.9% in less active subjects (p=0.03). Regression analysis showed a significant positive correlation between coronary vasodilation and physical activity (p=0.003), with a slope (beta) of 1.2% per kcal/kg/day. This finding remained significant after adjustment for cardiac risk factors, coronary calcium, the use of vasoactive or statin medications, and analysis of physical activity by quintiles (p < 0.05). Coronary vasodilation was also associated with physical activity intensity (p = 0.03). CONCLUSIONS: In an asymptomatic, community-based cohort of older adults, increased coronary vasodilatory response was independently associated with greater physical activity, supporting the benefits of exercise on the order of 1 h of walking per day.
Authors: Nguyen PK; Terashima M; Fair JM; Varady A; Taylor-Piliae RE; Iribarren C; Go AS; Haskell WL; Hlatky MA; Fortmann SP; McConnell MV
JACC Cardiovasc Imaging. 2011 Jun;4(6):622-9.
Change in body mass index between pregnancies and the risk of gestational diabetes in a second pregnancy
OBJECTIVE: To estimate the association between interpregnancy change in body mass index (BMI) and the risk of gestational diabetes mellitus (GDM) in a second pregnancy. METHODS: In a retrospective cohort analysis of 22,351 women, logistic regression models provided adjusted estimates of the risk of GDM in women gaining 3.0 or more 2.0-2.9, and 1.0-1.9 BMI units, or losing 1.0-2.0 and more than 2.0 units between pregnancies (one BMI unit corresponds to 5.9 pounds for the average height [5 feet 4 inches] of the study population). Women with stable BMIs (+/-1.0 BMI unit) comprised the reference. RESULTS: For those with GDM in the first pregnancy, the age-adjusted risk of GDM in the second pregnancy was 38.19% (95% confidence interval [CI] 34.96-41.42); for those whose first pregnancy was not complicated by GDM, the risk was 3.52% (95% CI 3.27-3.76). Compared with women who remained stable, interpregnancy BMI gains were associated with an increased risk of GDM in the second pregnancy (odds ratio [OR] 1.71 [95% CI 1.42-2.07] for gaining 1.0-1.9 BMI units; OR 2.46 [95% CI 2.00-3.02] for 2.0-2.9 BMI units; and OR 3.40 [95% CI 2.81-4.12] for 3.0 or more BMI units). The loss of BMI units was associated with a lower risk of GDM only among women who were overweight or obese in the first pregnancy (OR 0.26 [95% CI 0.14-0.47] for the loss of at least 2.0 BMI units). In overweight and obese women, those with GDM in the first pregnancy that did not develop the condition again gained fewer BMI units than those experiencing recurrent GDM (mean change 0.66 [95% CI 0.25-1.07] compared with 2.00 [95% CI 1.56-2.43] BMI units, respectively). CONCLUSION: Interpregnancy increases in BMI between the first and second pregnancy increases a woman’s risk of GDM pregnancy.
Authors: Ehrlich SF; Hedderson MM; Feng J; Davenport ER; Gunderson EP; Ferrara A
Obstet Gynecol. 2011 Jun;117(6):1323-30.
Eplerenone reduces risk of cardiovascular death or hospitalisation in heart failure patients with reduced ejection fraction.
Authors: Ambrosy, Andrew A; Gheorghiade, Mihai M
Evidence-based medicine. 2011 Aug 01;16(4):121-2. Epub 2011-05-10.
Ankle brachial index screening in asymptomatic older adults
BACKGROUND: Screening for peripheral arterial disease (PAD) by measuring ankle brachial index (ABI) in asymptomatic older adults is currently recommended to improve cardiovascular disease risk assessment and establish early treatment, but it is not clear if the strategy is useful in all populations. We examined the prevalence and independent predictors of an abnormal ABI (<0.90), in an asymptomatic sample of 1,017 adults, 60 to 69 years old, enrolled in the ADVANCE study. METHODS: Baseline data collected between December 2001 and January 2004 among the healthy older controls enrolled in ADVANCE was examined. Frequency distributions and prevalence estimates of an abnormal ABI were calculated, using both standard and modified definitions of ABI. Stepwise logistic regression was used to examine independent predictors of ABI <0.90. Signal detection analysis using recursive partitioning was employed to explore potential demographic and clinical variables related to ABI <0.90. RESULTS: The prevalence of ABI <0.90 was 2% when using the standard definition and 5% when using a modified definition. ABI prevalence did not differ by gender (P > .05). Compared with subjects who had a normal ABI (0.90-1.39), subjects with an ABI <0.90 were more likely to currently smoke, be physically inactive, have a coronary artery calcium score >10, and an FRS >20% (P 30 (all P values
Authors: Taylor-Piliae RE; Fair JM; Varady AN; Hlatky MA; Norton LC; Iribarren C; Go AS; Fortmann SP
Am Heart J. 2011 May;161(5):979-85.
Oral health considerations in older women receiving oral bisphosphonate therapy
Recent reports of bisphosphonate-related osteonecrosis of the jaw (BRONJ) have increased awareness of oral health in patients receiving osteoporosis therapy. This study describes the demographic, oral health, and clinical characteristics of a contemporary population of women aged 50 and older undergoing oral bisphosphonate treatment who returned a mailed questionnaire pertaining to dental symptoms. The study, as previously reported, was conducted within Kaiser Permanente Northern California, a large, integrated healthcare delivery system. The cohort included 7,909 women with bisphosphonate exposure of at least 1 year, with a subset of 923 women reporting dental symptoms who underwent clinical examination. Overall, the average age was 71 +/- 9; 70% were white, and 74% had at least some college education. Nearly two-thirds had received oral bisphosphonate therapy for 3 or more years. Most reported daily tooth brushing, 85% had had a dental examination in the past year, 22% reported denture use, and 6% reported moderate to severe periodontal disease. Oral healthcare patterns varied according to age and race and ethnicity. Five hundred seven (6.4%) women reported a tooth extraction in the prior year, of whom two developed BRONJ (0.4%). Tori or exostoses were found in 28% of examined participants with dental symptoms; these were predominantly in the lingual mandible and palate, with palatal BRONJ occurring in 1.6% of symptomatic participants with palatal tori. In summary, among older women with bisphosphonate exposure, oral health varied according to patient characteristics, and BRONJ occurred more frequently after tooth extraction or on palatal tori. These data support efforts to optimize oral health and to identify risk factors for BRONJ in older individuals receiving bisphosphonate drugs.
Authors: Lo JC; O'Ryan F; Yang J; Hararah MK; Gonzalez JR; Gordon N; Silver P; Ansfield A; Wang B; Go AS
J Am Geriatr Soc. 2011 May;59(5):916-22. Epub 2011 May 3.
A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium
OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism; central obesity; and high blood pressure; with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium; comprising 22;161 participants of European ancestry; underwent genome-wide association analyses of metabolic traits using a panel of approximately 2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL; CETP; APOA5 (and its cluster); GCKR (and its cluster); LIPC; TRIB1; LOC100128354/MTNR1B; ABCB11; and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small; together explaining from approximately 9% of the variance in triglycerides; 5.8% of high-density lipoprotein cholesterol; 3.6% of fasting glucose; and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
Authors: Kraja AT; Iribarren C; Borecki IB; et al.
Diabetes. 2011 Apr;60(4):1329-39. Epub 2011 Mar 8.
Association of vitamin D insufficiency with carotid intima-media thickness in HIV-infected persons
We observed an independent association between vitamin D insufficiency and higher carotid intima-media thickness in a cross-sectional analysis of 139 HIV-infected persons. If confirmed, these findings support a clinical trial of vitamin D supplementation to reduce cardiovascular events in HIV-infected persons.
Authors: Choi AI; Lo JC; Mulligan K; Schnell A; Kalapus SC; Li Y; Hunt PW; Martin JN; Deeks SG; Hsue PY
Clin Infect Dis. 2011 Apr 1;52(7):941-4. Epub 2011 Jan 27.
Duration of lactation and maternal adipokines at 3 years postpartum
OBJECTIVE: Lactation has been associated with reduced maternal risk of type 2 diabetes, the metabolic syndrome, and cardiovascular disease. We examined the relationship between breastfeeding duration and maternal adipokines at 3 years postpartum. RESEARCH DESIGN AND METHODS: We used linear regression to relate the duration of lactation to maternal leptin, adiponectin, ghrelin, and peptide YY (PYY) at 3 years postpartum among 570 participants with 3-year postpartum blood samples (178 fasting), prospectively collected lactation history, and no intervening pregnancy in Project Viva, a cohort study of mothers and children. RESULTS: A total of 88% of mothers had initiated breastfeeding, 26% had breastfed >/= 12 months, and 42% had exclusively breastfed for >/= 3 months. In multivariate analyses, we found that duration of total breastfeeding was directly related to PYY and ghrelin, and exclusive breastfeeding duration was directly related to ghrelin (predicted mean for never exclusively breastfeeding: 790.6 pg/mL vs. >/= 6 months of exclusive breastfeeding: 1,008.1 pg/mL; P < 0.01) at 3 years postpartum, adjusting for pregravid BMI, gestational weight gain, family history of diabetes, parity, smoking status, and age. We found a nonlinear pattern of association between exclusive breastfeeding duration and adiponectin in multivariate-adjusted models. CONCLUSIONS: In this prospective cohort study, we found a direct relationship between the duration of lactation and both ghrelin and PYY at 3 years postpartum.
Authors: Stuebe AM; Mantzoros C; Kleinman K; Gillman MW; Rifas-Shiman S; Gunderson EP; Rich-Edwards J
Diabetes. 2011 Apr;60(4):1277-85. Epub 2011 Feb 24.
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
Authors: Schunkert H; Iribarren C; Samani NJ; et al.
Nat Genet. 2011 Mar 6;43(4):333-8.
Heart failure in 2010: one step forward, two steps back.
Patients with heart failure (HF) fall into two categories—those who are stable and ambulatory with a relatively low event rate, and patients requiring hospitalization who are characterized by high post-discharge mortality and rates of rehospitalization. HF trials in 2010 contributed to the advancement of outpatient management, whereas the development of novel therapies with a survival benefit remains an unmet need in acute HF syndromes.
Authors: Gheorghiade, Mihai M; Ambrosy, Andrew A
Nature reviews. Cardiology. 2011 Feb 01;8(2):72-3. Epub 2011-03-15.
Acute heart failure syndromes: assessment and reconstructing the heart.
Heart failure is an international health problem, the magnitude of which is expected to continue to grow. It can be broadly divided into chronic (and relatively stable) ambulatory heart failure patients and patients hospitalized for worsening heart failure, also known as acute heart failure syndromes (AHFS). In contrast to the treatment of stable ambulatory HF patients, which has been revolutionized by evidence-based therapies with a survival benefit, the early management of patients hospitalized for AHFS has changed little over the past several decades and the postdischarge event rate (mortality and rehospitalization) within 60-90 days may be as high as 45%. Although heart failure patients frequently experience rapid and dramatic improvements in signs and symptoms of congestion in response to standard therapy alone, the early postdischarge event rate remains paradoxically elevated. Thus, even though admission for AHFS may be characterized by cardiac injury (‘destruction’), hospitalization represents a rare opportunity for assessment and evaluation, as well as initiation of targeted therapies aimed at ‘reconstructing’ the heart. This concept is clinically relevant since many patients may be discharged home without addressing potentially reversible underlying pathophysiologic processes including, but not limited to, viable but dysfunctional myocardium and cardiac dyssynchrony.
Authors: Ambrosy, Andrew A; Wilcox, Jane J; Nodari, Savina S; Gheorghiade, Mihai M
Journal of cardiovascular medicine (Hagerstown, Md.). 2011 Apr 01;12(4):258-63. Epub 2011-03-15.
Tolvaptan for the treatment of heart failure: a review of the literature.
INTRODUCTION: It has been > 25 years since it was first discovered that arginine vasopressin levels are elevated in heart failure and this elevation is proportional to the severity of heart failure. Tolvaptan is an oral nonpeptide V₂-selective antagonist and has been shown to induce free water excretion without increasing urine sodium, an effect termed ‘aquaresis’.AREAS COVERED: This paper aims to review the physiology, chemistry, pharmacokinetics, clinical efficacy and safety of tolvaptan in HF. A PubMed literature search was performed using ‘tolvaptan’ and the MeSH term ‘heart failure’, yielding 89 references.EXPERT OPINION: Clinical trials conducted in ambulatory and hospitalized patients with HF have found treatment with tolvaptan causes rapid and sustained body weight reductions concurrent with increases in urine output, improves and/or normalizes serum sodium in hyponatremic patients, reduces signs and symptoms of congestion and increases thirst. However, tolvaptan has not been shown to decrease HF re-hospitalization or mortality. As an adjunct to standard therapy, tolvaptan is unique in that it is virtually the only novel agent tested in patients hospitalized for acute heart failure syndrome (AHFS) to reach its primary end point for short-term efficacy without causing deleterious side effects. There is theoretical concern that chronic V₂ receptor blockade may cause harmful long-term side effects via enhanced V(1a) receptor activation, potentially offsetting any favorable effects on congestion and hyponatremia. The ‘vaptan’ class of drugs is an active and promising area for clinical investigation and future research is necessary to clarify the therapeutic role of selective and nonselective vasopressin inhibition in chronic HF and AHFS.
Authors: Ambrosy, Andrew A; Goldsmith, Steven R SR; Gheorghiade, Mihai M
Expert opinion on pharmacotherapy. 2011 Apr 01;12(6):961-76. Epub 2011-03-15.
Respiratory and skeletal muscle strength in chronic obstructive pulmonary disease: impact on exercise capacity and lower extremity function
PURPOSE: We sought to quantify the impact of respiratory muscle and lower extremity strength on exercise capacity and lower extremity function (LEF) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In 828 persons with COPD, we assessed the impact of reduced respiratory (maximum inspiratory pressure, MIP) and lower extremity muscle strength (quadriceps strength, QS) on exercise capacity (6-minute walk test, 6MWT), and LEF (short physical performance battery). Multiple regression analyses taking into account key covariates, including lung function and smoking, tested the associations between muscle strength and exercise and functional capacity. RESULTS: For each 0.5 SD decrement in QS, men walked 18.3 m less during 6MWT (95% confidence interval [CI], -24.1 to -12.4); women 25.1 m less (95% CI, -31.1 to -12.4). For each 0.5 SD decrement in MIP, men walked 9.4 m less during 6MWT (95% CI, -15.2 to -3.6); women 8.7 m less (95% CI, -14.1 to -3.4). For each 0.5 SD decrease in QS, men had a 1.32 higher odds (95% CI, 1.11-1.15) of poor LEF; women had a 1.87 higher odds (95% CI, 1.54-2.27). Lower MIP (per 0.5 SD) was associated with increased odds of poor LEF in women (odds ratio = 1.18; 95% CI, 1.00-1.39), but not in men (odds ratio = 1.10; 95% CI, 0.93-1.31). CONCLUSIONS: In COPD, reduced respiratory and lower extremity muscle strength are associated with decreased exercise and functional capacity. Muscle weakness is likely an important component of impairment and disability in patients with COPD.
Authors: Singer J; Yelin EH; Katz PP; Sanchez G; Iribarren C; Eisner MD; Blanc PD
J Cardiopulm Rehabil Prev. 2011 Mar-Apr;31(2):111-9.
Fracture risk tool validation in an integrated healthcare delivery system
OBJECTIVE: To evaluate the utility of the Fracture Risk Calculator (FRC, Foundation for Osteoporosis Research and Education) for predicting 10-year hip fracture risk within a ‘real world’ population. STUDY DESIGN: Retrospective cohort study. METHODS: We identified female members of Kaiser Permanente Northern California aged >/=50 years with bone mineral density (BMD) measured during 1997-2003. Hospitalization for hip fracture was ascertained up to 10 years following the BMD date, and 10-year observed hip fracture probabilities were calculated. Baseline data for fracture risk calculation were extracted from health plan databases, including age, race/ethnicity, smoking, body mass index, prior fracture, rheumatoid arthritis, glucocorticoid use, disorders associated with bone loss, and femoral neck BMD. Predicted 10-year FRC hip fracture probabilities were compared with observed 10-year hip fracture probabilities. RESULTS: Among 94,489 women (mean age 62.8 +/- 8.6 years, average femoral neck Z-score +0.1),the median duration of follow-up was 6.6 years, during which 1579 (1.7%) hip fractures occurred. Using the FRC, 23% met or exceeded the National Osteoporosis Foundation’s 3% hip fracture threshold. The FRC somewhat underestimated observed hip fracture probabilities; across 10-year risk categories <1%, 1% to 2.9%, and 3% to 4.9%, ratios of observed to median predicted probabilities ranged from 1.3 to 1.4. CONCLUSIONS: The FRC tool can be applied to assess fracture risk in large populations using data from administrative databases. Despite some underestimation, this relatively simple tool may assist targeting of at-risk populations for more complete fracture risk assessment.
Authors: Lo JC; Pressman AR; Chandra M; Ettinger B
Am J Manag Care. 2011 Mar;17(3):188-94.
Heart disease and stroke statistics–2011 update: a report from the American Heart Association
Authors: Roger VL; Go AS; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2011 Feb 1;123(4):e18-e209. Epub 2010 Dec 15.
Development of disability in chronic obstructive pulmonary disease: beyond lung function
BACKGROUND: COPD is a major cause of disability, but little is known about how disability develops in this condition. METHODS: The authors analysed data from the Function, Living, Outcomes and Work (FLOW) Study which enrolled 1202 Kaiser Permanente Northern California members with COPD at baseline and re-evaluated 1051 subjects at 2-year follow-up. The authors tested the specific hypothesis that the development of specific non-respiratory impairments (abnormal body composition and muscle strength) and functional limitations (decreased lower extremity function, poor balance, mobility-related dyspnoea, reduced exercise performance and decreased cognitive function) will determine the risk of disability in COPD, after controlling for respiratory impairment (FEV(1) and oxygen saturation). The Valued Life Activities Scale was used to assess disability in terms of a broad range of daily activities. The primary disability outcome measure was defined as an increase in the proportion of activities that cannot be performed of 3.3% or greater from baseline to 2-year follow-up (the estimated minimal important difference). Multivariable logistic regression was used for analysis. RESULTS: Respiratory impairment measures were related to an increased prospective risk of disability (multivariate OR 1.75; 95% CI 1.26 to 2.44 for 1 litre decrement of FEV(1) and OR 1.57 per 5% decrement in oxygen saturation; 95% CI 1.13 to 2.18). Non-respiratory impairment (body composition and lower extremity muscle strength) and functional limitations (lower extremity function, exercise performance, and mobility-related dyspnoea) were all associated with an increased longitudinal risk of disability after controlling for respiratory impairment (p<0.05 in all cases). Non-respiratory impairment and functional limitations were predictive of prospective disability, above-and-beyond sociodemographic characteristics, smoking status and respiratory impairment (area under the receiver operating characteristic curve increased from 0.65 to 0.75; p<0.001). CONCLUSIONS: Development of non-respiratory impairment and functional limitations, which reflect the systemic nature of COPD, appear to be critical determinants of disablement. Prevention and treatment of disability require a comprehensive approach to the COPD patient.
Authors: Eisner MD; Iribarren C; Blanc PD; Yelin EH; Ackerson L; Byl N; Omachi TA; Sidney S; Katz PP
Thorax. 2011 Feb;66(2):108-14. Epub 2010 Nov 3.
Vascular risk factors and cognitive impairment in chronic kidney disease: the Chronic Renal Insufficiency Cohort (CRIC) study
BACKGROUND AND OBJECTIVES: Cognitive impairment is common among persons with chronic kidney disease, but the extent to which nontraditional vascular risk factors mediate this association is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted cross-sectional analyses of baseline data collected from adults with chronic kidney disease participating in the Chronic Renal Insufficiency Cohort study. Cognitive impairment was defined as a Modified Mini-Mental State Exam score>1 SD below the mean score. RESULTS: Among 3591 participants, the mean age was 58.2+/-11.0 years, and the mean estimated GFR (eGFR) was 43.4+/-13.5 ml/min per 1.73 m2. Cognitive impairment was present in 13%. After adjustment for demographic characteristics, prevalent vascular disease (stroke, coronary artery disease, and peripheral arterial disease) and traditional vascular risk factors (diabetes, hypertension, smoking, and elevated cholesterol), an eGFR<30 ml/min per 1.73 m2 was associated with a 47% increased odds of cognitive impairment (odds ratio 1.47, 95% confidence interval 1.05, 2.05) relative to those with an eGFR 45 to 59 ml/min per 1.73 m2. This association was attenuated and no longer significant after adjustment for hemoglobin concentration. While other nontraditional vascular risk factors including C-reactive protein, homocysteine, serum albumin, and albuminuria were correlated with cognitive impairment in unadjusted analyses, they were not significantly associated with cognitive impairment after adjustment for eGFR and other confounders. CONCLUSIONS: The prevalence of cognitive impairment was higher among those with lower eGFR, independent of traditional vascular risk factors. This association may be explained in part by anemia.
Authors: Tamura MK; Xie D; Yaffe K; Cohen DL; Teal V; Kasner SE; Messe SR; Sehgal AR; Kusek J; DeSalvo KB; Cornish-Zirker D; Cohan J; Seliger SL; Chertow GM; Go AS
Clin J Am Soc Nephrol. 2011 Feb;6(2):248-56. Epub 2010 Oct 7.
Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation
BACKGROUND: Warfarin reduces the risk for ischemic stroke in patients with atrial fibrillation (AF) but increases the risk for hemorrhage. Dabigatran is a fixed-dose, oral direct thrombin inhibitor with similar or reduced rates of ischemic stroke and intracranial hemorrhage in patients with AF compared with those of warfarin. OBJECTIVE: To estimate the quality-adjusted survival, costs, and cost-effectiveness of dabigatran compared with adjusted-dose warfarin for preventing ischemic stroke in patients 65 years or older with nonvalvular AF. DESIGN: Markov decision model. DATA SOURCES: The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial and other published studies of anticoagulation. The cost of dabigatran was estimated on the basis of pricing in the United Kingdom. TARGET POPULATION: Patients aged 65 years or older with nonvalvular AF and risk factors for stroke (CHADS score >/=1 or equivalent) and no contraindications to anticoagulation. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Warfarin anticoagulation (target international normalized ratio, 2.0 to 3.0); dabigatran, 110 mg twice daily (low dose); and dabigatran, 150 mg twice daily (high dose). OUTCOME MEASURES: Quality-adjusted life-years (QALYs), costs (in 2008 U.S. dollars), and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: The quality-adjusted life expectancy was 10.28 QALYs with warfarin, 10.70 QALYs with low-dose dabigatran, and 10.84 QALYs with high-dose dabigatran. Total costs were $143 193 for warfarin, $164 576 for low-dose dabigatran, and $168 398 for high-dose dabigatran. The incremental cost-effectiveness ratios compared with warfarin were $51 229 per QALY for low-dose dabigatran and $45 372 per QALY for high-dose dabigatran. RESULTS OF SENSITIVITY ANALYSIS: The model was sensitive to the cost of dabigatran but was relatively insensitive to other model inputs. The incremental cost-effectiveness ratio increased to $50 000 per QALY at a cost of $13.70 per day for high-dose dabigatran but remained less than $85 000 per QALY over the full range of model inputs evaluated. The cost-effectiveness of high-dose dabigatran improved with increasing risk for stroke and intracranial hemorrhage. LIMITATION: Event rates were largely derived from a single randomized clinical trial and extrapolated to a 35-year time frame from clinical trials with approximately 2-year follow-up. CONCLUSION: In patients aged 65 years or older with nonvalvular AF at increased risk for stroke (CHADS score >/=1 or equivalent), dabigatran may be a cost-effective alternative to warfarin depending on pricing in the United States. PRIMARY FUNDING SOURCE: American Heart Association and Veterans Affairs Health Services Research & Development Service.
Authors: Freeman JV; Zhu RP; Owens DK; Garber AM; Hutton DW; Go AS; Wang PJ; Turakhia MP
Ann Intern Med. 2011 Jan 4;154(1):1-11. Epub 2010 Nov 1.
Yoga for heart failure patients: a feasibility pilot study with a multiethnic population
BACKGROUND: Congestive heart failure (CHF) is highly prevalent and the most costly cardiovascular illness in the United States. Yoga is known to be effective in lowering stress, lessening depression, and increasing physical fitness and may be used as an adjuvant management program for CHF patients. PRIMARY STUDY OBJECTIVE: To determine the feasibility of a yoga intervention program among a multiethnic CHF population living in underserved neighborhoods. METHODS: Uncontrolled intervention trial. Setting: Kaiser Permanente Medical Centers, Richmond and Oakland, California. PARTICIPANTS: 14 CHF patients (7 female), mean age 64 (SD=6.4) years, and 62% African-American. Intervention: Eight-week, 2x/week, 1-hr yoga classes that included meditation, breathing exercises, gentle yoga poses, and relaxation. PRIMARY OUTCOME MEASURES: The intervention feasibility was measured by recruitment rates, participant retention and adherence. Body weight and self-reported depression and quality of life were measured before and after the intervention. RESULTS: Among the 14 patients enrolled, 13 completed the intervention. Of those who completed the trial, 92% attended at least 50% of the classes. There was a significant reduction in weight (-3.5 lb, p=0.01) and improvement in the severity of depression (p<0.05), as well as a trend toward increased quality of life (p=08). No adverse events were observed. CONCLUSIONS: This pilot trial demonstrates that it is feasible for patients with CHF to incorporate yoga into their lifestyle. Yoga may help with routine disease management, prevention of fluid retention, and improvement of depression and quality of life. A larger trial is needed to confirm efficacy and to determine the long-term effects on other important outcomes, such as hospital re-admission rates or prognostic biomarkers.
Authors: Kubo A; Hung YY; Ritterman J
Int J Yoga Therap. 2011;(21):77-83.
Accounting for the mortality benefit of drug-eluting stents in percutaneous coronary intervention: a comparison of methods in a retrospective cohort study
ABSTRACT: BACKGROUND: Drug-eluting stents (DES) reduce rates of restenosis compared with bare metal stents (BMS). A number of observational studies have also found lower rates of mortality and non-fatal myocardial infarction with DES compared with BMS, findings not observed in randomized clinical trials. In order to explore reasons for this discrepancy, we compared outcomes after percutaneous coronary intervention (PCI) with DES or BMS by multiple statistical methods. METHODS: We compared short-term rates of all-cause mortality and myocardial infarction for patients undergoing PCI with DES or BMS using propensity-score adjustment, propensity-score matching, and a stent-era comparison in a large, integrated health system between 1998 and 2007. For the propensity-score adjustment and stent era comparisons, we used multivariable logistic regression to assess the association of stent type with outcomes. We used McNemar’s Chi-square test to compare outcomes for propensity-score matching. RESULTS: Between 1998 and 2007, 35,438 PCIs with stenting were performed among health plan members (53.9% DES and 46.1% BMS). After propensity-score adjustment, DES was associated with significantly lower rates of death at 30 days (OR 0.49, 95% CI 0.39 – 0.63, P < 0.001) and one year (OR 0.58, 95% CI 0.49 - 0.68, P < 0.001), and a lower rate of myocardial infarction at one year (OR 0.72, 95% CI 0.59 - 0.87, P < 0.001). Thirty day and one year mortality were also lower with DES after propensity-score matching. However, a stent era comparison, which eliminates potential confounding by indication, showed no difference in death or myocardial infarction for DES and BMS, similar to results from randomized trials. CONCLUSIONS: Although propensity-score methods suggested a mortality benefit with DES, consistent with prior observational studies, a stent era comparison failed to support this conclusion. Unobserved factors influencing stent selection in observational studies likely account for the observed mortality benefit of DES not seen in randomized clinical trials.
Authors: Yeh RW; Chandra M; McCulloch CE; Go AS
BMC Med. 2011 Jun 24;9:78.
Circulating angiopoietins-1 and -2, angiopoietin receptor Tie-2 and vascular endothelial growth factor-A as biomarkers of acute myocardial infarction: a prospective nested case-control study
BACKGROUND: Angiogenesis is up-regulated in myocardial ischemia. However, limited data exist assessing the value of circulating angiogenic biomarkers in predicting future incidence of acute myocardial infarction (AMI). Our aim was to examine the association between circulating levels of markers of angiogenesis with risk of incident acute myocardial infarction (AMI) in men and women. METHODS: We performed a case-control study (nested within a large cohort of persons receiving care within Kaiser Permanente of Northern California) including 695 AMI cases and 690 controls individually matched on age, gender and race/ethnicity. RESULTS: Median [inter-quartile range] serum concentrations of vascular endothelial growth factor-A (VEGF-A; 260 [252] vs. 235 [224] pg/mL; p = 0.01) and angiopoietin-2 (Ang-2; 1.18 [0.66] vs. 1.05 [0.58] ng/mL; p < 0.0001) were significantly higher in AMI cases than in controls. By contrast, endothelium-specific receptor tyrosine kinase (Tie-2; 14.2 [3.7] vs. 14.0 [3.1] ng/mL; p = 0.07) and angiopoietin-1 levels (Ang-1; 33.1 [13.6] vs. 32.5 [12.7] ng/mL; p = 0.52) did not differ significantly by case-control status. After adjustment for educational attainment, hypertension, diabetes, smoking, alcohol consumption, body mass index, LDL-C, HDL-C, triglycerides and C-reactive protein, each increment of 1 unit of Ang-2 as a Z score was associated with 1.17-fold (95 percent confidence interval, 1.02 to 1.35) increased odds of AMI, and the upper quartile of Ang-2, relative to the lowest quartile, was associated with 1.63-fold (95 percent confidence interval, 1.09 to 2.45) increased odds of AMI. CONCLUSIONS: Our data support a role of Ang-2 as a biomarker of incident AMI independent of traditional risk factors.
Authors: Iribarren C; Phelps BH; Darbinian JA; McCluskey ER; Quesenberry CP; Hytopoulos E; Vogelman JH; Orentreich N
BMC Cardiovasc Disord. 2011 Jun 14;11:31.
Metabolic syndrome, components, and cardiovascular disease prevalence in chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study
BACKGROUND/AIMS: Metabolic syndrome may increase the risk for incident cardiovascular disease (CVD) and all-cause mortality in the general population. It is unclear whether, and to what degree, metabolic syndrome is associated with CVD in chronic kidney disease (CKD). We determined metabolic syndrome prevalence among individuals with a broad spectrum of kidney dysfunction, examining the role of the individual elements of metabolic syndrome and their relationship to prevalent CVD. METHODS: We evaluated four models to compare metabolic syndrome or its components to predict prevalent CVD using prevalence ratios in the Chronic Renal Insufficiency Cohort (CRIC) Study. RESULTS: Among 3,939 CKD participants, the prevalence of metabolic syndrome was 65% and there was a significant association with prevalent CVD. Metabolic syndrome was more common in diabetics (87.5%) compared with non-diabetics (44.3%). Hypertension was the most prevalent component, and increased triglycerides the least prevalent. Using the bayesian information criterion, we found that the factors defining metabolic syndrome, considered as a single interval-scaled variable, was the best of four models of metabolic syndrome, both for CKD participants overall and for diabetics and non-diabetics separately. CONCLUSION: The predictive value of this model for future CVD outcomes will subsequently be validated in longitudinal analyses.
Authors: Townsend RR; Go AS; Xie D; et al.
Am J Nephrol. 2011;33(6):477-84. Epub 2011 Apr 27.
Study of Women, Infant Feeding, and Type 2 diabetes mellitus after GDM pregnancy (SWIFT), a prospective cohort study: methodology and design
BACKGROUND: Women with history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes within 5 years after delivery. Evidence that lactation duration influences incident type 2 diabetes after GDM pregnancy is based on one retrospective study reporting a null association. The Study of Women, Infant Feeding and Type 2 Diabetes after GDM pregnancy (SWIFT) is a prospective cohort study of postpartum women with recent GDM within the Kaiser Permanente Northern California (KPNC) integrated health care system. The primary goal of SWIFT is to assess whether prolonged, intensive lactation as compared to formula feeding reduces the 2-year incidence of type 2 diabetes mellitus among women with GDM. The study also examines whether lactation intensity and duration have persistent favorable effects on blood glucose, insulin resistance, and adiposity during the 2-year postpartum period. This report describes the design and methods implemented for this study to obtain the clinical, biochemical, anthropometric, and behavioral measurements during the recruitment and follow-up phases. METHODS: SWIFT is a prospective, observational cohort study enrolling and following over 1, 000 postpartum women diagnosed with GDM during pregnancy within KPNC. The study enrolled women at 6-9 weeks postpartum (baseline) who had been diagnosed by standard GDM criteria, aged 20-45 years, delivered a singleton, term (greater than or equal to 35 weeks gestation) live birth, were not using medications affecting glucose tolerance, and not planning another pregnancy or moving out of the area within the next 2 years. Participants who are free of type 2 diabetes and other serious medical conditions at baseline are screened for type 2 diabetes annually within the first 2 years after delivery. Recruitment began in September 2008 and ends in December 2011. Data are being collected through pregnancy and early postpartum telephone interviews, self-administered monthly mailed questionnaires (3-11 months postpartum), a telephone interview at 6 months, and annual in-person examinations at which a 75 g 2-hour OGTT is conducted, anthropometric measurements are obtained, and self- and interviewer-administered questionnaires are completed. DISCUSSION: This is the first, large prospective, community-based study involving a racially and ethnically diverse cohort of women with recent GDM that rigorously assesses lactation intensity and duration and examines their relationship to incident type 2 diabetes while accounting for numerous potential confounders not assessed previously.
Authors: Gunderson EP; Matias SL; Hurston SR; Dewey KG; Ferrara A; Quesenberry CP Jr; Lo JC; Sternfeld B; Selby JV
BMC Public Health. 2011 Dec 23;11:952.
Potential role of differential medication use in explaining excess risk of cardiovascular events and death associated with chronic kidney disease: A cohort study
BACKGROUND: Patients with chronic kidney disease (CKD) are less likely to receive cardiovascular medications. It is unclear whether differential cardiovascular drug use explains, in part, the excess risk of cardiovascular events and death in patients with CKD and coronary heart disease (CHD). METHODS: The ADVANCE Study enrolled patients with new onset CHD (2001-2003) who did (N = 159) or did not have (N = 1088) CKD at entry. The MDRD equation was used to estimate glomerular filtration rate (eGFR) using calibrated serum creatinine measurements. Patient characteristics, medication use, cardiovascular events and death were ascertained from self-report and health plan electronic databases through December 2008. RESULTS: Post-CHD event ACE inhibitor use was lower (medication possession ratio 0.50 vs. 0.58, P = 0.03) and calcium channel blocker use higher (0.47 vs. 0.38, P = 0.06) in CKD vs. non-CKD patients, respectively. Incidence of cardiovascular events and death was higher in CKD vs. non-CKD patients (13.9 vs. 11.5 per 100 person-years, P < 0.001, respectively). After adjustment for patient characteristics, the rate of cardiovascular events and death was increased for eGFR 45-59 ml/min/1.73 m2 (hazard ratio [HR] 1.47, 95% CI: 1.10 to 2.02) and eGFR < 45 ml/min/1.73 m2 (HR 1.58, 95% CI: 1.00 to 2.50). After further adjustment for statins, beta-blocker, calcium channel blocker, ACE inhibitor/ARB use, the association was no longer significant for eGFR 45-59 ml/min/1.73 m2 (HR 0.82, 95% CI: 0.25 to 2.66) or for eGFR < 45 ml/min/1.73 m2 (HR 1.19, 95% CI: 0.25 to 5.58). CONCLUSIONS: In adults with CHD, differential use of cardiovascular medications may contribute to the higher risk of cardiovascular events and death in patients with CKD.
Authors: Bansal N; Hsu CY; Chandra M; Iribarren C; Fortmann SP; Hlatky MA; Go AS
BMC Nephrol. 2011 Sep 14;12:44.
Symptoms characteristic of heart failure among CKD patients without diagnosed heart failure
BACKGROUND: Epidemiological studies typically diagnose heart failure (HF) at the time of hospitalization, and have not evaluated the prevalence of HF symptoms in CKD patients without a prior HF diagnosis. METHODS AND RESULTS: We modified the Kansas City Cardiomyopathy Questionnaire (KCCQ) to detect and quantify symptoms characteristic of HF (dyspnea, edema, and fatigue) among 2883 chronic kidney disease (CKD) patients without diagnosed heart failure in the Chronic Renal Insufficiency Cohort (CRIC). The KCCQ is a 23-item instrument that quantifies the impact of dyspnea, fatigue, and edema on physical, social, and emotional functions (scored 0 to 100). The median KCCQ score was 92, and 25% had KCCQ scores <75. Compared with cystatin Cbased estimated glomerular filtration rate >50 mL.min.1.73 m(2) (reference), estimated glomerular filtration rate 40 to 50, 30 to 40, and <30 were independently associated with lower KCCQ scores (<75); adjusted odds ratios and (95% CI): 1.38 (1.06-1.78), 1.39 (1.09-1.82), and 2.15 (1.54-3.00), respectively. Lower hemoglobin (Hb) levels also had independent associations with KCCQ <75: Hb >14 g/dL (reference), Hb 13 to 14 g/dL (1.03; 0.76-1.40), Hb 12 to 13 g/dL (1.41; 1.04-1.91), Hb 11 to 12 g/dL (1.56; 1.12-2.16); and Hb <1 g/dL (1.65; 1.15-2.37). CONCLUSION: CKD patients without diagnosed HF have a substantial burden of symptoms characteristic of HF, particularly among those with lower estimated glomerular filtration rate and hemoglobin levels.
Authors: Shlipak MG; Go AS; CRIC Investigators; et al.
J Card Fail. 2011 Jan;17(1):17-23.
Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations
BACKGROUND: Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH. METHODS AND RESULTS: We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01-2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03-2.15; p(trend) = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (chi(2) = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (chi(2) = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases. CONCLUSION: A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.
Authors: Mikhak B; Sidney S; McCulloch CE; Kim H; et al.
Cerebrovasc Dis. 2011;31(4):338-45. Epub 2011 Jan 7.
Association of maternal short sleep duration with adiposity and cardiometabolic status at 3 years postpartum
The purpose of this study was to examine the association of short sleep duration among women in the first year postpartum with adiposity and cardiometabolic status at 3 years postpartum. We studied 586 women in Project Viva, a prospective cohort. At 6 months and 1 year postpartum, women reported the number of hours they slept in a 24-h period, from which we calculated a weighted average of daily sleep. We used multivariable regression analyses to predict the independent effects of short sleep duration (5 h/day) on adiposity, glucose metabolism, lipid metabolism, and adipokines at 3 years postpartum. Women’s mean (s.d.) hours of daily sleep in the first year postpartum was 6.7 (0.97) h. After adjusting for age, race/ethnicity, education, parity, prepregnancy BMI, and excessive gestational weight gain, we found that postpartum sleep
Authors: Taveras EM; Rifas-Shiman SL; Rich-Edwards JW; Gunderson EP; Stuebe AM; Mantzoros CS
Obesity (Silver Spring). 2011 Jan;19(1):171-8. Epub 2010 May 20.
Racial variation in lipoprotein-associated phospholipase A in older adults
BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a predictor of cardiovascular events that has been shown to vary with race. The objective of this study was to examine factors associated with this racial variation. METHODS: We measured Lp-PLA(2) mass and activity in 714 healthy older adults with no clinical coronary heart disease and not taking dyslipidemia medication. We evaluated the association between race and Lp-PLA(2) mass and activity levels after adjustment for various covariates using multivariable linear regression. These covariates included age, sex, diabetes, hypertension, body mass index, lipid measurements, C-reactive protein, smoking status, physical activity, diet, income, and education level. We further examined genetic covariates that included three single nucleotide polymorphisms shown to be associated with Lp-PLA(2) activity levels. RESULTS: The mean age was 66 years. Whites had the highest Lp-PLA(2) mass and activity levels, followed by Hispanics and Asians, and then African-Americans; in age and sex adjusted analyses, these differences were significant for each non-White race as compared to Whites (p < 0.0001). For example, African-Americans were predicted to have a 55.0 ng/ml lower Lp-PLA(2) mass and 24.7 nmol/ml-min lower activity, compared with Whites, independent of age and sex (p < 0.0001). After adjustment for all covariates, race remained significantly correlated with Lp-PLA(2) mass and activity levels (p < 0.001) with African-Americans having 44.8 ng/ml lower Lp-PLA(2) mass and 17.3 nmol/ml-min lower activity compared with Whites (p < 0.0001). CONCLUSION: Biological, lifestyle, demographic, and select genetic factors do not appear to explain variations in Lp-PLA(2) mass and activity levels between Whites and non-Whites, suggesting that Lp-PLA(2) mass and activity levels may need to be interpreted differently for various races.
Authors: Lee KK; Fortmann SP; Varady A; Fair JM; Go AS; Quertermous T; Hlatky MA; Iribarren C
BMC Cardiovasc Disord. 2011 Jun 29;11:38.
Coffee, caffeine, and risk of hospitalization for arrhythmias
Context: Population study data about relations of coffee drinking to arrhythmia are sparse.Objective: To study relations of coffee drinking to risk of cardiac arrhythmia in 130,054 persons with previous data about coffee habits.Design and Outcome Measure: We used Cox proportional hazards models with 8 covariates to study coffee-related risk in 3137 persons hospitalized for cardiac arrhythmia. We conducted a similar analysis of total caffeine-related risk in a subgroup with data about other caffeine intake (11,679 study participants; 198 hospitalized).Results: With non-coffee-drinkers as the referent, the adjusted hazard ratio (HR) for any arrhythmia at the level of <1 cup of coffee per day was 1.0 (95% confidence interval [CI] = 0.9-1.1; p = 0.7); for 1-3 cups/day, it was 0.9 (CI, 0.8-1.0; p = 0.2), and for >/=4 cups/day, it was 0.8 (CI, 0.7-0.9; p = 0.002). With coffee intake as a continuous variable, the HR per cup per day was 0.97 (CI, 0.95-0.99; p = 0.001). Results were similar for several strata, including persons with history or symptoms of possible cardiore-spiratory disease and those without such history or symptoms. Coffee had similar relations to atrial fibrillation (48% of participants with arrhythmia) and most other specific arrhythmia diagnoses. Controlled for number of cups of coffee per day, total caffeine intake was inversely related to risk (HR highest quartile vs lowest = 0.6; p = 0.03).Conclusion: The inverse relations of coffee and caffeine intake to hospitalization for arrhythmias make it unlikely that moderate caffeine intake increases arrhythmia risk.
Authors: Klatsky AL; Hasan AS; Armstrong MA; Udaltsova N; Morton C
Perm J. 2011 Summer;15(3):19-25.
Socioeconomic status, race and COPD health outcomes
BACKGROUND: Although chronic obstructive pulmonary disease (COPD) is a common cause of death and disability, little is known about the effects of socioeconomic status (SES) and race-ethnicity on health outcomes. METHODS: The aim of this study is to determine the independent impacts of SES and race-ethnicity on COPD severity status, functional limitations and acute exacerbations of COPD among patients with access to healthcare. Data were used from the Function, Living, Outcomes and Work cohort study of 1202 Kaiser Permanente Northern California Medical Care Plan members with COPD. RESULTS: Lower educational attainment and household income were consistently related to greater disease severity, poorer lung function and greater physical functional limitations in cross-sectional analysis. Black race was associated with greater COPD severity, but these differences were no longer apparent after controlling for SES variables and other covariates (comorbidities, smoking, body mass index and occupational exposures). Lower education and lower income were independently related to a greater prospective risk of acute COPD exacerbation (HR 1.5; 95% CI 1.01 to 2.1; and HR 2.1; 95% CI 1.4 to 3.4, respectively). CONCLUSION: Low SES is a risk factor for a broad array of adverse COPD health outcomes. Clinicians and disease management programs should consider SES as a key patient-level marker of risk for poor outcomes.
Authors: Eisner MD; Blanc PD; Omachi TA; Yelin EH; Sidney S; Katz PP; Ackerson LM; Sanchez G; Tolstykh I; Iribarren C
J Epidemiol Community Health. 2011 Jan;65(1):26-34. Epub 2009 Oct 23.
Maintaining a high physical activity level over 20 years and weight gain
CONTEXT: Data supporting physical activity guidelines to prevent long-term weight gain are sparse, particularly during the period when the highest risk of weight gain occurs. OBJECTIVE: To evaluate the relationship between habitual activity levels and changes in body mass index (BMI) and waist circumference over 20 years. DESIGN, SETTING, AND PARTICIPANTS: The Coronary Artery Risk Development in Young Adults (CARDIA) study is a prospective longitudinal study with 20 years of follow-up, 1985-1986 to 2005-2006. Habitual activity was defined as maintaining high, moderate, and low activity levels based on sex-specific tertiles of activity scores at baseline. Participants comprised a population-based multicenter cohort (Chicago, Illinois; Birmingham, Alabama; Minneapolis, Minnesota; and Oakland, California) of 3554 men and women aged 18 to 30 years at baseline. MAIN OUTCOME MEASURES: Average annual changes in BMI and waist circumference. RESULTS: Over 20 years, maintaining high levels of activity was associated with smaller gains in BMI and waist circumference compared with low activity levels after adjustment for race, baseline BMI, age, education, cigarette smoking status, alcohol use, and energy intake. Men maintaining high activity gained 2.6 fewer kilograms (0.15 BMI units per year; 95% confidence interval [CI], 0.11-0.18 vs 0.20 in the lower activity group; 95% CI, 0.17-0.23), and women maintaining higher activity gained 6.1 fewer kilograms (0.17 BMI units per year; 95% CI, 0.12-0.21 vs 0.30 in the lower activity group; 95% CI, 0.25-0.34). Men maintaining high activity gained 3.1 fewer centimeters in waist circumference (0.52 cm per year; 95% CI, 0.43-0.61 cm vs 0.67 cm in the lower activity group; 95% CI,0.60-0.75 cm) and women maintaining higher activity gained 3.8 fewer centimeters(0.49 cm per year; 95% CI, 0.39-0.58 cm vs 0.67 cm in the lower activity group; 95% CI, 0.60-0.75 cm) [corrected]. CONCLUSION: Maintaining high activity levels through young adulthood may lessen weight gain as young adults transition to middle age, particularly in women.
Authors: Hankinson AL; Daviglus ML; Bouchard C; Carnethon M; Lewis CE; Schreiner PJ; Liu K; Sidney S
JAMA. 2010 Dec 15;304(23):2603-10.
Association of single-nucleotide polymorphisms from 17 candidate genes with baseline symptom-limited exercise test duration and decrease in duration over 20 years: the Coronary Artery Risk Development in Young Adults (CARDIA) fitness study
BACKGROUND: It is not known whether the genes involved with endurance performance during young adulthood are also involved with changes in performance. We examined the associations of gene variants with symptom-limited exercise test duration at baseline and decrease in duration over 20 years. METHODS AND RESULTS: A total of 3783 (1835 black, 1948 white) and 2335 (1035 black, 1300 white) participants from the Coronary Artery Risk Development in Young Adults study were included in the baseline and 20-year models, respectively. Two hundred seventeen single-nucleotide polymorphisms (SNPs) in black participants and 171 in white participants from 17 genes were genotyped. In blacks, 5 SNPs in the ATP1A2, HIF1A, NOS3, and PPARGC1A loci tended to be associated (P<0.05) with baseline duration in a multivariate regression model. Blacks (n=99) with at least 4 of the most-favorable genotypes at these loci had an approximately 2-minute longer baseline duration than those with only 2 such genotypes (P<0.0001). In whites, the HIF1A rs1957757 and PPARGC1A rs3774909 markers tended to be associated with baseline duration, but the association of a multimarker construct of the most-favorable genotypes at both SNPs with baseline duration was not statistically significant. In whites, 4 SNPs in the AGT, AMPD1, ANG, and PPARGC1A loci tended to be associated with decrease in exercise duration over 20 years, and those with all 4 favorable genotypes (n=40) had a 0.8-minute less decline in duration compared with those with none or 1 (n=232) (P<0.0001). CONCLUSIONS: In multimarker constructs, alleles at genes related to skeletal muscle Na(+)/K(+) transport, hypoxia, and mitochondrial metabolism are associated with symptom-limited exercise test duration over time in adults.
Authors: Sarzynski MA; Rankinen T; Sternfeld B; Grove ML; Fornage M; Sidney S; Bouchard C; Jacobs DR Jr
Circ Cardiovasc Genet. 2010 Dec 1;3(6):531-8. Epub 2010 Oct 15.
Longitudinal study of prepregnancy cardiometabolic risk factors and subsequent risk of gestational diabetes mellitus: The CARDIA study
This study examined prepregnancy cardiometabolic risk factors and gestational diabetes mellitus (GDM) in subsequent pregnancies. The authors selected 1,164 women without diabetes before pregnancy who delivered 1,809 livebirths between 5 consecutive examinations from 1985 to 2006 in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The authors measured prepregnancy cardiometabolic risk factors and performed multivariate repeated-measures logistic regression to compute the odds of GDM adjusted for race, age, parity, birth order, and other covariates. Impaired fasting glucose (100-125 vs. <90 mg/dL), elevated fasting insulin (>15-20 and >20 vs. <10 muU/mL), and low levels of high-density lipoprotein cholesterol (<40 vs. >50 mg/dL) before pregnancy were directly associated with GDM: The odds ratios = 4.74 (95% confidence interval (CI): 2.14, 10.51) for fasting glucose, 2.19 (95% CI: 1.15, 4.17) for middle insulin levels and 2.36 (95% CI: 1.20, 4.63) for highest insulin levels, and 3.07 (95% CI: 1.62, 5.84) for low levels of high-density lipoprotein cholesterol among women with a negative family history of diabetes; all P < 0.01. Among overweight women, 26.7% with 1 or more cardiometabolic risk factors developed GDM versus 7.4% with none. Metabolic impairment exists before GDM pregnancy in nondiabetic women. Interconceptual metabolic screening could be included in routine health assessments to identify high-risk women for GDM in a subsequent pregnancy and to potentially minimize fetal exposure to metabolic abnormalities that program future disease.
Authors: Gunderson EP; Feng J; Lewis CE; Sidney S; Quesenberry CP Jr; Jacobs DR Jr
Am J Epidemiol. 2010 Nov 15;172(10):1131-43. Epub 2010 Oct 7.
Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies
OBJECTIVES: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). BACKGROUND: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. METHODS: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. RESULTS: A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >/=2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. CONCLUSIONS: The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
Authors: Assimes TL; Iribarren C; Go A; Cardiogenics; et al.
J Am Coll Cardiol. 2010 Nov 2;56(19):1552-63.
Pre-pregnancy stress reactivity and pregnancy outcome
Stress has been proposed as a cause of preterm birth (PTB) and small-for-gestational age (SGA), but stress does not have the same effects on all women. It may be that a woman’s reaction to stress relates to her pregnancy health, and previous studies indicate that higher reactivity is associated with reduced birthweight and gestational age. The objective of this study was to examine the relationship between pre-pregnancy cardiovascular reactivity to stress and pregnancy outcome. The sample included 917 women in the Coronary Artery Risk Development in Young Adults Study who had cardiovascular reactivity measured in 1987-88 and at least one subsequent singleton livebirth within an 18-year period. Cardiovascular reactivity was measured using a video game, star tracing and cold pressor test. Gestational age and birthweight were based on the women’s self-report, with PTB defined as birth <37 weeks' gestation and SGA as weight <10th percentile for gestational age. Linear and Poisson regression and generalised estimating equations were used to model the relationship between reactivity to stress and birth outcomes with control for confounders. Few associations were seen between reactivity and pregnancy outcomes. Higher pre-pregnancy diastolic blood pressure (adjusted relative risk 1.14; 95% confidence interval [CI] 0.98, 1.34) and mean arterial pressure reactivity (1.15; 0.98, 1.36) were associated with risk of PTB at first pregnancy, while SGA was associated with lower systolic blood pressure reactivity (0.76; 0.60, 0.95). No associations were seen with other measures of reactivity. Contrary to hypothesis, the association between heart rate reactivity and PTB in first pregnancy was stronger in whites (adjusted relative risk 1.39; 1.03, 1.88) than in blacks (1.00; 0.83, 1.20; P for interaction = 0.08). Similar results were found for mean arterial pressure. No strong associations were found between higher pre-pregnancy stress reactivity and SGA or PTB, and stress reactivity did not have a stronger association with birth outcomes in blacks than whites.
Authors: Harville EW; Gunderson EP; Matthews KA; Lewis CE; Carnethon M
Paediatr Perinat Epidemiol. 2010 Nov;24(6):564-71. Epub 2010 Aug 12.
Warfarin discontinuation after starting warfarin for atrial fibrillation
BACKGROUND: Although warfarin is widely recommended to prevent atrial fibrillation-related thromboembolism, many eligible patients do not take warfarin. The objective of this study was to describe factors associated with warfarin discontinuation in patients newly starting warfarin for atrial fibrillation. METHODS AND RESULTS: We identified 4188 subjects newly starting warfarin in the Anticoagulation and Risk Factors in Atrial Fibrillation Study and tracked longitudinal warfarin use through pharmacy and laboratory databases. Data on patient characteristics, international normalized ratio (INR) tests, and incident hospitalizations for hemorrhage were obtained from clinical and laboratory databases. Multivariable Cox regression analysis was used to identify independent predictors of prolonged warfarin discontinuation, defined as >/=180 consecutive days off warfarin. Within 1 year after warfarin initiation, 26.3% of subjects discontinued therapy despite few hospitalizations for hemorrhage (2.3% of patients). The risk of discontinuation was higher in patients aged <65 years (adjusted hazard ratio [HR], 1.33 [95% CI, 1.03 to 1.72] compared to those aged >/=85 years), patients with poorer anticoagulation control (HR, 1.46 [95% CI, 1.42 to 1.49] for every 10% decrease in time in therapeutic INR range), and patients with lower stroke risk (HR, 2.54 [95% CI, 1.86 to 3.47] for CHADS(2) stroke risk index of 0 compared to 4 to 6). CONCLUSIONS: More than 1 in 4 patients newly starting warfarin for atrial fibrillation discontinued therapy in the first year despite a low overall hemorrhage rate. Individuals deriving potentially less benefit from warfarin, including those with younger age, fewer stroke risk factors, and poorer INR control, were less likely to remain on warfarin. Maximizing the benefits of anticoagulation for atrial fibrillation depends on determining which patients are most appropriately initiated and maintained on therapy.
Authors: Fang MC; Go AS; Chang Y; Borowsky LH; Pomernacki NK; Udaltsova N; Singer DE
Circ Cardiovasc Qual Outcomes. 2010 Nov;3(6):624-31. Epub 2010 Oct 19.
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Authors: Speliotes EK; Iribarren C; Procardis Consortium; et al.
Nat Genet. 2010 Nov;42(11):937-48. Epub 2010 Oct 10.
Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 x 10 to P = 1.8 x 10) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 x 10(3) to P = 1.2 x 10(1)(3)). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Authors: Heid IM; Iribarren C; MAGIC; et al.
Nat Genet. 2010 Nov;42(11):949-60. Epub 2010 Oct 10.
Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women
CONTEXT: In the Women’s Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported. OBJECTIVE: To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009. DESIGN, SETTING, AND PARTICIPANTS: A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants. MAIN OUTCOME MEASURES: Invasive breast cancer incidence and breast cancer mortality. RESULTS: In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group. CONCLUSIONS: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.
Authors: Chlebowski RT; Ockene J; WHI Investigators; et al.
JAMA. 2010 Oct 20;304(15):1684-92.
Hundreds of variants clustered in genomic loci and biological pathways affect human height
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Authors: Lango Allen H; Iribarren C; Hirschhorn JN; et al.
Nature. 2010 Oct 14;467(7317):832-8. Epub 2010 Sep 29.
Cost-effectiveness of using high-sensitivity C-reactive protein to identify intermediate- and low-cardiovascular-risk individuals for statin therapy
BACKGROUND: Many myocardial infarctions and strokes occur in individuals with low-density lipoprotein cholesterol levels below recommended treatment thresholds. High sensitivity C-reactive protein (hs-CRP) testing has been advocated to identify low- and intermediate-risk individuals who may benefit from statin therapy. METHODS AND RESULTS: A decision analytic Markov model was used to follow hypothetical cohorts of individuals with normal lipid levels but without coronary artery disease, peripheral arterial disease, or diabetes mellitus. The model compared current Adult Treatment Panel III practice guidelines, a strategy of hs-CRP screening in those without an indication for statin treatment by current practice guidelines followed by treatment only in those with elevated hs-CRP levels, and a strategy of statin therapy at specified predicted risk thresholds without hs-CRP testing. Risk-based treatment without hs-CRP testing was the most cost-effective strategy, assuming that statins were equally effective regardless of hs-CRP status. However, if normal hs-CRP levels identified a subgroup with little or no benefit from statin therapy (<20% relative risk reduction), then hs-CRP screening would be the optimal strategy. If harms from statin use were greater than generally recognized, then use of current clinical guidelines would be the optimal strategy. CONCLUSION: Risk-based statin treatment without hs-CRP testing is more cost-effective than hs-CRP screening, assuming that statins have good long-term safety and provide benefits among low-risk people with normal hs-CRP.
Authors: Lee KK; Cipriano LE; Owens DK; Go AS; Hlatky MA
Circulation. 2010 Oct 12;122(15):1478-87. Epub 2010 Sep 27.
Trends in time to confirmation and recognition of new-onset hypertension, 2002-2006
Achieving full benefits of blood pressure control in populations requires prompt recognition of previously undetected hypertension. In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure provided definitions of hypertension and recommended that single elevated readings be confirmed within 1 to 2 months. We sought to determine whether the time required to confirm and recognize (ie, diagnose and/or treat) new-onset hypertension decreased from 2002 to 2006 for adult members of 2 large integrated healthcare delivery systems, Kaiser Permanente Northern California and Colorado. Using electronically stored office blood pressure readings, physician diagnoses, and pharmacy prescriptions, we identified 200 587 patients with new-onset hypertension (2002-2006) marked by 2 consecutive elevated blood pressure readings in previously undiagnosed, untreated members. Mean confirmation intervals (time from the first to second consecutive elevated reading) declined steadily from 103 to 89 days during this period. For persons recognized within 12 months after confirmation, the mean interval to recognition declined from 78 to 61 days. However, only 33% of individuals were recognized within 12 months. One third were never recognized during observed follow-up. For these patients, most subsequent blood pressure recordings were not elevated. Higher initial blood pressure levels, history of previous cardiovascular disease, and older age were associated with shorter times to recognition. Times to confirmation and recognition of new-onset hypertension have become shorter in recent years, especially for patients with higher cardiovascular disease risk. Variability in office-based blood pressure readings suggests that further improvements in recognition and treatment may be achieved with more specific automated approaches to identifying hypertension.
Authors: Selby JV; Lee J; Swain BE; Tavel HM; Ho PM; Margolis KL; O'Connor PJ; Fine L; Schmittdiel JA; Magid DJ
Hypertension. 2010 Oct;56(4):605-11. Epub 2010 Aug 23.
CHA2DS2-VASc risk scheme: not ready for clinical use
Authors: Singer DE; Fang MC; Go AS
Chest. 2010 Oct;138(4):1020; author reply 1020-1.
Gender differences in treatment of severe carotid stenosis after transient ischemic attack
BACKGROUND AND PURPOSE: Gender differences in carotid endarterectomy (CEA) rates after transient ischemic attack are not well studied, although some reports suggest that eligible men are more likely to have CEA than women after stroke. METHODS: We retrospectively identified all patients diagnosed with transient ischemic attack and >or=70% carotid stenosis on ultrasound in 2003 to 2004 from 19 emergency departments. Medical records were abstracted for clinical data; 90-day follow-up events, including stroke, cardiovascular events, or death; CEA within 6 months; and postoperative 30-day outcomes. We assessed gender as a predictor of CEA and its complications adjusting for demographic and clinical variables as well as time to CEA between groups. RESULTS: Of 299 patients identified, 47% were women. Women were older with higher presenting systolic blood pressure and less likely to smoke or to have coronary artery disease or diabetes. Fewer women (36.4%) had CEA than men (53.8%; P=0.004). Reasons for withholding surgical treatment were similar in women and men, and there were no differences in follow-up stroke, cardiovascular event, postoperative complications, or death. Time to CEA was also significantly delayed in women. CONCLUSIONS: Women with severe carotid stenosis and recent transient ischemic attack are less likely to undergo CEA than men, and surgeries are more delayed.
Authors: Poisson SN; Johnston SC; Sidney S; Klingman JG; Nguyen-Huynh MN
Stroke. 2010 Sep;41(9):1891-5. Epub 2010 Jul 22.
Central pulse pressure in chronic kidney disease: a chronic renal insufficiency cohort ancillary study
Central pulse pressure (PP) can be noninvasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central PP cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort Study to determine correlates of the magnitude of central PP in the setting of chronic kidney disease. Tertiles of central PP were <36 mm Hg, 36 to 51 mm Hg, and >51 mm Hg with an overall mean (+/-SD) of 46+/-19 mm Hg. Multivariable regression identified the following independent correlates of central PP: age, sex, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose, and parathyroid hormone parathyroid hormone concentrations. Additional adjustment for brachial mean arterial pressure and brachial PP showed associations for age, sex, diabetes mellitus, weight, and heart rate. Discrete intervals of brachial PP stratification showed substantial overlap within the associated central PP values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence.
Authors: Townsend RR; Go AS; Chronic Renal Insufficiency Cohort Investigators; et al.
Hypertension. 2010 Sep;56(3):518-24. Epub 2010 Jul 26.
Prospective association of serum androgens and sex hormone-binding globulin with subclinical cardiovascular disease in young adult women: the ‘Coronary Artery Risk Development in Young Adults’ women’s study
CONTEXT: The role of endogenous androgens and SHBG in the development of cardiovascular disease in young adult women is unclear. OBJECTIVE: Our objective was to study the prospective association of serum androgens and SHBG with subclinical coronary and carotid disease among young to middle-aged women. DESIGN AND SETTING: This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort study with 20 yr of follow-up. PARTICIPANTS: Participants included 1629 women with measurements of serum testosterone and SHBG from yr 2, 10, or 16 and subclinical disease assessment at yr 20 (ages 37-52 yr). MAIN OUTCOME MEASURES: Coronary artery calcified plaques (CAC) and carotid artery intima-media thickness (IMT) were assessed at yr 20. The IMT measure incorporated the common carotid arteries, bifurcations, and internal carotid arteries. RESULTS: SHBG (mean of yr 2, 10, and 16) was inversely associated with the presence of CAC (multivariable adjusted odds ratio for women with SHBG levels above the median = 0.59; 95% confidence interval = 0.40-0.87; P = 0.008). SHBG was also inversely associated with the highest quartile of carotid-IMT (odds ratio for women with SHBG levels in the highest quartile = 0.56; 95% confidence interval = 0.37-0.84; P for linear trend across quartiles = 0.005). No associations were observed for total or free testosterone with either CAC or IMT. CONCLUSION: SHBG levels were inversely associated with subclinical cardiovascular disease in young to middle-aged women. The extent to which low SHBG is a risk marker or has its own independent effects on atherosclerosis is yet to be determined.
Authors: Calderon-Margalit R; Sternfeld B; Siscovick DS; et al.
J Clin Endocrinol Metab. 2010 Sep;95(9):4424-31. Epub 2010 Jun 16.
Prevalence of electrocardiographic abnormalities in a middle-aged, biracial population: Coronary Artery Risk Development in Young Adults study
BACKGROUND: Few studies to date have described the prevalence of electrocardiographic (ECG) abnormalities in a biracial middle-aged cohort. METHODS AND RESULTS: Participants underwent measurement of traditional risk factors and 12-lead ECGs coded using both Minnesota Code and Novacode criteria. Among 2585 participants, of whom 57% were women and 44% were black (mean age 45 years), the prevalence of major and minor abnormalities was significantly higher (all P < .001) among black men and women compared to whites. These differences were primarily due to higher QRS voltage and ST/T-wave abnormalities among blacks. There was also a higher prevalence of Q waves (Minnesota Code 1-1, 1-2, 1-3) than described by previous studies. These racial differences remained after multivariate adjustment for traditional cardiovascular (CV) risk factors. CONCLUSIONS: Black men and women have a significantly higher prevalence of ECG abnormalities, independent of traditional cardiovascular risk factors, than whites in a contemporary cohort of middle-aged participants.
Authors: Walsh JA 3rd; Prineas R; Daviglus ML; Ning H; Liu K; Lewis CE; Sidney S; Schreiner PJ; Iribarren C; Lloyd-Jones DM
J Electrocardiol. 2010 Sep-Oct;43(5):385.e1-9. Epub 2010 Apr 5.
Radiographic findings in bisphosphonate-treated patients with stage 0 disease in the absence of bone exposure
PURPOSE: Radiographic features in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) are well described, but less is known in bisphosphonate-exposed individuals with stage 0 disease (clinical symptoms without exposed necrotic bone) considered at risk for BRONJ. We sought to characterize radiographic findings in a subgroup of patients with concerning clinical symptoms and bisphosphonate exposure to identify imaging features that may presage development of BRONJ. MATERIALS AND METHODS: A dental symptom survey was returned by 8,572 Kaiser Permanente Health Plan members receiving chronic oral bisphosphonate therapy, and 1,005 patients reporting pertinent dental symptoms or complications after dental procedures were examined. Those without BRONJ but with concerning symptoms were referred for clinical evaluation, including imaging. Among the subset who received maxillofacial imaging, we identified those with stage 0 disease and abnormal radiographic features. RESULTS: There were a total of 30 patients without exposed bone but with concerning symptoms who received maxillofacial imaging (panoramic radiography or computed tomography) in the context of clinical care. Among these 30 patients, 10 had stage 0 disease with similar radiographic features of regional or diffuse osteosclerosis in clinically symptomatic areas, most with extension beyond the involved site. Other findings in these 10 patients included density confluence of cortical and cancellous bone, prominence of the inferior alveolar nerve canal, markedly thickened and sclerotic lamina dura, uniform periradicular radiolucencies, cortical disruption, lack of bone fill after extraction, and a persisting alveolar socket. None had exposed bone develop during 1-year follow-up. The remaining 20 patients had normal or localized radiographic findings consistent with odontogenic pathology. CONCLUSION: In 10 of 30 symptomatic patients referred for clinical evaluation and imaging, a consistent finding was conspicuous osteosclerosis in clinically symptomatic areas characteristic of stage 0 disease. These data support the need to better understand radiographic features associated with bisphosphonate exposure and to determine whether osteosclerosis is a specific finding indicative of the risk for progression to BRONJ.
Authors: Hutchinson M; O'Ryan F; Chavez V; Lathon PV; Sanchez G; Hatcher DC; Indresano AT; Lo JC
J Oral Maxillofac Surg. 2010 Sep;68(9):2232-40.
Nonoptimal lipids commonly present in young adults and coronary calcium later in life: the CARDIA (Coronary Artery Risk Development in Young Adults) study
BACKGROUND: Dyslipidemia causes coronary heart disease in middle-aged and elderly adults, but the consequences of lipid exposure during young adulthood are unclear. OBJECTIVE: To assess whether nonoptimal lipid levels during young adulthood cause atherosclerotic changes that persist into middle age. DESIGN: Prospective cohort study. SETTING: 4 cities in the United States. PARTICIPANTS: 3258 participants from the 5115 black and white men and women recruited at age 18 to 30 years in 1985 to 1986 for the CARDIA (Coronary Artery Risk Development in Young Adults) study. MEASUREMENTS: Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides, and coronary calcium. Time-averaged cumulative exposures to lipids between age 20 and 35 years were estimated by using repeated serum lipid measurements over 20 years in the CARDIA study; these measurements were then related to coronary calcium scores assessed later in life (45 years [SD, 4]). RESULTS: 2824 participants (87%) had nonoptimal levels of LDL cholesterol (>or=2.59 mmol/L [>or=100 mg/dL]), HDL cholesterol (<1.55 mmol/L [<60 mg/dL]), or triglycerides (>or=1.70 mmol/L [>or=150 mg/dL]) during young adulthood. Coronary calcium prevalence 2 decades later was 8% in participants who maintained optimal LDL levels (<1.81 mmol/L [<70 mg/dL]), and 44% in participants with LDL cholesterol levels of 4.14 mmol/L (160 mg/dL) or greater (P < 0.001). The association was similar across race and sex and strongly graded, with odds ratios for coronary calcium of 1.5 (95% CI, 0.7 to 3.3) for LDL cholesterol levels of 1.81 to 2.56 mmol/L (70 to 99 mg/dL), 2.4 (CI, 1.1 to 5.3) for levels of 2.59 to 3.34 mmol/L (100 to 129 mg/dL), 3.3 (CI, 1.3 to 7.8) for levels of 3.37 to 4.12 mmol/L (130 to 159 mg/dL), and 5.6 (CI, 2.0 to 16) for levels of 4.14 mmol/L (160 mg/dL) or greater, compared with levels less than 1.81 mmol/L (<70 mg/dL), after adjustment for lipid exposure after age 35 years and other coronary risk factors. Both LDL and HDL cholesterol levels were independently associated with coronary calcium after participants who were receiving lipid-lowering medications or had clinically abnormal lipid levels were excluded. LIMITATION: Coronary calcium, although a strong predictor of future coronary heart disease, is not a clinical outcome. CONCLUSION: Nonoptimal levels of LDL and HDL cholesterol during young adulthood are independently associated with coronary atherosclerosis 2 decades later. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.
Authors: Pletcher MJ; Bibbins-Domingo K; Liu K; Sidney S; Lin F; Vittinghoff E; Hulley SB
Ann Intern Med. 2010 Aug 3;153(3):137-46.
Longitudinal examination of age-predicted symptom-limited exercise maximum HR
PURPOSE: To estimate the association of age with maximal HR (MHR). METHODS: Data were obtained from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants were black and white men and women aged 18-30 yr in 1985-1986 (year 0). A symptom-limited maximal graded exercise test was completed at years 0, 7, and 20 by 4969, 2583, and 2870 participants, respectively. After exclusion, 9622 eligible tests remained. RESULTS: In all 9622 tests, estimated MHR (eMHR, bpm) had a quadratic relation to age in the age range of 18-50 yr, eMHR = 179 + 0.29 x age – 0.011 x age(2). The age-MHR association was approximately linear in the restricted age ranges of consecutive tests. In 2215 people who completed tests of both years 0 and 7 (age range = 18-37 yr), eMHR =.
Authors: Zhu N; Suarez-Lopez JR; Sidney S; Sternfeld B; Schreiner PJ; Carnethon MR; Lewis CE; Crow RS; Bouchard C; Haskell WL; Jacobs DR Jr
Med Sci Sports Exerc. 2010 Aug;42(8):1519-27.
Low cardiovascular risk is associated with favorable left ventricular mass, left ventricular relative wall thickness, and left atrial size: the CARDIA study
BACKGROUND: Echocardiographic measures of left ventricular (LV) mass and relative wall thickness and left atrial (LA) size predict future cardiovascular morbidity and mortality. The aim of this study was to compare young adults with low cardiovascular risk (body mass index, 18.5-24.9 kg/m(2); blood pressure < 120/80 mmHg; no tobacco use, no diabetes, and physical fitness) with those without these characteristics with regard to LV mass and relative wall thickness and LA size, to determine the protective effect of a healthy lifestyle on the development of these characteristics. METHODS: Cross-sectional assessment of 4059 black and white men and women aged 23 to 35 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study at the year 5-examination, when risk factors were measured, and echocardiography to assess LV mass and relative wall thickness were performed. Physical fitness was measured at baseline using a symptom-limited maximal treadmill test. All other covariates were measured concurrently with echocardiography. RESULTS: Gender, body mass index, and systolic blood pressure were associated with LV mass and relative wall thickness and LA size in multivariate models. Additional correlates of LV mass/height(2.7) ratio were tobacco use, resting heart rate (inverse), self-reported physical activity, gender (male higher), and age. Age was associated with LV relative wall thickness but not other measures of LV size. Additional correlates of LA diameter/height ratio were tobacco use, resting heart rate (inverse), serum glucose, and self-reported physical activity. Seven hundred ninety of 4059 subjects (19%) were classified as having low risk; black race was less likely in the low-risk group. Those with low risk had lower LV mass/height(2.7) ratios (32.0 vs 34.6 g/m(2.7), P < .0001), better LV relative wall thickness (0.33 vs 0.35, P < .0001), and lower LA diameter/height ratios (2.02 vs 2.08 cm/m, P < .01). CONCLUSIONS: A low cardiovascular risk profile in young adulthood is associated with more favorable LV mass, LV relative wall thickness, and LA size. This may be one mechanism of lifestyle protection against cardiovascular morbidity and mortality.
Authors: Gidding SS; Carnethon MR; Daniels S; Liu K; Jacobs DR Jr; Sidney S; Gardin J
J Am Soc Echocardiogr. 2010 Aug;23(8):816-22. Epub 2010 Jul 1.
Prepregnancy lipids related to preterm birth risk: the coronary artery risk development in young adults study
CONTEXT: Preterm birth is associated with maternal cardiovascular risk, but mechanisms are unknown. OBJECTIVE: We considered that dyslipidemia may predispose women to both conditions and that prepregnancy lipids may be related to preterm birth risk. We hypothesized that low or high prepregnancy plasma lipids would be associated with preterm birth. DESIGN, SETTING, AND PARTICIPANTS: A total of 1010 women (49% black) enrolled in the multicenter, prospective Coronary Artery Risk Development in Young Adults study with at least one singleton birth during 20 yr of follow-up were evaluated. MAIN OUTCOME MEASURE: Postbaseline preterm births less than 34 wk or 34 to less than 37 wk vs. greater than 37 wk gestation. RESULTS: We detected a U-shaped relationship between prepregnancy cholesterol concentrations and preterm birth risk. Women with prepregnancy cholesterol in the lowest quartile compared with the second quartile (<156 vs. 156-171 mg/dl) had an increased risk for preterm birth 34 to less than 37 wk (odds ratio 1.86; 95% confidence interval 1.10, 3.15) and less than 34 wk (odds ratio 3.04; 1.35, 6.81) independent of race, age, parity, body mass index, hypertension during pregnancy, physical activity, and years from measurement to birth. Prepregnancy cholesterol in the highest quartile (>195 mg/dl) was also associated with preterm birth less than 34 wk among women with normotensive pregnancies (odds ratio 3.80; 95% confidence interval 1.07, 7.57). There were no associations between prepregnancy triglycerides, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol and preterm birth. CONCLUSIONS: Both low and high prepregnancy cholesterol were related to preterm birth risk. These may represent distinct pathways to the heterogeneous outcome of preterm birth. Additional studies are needed to elucidate mechanisms that link low or high cholesterol to preterm birth and later-life sequelae.
Authors: Catov JM; Ness RB; Wellons MF; Jacobs DR; Roberts JM; Gunderson EP
J Clin Endocrinol Metab. 2010 Aug;95(8):3711-8. Epub 2010 May 25.
Calcium/vitamin D supplementation and coronary artery calcification in the Women’s Health Initiative
OBJECTIVE: Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D (calcium/D) supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared CAC scores after trial completion between women randomized to calcium/vitamin D supplementation and women randomized to placebo. METHODS: In an ancillary substudy of women randomized to calcium carbonate (1,000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) or placebo, nested within the Women’s Health Initiative trial of estrogen among women who underwent hysterectomy, we measured CAC with cardiac CT in 754 women aged 50 to 59 years at randomization. Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment, and scans were read centrally. CAC scores were measured by a central reading center with masking to randomization assignments. RESULTS: Posttrial CAC measurements were similar in women randomized to calcium/D supplementation and those receiving placebo. The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo (rank test P value = 0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC >0, > or =10, and > or =100) for calcium/D versus placebo were 0.92 (95% CI, 0.64-1.34), 1.29 (0.88-1.87), and 0.90 (0.56-1.44), respectively. Corresponding odds ratios among women with a 50% or higher adherence to study pills and for higher levels of CAC (>300) were similar. CONCLUSIONS: Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women. Whether higher or lower doses would affect this outcome remains uncertain.
Authors: Manson JE; Carr JJ; Women's Health Initiative and Women's Health Initiative-Coronary Artery Calcium Study Investigators; et al.
Menopause. 2010 Jul;17(4):683-91.
An ‘almost exhaustive’ search-based sequential permutation method for detecting epistasis in disease association studies
Due to the complex nature of common diseases, their etiology is likely to involve ‘uncommon but strong’ (UBS) interactive effects–i.e. allelic combinations that are each present in only a small fraction of the patients but associated with high disease risk. However, the identification of such effects using standard methods for testing association can be difficult. In this work, we introduce a method for testing interactions that is particularly powerful in detecting UBS effects. The method consists of two modules–one is a pattern counting algorithm designed for efficiently evaluating the risk significance of each marker combination, and the other is a sequential permutation scheme for multiple testing correction. We demonstrate the work of our method using a candidate gene data set for cardiovascular and coronary diseases with an injected UBS three-locus interaction. In addition, we investigate the power and false rejection properties of our method using data sets simulated from a joint dominance three-locus model that gives rise to UBS interactive effects. The results show that our method can be much more powerful than standard approaches such as trend test and multifactor dimensionality reduction for detecting UBS interactions.
Authors: Ma L; Assimes TL; Asadi NB; Iribarren C; Quertermous T; Wong WH
Genet Epidemiol. 2010 Jul;34(5):434-43.
Modeling multisystem biological risk in young adults: The Coronary Artery Risk Development in Young Adults Study
Although much prior research has focused on identifying the roles of major regulatory systems in health risks, the concept of allostatic load (AL) focuses on the importance of a more multisystems view of health risks. How best to operationalize allostatic load, however, remains the subject of some debate. We sought to test a hypothesized metafactor model of allostatic load composed of a number of biological system factors, and to investigate model invariance across sex and ethnicity. Biological data from 782 men and women, aged 32-47, from the Oakland, CA and Chicago, IL sites of the Coronary Artery Risk Development in Young Adults Study (CARDIA) were collected as part of the Year 15exam in 2000. These include measures of blood pressure, metabolic parameters (glucose, insulin, lipid profiles, and waist circumference), markers of inflammation (interleukin-6, C-reactive protein, and fibrinogen), heart rate variability, sympathetic nervous system activity (12-hr urinary norepinephrine and epinephrine) and hypothalamic-pituitary-adrenal axis activity (diurnal salivary free cortisol). A ‘metafactor’ model of AL as an aggregate measure of six underlying latent biological subfactors was found to fit the data, with the metafactor structure capturing 84% of variance of all pairwise associations among biological subsystems. There was little evidence of model variance across sex and/or ethnicity. These analyses extend work operationalizing AL as a multisystems index of biological dysregulation, providing initial support for a model of AL as a metaconstruct of inter-relationships among multiple biological regulatory systems, that varies little across sex or ethnicity.
Authors: Seeman T; Gruenewald T; Karlamangla A; Sidney S; Liu K; McEwen B; Schwartz J
Am J Hum Biol. 2010 Jul-Aug;22(4):463-72.
Joint associations of physical activity and aerobic fitness on the development of incident hypertension: coronary artery risk development in young adults
Fitness and physical activity are each inversely associated with the development of hypertension. We tested whether fitness and physical activity were independently associated with the 20-year incidence of hypertension in 4618 men and women. Hypertension was determined in participants who had systolic blood pressure >or=140 mm Hg or diastolic blood pressure >or=90 mm Hg or who reported antihypertensive medication use. Fitness was estimated based on the duration of a symptom-limited graded exercise treadmill test, and physical activity was self-reported. The incidence rate of hypertension was 13.8 per 1000 person-years (n=1022). Both baseline fitness (hazard ratio: 0.63 [95% CI: 0.56 to 0.70 per SD]; 2.9 minutes) and physical activity (hazard ratio: 0.86 [95% CI: 0.79 to 0.84 per SD]; 297 exercise units) were inversely associated with incident hypertension when included jointly in a model that also adjusted for age, sex, race, baseline smoking status, systolic blood pressure, alcohol intake, high-density lipoprotein cholesterol, dietary fiber, dietary sodium, fasting glucose, and body mass index. The magnitude of association between physical activity and hypertension was strongest among participants in the high fitness (hazard ratio: 0.80 [95% CI: 0.68 to 0.94]) category, whereas the magnitude of association between fitness and hypertension was similar across tertiles of physical activity. The estimated proportion of hypertension cases that could be prevented if participants moved to a higher fitness category (ie, preventive fraction) was 34% and varied by race and sex group. Fitness and physical activity are each associated with incident hypertension, and low fitness may account for a substantial proportion of hypertension incidence.
Authors: Carnethon MR; Evans NS; Church TS; Lewis CE; Schreiner PJ; Jacobs DR Jr; Sternfeld B; Sidney S
Hypertension. 2010 Jul;56(1):49-55. Epub 2010 Jun 1.
Comparison of 2 approaches for determining the natural history risk of brain arteriovenous malformation rupture
Estimating risk of intracranial hemorrhage (ICH) for patients with unruptured brain arteriovenous malformations (AVMs) in the natural course is essential for assessing risks and benefits of treatment. Traditionally, the survival period starts at the time of diagnosis and ends at ICH, but most patients are quickly censored because of treatment. Alternatively, a survival period from birth to first ICH, censoring at the date of diagnosis, has been proposed. The authors quantitatively compared these 2 timelines using survival analysis in 1,581 Northern California brain AVM patients (2000-2007). Time-shift analysis of the birth-to-diagnosis timeline and maximum pseudolikelihood identified the point at which the 2 survival curves overlapped; the 95% confidence interval was determined using bootstrapping. Annual ICH rates per 100 patient-years were similar for both the birth-to-diagnosis (1.27, 95% confidence interval (CI): 1.18, 1.36) and the diagnosis-to-ICH (1.17, 95% CI: 0.89, 1.53) timelines, despite differences in curve morphology. Shifting the birth-to-diagnosis timeline an optimal amount (10.3 years, 95% CI: 3.3, 17.4) resulted in similar ICH survival curves (P = 0.979). These results suggest that the unconventional birth-to-diagnosis approach can be used to analyze risk factors for natural history risk in unruptured brain AVM patients, providing greater statistical power. The data also suggest a biologic change around age 10 years influencing ICH rate.
Authors: Kim H; McCulloch CE; Johnston SC; Lawton MT; Sidney S; Young WL
Am J Epidemiol. 2010 Jun 15;171(12):1317-22. Epub 2010 May 14.
Population trends in the incidence and outcomes of acute myocardial infarction
BACKGROUND: Few studies have characterized recent population trends in the incidence and outcomes of myocardial infarction. METHODS: We identified patients 30 years of age or older in a large, diverse, community-based population who were hospitalized for incident myocardial infarction between 1999 and 2008. Age- and sex-adjusted incidence rates were calculated for myocardial infarction overall and separately for ST-segment elevation and non-ST-segment elevation myocardial infarction. Patient characteristics, outpatient medications, and cardiac biomarker levels during hospitalization were identified from health plan databases, and 30-day mortality was ascertained from administrative databases, state death data, and Social Security Administration files. RESULTS: We identified 46,086 hospitalizations for myocardial infarctions during 18,691,131 person-years of follow-up from 1999 to 2008. The age- and sex-adjusted incidence of myocardial infarction increased from 274 cases per 100,000 person-years in 1999 to 287 cases per 100,000 person-years in 2000, and it decreased each year thereafter, to 208 cases per 100,000 person-years in 2008, representing a 24% relative decrease over the study period. The age- and sex-adjusted incidence of ST-segment elevation myocardial infarction decreased throughout the study period (from 133 cases per 100,000 person-years in 1999 to 50 cases per 100,000 person-years in 2008, P<0.001 for linear trend). Thirty-day mortality was significantly lower in 2008 than in 1999 (adjusted odds ratio, 0.76; 95% confidence interval, 0.65 to 0.89). CONCLUSIONS: Within a large community-based population, the incidence of myocardial infarction decreased significantly after 2000, and the incidence of ST-segment elevation myocardial infarction decreased markedly after 1999. Reductions in short-term case fatality rates for myocardial infarction appear to be driven, in part, by a decrease in the incidence of ST-segment elevation myocardial infarction and a lower rate of death after non-ST-segment elevation myocardial infarction.
Authors: Yeh RW; Sidney S; Chandra M; Sorel M; Selby JV; Go AS
N Engl J Med. 2010 Jun 10;362(23):2155-65.
Increased risk of bleeding in patients on clopidogrel therapy after drug-eluting stents implantation: insights from the HMO Research Network-Stent Registry (HMORN-stent)
BACKGROUND: Studies suggest that extended clopidogrel use after drug-eluting stent (DES) implantation may decrease the risk of myocardial infarction (MI) and death. Little is known about the competing risk of bleeding from clopidogrel in ‘real world’ clinical practice. METHODS AND RESULTS: We studied 7689 patients undergoing drug-eluting stent implantation enrolled in the HMO Research Network-Stent Registry between 2004 and 2007. Patients were analyzed in 6-month intervals for the occurrence of major bleeding, MI, and death. Clopidogrel use was determined by pharmacy dispensing data. Regression models assessed the association between clopidogrel use and outcomes. Overall, 3603 patients (49.1%) received clopidogrel for >6 months. During a mean follow-up of 418 days (SD, +/-168 days), 217 (2.9%) patients died, 279 (3.7%) had a MI, and 271 (3.6%) had major bleeding. After adjustment, patients on clopidogrel therapy were associated with increased major bleeding in all time intervals (0 to 6 months: relative risk (RR)=2.70, 95% CI=1.41 to 5.19; 7 to 12 months: RR=1.71, 95% CI=1.05 to 2.79; 13 to 18 months: RR=2.34, 95% CI=1.26 to 4.34), compared with patients off clopidogrel. Clopidogrel use was also associated with decreased risk of MI for all time intervals (0 to 6 months: RR=0.52, 95% CI=0.36 to 0.77; 7 to 12 months: RR=0.46, 95% CI=0.30 to 0.70; 13 to 18 months: RR=0.53, 95% CI=0.29 to 0.99) and decreased death in the 7 to 12 month interval (RR=0.50, 95% CI=0.30 to 0.83). CONCLUSIONS: Clopidogrel use was associated with increased major bleeding and decreased MI persisting to 18 months. Bleeding risks on clopidogrel therapy deserve consideration in the ongoing debate regarding optimal clopidogrel duration after PCI.
Authors: Tsai TT; Ho PM; Xu S; Powers JD; Carroll NM; Shetterly SM; Maddox TM; Rumsfeld JS; Margolis K; Go AS; Magid DJ
Circ Cardiovasc Interv. 2010 Jun 1;3(3):230-5. Epub 2010 May 4.
Effect of inter-reader variability on outcomes in studies using carotid intima media thickness quantified by carotid ultrasonography
Systematic differences between readers or equipment in imaging studies are not uncommon; failure to account for such differences when using Carotid Ultrasonography may introduce bias into associations between carotid intima media thickness (cIMT) and outcomes. We demonstrate the impact of this source of systematic measurement error (SME) using data on 5,521 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) and 661 participants from the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM). Participants were between 37 and 78 years old. Two outcomes were considered: (1) the effect of HIV infection on cIMT (between study) and (2) the association of cIMT with cardiovascular events (within study). All estimates were adjusted for demographics (age, gender, and ethnicity) and for traditional cardiovascular disease risk factors (smoking, blood pressure, diabetes and cholesterol). When comparing the FRAM and MESA cohorts to estimate the association of HIV infection on common cIMT, accounting for machine and reader variability (between study variability) reduced the difference associated with HIV infection from +0.080 mm (95% Confidence Interval (CI):0.065-0.095) to +0.037 mm (95% CI:0.003 to 0.072) while internal cIMT declined from +0.254 mm (95% CI:0.205-0.303) to +0.192 mm (95% CI:0.076-0.308). Attenuation of the association between cIMT and cardiovascular endpoints occurred when within study reader variability was not accounted for. The effect of SME due to use of multiple readers or machines is most important when comparisons are made between two different study populations. Within-cohort measurement error dilutes the association with events.
Authors: Delaney JA; Scherzer R; Polak J; Biggs ML; Kronmal R; Chen H; Sidney S; Grunfeld C
Eur J Epidemiol. 2010 Jun;25(6):385-92. Epub 2010 Mar 23.
Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC)
BACKGROUND: The epidemiology of atrial fibrillation (AF) has been mainly investigated in patients with end-stage renal disease, with limited data on less advanced chronic kidney disease (CKD) stages. METHODS: A total of 3,267 adult participants (50% non-Hispanic blacks, 46% women) with CKD from the Chronic Renal Insufficiency Cohort were included in this study. None of the study participants had been on dialysis. Those with self-identified race/ethnicity other than non-Hispanic black or white (n = 323) or those without electrocardiographic data (n = 22) were excluded. Atrial fibrillation was ascertained by a 12-lead electrocardiogram and self-report. Age-, sex-, and race/ethnicity-specific prevalence rates of AF were estimated and compared between subgroups. Cross-sectional associations and correlates with prevalent AF were examined using unadjusted and multivariable-adjusted logistic regression analysis. RESULTS: The mean estimated glomerular filtration rate was 43.6 (+/-13.0) mL/(min 1.73 m(2)). Atrial fibrillation was present in 18% of the study population and in >25% of those > or =70 years old. In multivariable-adjusted models, 1-SD increase in age (11 years) (odds ratio 1.27, CI 95% 1.13-1.43, P < .0001), male [corrected] sex (0.80, 0.65-0.98, P = .0303), smoking (former vs never) (1.34, 1.08-1.66, P = .0081), history of heart failure (3.28, 2.47-4.36, P < .001), and history of cardiovascular disease (1.94, 1.56-2.43, P < .0001) were significantly associated with AF. Race/ethnicity, hypertension, diabetes, body mass index, physical activity, education, high-sensitivity C-reactive protein, total cholesterol, and alcohol intake were not significantly associated with AF. An estimated glomerular filtration rate <45 mL/(min 1.73 m(2)) was associated with AF in an unadjusted model (1.35, 1.13-1.62, P = .0010), but not after multivariable adjustment (1.12, 0.92-1.35, P = .2710). CONCLUSIONS: Nearly 1 in 5 participants in Chronic Renal Insufficiency Cohort, a national study of CKD, had evidence of AF at study entry, a prevalence similar to that reported among patients with end-stage renal disease and 2 to 3 times of that reported in the general population. Risk factors for AF in this CKD population do not mirror those reported in the general population.
Authors: Soliman EZ; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Group; et al.
Am Heart J. 2010 Jun;159(6):1102-7.
Rethinking the epidemiology of acute myocardial infarction: challenges and opportunities
BACKGROUND: During the previous decade, many strategies for preventing acute myocardial infarction found to be efficacious in randomized controlled trials have been adopted by physicians in the community. Although evaluations of quality improvement typically focus on process measures at the hospital, practice, or clinician level, assessment of improvements in health outcomes remains the true test for the successful translation of evidence into practice. METHODS: We performed a review of the current literature examining trends in the incidence of myocardial infarction in communities. We focused specifically on the group of population-based studies that have examined trends in myocardial infarction incidence. RESULTS: Few population-based studies have examined recent temporal trends in the incidence of myocardial infarction, overall and by type. Existing studies have been largely limited by modest sample sizes, limited diversity within the study populations, the use of composite end points that combine disparate outcomes, and the inability to characterize the effect of long-term outpatient medication use on observed trends in incidence and severity of myocardial infarction. CONCLUSION: More contemporary assessments of community-wide changes in the epidemiology of myocardial infarction are needed to help assess the effectiveness of primary prevention and to identify areas for potential improvement.
Authors: Yeh RW; Go AS
Arch Intern Med. 2010 May 10;170(9):759-64.
Genome-wide meta-analyses identify multiple loci associated with smoking behavior
Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
Authors: Tobacco and Genetics Consortium
Nat Genet. 2010 May;42(5):441-7. Epub 2010 Apr 25.
Delays in filling clopidogrel prescription after hospital discharge and adverse outcomes after drug-eluting stent implantation: implications for transitions of care
BACKGROUND: Adjuvant clopidogrel therapy is essential after drug-eluting stent (DES) implantation. The frequency with which patients delay filling a clopidogrel prescription after DES implantation and the association of this delay with adverse outcomes is unknown. METHODS AND RESULTS: This was a retrospective cohort study of patients discharged after DES implantation from 3 large integrated health care systems. Filling a clopidogrel prescription was based on pharmacy dispensing data. The primary end point was all-cause mortality or myocardial infarction (MI). Of 7402 patients discharged after DES implantation, 16% (n=1210) did not fill a clopidogrel prescription on day of discharge and the median time delay was 3 days (interquartile range, 1 to 23 days). Compared with patients filling clopidogrel on day of discharge, patients with any delay in filling clopidogrel had higher death/MI rates during follow-up (14.2% versus 7.9%; P<0.001). In multivariable analysis, patients with any delay had increased risk of death/MI (hazard ratio, 1.53; 95% confidence interval, 1.25 to 1.87). Patients with any delay remained at increased risk of adverse outcomes when the delay cutoff was changed to >1, >3, or >5 days after discharge. Factors associated with delay included older age, prior MI, diabetes, renal failure, prior revascularization, cardiogenic shock, in-hospital bleeding, and clopidogrel use within 24 hours of admission. CONCLUSIONS: One in 6 patients delay filling their index clopidogrel prescription after hospital discharge after DES implantation. This delay was associated with increased risk of adverse outcomes and highlights the importance of the transition period from hospital discharge to outpatient setting as a potential opportunity to improve care delivery and patient outcomes.
Authors: Ho PM; Tsai TT; Maddox TM; Powers JD; Carroll NM; Jackevicius C; Go AS; Margolis KL; DeFor TA; Rumsfeld JS; Magid DJ
Circ Cardiovasc Qual Outcomes. 2010 May;3(3):261-6. Epub 2010 Apr 20.
Adverse events after stopping clopidogrel in post-acute coronary syndrome patients: Insights from a large integrated healthcare delivery system
BACKGROUND: A prior study from the Veterans Health Administration found a clustering of cardiovascular events after clopidogrel cessation. We sought to confirm and expand these findings. METHODS AND RESULTS: This was a retrospective cohort study of 2017 patients with acute coronary syndrome discharged on clopidogrel from an integrated health care delivery system. Rates of all-cause mortality or acute myocardial infarction (MI) within 1 year after stopping clopidogrel were assessed among patients who did not have an event before stopping clopidogrel. Death/MI occurred in 4.3% (n=71) of patients. The rates of death/MI were 3.07, 1.62, 0.70, and 0.95 per 10 000 patient-days for the time intervals of 0 to 90, 91 to 180, 181 to 270, and 271 to 360 days after stopping clopidogrel. In multivariable analysis, the 0- to 90-day interval after stopping clopidogrel was associated with higher risk of death/MI (incidence rate ratio, 2.74; 95% confidence interval, 1.69 to 4.44) compared with 91- to 360-day interval. There was a similar trend of increased events after stopping clopidogrel for various subgroups (women versus men, medical therapy versus percutaneous coronary intervention, stent type, and > or =6 months or <6 months of clopidogrel treatment). Among patients taking clopidogrel but stopping ACE inhibitor medications, the event rates were similar in the 0- to 90-day versus the 91- to 360-day interval (2.67 versus 2.91 per 10 000 patient-days; P=0.91). CONCLUSIONS: We observed a clustering of adverse events in the 0 to 90 days after stopping clopidogrel. This clustering of events was not present among patients stopping ACE inhibitors. These findings are consistent with a possible rebound platelet hyper-reactivity after stopping clopidogrel and additional platelet studies are needed to confirm this effect.
Authors: Ho PM; Tsai TT; Wang TY; Shetterly SM; Clarke CL; Go AS; Sedrakyan A; Rumsfeld JS; Peterson ED; Magid DJ
Circ Cardiovasc Qual Outcomes. 2010 May;3(3):303-8. Epub 2010 Mar 30.
Duration of lactation and maternal metabolism at 3 years postpartum
OBJECTIVE: Lactation has been associated with reduced risk of type 2 diabetes and the metabolic syndrome in mothers. We examined the relation between breastfeeding duration and metabolic markers at 3 years postpartum. METHODS: We used linear regression to relate duration of lactation to maternal glucose and lipid metabolism, inflammatory markers, and anthropometry at 3 years postpartum among 570 participants with 3-year blood samples (175 fasting) in Project Viva, a cohort study of mothers and children. RESULTS: Among the participants, 88% had initiated breastfeeding, and 26% had breastfed >or=12 months. In multivariate analyses, we observed no consistent trends relating duration of lactation to maternal metabolism at 3 years postpartum. Women who exclusively breastfed for >6 months had lower postpartum weight retention at 3 years than women with shorter durations of exclusive breastfeeding (multivariate adjusted predicted mean -0.5, -3.6-2.6 kg vs. 4.8, 2.0-7.6 kg for those who never exclusively breastfed, partial F p = 0.03). CONCLUSIONS: In this prospective cohort study, we did not observe a dose-response relationship between duration of lactation and metabolic risk at 3 years postpartum.
Authors: Stuebe AM; Kleinman K; Gillman MW; Rifas-Shiman SL; Gunderson EP; Rich-Edwards J
J Womens Health (Larchmt). 2010 May;19(5):941-50.
Standardized discharge orders after stroke: results of the quality improvement in stroke prevention (QUISP) cluster randomized trial
OBJECTIVE: Proven strategies to reduce risk of stroke recurrence are under-utilized. We sought to evaluate the impact of standardized stroke discharge orders on treatment practices in a cluster-randomized trial. METHODS: The Quality Improvement in Stroke Prevention (QUISP) trial randomized 12 hospitals to continue usual care or to receive assistance in the development and implementation of standardized stroke discharge orders. All patients with ischemic stroke were identified during a 12-month period prior to implementation and for 12 months afterward, and were followed for 6 months after discharge. The primary outcome was optimal treatment at 6 months, defined as taking a statin, having blood pressure <140/90mmHg, and receiving anticoagulation if atrial fibrillation was diagnosed. The primary analysis treated the hospital as the unit of analysis, comparing optimal treatment rates-adjusted for race, age, dementia, atrial fibrillation, and history of bleeding-between intervention and non-intervention hospitals using a paired t test. RESULTS: In the primary analysis with hospital as the unit of analysis, the odds of optimal treatment was not significantly increased at intervention compared to non-intervention hospitals (odds ratio, 1.39; 95% confidence interval, 0.71-2.76; p = 0.27). However, in analyses conducted at the level of the individual patients (N = 3,361), rates of optimal treatment increased from 37% to 45% in the intervention hospitals (p = 0.001) and did not change significantly in the non-intervention hospitals (39% to 40%; p = 0.27). INTERPRETATION: Implementation of standardized discharge orders after stroke was associated with increased rates of optimal secondary prevention; this improvement was not significant in the primary analysis at the hospital level.
Authors: Johnston SC; Sidney S; Hills NK; Grosvenor D; Klingman JG; Bernstein A; Levin E
Ann Neurol. 2010 May;67(5):579-89.
Prevalence of ocular fundus pathology in patients with chronic kidney disease
BACKGROUND AND OBJECTIVES: The objective of this study was to describe the prevalence of ocular fundus pathology in the Chronic Renal Insufficiency Cohort (CRIC) study, a multicenter, longitudinal study of individuals with varying stages of chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this cross-sectional study, 45 degree digital photos of the disc and macula in both eyes were obtained by nonophthalmologic personnel using a nonmydriatic Canon CR-DGI fundus camera in 1936 individuals who participated in the CRIC study. Photographs were assessed in a masked manner by graders and a retinal specialist at a central photograph reading center. The purpose of this review was to inform participants quickly of conditions that warranted a complete eye examination by an ophthalmologist. RESULTS: Among the 1936 participants who were photographed, 1904 (98%) had assessable photographs in at least one eye. Eye pathologies that required a follow-up examination by an ophthalmologist were identified in 864 (45%) of these 1904 participants. These eye pathologies included, among others, retinopathy (diabetic and/or hypertensive), a finding that was observed in 482 (25%) of these 1904 participants. Three percent (65 participants) of the 1904 participants had serious eye conditions that required urgent follow-up and treatment. Lower estimated GFR and cardiovascular disease were associated with greater eye pathology. Estimated GFR <30 ml/min per 1.73 m(2) was associated with a three times higher risk for retinopathy. CONCLUSIONS: We found a high prevalence of fundus pathology in participants with CKD. This finding supports recommendations for regular complete eye examinations in the CKD population.
Authors: Grunwald JE; Lo JC; CRIC Study Group; et al.
Clin J Am Soc Nephrol. 2010 May;5(5):867-73. Epub 2010 Mar 18.
Asthma and the prospective risk of anaphylactic shock and other allergy diagnoses in a large integrated health care delivery system
BACKGROUND: The association between asthma and anaphylaxis remains poorly understood. OBJECTIVE: To ascertain, in a managed care organization in northern California, the association of asthma and asthma severity with future risk of anaphylactic shock and other selected allergy diagnoses. METHODS: Using electronic data and validated algorithms, we assembled a cohort of 526,406 patients who met the criteria for asthma between 1996 and 2006 and a referent cohort (with no utilization for asthma) individually matched on age, sex, and race/ethnicity. In each cohort, 54% of patients were female and 55% were white; their mean (SD) age was 24 (20) years. The main outcome measures were anaphylactic shock (caused by an adverse food reaction, caused by serum, or other/idiopathic), allergic urticaria, anaphylaxis after sting(s), and angioedema. RESULTS: The incidence of anaphylactic shock was 109.0 per 100,000 person-years in the asthma cohort and 19.9 per 100,000 person-years in the referent cohort. After adjustment for age, sex, race/ethnicity, comorbidities, and immunotherapy, asthma was associated with a 5.2-fold (95% confidence interval, 4.7- to 5.6-fold) increased hazard of anaphylactic shock. Asthma was also significantly associated with an increased risk of the 3 selected allergy diagnoses, with hazard ratios of 1.4 to 1.9. A significant trend by severity of asthma was apparent for food-related and other/idiopathic anaphylactic shock and for anaphylaxis after sting(s). CONCLUSIONS: In this insured population, asthma was prospectively associated with increased risk of anaphylactic shock and other allergy diagnoses. However, the effect of asthma severity was not consistent across outcome measures.
Authors: Iribarren C; Tolstykh IV; Miller MK; Eisner MD
Ann Allergy Asthma Immunol. 2010 May;104(5):371-7.
Association of adolescent obesity and lifetime nulliparity–the Study of Women’s Health Across the Nation (SWAN)
OBJECTIVE: To evaluate whether adolescent obesity is associated with difficulties in becoming pregnant later in life. DESIGN: Cross-sectional analysis of baseline data from a longitudinal cohort. SETTING: Multiethnic, community-based observational study of U.S. women. PATIENT(S): Three thousand one hundred fifty-four midlife women. MAIN OUTCOME MEASURE(S): Lifetime nulliparity and lifetime nulligravidity. RESULT(S): Five hundred twenty-seven women (16.7%) women had never delivered a baby. Participants were categorized by self-reported high school body mass index (BMI): underweight (<18.5 kg/m(2)), normal (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (>30 kg/m(2)). The prevalence of lifetime nulliparity increased progressively across the high school BMI categories: 12.7%, 16.7%, 19.2%, and 30.9%, respectively. Multivariable logistic regression analysis confirmed that women who were obese adolescents had significantly higher odds of remaining childless compared with normal weight women (odds ratio [OR] 2.84; 95% confidence interval [CI], 1.59-5.10) after adjusting for adult BMI, history of nongestational amenorrhea, marital status, ethnicity, study site, and measures of socioeconomic status. Furthermore, adolescent obesity was associated with lifetime nulligravidity (OR = 3.93; 95% CI, 2.12-7.26). CONCLUSION(S): Adolescent obesity is associated with lifetime nulliparity and nulligravidity in midlife U.S. women.
Authors: Polotsky AJ; Hailpern SM; Skurnick JH; Lo JC; Sternfeld B; Santoro N
Fertil Steril. 2010 Apr;93(6):2004-11. Epub 2009 Jan 30.
The COPD Helplessness Index: a new tool to measure factors affecting patient self-management
BACKGROUND: Psychologic factors affect how patients with COPD respond to attempts to improve their self-management skills. Learned helplessness may be one such factor, but there is no validated measure of helplessness in COPD. METHODS: We administered a new COPD Helplessness Index (CHI) to 1,202 patients with COPD. Concurrent validity was assessed through association of the CHI with established psychosocial measures and COPD severity. The association of helplessness with incident COPD exacerbations was then examined by following subjects over a median 2.1 years, defining COPD exacerbations as COPD-related hospitalizations or ED visits. RESULTS: The CHI demonstrated internal consistency (Cronbach alpha = 0.75); factor analysis was consistent with the CHI representing a single construct. Greater CHI-measured helplessness correlated with greater COPD severity assessed by the BODE (Body-mass, Obstruction, Dyspnea, Exercise) Index (r = 0.34; P < .001). Higher CHI scores were associated with worse generic (Short Form-12, Physical Component Summary Score) and respiratory-specific (Airways Questionnaire 20) health-related quality of life, greater depressive symptoms, and higher anxiety (all P < .001). Controlling for sociodemographics and smoking status, helplessness was prospectively associated with incident COPD exacerbations (hazard ratio = 1.31; P < .001). After also controlling for the BODE Index, helplessness remained predictive of COPD exacerbations among subjects with BODE Index
Authors: Omachi TA; Katz PP; Yelin EH; Iribarren C; Knight SJ; Blanc PD; Eisner MD
Chest. 2010 Apr;137(4):823-30. Epub 2009 Oct 16.
Measurement of COPD severity using a survey-based score: validation in a clinically and physiologically characterized cohort
BACKGROUND: A comprehensive survey-based COPD severity score has usefulness for epidemiologic and health outcomes research. We previously developed and validated the survey-based COPD Severity Score without using lung function or other physiologic measurements. In this study, we aimed to further validate the severity score in a different COPD cohort and using a combination of patient-reported and objective physiologic measurements. METHODS: Using data from the Function, Living, Outcomes, and Work cohort study of COPD, we evaluated the concurrent and predictive validity of the COPD Severity Score among 1,202 subjects. The survey instrument is a 35-point score based on symptoms, medication and oxygen use, and prior hospitalization or intubation for COPD. Subjects were systemically assessed using structured telephone survey, spirometry, and 6-min walk testing. RESULTS: We found evidence to support concurrent validity of the score. Higher COPD Severity Score values were associated with poorer FEV(1) (r = -0.38), FEV(1)% predicted (r = -0.40), Body mass, Obstruction, Dyspnea, Exercise Index (r = 0.57), and distance walked in 6 min (r = -0.43) (P < .0001 in all cases). Greater COPD severity was also related to poorer generic physical health status (r = -0.49) and disease-specific health-related quality of life (r = 0.57) (P < .0001). The score also demonstrated predictive validity. It was also associated with a greater prospective risk of acute exacerbation of COPD defined as ED visits (hazard ratio [HR], 1.31; 95% CI, 1.24-1.39), hospitalizations (HR, 1.59; 95% CI, 1.44-1.75), and either measure of hospital-based care for COPD (HR, 1.34; 95% CI, 1.26-1.41) (P < .0001 in all cases). CONCLUSION: The COPD Severity Score is a valid survey-based measure of disease-specific severity, both in terms of concurrent and predictive validity. The score is a psychometrically sound instrument for use in epidemiologic and outcomes research in COPD.
Authors: Eisner MD; Omachi TA; Katz PP; Yelin EH; Iribarren C; Blanc PD
Chest. 2010 Apr;137(4):846-51. Epub 2009 Dec 29.
Influence of anxiety on health outcomes in COPD
BACKGROUND: Psychological functioning is an important determinant of health outcomes in chronic lung disease. To better define the role of anxiety in chronic obstructive pulmonary disease (COPD), a study was conducted of the inter-relations between anxiety and COPD in a large cohort of subjects with COPD and a matched control group. METHODS: Data were used from the FLOW (Function, Living, Outcomes, and Work) cohort of patients with COPD (n=1202) and matched controls without COPD (n=302). Anxiety was measured using the Anxiety subscale of the Hospital Anxiety and Depression Scale. RESULTS: COPD was associated with a greater risk of anxiety in multivariable analysis (OR 1.85; 95% CI 1.072 to 3.18). Among patients with COPD, anxiety was related to poorer health outcomes including worse submaximal exercise performance (less distance walked during the 6-min walk test: -66.3 feet for anxious vs non-anxious groups; 95% CI -127.3 to -5.36) and a greater risk of self-reported functional limitations (OR 2.41; 95% CI 1.71 to 3.41). Subjects with COPD with anxiety had a higher longitudinal risk of COPD exacerbation in Cox proportional hazards analysis after controlling for covariates (HR 1.39; 95% CI 1.007 to 1.90). CONCLUSION: COPD is associated with a higher risk of anxiety. Once anxiety develops among patients with COPD, it is related to poorer health outcomes. Further research is needed to determine whether systematic screening and treatment of anxiety in COPD will improve health outcomes and prevent functional decline and disability.
Authors: Eisner MD; Blanc PD; Yelin EH; Katz PP; Sanchez G; Iribarren C; Omachi TA
Thorax. 2010 Mar;65(3):229-34.
Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury
Studies of acute kidney injury usually lack data on pre-admission kidney function and often substitute an inpatient or imputed serum creatinine as an estimate for baseline renal function. In this study, we compared the potential error introduced by using surrogates such as (1) an estimated glomerular filtration rate of 75 ml/min per 1.73 m(2) (suggested by the Acute Dialysis Quality Initiative), (2) a minimum inpatient serum creatinine value, and (3) the first admission serum creatinine value, with values computed using pre-admission renal function. The study covered a 12-month period and included a cohort of 4863 adults admitted to the Vanderbilt University Hospital. Use of both imputed and minimum baseline serum creatinine values significantly inflated the incidence of acute kidney injury by about half, producing low specificities of 77-80%. In contrast, use of the admission serum creatinine value as baseline significantly underestimated the incidence by about a third, yielding a low sensitivity of 39%. Application of any surrogate marker led to frequent misclassification of patient deaths after acute kidney injury and differences in both in-hospital and 60-day mortality rates. Our study found that commonly used surrogates for baseline serum creatinine result in bi-directional misclassification of the incidence and prognosis of acute kidney injury in a hospital setting.
Authors: Siew ED; Matheny ME; Ikizler TA; Lewis JB; Miller RA; Waitman LR; Go AS; Parikh CR; Peterson JF
Kidney Int. 2010 Mar;77(6):536-42. Epub 2009 Dec 30.
Characteristics of implant failures in patients with a history of oral bisphosphonate therapy
PURPOSE: This study examines the pattern of implant failures reported in a large cohort of patients who received oral bisphosphonate therapy. MATERIALS AND METHODS: A total of 8,572 individuals who received oral bisphosphonate drugs returned a dental survey that obtained information pertaining to implant placement and related complications. Among the 589 individuals reporting dental implants, 16 reported implant failures that were verified by dental records. Implant placement, timing of failure, and bisphosphonate duration were ascertained to determine the characteristics of implant loss in the setting of oral bisphosphonate exposure. RESULTS: Among the 16 patients (all women, aged 70.2 +/- 7.6 yrs) there were 26 implant failures; 8 had failure of 12 implants in the maxilla and 9 had failure of 14 implants in the mandible. Early failure (
Authors: Martin DC; O'Ryan FS; Indresano AT; Bogdanos P; Wang B; Hui RL; Lo JC
J Oral Maxillofac Surg. 2010 Mar;68(3):508-14.
Aortic PWV in chronic kidney disease: a CRIC ancillary study
BACKGROUND: Aortic pulse wave velocity (PWV) is a measure of arterial stiffness and has proved useful in predicting cardiovascular morbidity and mortality in several populations of patients, including the healthy elderly, hypertensives and those with end-stage renal disease receiving hemodialysis. Little data exist characterizing aortic stiffness in patients with chronic kidney disease (CKD) who are not receiving dialysis, and in particular the effect of reduced kidney function on aortic PWV. METHODS: We performed measurements of aortic PWV in a cross-sectional cohort of participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased aortic PWV in CKD. RESULTS: PWV measurements were obtained in 2,564 participants. The tertiles of aortic PWV (adjusted for waist circumference) were <7.7 m/s, 7.7-10.2 m/s, and >10.2 m/s with an overall mean (+/- s.d.) value of 9.48 +/- 3.03 m/s (95% confidence interval = 9.35-9.61 m/s). Multivariable regression identified significant independent positive associations of age, blood glucose concentrations, race, waist circumference, mean arterial blood pressure, gender, and presence of diabetes with aortic PWV and a significant negative association with the level of kidney function. CONCLUSIONS: The large size of this unique cohort, and the targeted enrollment of CKD participants provides an ideal situation to study the role of reduced kidney function as a determinant of arterial stiffness. Arterial stiffness may be a significant component of the enhanced cardiovascular risk associated with kidney failure.
Authors: Townsend RR; Go AS; Joffe M; et al.
Am J Hypertens. 2010 Mar;23(3):282-9. Epub 2009 Dec 17.
Gestational weight gain and risk of gestational diabetes mellitus
OBJECTIVE: To estimate the relationship between the rate of gestational weight gain before the 50-g, 1-hour oral glucose challenge test screening for gestational diabetes mellitus (GDM) and subsequent risk of GDM. METHODS: We conducted a nested case-control study (345 women with GDM and 800 women in the control group) within a multiethnic cohort of women delivering between 1996 and 1998 who were screened for GDM at 24-28 weeks of gestation. GDM was diagnosed according to the National Diabetes Data Group plasma glucose cut-offs for the 100-g, 3-hour oral glucose tolerance test. Women’s plasma glucose levels, weights, and covariate data were obtained by medical record chart review. RESULTS: After adjusting for age at delivery, race/ethnicity, parity, and prepregnancy body mass index, the risk of GDM increased with increasing rates of gestational weight gain. Compared with the lowest tertile of rate of gestational weight gain (less than 0.27 kg/week [less than 0.60 lb/wk]), a rate of weight gain from 0.27-0.40 kg/wk (0.60-0.88 lb/wk) and 0.41 kg/wk (0.89 lb/wk) or more, were associated with increased risks of GDM (odds ratio 1.43, 95% confidence interval 0.96-2.14; and odds ratio 1.74, 95% confidence interval 1.16-2.60, respectively). The association between the rate of gestational weight gain and GDM was primarily attributed to increased weight gain in the first trimester. The association was stronger in overweight [corrected] and nonwhite women. CONCLUSION: High rates of gestational weight gain, especially early in pregnancy, may increase a woman’s risk of GDM. Gestational weight gain during early pregnancy may represent a modifiable risk factor for GDM and needs more attention from health care providers.
Authors: Hedderson MM; Gunderson EP; Ferrara A
Obstet Gynecol. 2010 Mar;115(3):597-604.
The 5-year direct medical cost of neonatal and childhood stroke in a population-based cohort
BACKGROUND: Despite increasing awareness of the long-term impact of pediatric stroke, there are few estimates of the costs of care. We examined acute and 5-year direct costs of neonatal and childhood stroke in a population-based cohort in Northern California. METHODS: We obtained electronic cost data for 266 children with neurologist-confirmed strokes, and 786 age-matched stroke-free controls, within the population of all children (<20 years) enrolled in a large managed care plan from 1996 through 2003. Cost data included all inpatient and outpatient health service costs including care at out-of-plan facilities. Costs were assessed for 5 years after stroke, expressed in 2003 US dollars, and stratified by age at stroke onset (neonatal, defined as <29 days of life, vs childhood). Stroke costs were adjusted for costs in stroke-free age-matched controls. RESULTS: Average adjusted 5-year costs for pediatric stroke are substantial: $51,719 for neonatal stroke and $135,161 for childhood stroke. The average cost of a childhood stroke admission was $81,869. The average birth admission cost for a neonatal stroke was $39,613; adjustment for control birth admission costs reduced this by only $4,792, suggesting the stroke accounted for 88% of costs. Even among neonates whose strokes were not recognized until later in childhood ('presumed perinatal strokes'), admission costs exceeded those of controls. Chronic costs were highest in the first year poststroke, but continued to exceed control costs even in the fifth year by an average of $2,016. CONCLUSIONS: The economic burden of neonatal and childhood stroke is both large and sustained.
Authors: Gardner MA; Hills NK; Sidney S; Johnston SC; Fullerton HJ
Neurology. 2010 Feb 2;74(5):372-8. Epub 2010 Jan 6.
Chronic kidney disease and cognitive function in older adults: findings from the chronic renal insufficiency cohort cognitive study
OBJECTIVES: To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors. DESIGN: Cross-sectional. SETTING: Chronic Renal Insufficiency Cohort Study. PARTICIPANTS: Eight hundred twenty-five adults aged 55 and older with CKD. MEASUREMENTS: Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m(2)) was estimated using the four-variable Modification of Diet in Renal Disease equation. Cognitive scores on six cognitive tests were compared across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score < or =1 standard deviations from the mean). RESULTS: Mean age of the participants was 64.9, 50.4% were male, and 44.5% were black. After multivariable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains (P<.05). In addition, participants with advanced CKD (eGFR<30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio (AOR) 2.0, 95% CI=1.1-3.9), naming (AOR=1.9, 95% CI=1.0-3.3), attention (AOR=2.4, 95% CI=1.3-4.5), executive function (AOR=2.5, 95% CI=1.9-4.4), and delayed memory (AOR=1.5, 95% CI=0.9-2.6) but not on category fluency (AOR=1.1, 95% CI=0.6-2.0) than those with mild to moderate CKD (eGFR 45-59). CONCLUSION: In older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. These results suggest that older patients with advanced CKD should be screened for cognitive impairment.
Authors: Yaffe K; Go AS; Chronic Renal Insufficiency Cohort Investigators; et al.
J Am Geriatr Soc. 2010 Feb;58(2):338-45. Epub 2010 Jan 26.
Duration of lactation and incidence of the metabolic syndrome in women of reproductive age according to gestational diabetes mellitus status: a 20-Year prospective study in CARDIA (Coronary Artery Risk Development in Young Adults)
OBJECTIVE: The objective of the study was to prospectively assess the association between lactation duration and incidence of the metabolic syndrome among women of reproductive age. RESEARCH DESIGN AND METHODS: Participants were 1,399 women (39% black, aged 18-30 years) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, an ongoing multicenter, population-based, prospective observational cohort study conducted in the U.S. Women were nulliparous and free of the metabolic syndrome at baseline (1985-1986) and before subsequent pregnancies, and reexamined 7, 10, 15, and/or 20 years after baseline. Incident metabolic syndrome case participants were identified according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Complementary log-log models estimated relative hazards of incident metabolic syndrome among time-dependent lactation duration categories by gestational diabetes mellitus (GDM) adjusted for age, race, study center, baseline covariates (BMI, metabolic syndrome components, education, smoking, physical activity), and time-dependent parity. RESULTS: Among 704 parous women (620 non-GDM, 84 GDM), there were 120 incident metabolic syndrome case participants in 9,993 person-years (overall incidence rate 12.0 per 1,000 person-years; 10.8 for non-GDM, 22.1 for GDM). Increased lactation duration was associated with lower crude metabolic syndrome incidence rates from 0-1 month through >9 months (P < 0.001). Fully adjusted relative hazards showed that risk reductions associated with longer lactation were stronger among GDM (relative hazard range 0.14-0.56; P = 0.03) than non-GDM groups (relative hazard range 0.44-0.61; P = 0.03). CONCLUSIONS: Longer duration of lactation was associated with lower incidence of the metabolic syndrome years after weaning among women with a history of GDM and without GDM, controlling for preconception measurements, BMI, and sociodemographic and lifestyle traits. Lactation may have persistent favorable effects on women's cardiometabolic health.
Authors: Gunderson EP; Jacobs DR Jr; Chiang V; Lewis CE; Feng J; Quesenberry CP Jr; Sidney S
Diabetes. 2010 Feb;59(2):495-504. Epub 2009 Dec 3.
Transplant nephrectomy improves survival following a failed renal allograft
There is a growing number of patients returning to dialysis after a failed kidney transplant, and there is increasing evidence of higher mortality among this population. Whether removal of the failed renal allograft affects survival while receiving long-term dialysis is not well understood. We identified all adults who received a kidney transplant and returned to long-term dialysis after renal allograft failure between January 1994 and December 2004 from the US Renal Data System. Among 10,951 transplant recipients who returned to long-term dialysis, 3451 (31.5%) received an allograft nephrectomy during follow-up. Overall, 34.6% of these patients died during follow-up. Receiving an allograft nephrectomy associated with a 32% lower adjusted relative risk for all-cause death (adjusted hazard ratio 0.68; 95% confidence interval 0.63 to 0.74) after adjustment for sociodemographic characteristics, comorbidity burden, donor characteristics, interim clinical conditions associated with receiving allograft nephrectomy, and propensity to receive an allograft nephrectomy. In conclusion, within a large, nationally representative sample of high-risk patients returning to long-term dialysis after failed kidney transplant, receipt of allograft nephrectomy independently associated with improved survival.
Authors: Ayus JC; Achinger SG; Lee S; Sayegh MH; Go AS
J Am Soc Nephrol. 2010 Feb;21(2):374-80. Epub 2009 Oct 29.
Reduced expression of integrin alphavbeta8 is associated with brain arteriovenous malformation pathogenesis
Brain arteriovenous malformations (BAVMs) are a rare but potentially devastating hemorrhagic disease. Transforming growth factor-beta signaling is required for proper vessel development, and defective transforming growth factor-beta superfamily signaling has been implicated in BAVM pathogenesis. We hypothesized that expression of the transforming growth factor-beta activating integrin, alphavbeta8, is reduced in BAVMs and that decreased beta8 expression leads to defective neoangiogenesis. We determined that beta8 protein expression in perivascular astrocytes was reduced in human BAVM lesional tissue compared with controls and that the angiogenic response to focal vascular endothelial growth factor stimulation in adult mouse brains with local Cre-mediated deletion of itgb8 and smad4 led to vascular dysplasia in newly formed blood vessels. In addition, common genetic variants in ITGB8 were associated with BAVM susceptibility, and ITGB8 genotypes associated with increased risk of BAVMs correlated with decreased beta8 immunostaining in BAVM tissue. These three lines of evidence from human studies and a mouse model suggest that reduced expression of integrin beta8 may be involved in the pathogenesis of sporadic BAVMs.
Authors: Su H; Bollen AW; Nishimura SL; et al.
Am J Pathol. 2010 Feb;176(2):1018-27. Epub 2009 Dec 17.
Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure
PURPOSE: Osteonecrosis of the jaw (ONJ) is a serious complication associated with bisphosphonate therapy, but its epidemiology in the setting of oral bisphosphonate therapy is poorly understood. The present study examined the prevalence of ONJ in patients receiving chronic oral bisphosphonate therapy. MATERIALS AND METHODS: We mailed a survey to 13,946 members who had received chronic oral bisphosphonate therapy as of 2006 within a large integrated health care delivery system in Northern California. Respondents who reported ONJ, exposed bone or gingival sores, moderate periodontal disease, persistent symptoms, or complications after dental procedures were invited for examination or to have their dental records reviewed. ONJ was defined as exposed bone (of >8 weeks’ duration) in the maxillofacial region in the absence of previous radiotherapy. RESULTS: Of the 8,572 survey respondents (71 +/- 9 years, 93% women), 2,159 (25%) reported pertinent dental symptoms. Of these 2,159 patients, 1,005 were examined and an additional 536 provided dental records. Nine ONJ cases were identified, representing a prevalence of 0.10% (95% confidence interval 0.05% to 0.20%) among the survey respondents. Of the 9 cases, 5 had occurred spontaneously (3 in palatal tori) and 4 occurred in previous extraction sites. An additional 3 patients had mandibular osteomyelitis (2 after extraction and 1 with implant failure) but without exposed bone. Finally, 7 other patients had bone exposure that did not fulfill the criteria for ONJ. CONCLUSIONS: ONJ occurred in 1 of 952 survey respondents with oral bisphosphonate exposure (minimum prevalence of 1 in 1,537 of the entire mailed cohort). A similar number had select features concerning for ONJ that did not meet the criteria. The results of the present study provide important data on the spectrum of jaw complications among patients with oral bisphosphonate exposure.
Authors: Lo JC; Gordon NP; Go AS; Predicting Risk of Osteonecrosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) Investigators; et al.
J Oral Maxillofac Surg. 2010 Feb;68(2):243-53. Epub 2009 Sep 24.
Recurrent headaches in children: an epidemiological survey of two middle schools in inner city Chicago.
OBJECTIVES: The aim of this study was to longitudinally evaluate the epidemiological characteristics of headaches in a school-based, community setting and to determine the impact of headache symptoms on the health of children.METHODS: After institutional review board approval, a prospective cohort study was conducted at two Chicago public schools for a period of 6 months. Members of the research team surveyed both schools weekly for headache and other pain symptoms. The students rated each pain symptom on a 5-point scale from 0 ("not at all") to 4 ("a whole lot"). Demographic information was collected at the time of enrollment, and all participants were asked to complete age-appropriate and validated pediatric surveys to assess the severity of concurrent somatic complaints, anxiety symptoms, functional limitations, and quality of life issues.RESULTS: Of the participating children, 89.5% reported at least one headache during the study period. Females experienced more frequent headaches compared with males (P < 0.05). Children reporting headaches had a significantly increased risk of experiencing other troubling somatic symptoms (P < 0.05). Headache severity showed a moderate correlation with increased feelings of anxiety, functional disability, and a diminished quality of life (P < 0.05).CONCLUSIONS: School-aged children commonly experience headaches. Children experiencing headaches are more likely to report other somatic symptoms, feelings of anxiety, functional limitations, and quality of life impairments.
Authors: Nyame, Yaw A YA; Ambrosy, Andrew P AP; Saps, Miguel M; Adams, Papa N PN; Dhroove, Gati N GN; Suresh, Santhanam S
Pain practice : the official journal of World Institute of Pain. 2011 Feb 01;10(3):214-21. Epub 2010-01-08.
Parent-assisted or nurse-assisted epidural analgesia: is this feasible in pediatric patients?
AIM: The aim of this study was to assess the feasibility of parent-assisted or nurse-assisted epidural analgesia (PNEA) for control of postoperative pain in a pediatric surgical population.METHODS: After the institutional review board (IRB) approval was obtained, an analysis of our pain treatment services database of pediatric surgical patients with epidural catheters in whom the parent and/or nurse were empowered to activate the epidural demand-dose button was evaluated.RESULTS: Over a 10 -year period between 1999 and 2008, 128 procedures in 126 patients were provided parent or nurse assistance of the epidural demand dose. Satisfactory analgesia was obtained in 86% of patients with no or minor adjustments in PNEA parameters. Fourteen percent of patients were converted to intravenous patient-controlled analgesia (PCA) for inadequate analgesia (7%) or side effects (7%). None of the patients in this cohort required treatment for respiratory depression or excessive sedation.CONCLUSIONS: Parent-assisted or nurse-assisted epidural analgesia can be safely administered to children undergoing surgery who are physically or cognitively unable or unwilling to self-activate a demand dose. Additional studies are needed to compare the efficacy of PNEA with other modalities for postoperative pain control in children.
Authors: Birmingham, Patrick K PK; Suresh, Santhanam S; Ambrosy, Andrew A; Porfyris, Suzanne S
Paediatric anaesthesia. 2009 Nov 01;19(11):1084-9. Epub 2010-01-08.
The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods
BACKGROUND: The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors. METHODS: The Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study was established to examine how a hospitalized episode of AKI independently affects the risk of chronic kidney disease development and progression, cardiovascular events, death, and other important patient-centered outcomes. This prospective study will enroll a cohort of 1100 adult participants with a broad range of AKI and matched hospitalized participants without AKI at three Clinical Research Centers, as well as 100 children undergoing cardiac surgery at three Clinical Research Centers. Participants will be followed for up to four years, and will undergo serial evaluation during the index hospitalization, at three months post-hospitalization, and at annual clinic visits, with telephone interviews occurring during the intervening six-month intervals. Biospecimens will be collected at each visit, along with information on lifestyle behaviors, quality of life and functional status, cognitive function, receipt of therapies, interim renal and cardiovascular events, electrocardiography and urinalysis. CONCLUSIONS: ASSESS-AKI will characterize the short-term and long-term natural history of AKI, evaluate the incremental utility of novel blood and urine biomarkers to refine the diagnosis and prognosis of AKI, and identify a subset of high-risk patients who could be targeted for future clinical trials to improve outcomes after AKI.
Authors: Go AS; Assessment Serial Evaluation aSSoAKISI; et al.
BMC Nephrol. 2010 Aug 27;11:22.
Validation of the Stanford Brief Activity Survey: examining psychological factors and physical activity levels in older adults
BACKGROUND: This study examined the construct validity and reliability of the new 2-item Stanford Brief Activity Survey (SBAS). METHODS: Secondary analysis was conducted using data collected from the healthy older controls (n = 1023) enrolled in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. Construct validity was examined by regression analyses to evaluate significant trends (P < or = .05) across the SBAS activity categories for the selected psychological health factors measured at baseline and year 2, adjusted for gender, ethnicity and education level. Test-retest reliability was performed using Spearman's rank correlation. RESULTS: At baseline, subjects were 66 +/- 2.8 years old, 38% female, 77% married, 61% retired, 24% college graduate, and 68% Caucasian. At baseline, lower self-reported stress, anxiety, depression, and cynical distrust, and higher self-reported mental and physical well-being were significantly associated with higher levels of physical activity (p trend < or = 0.01). These associations held at year 2. The test-retest reliability of the SBAS was statistically significant (r(s)= 0.62, P < .001). CONCLUSION: These results provide evidence of the construct validity and reliability of the SBAS in older adults. We also found a strong dose-response relationship between regular physical activity and psychological health in older adults, independent of gender, education level and ethnicity.
Authors: Taylor-Piliae RE; Fair JM; Haskell WL; Varady AN; Iribarren C; Hlatky MA; Go AS; Fortmann SP
J Phys Act Health. 2010 Jan;7(1):87-94.
Distribution of asymmetric dimethylarginine among 980 healthy, older adults of different ethnicities
BACKGROUND: Endothelium-derived nitric oxide plays a crucial role in the regulation of vascular tone and the development of cardiovascular disease. The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) has emerged as a novel cardiovascular risk factor. ADMA appears to be an independent predictor for cardiovascular and overall mortality. However, the majority of studies investigating the clinical role of ADMA were performed in European study populations with few individuals of other ethnicities. METHODS: We performed a cross-sectional study of 980 healthy, older (age 60-72 years) individuals of different ethnicities living in the San Francisco Bay area and analyzed ADMA plasma concentrations and their relationship to other cardiovascular risk factors. Plasma ADMA concentrations were measured using a recently developed, highly sensitive ELISA. RESULTS: In our entire sample, we were able to define a reference interval for ADMA plasma concentrations of 0.47 (90% CI 0.46-0.48) mumol/L to 0.85 (0.84-0.89) mumol/L. The mean ADMA concentration was 0.63 (SD 0.11) mumol/L (median 0.61 mumol/L). Mean ADMA concentrations were significantly lower in African Americans (0.60 mumol/L; P < 0.01) and mixed non-Hispanics (0.60 mumol/L; P < 0.05) compared with whites (0.63 mumol/L). ADMA was positively correlated with cystatin-C in both men (rho = 0.29) and women (rho = 0.37), and median plasma ADMA concentrations increased across cystatin-C quintiles. CONCLUSIONS: ADMA varies nearly 2-fold across a healthy sample of older men and women, correlates with age, body mass index, and renal function, and is different across ethnic groups. Additional studies in a wider age range and including larger ethnic subgroups would be useful.
Authors: Sydow K; Fortmann SP; Fair JM; Varady A; Hlatky MA; Go AS; Iribarren C; Tsao PS; ADVANCE Investigators
Clin Chem. 2010 Jan;56(1):111-20. Epub 2009 Nov 5.
COPD and cognitive impairment: the role of hypoxemia and oxygen therapy
BACKGROUND: several studies have shown an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment. These studies have been limited by methodological issues such as diagnostic uncertainty, cross-sectional design, small sample size, or lack of appropriate referent group. This study aimed to elucidate the association between COPD and the risk of cognitive impairment compared to referent subjects without COPD. In patients with established COPD, we evaluated the impact of disease severity and impairment of respiratory physiology on cognitive impairment and the potential mitigating role of oxygen therapy. METHODS: we used the Function, Living, Outcomes and Work (FLOW) cohort study of adults with COPD (n = 1202) and referent subjects matched by age, sex, and race (n = 302) to study the potential risk factors for cognitive impairment among subjects with COPD. Cognitive impairment was defined as a Mini-Mental State Exam score of <24 points. Disease severity was using Forced Expiratory Volume in one second (FEV(1)); the validated COPD Severity Score; and the BMI (Body Mass Index), Obstruction, Dyspnea, Exercise Capacity (BODE) Index. Multivariable analysis was used to control for confounding by age, sex, race, educational attainment, and cigarette smoking. RESULTS: COPD was associated with a substantive risk of cognitive impairment compared to referent subjects (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.043-6.64). Among COPD patients, none of the COPD severity measures were associated with the risk of cognitive impairment (P > 0.20 in all cases). Low baseline oxygen saturation was related to increased risk of cognitive impairment (OR for oxygen saturation
Authors: Thakur N; Blanc PD; Julian LJ; Yelin EH; Katz PP; Sidney S; Iribarren C; Eisner MD
Int J Chron Obstruct Pulmon Dis. 2010 Sep 7;5:263-9.
Alcohol and lung airways function
BACKGROUND: Limited data suggest that moderate alcohol drinkers may have better lung airways function than abstainers. Because few studies have fully accounted for confounders (including smoking and coronary disease), and some might have been biased by the inclusion with nondrinkers of alcohol drinkers who quit because of illness, we performed a cross-sectional analysis in a large free-living population. METHODS: We studied the relation between alcohol and airways function in 177,721 members of a comprehensive health plan. An item on a questionnaire administered as part of a health examination asked for ‘usual number of drinks in the past year.’ Respondents were asked to lump ‘wine, beer, whiskey, and cocktails’ together. Health history queries included 47 items indicative of possible cardiorespiratory (CR) illness; participants with one or more positive response (61.0%) were classified as ‘CR yes.’ Lung function measurements were part of the health examination; we studied one-second forced expiratory volume (FEV(1)), forced vital capacity (FVC), and FEV(1)/FVC by analysis of covariance and FEV(1)/FVC <0.7 by logistic regression. Nondrinkers were the referent for alcohol categories; covariates were age, sex, ethnicity, smoking, education, body mass index, and CR composite yes/no. RESULTS: For each measure studied, persons reporting two or fewer drinks per day or three to five drinks per day had better airways function than nondrinkers (p < 0.001), but heavier drinkers had worse function. This J-shaped relation was consistent across multiple strata, including CR 'yes' or 'no.' CONCLUSION: Independent of smoking and evident lung or heart disease, light to moderate drinkers of alcohol had better FEV(1), FVC, and FEV(1)/FVC than abstainers did. Although this association does not prove causality, drinking moderate amounts of alcoholic beverages may have some benefit for lung function.
Authors: Siu ST; Udaltsova N; Iribarren C; Klatsky AL
Perm J. 2010 Spring;14(1):11-8.
Lactation and diabetes among women with a history of GDM pregnancy
Authors: Gunderson EP
In: Kim C, Ferrara A, editors. Gestational diabetes during and after pregnancy. London: Springer; 2010.
Lipoprotein-associated phospholipase A2 and C-reactive protein for measurement of inflammatory risk: Independent or complementary?
The purpose of this article is to review the evidence concerning the utility of lipoprotein-associated phospholipase A2 (Lp-PLA2), a key promoter of vascular inflammation, as a biomarker of future risk of cardiovascular disease. In addition, the evidence of complementary action of Lp-PLA2 and C-reactive protein (CRP) is evaluated. On balance, there is a great deal of consistency across studies supporting Lp-PLA2 as a risk factor for coronary disease and ischemic stroke (independently of traditional risk factors and CRP) among persons with and without clinical coronary artery disease. On the other hand, there is yet limited and inconsistent evidence for a synergistic effect of Lp-PLA2 and CRP on cardiovascular disease risk. Additional studies are thus needed before widespread Lp-PLA2 and CRP testing with regard to incremental cardiovascular disease risk prediction can be recommended.
Authors: Iribarren C
Curr Cardiovasc Risk Rep. 2010;4(1):57-67.
Right coronary wall CMR in the older asymptomatic advance cohort: positive remodeling and associations with type 2 diabetes and coronary calcium
BACKGROUND: Coronary wall cardiovascular magnetic resonance (CMR) is a promising noninvasive approach to assess subclinical atherosclerosis, but data are limited in subjects over 60 years old, who are at increased risk. The purpose of the study was to evaluate coronary wall CMR in an asymptomatic older cohort. RESULTS: Cross-sectional images of the proximal right coronary artery (RCA) were acquired using spiral black-blood coronary CMR (0.7 mm resolution) in 223 older, community-based patients without a history of cardiovascular disease (age 60-72 years old, 38% female). Coronary measurements (total vessel area, lumen area, wall area, and wall thickness) had small intra- and inter-observer variabilities (r = 0.93~0.99, all p < 0.0001), though one-third of these older subjects had suboptimal image quality. Increased coronary wall thickness correlated with increased coronary vessel area (p < 0.0001), consistent with positive remodeling. On multivariate analysis, type 2 diabetes was the only risk factor associated with increased coronary wall area and thickness (p = 0.03 and p = 0.007, respectively). Coronary wall CMR measures were also associated with coronary calcification (p = 0.01-0.03). CONCLUSIONS: Right coronary wall CMR in asymptomatic older subjects showed increased coronary atherosclerosis in subjects with type 2 diabetes as well as coronary calcification. Coronary wall CMR may contribute to the noninvasive assessment of subclinical coronary atherosclerosis in older, at-risk patient groups.
Authors: Terashima M; Iribarren C; Go AS; McConnell MV; et al.
J Cardiovasc Magn Reson. 2010 Dec 30;12:75.
Passive smoke exposure and circulating carotenoids in the CARDIA study
Background/Aims: Our objective was to assess associations between passive smoke exposure in various venues and serum carotenoid concentrations. Methods: CARDIA is an ongoing longitudinal study of the risk factors for subclinical and clinical cardiovascular disease. At baseline in 1985/1986, serum carotenoids were assayed and passive smoke exposure inside and outside of the home and diet were assessed by self-report. Our analytic sample consisted of 2,633 black and white non-smoking adults aged 18-30 years. Results: Greater total passive smoke exposure was associated with lower levels of the sum of the three provitamin A carotenoids, alpha-carotene, beta-carotene, and beta-cryptoxanthin (-0.048 nmol/l per hour of passive smoke exposure, p = 0.001), unassociated with lutein/zeaxanthin, and associated with higher levels of lycopene (0.027 nmol/l per hour of passive smoke exposure, p = 0.010) after adjustment for demographics, diet, lipid profile, and supplement use. Exposure in both home and non-home spaces was also associated with lower levels of the provitamin A carotenoid index. Conclusion: Cross-sectionally, in 1985/86, passive smoke exposure in various venues was associated with reduced levels of provitamin A serum carotenoids.
Authors: Widome R; Jacobs DR Jr; Hozawa A; Sijtsma F; Gross M; Schreiner PJ; Iribarren C
Ann Nutr Metab. 2010;56(2):113-8. Epub 2010 Jan 29.
Segment-specific associations of carotid intima-media thickness with cardiovascular risk factors: the Coronary Artery Risk Development in Young Adults (CARDIA) study
BACKGROUND AND PURPOSE: We propose to study possible differences in the associations between risk factors for cardiovascular disease (myocardial infarction and stroke) and carotid intima-media thickness (IMT) measurements made at 3 different levels of the carotid bifurcation. METHODS: We conducted a cross-sectional study of a cohort of whites and blacks of both genders with a mean age of 45 years. Traditional cardiovascular risk factors were determined in cohort members. Carotid IMT was measured from high-resolution B-mode ultrasound images at 3 levels: the common carotid artery, the carotid artery bulb (bulb), and the internal carotid artery. Associations with risk factors were evaluated by multivariate linear regression analyses. RESULTS: Of 3258 who underwent carotid IMT measurements, common carotid artery, bulb, and internal carotid artery IMT were measured at all 3 separate levels in 3023 (92.7%). A large proportion of the variability of common carotid artery IMT was explained by cardiovascular risk factors (26.8%) but less so for the bulb (11.2%) and internal carotid artery (8.0%). Carotid IMT was consistently associated with age, low-density lipoprotein cholesterol, smoking, and hypertension in all segments. Associations with fasting glucose and diastolic blood pressure were stronger for common carotid artery than for the other segments. Hypertension, diabetes, and current smoking had qualitatively stronger associations with bulb IMT and low-density lipoprotein cholesterol with internal carotid artery IMT. CONCLUSIONS: In our cohort of relatively young white and black men and women, a greater proportion of the variability in common carotid IMT can be explained by traditional cardiovascular risk factors than for the carotid artery bulb and internal carotid arteries.
Authors: Polak JF; Person SD; Wei GS; Godreau A; Jacobs DR Jr; Harrington A; Sidney S; O'Leary DH
Stroke. 2010 Jan;41(1):9-15. Epub 2009 Nov 12.
Ten-year detection rate of brain arteriovenous malformations in a large, multiethnic, defined population
BACKGROUND AND PURPOSE: To evaluate whether increased neuroimaging use is associated with increased brain arteriovenous malformation (BAVM) detection, we examined detection rates in the Kaiser Permanente Medical Care Program of northern California between 1995 and 2004. METHODS: We reviewed medical records, radiology reports, and administrative databases to identify BAVMs, intracranial aneurysms (IAs: subarachnoid hemorrhage [SAH] and unruptured aneurysms), and other vascular malformations (OVMs: dural fistulas, cavernous malformations, Vein of Galen malformations, and venous malformations). Poisson regression (with robust standard errors) was used to test for trend. Random-effects meta-analysis generated a pooled measure of BAVM detection rate from 6 studies. RESULTS: We identified 401 BAVMs (197 ruptured, 204 unruptured), 570 OVMs, and 2892 IAs (2079 SAHs and 813 unruptured IAs). Detection rates per 100 000 person-years were 1.4 (95% CI, 1.3 to 1.6) for BAVMs, 2.0 (95% CI, 1.8 to 2.3) for OVMs, and 10.3 (95% CI, 9.9 to 10.7) for IAs. Neuroimaging utilization increased 12% per year during the time period (P<0.001). Overall, rates increased for IAs (P<0.001), remained stable for OVMs (P=0.858), and decreased for BAVMs (P=0.001). Detection rates increased 15% per year for unruptured IAs (P<0.001), with no change in SAHs (P=0.903). However, rates decreased 7% per year for unruptured BAVMs (P=0.016) and 3% per year for ruptured BAVMs (P=0.005). Meta-analysis yielded a pooled BAVM detection rate of 1.3 (95% CI, 1.2 to 1.4) per 100 000 person-years, without heterogeneity between studies (P=0.25). CONCLUSIONS: Rates for BAVMs, OVMs, and IAs in this large, multiethnic population were similar to those in other series. During 1995 to 2004, a period of increasing neuroimaging utilization, we did not observe an increased rate of detection of unruptured BAVMs, despite increased detection of unruptured IAs.
Authors: Gabriel RA; Kim H; Sidney S; McCulloch CE; Singh V; Johnston SC; Ko NU; Achrol AS; Zaroff JG; Young WL
Stroke. 2010 Jan;41(1):21-6. Epub 2009 Nov 19.
Ethnic differences in anemia among patients with diabetes mellitus: the Diabetes Study of Northern California (DISTANCE)
To examine ethnic differences in hemoglobin testing practices and to test the hypothesis that ethnicity is an independent predictor of anemia among patients with diabetes mellitus. We conducted a panel study to assess the rate of hemoglobin testing during 1999-2001 and the period prevalence and incidence of anemia among 79,985 adults with diabetes mellitus receiving care within Kaiser Permanente of Northern California. Anemia was defined as hemoglobin <13.0 g/dL in men or < 12.0 g/dL in women. Overall, 82.1% of the cohort was tested for anemia at least once during the 3-year study period. Mixed ethnicity patients were most likely to be tested, followed by whites, blacks, Latinos, and Asians (P < 0.0001). Fifteen percent of the cohort had prevalent anemia at baseline, and an additional 22% of those tested developed anemia during the study period. Anemia was more prevalent among blacks and mixed ethnicity persons compared with other racial/ethnic groups. Anemia was also more prevalent among those >/=70 years of age or with estimated glomerular filtration rate <60 ml/min/1.73 m(2). In multivariable models, blacks had higher and Asians had lower odds of prevalent anemia and hazard ratios of incident anemia compared with whites. Within a large, diverse cohort with diabetes, ethnicity was predictive of anemia, even after adjustment for age, level of kidney function, and other potential confounders. Blacks with diabetes are at increased risk of anemia relative to whites. These differences may account for some of the observed ethnic disparities in diabetes complications.
Authors: Ahmed AT; Go AS; Warton EM; Parker MM; Karter AJ
Am J Hematol. 2010 Jan;85(1):57-61.
Patients diagnosed with diabetes are at increased risk for asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and pneumonia but not lung cancer
OBJECTIVE: There are limited data on the risk of pulmonary disease in patients with diabetes. The aim of this study was to evaluate and compare the incidence of asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumonia, and lung cancer in patients with and without a diagnosis of diabetes. RESEARCH DESIGN AND METHODS: We conducted a retrospective, longitudinal cohort study using the electronic records of a large health plan in northern California. Age and sex data were available for all cohort members (n = 1,811,228). Data on confounders were available for a subcohort that responded to surveys (n = 121,886), among whom Cox proportional hazards regression models were fit. RESULTS: Age- and sex-adjusted incidence rates and 95% CIs were calculated for members with and without diabetes in the full cohort and the subcohort. No difference was observed for lung cancer, but the incidence of asthma, COPD, fibrosis, and pneumonia was significantly higher in those members with a diagnosis of diabetes. These differences remained significant in regression models adjusted for age, sex, race/ethnicity, smoking, BMI, education, alcohol consumption, and outpatient visits (asthma hazard ratio [HR] 1.08 [95% CI 1.03-1.12], COPD HR 1.22 [1.15-1.28], pulmonary fibrosis HR 1.54 [1.31-1.81], and pneumonia HR 1.92 [1.84-1.99]). The risk of pneumonia and COPD increased significantly with increasing A1C. CONCLUSIONS: Individuals with diabetes are at increased risk of several pulmonary conditions (asthma, COPD, fibrosis, and pneumonia) but not lung cancer. This increased risk may be a consequence of declining lung function in patients with diabetes.
Authors: Ehrlich SF; Quesenberry CP Jr; Van Den Eeden SK; Shan J; Ferrara A
Diabetes Care. 2010 Jan;33(1):55-60. Epub 2009 Oct 6.
Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition?
OBJECTIVES: This prospective study examined whether changes in traditional and novel coronary heart disease (CHD) risk factors are greater within a year of the final menstrual period (FMP), relative to changes that occur before or after that interval, in a multiethnic cohort. BACKGROUND: Understanding the influence of menopause on CHD risk remains elusive and has been evaluated primarily in Caucasian samples. METHODS: SWAN (Study of Women’s Health Across the Nation) is a prospective study of the menopausal transition in 3,302 minority (African American, Hispanic, Japanese, or Chinese) and Caucasian women. After 10 annual examinations, 1,054 women had achieved an FMP not due to surgery and without hormone therapy use before FMP. Measured CHD risk factors included lipids and lipoproteins, glucose, insulin, blood pressure, fibrinogen, and C-reactive protein. We assessed which of 2 models provided a better fit with the observed risk factor changes over time in relation to the FMP: a linear model, consistent with chronological aging, or a piecewise linear model, consistent with ovarian aging. RESULTS: Only total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B demonstrated substantial increases within the 1-year interval before and after the FMP, consistent with menopause-induced changes. This pattern was similar across ethnic groups. The other risk factors were consistent with a linear model, indicative of chronological aging. CONCLUSIONS: Women experience a unique increase in lipids at the time of the FMP. Monitoring lipids in perimenopausal women should enhance primary prevention of CHD.
Authors: Matthews KA; Crawford SL; Chae CU; Everson-Rose SA; Sowers MF; Sternfeld B; Sutton-Tyrrell K
J Am Coll Cardiol. 2009 Dec 15;54(25):2366-73.
Vision and creation of the American Heart Association pharmaceutical roundtable outcomes research centers
BACKGROUND: The field of outcomes research seeks to define optimal treatment in practice and to promote the rapid full adoption of efficacious therapies into routine clinical care. The American Heart Association (AHA) formed the AHA Pharmaceutical Roundtable (PRT) Outcomes Research Centers Network to accelerate attainment of these goals. Participating centers were intended to carry out state-of-the-art outcomes research in cardiovascular disease and stroke, to train the next generation of investigators, and to support the formation of a collaborative research network. PROGRAM: After a competitive application process, 4 AHA PRT Outcomes Research Centers were selected: Duke Clinical Research Institute; Saint Luke’s Mid America Heart Institute; Stanford University-Kaiser Permanente of Northern California; and University of California, Los Angeles. Each center proposed between 1 and 3 projects organized around a single theme in cardiovascular disease or stroke. Additionally, each center will select and train up to 6 postdoctoral fellows over the next 4 years, and will participate in cross-collaborative activities among the centers. CONCLUSIONS: The AHA PRT Outcomes Research Centers Network is designed to further strengthen the field of cardiovascular disease and stroke outcomes research by fostering innovative research, supporting high quality training, and encouraging center-to-center collaborations.
Authors: Peterson ED; Spertus JA; Cohen DJ; Hlatky MA; Go AS; Vickrey BG; Saver JL; Hinton PC
Circ Cardiovasc Qual Outcomes. 2009 Nov;2(6):663-70.
Disparities in outpatient and home health service utilization following stroke: results of a 9-year cohort study in Northern California
OBJECTIVE: To examine whether there are disparities in utilization of outpatient and home care services after stroke. DESIGN: Retrospective cohort study. SETTING: The Kaiser Permanente of Northern California health care system, which provides health care for approximately 3.3 million members. PARTICIPANTS: A total of 11,119 patients hospitalized for a stroke between 1996 and 2003 and followed for 1 year. MAIN OUTCOME MEASURES: Receipt of outpatient rehabilitation (physical therapy, occupational therapy, speech pathology, or physical medicine and rehabilitation/physiatry visits), and/or home health care. RESULTS: There were significant differences in outpatient rehabilitation visits and home health enrollment during the year after acute care discharge for all the parameters under study. Older age and female gender were associated with less outpatient rehabilitation treatment, but these subpopulations were more likely to be enrolled in home health care. Non-whites, patients from urban areas, those with ischemic strokes, and those with longer acute care hospital stays had relatively more outpatient rehabilitation and were also more likely to be enrolled in the home health program. In addition, patients living in geographic areas with a median household income of $80,000 or more had significantly more outpatient rehabilitation visits than did patients living in lower income areas. CONCLUSIONS: Variations in outpatient rehabilitation visits and in home health care exist in this large integrated health system in terms of age, gender, race/ethnicity, residence area, type of stroke, and length of stay in an acute care hospital. The Kaiser Permanente integrated health care system seems to have outpatient stroke rehabilitation and home health programs that are providing care without disparities in relation to non-white populations, but other disparities appear to exist that may be related to socioeconomic factors, referral patterns, family support systems, or other cultural factors that have not been identified.
Authors: Chan L; Wang H; Terdiman J; Hoffman J; Ciol MA; Lattimore BF; Sidney S; Quesenberry C; Lu Q; Sandel ME
PM R. 2009 Nov;1(11):997-1003.
Imaging data reveal a higher pediatric stroke incidence than prior US estimates
BACKGROUND AND PURPOSE: Prior annualized estimates of pediatric ischemic stroke incidence have ranged from 0.54 to 1.2 per 100,000 US children but relied purely on diagnostic code searches to identify cases. We sought to obtain a new estimate using both diagnostic code searches and searches of radiology reports and to assess the relative value of these 2 strategies. METHODS: Using the population of 2.3 million children (<20 years old) enrolled in a Northern Californian managed care plan (1993 to 2003), we performed electronic searches of (1) inpatient and outpatient diagnoses for International Classification of Diseases, 9th Revision codes suggestive of stroke and cerebral palsy; and (2) radiology reports for key words suggestive of infarction. Cases were confirmed through chart review. We calculated sensitivities and positive predictive values for the 2 search strategies. RESULTS: We identified 1307 potential cases from the International Classification of Diseases, 9th Revision code search and 510 from the radiology search. A total of 205 ischemic stroke cases were confirmed, yielding an ischemic stroke incidence of 2.4 per 100,000 person-years. The radiology search had a higher sensitivity (83%) than the International Classification of Diseases, 9th Revision code search (39%), although both had low positive predictive values. For perinatal stroke, the sensitivity of the stroke International Classification of Diseases, 9th Revision codes alone was 12% versus 57% for stroke and cerebral palsy codes combined; the radiology search was again the most sensitive (87%). CONCLUSIONS: Our incidence estimate doubles that of prior US reports, a difference at least partially explained by our use of radiology searches for case identification. Studies relying purely on International Classification of Diseases, 9th Revision code searches may underestimate childhood ischemic stroke rates, particularly for neonates.
Authors: Agrawal N; Johnston SC; Wu YW; Sidney S; Fullerton HJ
Stroke. 2009 Nov;40(11):3415-21. Epub 2009 Sep 17.
The dilemma of incidental findings on cardiac computed tomography
Authors: Hlatky MA; Iribarren C
J Am Coll Cardiol. 2009 Oct 13;54(16):1542-3.
EPHB4 gene polymorphisms and risk of intracranial hemorrhage in patients with brain arteriovenous malformations
BACKGROUND: Brain arteriovenous malformations (BAVMs) are a tangle of abnormal vessels directly shunting blood from the arterial to venous circulation and an important cause of intracranial hemorrhage (ICH). EphB4 is involved in arterial-venous determination during embryogenesis; altered signaling could lead to vascular instability resulting in ICH. We investigated the association of single-nucleotide polymorphisms (SNPs) and haplotypes in EPHB4 with risk of ICH at clinical presentation in patients with BAVM. METHODS AND RESULTS: Eight haplotype-tagging SNPs spanning approximately 29 kb were tested for association with ICH presentation in 146 white patients with BAVM (phase I: 56 ICH, 90 non-ICH) using allelic, haplotypic, and principal components analysis. Associated SNPs were then genotyped in 102 additional cases (phase II: 37 ICH, 65 non-ICH), and data were combined for multivariable logistic regression. Minor alleles of 2 SNPs were associated with reduced risk of ICH presentation (rs314313_C, P=0.005; rs314308_T, P=0.0004). Overall, haplotypes were also significantly associated with ICH presentation (chi(2)=17.24, 6 df, P=0.008); 2 haplotypes containing the rs314308 T allele (GCCTGGGT, P=0.003; GTCTGGGC, P=0.036) were associated with reduced risk. In principal components analysis, 2 components explained 91% of the variance and complemented haplotype results by implicating 4 SNPs at the 5′ end, including rs314308 and rs314313. These 2 SNPs were replicated in the phase II cohort, and combined data resulted in greater significance (rs314313, P=0.0007; rs314308, P=0.00008). SNP association with ICH presentation persisted after adjusting for age, sex, BAVM size, and deep venous drainage. CONCLUSIONS: EPHB4 polymorphisms are associated with risk of ICH presentation in patients with BAVM, warranting further study.
Authors: Weinsheimer S; Kim H; Pawlikowska L; Chen Y; Lawton MT; Sidney S; Kwok PY; McCulloch CE; Young WL
Circ Cardiovasc Genet. 2009 Oct;2(5):476-82. Epub 2009 Aug 22.
A walk (or cycle) to the park: active transit to neighborhood amenities, the CARDIA study
BACKGROUND: Building on known associations between active commuting and reduced cardiovascular disease (CVD) risk, this study examines active transit to neighborhood amenities and differences between walking and cycling for transportation. METHODS: Year-20 data from the Coronary Artery Risk Development in Young Adults study (3549 black and white adults aged 38-50 years in 2005-2006) were analyzed in 2008-2009. Sociodemographic correlates of transportation mode (car-only, walk-only, any cycling, other) to neighborhood amenities were examined in multivariable multinomial logistic models. Gender-stratified multivariable linear or multinomial regression models compared CVD risk factors across transit modes. RESULTS: Active transit was most common to parks and public transit stops; walking was more common than cycling. Among those who used each amenity, active transit (walk-only and any cycling versus car-only transit) was more common in men and those with no live-in partner and less than full-time employment (significant ORs [95% CI] ranging from 1.56 [1.08, 2.27] to 4.54 [1.70, 12.14]), and less common in those with children. Active transit to any neighborhood amenity was associated with more favorable BMI, waist circumference, and fitness (largest coefficient [95% CI] -1.68 [-2.81, -0.55] for BMI, -3.41 [-5.71, -1.11] for waist circumference [cm], and 36.65 [17.99, 55.31] for treadmill test duration [seconds]). Only cycling was associated with lower lifetime CVD risk classification. CONCLUSIONS: Active transit to neighborhood amenities was related to sociodemographics and CVD risk factors. Variation in health-related benefits by active transit mode, if validated in prospective studies, may have implications for transportation planning and research.
Authors: Boone-Heinonen J; Jacobs DR Jr; Sidney S; Sternfeld B; Lewis CE; Gordon-Larsen P
Am J Prev Med. 2009 Oct;37(4):285-92.
Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease
To determine whether acute renal failure (ARF) increases the long-term risk of progressive chronic kidney disease (CKD), we studied the outcome of patients whose initial kidney function was normal or near normal but who had an episode of dialysis-requiring ARF and did not develop end-stage renal disease within 30 days following hospital discharge. The study encompassed 556,090 adult members of Kaiser Permanente of Northern California hospitalized over an 8 year period, who had pre-admission estimated glomerular filtration rates (eGFR) equivalent to or greater than 45 ml/min/1.73 m(2) and who survived hospitalization. After controlling for potential confounders such as baseline level of eGFR and diabetes status, dialysis-requiring ARF was independently associated with a 28-fold increase in the risk of developing stage 4 or 5 CKD and more than a twofold increased risk of death. Our study shows that in a large, community-based cohort of patients with pre-existing normal or near normal kidney function, an episode of dialysis-requiring ARF was a strong independent risk factor for a long-term risk of progressive CKD and mortality.
Authors: Lo LJ; Go AS; Chertow GM; McCulloch CE; Fan D; Ordonez JD; Hsu CY
Kidney Int. 2009 Oct;76(8):893-9. Epub 2009 Jul 29.
Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study
BACKGROUND: Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. METHODS: Cross-sectional study of HIV-infected participants and controls without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Preclinical atherosclerosis was assessed by carotid intima-medial thickness (cIMT) measurements in the internal/bulb and common regions in HIV-infected participants and controls after adjusting for traditional CVD risk factors. RESULTS: For internal carotid, mean IMT was 1.17 +/- 0.50 mm for HIV-infected participants and 1.06 +/- 0.58 mm for controls (P < 0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected participants vs. controls was 0.188 mm [95% confidence interval (CI) 0.113-0.263, P < 0.0001]. Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (0.148 mm, 95% CI 0.072-0.224, P = 0.0001). For the common carotid, HIV infection was independently associated with greater IMT (0.033 mm, 95% CI 0.010-0.056, P = 0.005). The association of HIV infection with IMT was similar to that of smoking, which was also associated with greater IMT (internal 0.173 mm, common 0.020 mm). CONCLUSION: Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared with the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
Authors: Grunfeld C; Polak JF; Kronmal RA; et al.
AIDS. 2009 Sep 10;23(14):1841-9.
Physical fitness and carotid atherosclerosis in men
We investigated the association between cardiorespiratory fitness (CRF) and carotid atherosclerosis in 9 871 Korean men aged 40-81 years. We measured carotid intima-media thickness by using B-mode ultrasonography, and cardiorespiratory fitness was measured by a maximal treadmill exercise test using the Bruce protocol. Carotid atherosclerosis was defined as an intima-media wall thickness greater than 1.2 mm or stenosis >25% of carotid arteries, while CRF was classified as low fit (<20%), moderately fit (20-<60%), or high fit (> or =60%) categories based on age-specific VO (2peak) (ml/kg/min) percentiles. The presence of carotid atherosclerosis across CRF categories was 11.7% (low fit), 9.6%, and 7.7%, respectively. After adjustment for age, cigarette smoking, body mass index, physical activity, there was an inverse association between CRF and carotid atherosclerosis (p for trend <0.001). The odds ratio of presence of carotid atherosclerosis in the high-fit men versus the low-fit men was 0.67 (95% CI, 0.55, 0.80). After additional adjustment for high cholesterol, hypertension, and diabetes mellitus, the results remain unchanged and the odds ratios across CRF levels were (95% CI): 1.00 (low fit, referent), 0.85 (0.71, 1.01), 0.71 (0.59, 0.85) (p for trend <0.001), respectively. High levels of cardiorespiratory fitness were associated with a lower risk of having carotid atherosclerosis in middle-aged and elderly men.
Authors: Lee CD; Jae SY; Iribarren C; Pettee KK; Choi YH
Int J Sports Med. 2009 Sep;30(9):672-6. Epub 2009 Jun 30.
The net clinical benefit of warfarin anticoagulation in atrial fibrillation
BACKGROUND: Guidelines recommend warfarin use in patients with atrial fibrillation solely on the basis of risk for ischemic stroke without antithrombotic therapy. These guidelines rely on ischemic stroke rates observed in older trials and do not explicitly account for increased risk for hemorrhage. OBJECTIVE: To quantify the net clinical benefit of warfarin therapy in a cohort of patients with atrial fibrillation. DESIGN: Mixed retrospective and prospective cohort study of patients with atrial fibrillation between 1996 and 2003. SETTING: An integrated health care delivery system. PATIENTS: 13 559 adults with nonvalvular atrial fibrillation. MEASUREMENTS: Warfarin exposure, patient characteristics, CHADS(2) score (1 point for each of congestive heart failure, hypertension, age, and diabetes and 2 points for stroke), and outcome events were ascertained from health plan records and databases. Net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by warfarin minus intracranial hemorrhages attributable to warfarin, multiplied by an impact weight. The base-case impact weight was 1.5, reflecting the greater clinical impact of intracranial hemorrhage versus thromboembolism. RESULTS: Patients accumulated more than 66 000 person-years of follow-up. The adjusted net clinical benefit of warfarin for the cohort overall was 0.68% per year (95% CI, 0.34% to 0.87%). Adjusted net clinical benefit was greatest for patients with a history of ischemic stroke (2.48% per year [CI, 0.75% to 4.22%]) and for those 85 years or older (2.34% per year [CI, 1.29% to 3.30%]). The net clinical benefit of warfarin increased from essentially zero in CHADS(2) stroke risk categories 0 and 1 to 2.22% per year (CI, 0.58% to 3.75%) in CHADS(2) categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used. LIMITATIONS: Residual confounding is a possibility. Some outcome events were probably missed by the screening algorithm or when medical records were unavailable. CONCLUSION: Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. Risk assessment that incorporates both risk for thromboembolism and risk for intracranial hemorrhage provides a more quantitatively informed basis for the decision on antithrombotic therapy in patients with atrial fibrillation. PRIMARY FUNDING SOURCE: National Institute on Aging; National Heart, Lung, and Blood Institute; and Massachusetts General Hospital.
Authors: Singer DE; Chang Y; Fang MC; Borowsky LH; Pomernacki NK; Udaltsova N; Go AS
Ann Intern Med. 2009 Sep 1;151(5):297-305.
Depression and health-related quality of life in chronic obstructive pulmonary disease
BACKGROUND: Prior research on the risk of depression in chronic obstructive pulmonary disease (COPD) has yielded conflicting results. Furthermore, we have an incomplete understanding of how much depression versus respiratory factors contributes to poor health-related quality of life. METHODS: Among 1202 adults with COPD and 302 demographically matched referents without COPD, depressive symptoms were assessed using the 15-item Geriatric Depression Score. We measured COPD severity using a multifaceted approach, including spirometry, dyspnea, and exercise capacity. We used the Airway Questionnaire 20 and the Physical Component Summary Score to assess respiratory-specific and overall physical quality of life, respectively. RESULTS: In multivariate analysis adjusting for potential confounders including sociodemographics and all examined comorbidities, COPD subjects were at higher risk for depressive symptoms (Geriatric Depression Score >or=6) than referents (odds ratio [OR] 3.6; 95% confidence interval [CI], 2.1-6.1; P <.001). Stratifying COPD subjects by degree of obstruction on spirometry, all subgroups were at increased risk of depressive symptoms relative to referents (P <.001 for all). In multivariate analysis controlling for COPD severity as well as sociodemographics and comorbidities, depressive symptoms were strongly associated with worse respiratory-specific quality of life (OR 3.6; 95% CI, 2.7-4.8; P <.001) and worse overall physical quality of life (OR 2.4; 95% CI, 1.8-3.2; P <.001). CONCLUSIONS: Patients with COPD are at significantly higher risk of having depressive symptoms than referents. Such symptoms are strongly associated with worse respiratory-specific and overall physical health-related quality of life, even after taking COPD severity into account.
Authors: Omachi TA; Katz PP; Yelin EH; Gregorich SE; Iribarren C; Blanc PD; Eisner MD
Am J Med. 2009 Aug;122(8):778.e9-15.
Childbearing is associated with higher incidence of the metabolic syndrome among women of reproductive age controlling for measurements before pregnancy: the CARDIA study
OBJECTIVE: We sought to prospectively examine whether childbearing is associated with higher incidence of the metabolic syndrome (MetS) after delivery among women of reproductive age. STUDY DESIGN: In 1451 nulliparas who were aged 18-30 years and free of the MetS at baseline (1985-1986) and reexamined up to 4 times during 20 years, we ascertained incident MetS defined by the National Cholesterol Education Program Adult Treatment Panel III criteria among time-dependent interim birth groups by gestational diabetes mellitus (GDM): (0 [referent], 1 non-GDM, 2+ non-GDM, 1+ GDM births). Complementary log-log models estimated relative hazards of the MetS among birth groups adjusted for race, age, and baseline and follow-up covariates. RESULTS: We identified 259 incident MetS cases in 25,246 person-years (10.3/1000 person-years). Compared with 0 births, adjusted relative hazards (95% confidence interval [CI]) were 1.33 (95% CI, 0.93-1.90) for 1 non-GDM, 1.62 (95% CI, 1.16-2.26) for 2+ non-GDM (P trend = .02), and 2.43 (95% CI, 1.53-3.86) for 1+ GDM births. CONCLUSION: Increasing parity is associated with future development of the MetS independent of prior obesity and pregnancy-related weight gain. Risk varies by GDM status.
Authors: Gunderson EP; Jacobs DR Jr; Chiang V; Lewis CE; Tsai A; Quesenberry CP Jr; Sidney S
Am J Obstet Gynecol. 2009 Aug;201(2):177.e1-9. Epub 2009 Jun 26.
Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function
BACKGROUND AND OBJECTIVES: The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants. RESULTS: A total of 3612 participants were enrolled with mean age +/- SD of 58.2 +/- 11.0 yr; 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 +/- 7.9 kg/m(2), and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 +/- 13.5 ml/min per 1.73 m(2), and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP. CONCLUSIONS: Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes.
Authors: Lash JP; Go AS; Chronic Renal Insufficiency Cohort (CRIC) Study Group; et al.
Clin J Am Soc Nephrol. 2009 Aug;4(8):1302-11. Epub 2009 Jun 18.
Unilateral groin surgery in children: will the addition of an ultrasound-guided ilioinguinal nerve block enhance the duration of analgesia of a single-shot caudal block?
BACKGROUND: Inguinal hernia repair, hydrocelectomy, and orchidopexy are commonly performed surgical procedures in children. Postoperative pain control is usually provided with a single-shot caudal block. Blockade of the ilioinguinal nerve may lead to additional analgesia. The aim of this double-blind, randomized controlled trial was to evaluate the efficacy of an adjuvant blockade of the ilioinguinal nerve using ultrasound (US) guidance at the end of the procedure with local anesthetic vs normal saline and to explore the potential for prolongation of analgesia with decreased need for postoperative pain medication.METHODS: Fifty children ages 1-6 years scheduled for unilateral inguinal hernia repair, hydrocelectomy, orchidopexy, or orchiectomy were prospectively randomized into one of two groups: Group S that received an US-guided ilioinguinal nerve block with 0.1 ml x kg(-1) of preservative-free normal saline and Group B that received an US-guided nerve block with 0.1 ml x kg(-1) of 0.25% bupivacaine with 1 : 200,000 epinephrine at the conclusion of the surgery. After induction of anesthesia but prior to surgical incision, all patients received caudal anesthesia with 0.7 ml x kg(-1) of 0.125% bupivacaine with 1 : 200,000 epinephrine. Patients were observed by a blinded observer for (i) pain scores using the Children and Infants Postoperative Pain Scale, (ii) need for rescue medication in the PACU, (iii) need for oral pain medications given by the parents at home.RESULTS: Forty-eight patients, consisting of 46 males and two females, with a mean age of 3.98 (SD +/- 1.88) were enrolled in the study. Two patients were excluded from the study because of study protocol violation and/or alteration in surgical procedure. The average pain scores reported for the entire duration spent in the recovery room for the caudal and caudal/ilioinguinal block groups were 1.92 (SD +/- 1.59) and 1.18 (SD +/- 1.31), respectively. The average pain score difference was 0.72 (SD +/- 0.58) and was statistically significant (P < 0.05). In addition, when examined by procedure type, it was found that the difference in the average pain scores between the caudal and caudal/ilioinguinal block groups was statistically significant for the inguinal hernia repair patients (P < 0.05) but not for the other groin surgery patients (P = 0.13). For all groin surgery patients, six of the 23 patients in the caudal group and eight of the 25 patients in the caudal/ilioinguinal block group required pain rescue medications throughout their entire hospital stay or at home (P = 0.76). Overall, the caudal group received an average of 0.54 (SD +/- 1.14) pain rescue medication doses, while the caudal/ilioinguinal block group received an average of 0.77 (SD +/- 1.70) pain rescue medication doses; this was, however, not statistically significant (P = 0.58).CONCLUSIONS: The addition of an US-guided ilioinguinal nerve block to a single-shot caudal block decreases the severity of pain experienced by pediatric groin surgery patients. The decrease in pain scores were particularly pronounced in inguinal hernia repair patients.
Authors: Jagannathan, Narasimhan N; Sohn, Lisa L; Sawardekar, Amod A; Ambrosy, Andrew A; Hagerty, Jennifer J; Chin, Anthony A; Barsness, Kathleen K; Suresh, Santhanam S
Paediatric anaesthesia. 2009 Sep 01;19(9):892-8. Epub 2009-07-13.
Active commuting and cardiovascular disease risk: the CARDIA study
BACKGROUND: There is little research on the association of lifestyle exercise, such as active commuting (walking or biking to work), with obesity, fitness, and cardiovascular disease (CVD) risk factors. METHODS: This cross-sectional study included 2364 participants enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study who worked outside the home during year 20 of the study (2005-2006). Associations between walking or biking to work (self-reported time, distance, and mode of commuting) with body weight (measured height and weight); obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >or= 30); fitness (symptom-limited exercise stress testing); objective moderate-vigorous physical activity (accelerometry); CVD risk factors (blood pressure [oscillometric systolic and diastolic]); and serum measures (fasting measures of lipid, glucose, and insulin levels) were separately assessed by sex-stratified multivariable linear (or logistic) regression modeling. RESULTS: A total of 16.7% of participants used any means of active commuting to work. Controlling for age, race, income, education, smoking, examination center, and physical activity index excluding walking, men with any active commuting (vs none) had reduced likelihood of obesity (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.33-0.76), reduced CVD risk: ratio of geometric mean triglyceride levels (trig(active))/(trig(nonactive)) = 0.88 (95% CI, 0.80 to 0.98); ratio of geometric mean fasting insulin (FI(active))/(FI(nonactive)) = 0.86 (95% CI, 0.78 to 0.93); difference in mean diastolic blood pressure (millimeters of mercury) (DBP(active)) – (DBP(nonactive)) = -1.67 (95% CI, -3.20 to -0.15); and higher fitness: mean difference in treadmill test duration (in seconds) in men (TT(active)) – (TT(nonactive)) = 50.0 (95% CI, 31.45 to 68.59) and women (TT(active)) – (TT(nonactive)) = 28.77 (95% CI, 11.61 to 45.92). CONCLUSIONS: Active commuting was positively associated with fitness in men and women and inversely associated with BMI, obesity, triglyceride levels, blood pressure, and insulin level in men. Active commuting should be investigated as a modality for maintaining or improving health.
Authors: Gordon-Larsen P; Boone-Heinonen J; Sidney S; Sternfeld B; Jacobs DR Jr; Lewis CE
Arch Intern Med. 2009 Jul 13;169(13):1216-23.
Statin use and risk of basal cell carcinoma
OBJECTIVE: We examined the association between statin use and basal cell carcinoma (BCC) risk. METHODS: We identified all members of a large integrated health care delivery system with a diagnosis of a histologically proven BCC in 1997. Subsequent BCCs were identified through 2006 from health plan electronic pathology records. Longitudinal exposure to statins and other lipid-lowering agents was determined from automated pharmacy records. We used extended Cox regression to examine the independent association between receipt of statin therapy (ever vs never, cumulative duration) and risk of subsequent BCC. To minimize confounding by indication, we conducted sensitivity analyses in the subset of individuals considered eligible for lipid-lowering therapy based on national guidelines. RESULTS: Among 12,123 members given a diagnosis of BCC who had no prior statin exposure, 6381 developed a subsequent BCC during follow-up. Neither ‘ever use of statins’ (adjusted hazard ratio 1.02, 95% confidence interval: 0.92-1.12) or cumulative duration of statin (adjusted hazard ratio 1.02/year, 95% confidence interval: 0.99-1.11) was associated with subsequent BCC after adjustment for age, sex, and health care use. Risk estimates did not change appreciably when the analysis was limited to the subset of individuals who met eligibility criteria for initiating statin therapy. There was also no significant association between use of non-statin antilipemics and subsequent BCC (adjusted hazard ratio 1.10, 95% confidence interval: 0.76-1.58). LIMITATIONS: No information was available for BCC risk factors, such as sun sensitivity and sun exposure. CONCLUSIONS: Among a large cohort of individuals with BCC, statin therapy was not significantly associated with risk of subsequent BCC.
Authors: Asgari MM; Tang J; Epstein EH Jr; Chren MM; Warton EM; Quesenberry CP Jr; Go AS; Friedman GD
J Am Acad Dermatol. 2009 Jul;61(1):66-72. Epub 2009 May 21.
Association of 20-year changes in cardiorespiratory fitness with incident type 2 diabetes: the coronary artery risk development in young adults (CARDIA) fitness study
OBJECTIVE: To test the association of fitness changes over 7 and 20 years on the development of diabetes in middle age. RESEARCH DESIGN AND METHODS: Fitness was determined based on the duration of a maximal graded exercise treadmill test (Balke protocol) at up to three examinations over 20 years from 3,989 black and white men and women from the Coronary Artery Risk Development in Young Adults study. Relative fitness change (percent) was calculated as the difference between baseline and follow-up treadmill duration/baseline treadmill duration. Diabetes was identified as fasting glucose >or=126 mg/dl, postload glucose >or=200 mg/dl, or use of diabetes medications. RESULTS: Diabetes developed at a rate of 4 per 1,000 person-years in women (n = 149) and men (n = 122), and lower baseline fitness was associated with a higher incidence of diabetes in all race-sex groups (hazard ratios [HRs] from 1.8 to 2.3). On average, fitness declined 7.6% in women and 9.2% in men over 7 years. The likelihood of developing diabetes increased per SD decrease (19%) from the 7-year population mean change (-8.3%) in women (HR 1.22 [95% CI 1.09-1.39]) and men (1.45 [1.20-1.75]) after adjustment for age, race, smoking, family history of diabetes, baseline fitness, BMI, and fasting glucose. Participants who developed diabetes over 20 years experienced significantly larger declines in relative fitness over 20 years versus those who did not. CONCLUSIONS: Low fitness is significantly associated with diabetes incidence and explained in large part by the relationship between fitness and BMI.
Authors: Carnethon MR; Sternfeld B; Schreiner PJ; Jacobs DR Jr; Lewis CE; Liu K; Sidney S
Diabetes Care. 2009 Jul;32(7):1284-8. Epub 2009 Mar 26.
Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study
BACKGROUND: Randomized trials and observational studies support using an international normalized ratio (INR) target of 2.0 to 3.0 for preventing ischemic stroke in atrial fibrillation. We assessed whether the INR target should be adjusted based on selected patient characteristics. METHODS AND RESULTS: We conducted a case-control study nested within the ATRIA cohort’s 9217 atrial fibrillation patients taking warfarin to define the relationship between INR level and the odds of thromboembolism (TE; mainly stroke) and of intracranial hemorrhage (ICH) relative to INR 2.0 to 2.5. We identified 396 TE cases and 164 ICH cases during follow-up. Each case was compared with 4 randomly selected controls matched on calendar date and stroke risk factors using matched univariable analyses and conditional logistic regression. We explored modification of the INR-outcome relationships by the following stroke risk factors: prior stroke, age, and CHADS(2) risk score. Overall, the odds of TE were low and stable above INR 1.8. Compared with INR 2.0 to 2.5, the relative odds of TE increased strikingly at INR <1.8 (eg, odds ratio, 3.72; 95% CI, 2.67 to 5.19, at INR 1.4 to 1.7). The odds of ICH increased markedly at INR values >3.5 (eg, odds ratio, 3.56; 95% CI: 1.70 to 7.46, at INR 3.6 to 4.5). The relative odds of ICH were consistently low at INR <3.6. There was no evidence of lower ICH risk at INR levels <2.0. These patterns of risk did not differ substantially by history of stroke, age, or CHADS(2) risk score. CONCLUSIONS: Our results confirm that the current standard of INR 2.0 to 3.0 for atrial fibrillation falls in the optimal INR range. Our findings do not support adjustment of INR targets according to previously defined stroke risk factors.
Authors: Singer DE; Chang Y; Fang MC; Borowsky LH; Pomernacki NK; Udaltsova N; Go AS
Circ Cardiovasc Qual Outcomes. 2009 Jul;2(4):297-304. Epub 2009 Jun 9.
Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator
PURPOSE: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is recognized as a serious complication among patients receiving bisphosphonate therapy. However, methods for early detection and identification of patients at risk for osteonecrosis of the jaw (ONJ) need further investigation. The purpose of this study was to characterize BRONJ among patients receiving intravenous bisphosphonates and to examine bone scintigraphy findings that preceded manifestation of frank ONJ. MATERIALS AND METHODS: We identified all known cases of BRONJ (defined according to 2006 American Association of Oral and Maxillofacial Surgeons criteria) diagnosed between January 2004 and September 2008 among patients who received intravenous bisphosphonate therapy (IVBP). The medical records were abstracted, and the clinical and radiographic features of BRONJ and relevant comorbidities were characterized. Technetium Tc 99 bone scintigrams were systematically reviewed among the subset of patients who received these imaging studies for oncologic care and imaging findings were correlated with the temporal development of ONJ. RESULTS: We identified 59 cases of intravenous BRONJ (median age, 61.4 +/- 10.7 years; 57.6% female), of whom 44.1% had breast cancer, 33.9% had multiple myeloma, and the remainder had metastatic prostate cancer (15.3%) or other cancers (6.8%). One third (32.2%) of the cohort was diabetic. In addition to IVBP, the vast majority (86.4%) had also received prior systemic glucocorticoid therapy. The median cumulative number of IVBP doses was 25 (interquartile range, 16-39) at the time of BRONJ diagnosis. Half of the patients had prior invasive dental procedures; ONJ developed spontaneously in 27.1%, and in the remainder ONJ developed in the setting of periodontal disease (10.1%) or local trauma (8.4%). Most patients presented with painful stage 2 disease involving the mandible (75%), and Actinomyces was present in more than 77% of available histologic specimens. During the median follow-up of 1.5 years, 15 patients (25.4%) regressed to a less severe stage, with healing in 6 patients; 16 (27.1%) worsened; and the remainder stayed within the same stage, but in almost half of these patients, the extent of involvement progressed. Of the 38 patients who had 99Tc bone scintigraphy, 35 had bone scans before development of BRONJ, and among these patients, 23 (67.5%) had positive tracer uptake in areas that subsequently developed BRONJ. CONCLUSIONS: In this study bone scintigraphy showed positive tracer uptake before the development of BRONJ in almost 66% of patients who had these scans before clinical evidence of frank osteonecrosis. BRONJ subsequently developed in the areas identified on scintigraphy in these patients. Further studies should explore the role of bone scintigraphy in the detection of early subclinical BRONJ.
Authors: O'Ryan FS; Khoury S; Liao W; Han MM; Hui RL; Baer D; Martin D; Liberty D; Lo JC
J Oral Maxillofac Surg. 2009 Jul;67(7):1363-72.
Childbearing and obesity in women: weight before, during, and after pregnancy
Weight gain and the development of obesity during midlife are strong independent predictors of cardiovascular disease, particularly among women, as well as the metabolic syndrome, type 2 diabetes, and early mortality. Primiparity and maternal body size before pregnancy affect long-term postpartum weight retention and the development of obesity among women of reproductive age. As a modifiable risk factor, body weight during the preconception, prenatal, and postpartum periods may present critical windows to implement interventions to prevent weight retention and the development of overweight and obesity in women of childbearing age.
Authors: Gunderson EP
Obstet Gynecol Clin North Am. 2009 Jun;36(2):317-32, ix.
Chiari type I malformation in a pediatric population
The natural history of Chiari I malformation in children remains unclear. A population-based retrospective cohort study was therefore conducted. Radiology reports from all head and spine magnetic resonance imaging scans (n = 5248) performed among 741,815 children under age 20 within Kaiser Northern California, 1997-1998, were searched for Chiari I. Medical records and imaging studies were reviewed to determine clinical and radiographic predictors of significant neurologic symptoms, defined as moderate to severe headache, neck pain, vertigo, or ataxia. The 51 patients identified with Chiari I represented 1% of the children who had head or spine magnetic resonance imaging scans performed during the study period. Headache (55%) and neck pain (12%) were the most common symptoms. Syringomyelia was present in 6 patients (12%) at initial diagnosis; no new syrinxes developed during follow-up. Older age at time of diagnosis was associated with increased risk of headache (odds ratio OR = 1.3, 95% confidence interval CI = 1.1-1.5) and significant neurologic symptoms (OR = 1.2, 95% CI = 1.04-1.4). Chiari I, an underrecognized cause of headaches in children, is also frequently discovered incidentally in children without symptoms. Larger and longer-term studies are needed to determine the prognosis and optimal treatment of pediatric Chiari I.
Authors: Aitken LA; Lindan CE; Sidney S; Gupta N; Barkovich AJ; Sorel M; Wu YW
Pediatr Neurol. 2009 Jun;40(6):449-54.
The ACTIVE pursuit of stroke prevention in patients with atrial fibrillation
Authors: Go AS
N Engl J Med. 2009 May 14;360(20):2127-9.
Insulin resistance independently predicts the progression of coronary artery calcification
BACKGROUND: Change in coronary artery calcification is a surrogate marker of subclinical coronary artery disease (CAD). In the only large prospective study, CAD risk factors predicted progression of coronary artery calcium (CAC). METHODS: We measured CAC at enrollment and after 24 months in a community-based sample of 869 healthy adults aged 60 to 72 years who were free of clinical CAD. We assessed predictors of the progression of CAC using univariate and multivariate models after square root transformation of the Agatston scores. Predictors tested included age, sex, race/ethnicity, smoking status, body mass index, family history of CAD, C-reactive protein and several measures of diabetes, insulin levels, blood pressure, and lipids. RESULTS: The mean age of the cohort was 66 years, and 62% were male. The median CAC at entry was 38.6 Agatston units and increased to 53.3 Agatston units over 24 months (P < .01). The CAC progression was associated with white race, diabetes, dyslipidemia, hypertension, lower diastolic blood pressure, and higher pulse pressure. After controlling for these variables, higher fasting insulin levels independently predicted CAC progression. CONCLUSIONS: Insulin resistance, in addition to the traditional cardiac risk factors, independently predicts progression of CAC in a community-based population without clinical CAD.
Authors: Lee KK; Fortmann SP; Fair JM; Iribarren C; Rubin GD; Varady A; Go AS; Quertermous T; Hlatky MA
Am Heart J. 2009 May;157(5):939-45.
Nonrecovery of kidney function and death after acute on chronic renal failure
BACKGROUND AND OBJECTIVES: Relatively little is known about clinical outcomes, especially long-term outcomes, among patients who have chronic kidney disease (CKD) and experience superimposed acute renal failure (ARF; acute on chronic renal failure). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We tracked 39,805 members of an integrated health care delivery system in northern California who were hospitalized during 1996 through 2003 and had prehospitalization estimated GFR (eGFR) <45 ml/min per 1.73 m(2). Superimposed ARF was defined as having both a peak inpatient serum creatinine greater than the last outpatient serum creatinine by > or =50% and receipt of acute dialysis. RESULTS: Overall, 26% of CKD patients who suffered superimposed ARF died during the index hospitalization. There was a high risk for developing ESRD within 30 d of hospital discharge that varied with preadmission renal function, being 42% among hospital survivors with baseline eGFR 30-44 ml/min per 1.73 m(2) and 63% among hospital survivors with baseline eGFR 15-29 ml/min per 1.73 m(2). Compared with patients who had CKD and did not experience superimposed ARF, those who did had a 30% higher long-term risk for death or ESRD. CONCLUSIONS: In a large, community-based cohort of patients with CKD, an episode of superimposed dialysis-requiring ARF was associated with very high risk for nonrecovery of renal function. Dialysis-requiring ARF also seemed to be an independent risk factor for long-term risk for death or ESRD.
Authors: Hsu CY; Chertow GM; McCulloch CE; Fan D; Ordonez JD; Go AS
Clin J Am Soc Nephrol. 2009 May;4(5):891-8. Epub 2009 Apr 30.
Utilization of TCD screening for primary stroke prevention in children with sickle cell disease
BACKGROUND: In 1998, the Stroke Prevention Trial in Sickle Cell Anemia showed a >90% reduction in stroke rates after blood transfusion therapy in children with sickle cell disease (SCD) identified as high risk with transcranial Doppler ultrasonography (TCD) screening. METHODS: We studied the utilization of TCD screening in a retrospective cohort of all children with SCD within a large managed care plan from January 1993 to December 2005. Rates of first TCD screening were estimated using life table methods; predictors of TCD were evaluated using Cox proportional hazards regression. Stroke incidence rates were estimated in person-time before (pre-TCD) and after (post-TCD) first TCD. RESULTS: The average annual rate of TCD screening in 157 children with SCD was 1.8 per 100 person-years pre-1998, 5.0 from January 1, 1998, to December 31, 1999, and 11.4 after 1999. The only independent predictor of TCD screening was proximity to the vascular laboratory. The annualized stroke rate pre-TCD was 0.44 per 100 person-years, compared to 0.19 post-TCD. CONCLUSIONS: Since the Stroke Prevention Trial in Sickle Cell Anemia, the rate of transcranial Doppler ultrasonography (TCD) screening in sickle cell disease (SCD) has increased sixfold within a large health care plan. Children living farther from a vascular laboratory are less likely to be screened. Increased availability of TCD screening could improve the utilization of this effective primary stroke prevention strategy.
Authors: Armstrong-Wells J; Grimes B; Sidney S; Kronish D; Shiboski SC; Adams RJ; Fullerton HJ
Neurology. 2009 Apr 14;72(15):1316-21.
Longitudinal study of growth and adiposity in parous compared with nulligravid adolescents
OBJECTIVE: To examine the impact of pregnancy on adolescent growth and adiposity relative to nulligravidas of similar maturation stage. DESIGN: Prospective cohort study. SETTING: The multicenter National Heart, Lung and Blood Growth and Health Study with annual examinations from 1987-1988 through 1996-1997. PARTICIPANTS: One thousand eight hundred ninety girls (983 black and 907 white) aged 9 to 10 years at enrollment. MAIN EXPOSURE: Self-reported number of pregnancies and births during adolescence and young adulthood (age, 15-19 years): 311 primiparas (17%), 84 multiparas (4%), 196 nulliparous gravidas (10%), and 1299 nulligravidas (69%). OUTCOME MEASURES: Estimated race-specific changes in body weight, height, body mass index, waist circumference, hip circumference, waist to hip ratio, and percent body fat, defined as the difference between baseline and measurements 9 to 10 years later. RESULTS: Thirty-one percent of black and 10% of white girls gave birth during adolescence and young adulthood. We found evidence of race by pregnancy interactions (P < .10) for changes in weight, body mass index, hip circumference, and percent body fat. Black primiparas and multiparas, respectively, had smaller decrements in waist to hip ratio (0.019 and 0.023) and greater increments in weight (3.6 and 6.0 kg), body mass index (1.3 and 2.3), waist circumference (3.5 and 5.2 cm), hip circumference (2.1 and 4.0 cm), and percent body fat (3.4% and 4.6%) than black nulligravidas after adjustment for baseline measurements, age, study center, family income, parental education, age at menarche, hours of television and video viewing, and height at visit 9 or 10 in weight models (P < .01). White primiparas had borderline greater increments in waist circumference (2.4 cm) and percent body fat (0.9%) and smaller decrements in waist to hip ratio (0.017) than white nulligravidas (P < .05). Height did not differ by pregnancy status. CONCLUSIONS: Women who give birth during adolescence and young adulthood have substantially greater increments in overall and central adiposity than adolescents who do not experience pregnancy independent of other known correlates of weight gain.
Authors: Gunderson EP; Striegel-Moore R; Schreiber G; Hudes M; Biro F; Daniels S; Crawford P
Arch Pediatr Adolesc Med. 2009 Apr;163(4):349-56.
Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study
BACKGROUND: Atrial fibrillation (AF) substantially increases the risk of ischemic stroke, but this risk varies among individual patients with AF. Existing risk stratification schemes have limited predictive ability. Chronic kidney disease is a major cardiovascular risk factor, but whether it independently increases the risk for ischemic stroke in persons with AF is unknown. METHODS AND RESULTS: We examined how chronic kidney disease (reduced glomerular filtration rate or proteinuria) affects the risk of thromboembolism off anticoagulation in patients with AF. We estimated glomerular filtration rate using the Modification of Diet in Renal Disease equation and proteinuria from urine dipstick results found in laboratory databases. Patient characteristics, warfarin use, and thromboembolic events were ascertained from clinical databases, with validation of thromboembolism by chart review. During 33,165 person-years off anticoagulation among 10,908 patients with AF, we observed 676 incident thromboembolic events. After adjustment for known risk factors for stroke and other confounders, proteinuria increased the risk of thromboembolism by 54% (relative risk, 1.54; 95% CI, 1.29 to 1.85), and there was a graded, increased risk of stroke associated with a progressively lower level of estimated glomerular filtration rate compared with a rate > or =60 mL x min(-1) x 1.73 m(-2): relative risk of 1.16 (95% CI, 0.95 to 1.40) for estimated glomerular filtration rate of 45 to 59 mL x min(-1) x 1.73 m(-2) and 1.39 (95% CI, 1.13 to 1.71) for estimated glomerular filtration rate <45 mL x min(-1) x 1.73 m(-2) (P=0.0082 for trend). CONCLUSIONS: Chronic kidney disease increases the risk of thromboembolism in AF independently of other risk factors. Knowing the level of kidney function and the presence of proteinuria may improve risk stratification for decision making about the use of antithrombotic therapy for stroke prevention in AF.
Authors: Go AS; Fang MC; Udaltsova N; Chang Y; Pomernacki NK; Borowsky L; Singer DE; ATRIA Study Investigators
Circulation. 2009 Mar 17;119(10):1363-9. Epub 2009 Mar 2.
Reproducibility of breast arterial calcium mass quantification using digital mammography
RATIONALE AND OBJECTIVES: Breast arterial calcification (BAC) detected on mammography is frequently not included in final reports. However, previous studies have indicated that BAC may be evidence of general atherosclerotic vascular disease, and it can potentially be a useful marker of coronary artery disease. In addition, there are currently no available techniques for the quantification of calcium mass using mammography. The purpose of this study was to evaluate the reproducibility and inter-reader agreement of a technique for the quantification of BAC using standard digital mammography. MATERIALS AND METHODS: BAC mass was measured in a convenient, consecutive sample of 39 women aged 49 to 82 years attending routine mammographic examinations. BAC mass measurements were performed in standard mediolateral oblique (MLO) and craniocaudal (CC) views. To assess reproducibility, the BAC measurements obtained in MLO and CC views were compared. RESULTS: The measured BAC masses in CC (M(CC)) and MLO (M(MLO)) projections were related by M(CC) = 0.82(M(MLO)) + 0.27 mg (r = 0.97; standard error of estimation [SEE], 3.44 mg). The measured BAC masses in the left (M(L)) and right (M(R)) breasts were related by M(L) = 0.86(M(R)) – 0.06 mg (r = 0.95; SEE, 4.30 mg). The intraclass correlation coefficients for the measurement of calcium mass ranged from 0.94 in the left CC view to 0.99 in the right CC view. CONCLUSION: A densitometry technique for the quantification of BAC mass was evaluated in patients using standard full-field digital mammography. The results demonstrated that this densitometric technique for the quantification of BAC mass is highly reproducible and has excellent inter-reader agreement. This technique may provide a quantitative metric for future studies relating the severity of BAC and cardiovascular risk.
Authors: Molloi S; Mehraien T; Iribarren C; Smith C; Ducote JL; Feig SA
Acad Radiol. 2009 Mar;16(3):275-82.
Cardiorespiratory fitness and coronary artery calcification in young adults: The CARDIA Study
Whether cardiorespiratory fitness relates to early subclinical atherosclerotic vascular disease remains unknown. We investigated the relation of cardiorespiratory fitness to coronary artery calcification (CAC) in 2373 African-American and White young adults from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We measured cardiorespiratory fitness in 1985-1986 (baseline) using a symptom-limited exercise test on a treadmill. Coronary calcium scores were measured in 2001-2002 (year 15) using electron-beam or multi-detector computed tomography. CAC was classified as present or absent, while cardiorespiratory fitness was classified as sex-specific low, moderate, and high fitness categories. After adjustment for age, sex, race, clinical center, education, cigarette smoking, waist girth, alcohol intake, physical activity, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and fasting insulin, baseline cardiorespiratory fitness was inversely associated with prevalence of CAC in young adults (P for trend=0.03). The odds ratios of having CAC for persons in the moderately and highly fit individuals were 0.80 (95% confidence interval (CI), 0.55-1.15) and 0.59 (95% CI, 0.36-0.97), respectively, as compared with the low-fit individuals. High levels of cardiorespiratory fitness were associated with a lower risk of having coronary calcification 15 years later in African-American and White young adults.
Authors: Lee CD; Jacobs DR Jr; Hankinson A; Iribarren C; Sidney S
Atherosclerosis. 2009 Mar;203(1):263-8. Epub 2008 Jun 22.
Prevalence and predictors of perinatal hemorrhagic stroke: results from the kaiser pediatric stroke study
OBJECTIVES: Predictors for perinatal arterial ischemic stroke include both maternal and intrapartum factors, but predictors of perinatal hemorrhagic stroke have not been studied. We sought to determine both the prevalence and predictors of perinatal hemorrhagic stroke within a large, multiethnic population. PATIENTS AND METHODS: We performed a case-control study nested within the cohort of all infants born from 1993 to 2003 in the Northern California Kaiser Permanente Medical Care Program, a health maintenance organization providing care for >3 million members. Cases of symptomatic perinatal hemorrhagic stroke and perinatal arterial ischemic stroke in neonates (28 weeks’ gestational age through 28 days of life) were identified through electronic searches of diagnosis and radiology databases and confirmed by medical chart review. Three controls per case were randomly selected and matched on birth year and facility. This analysis included cases of perinatal hemorrhagic stroke (intracerebral hemorrhage or subarachnoid hemorrhage, excluding pure intraventricular hemorrhage) and all controls. Predictors of perinatal hemorrhagic stroke were assessed by using logistic regression, adjusting for the matching criteria. RESULTS: Among 323 532 live births, we identified 20 cases of perinatal hemorrhagic stroke (19 intracerebral hemorrhage and 1 subarachnoid hemorrhage), which yielded a population prevalence for perinatal hemorrhagic stroke of 6.2 in 100 000 live births. Cases presented with encephalopathy (100%) and seizures (65%). Perinatal hemorrhagic stroke was typically unifocal (74%) and unilateral (83%). Etiologies included thrombocytopenia (n = 4) and cavernous malformation (n = 1); 15 (75%) were idiopathic. Univariate predictors of perinatal hemorrhagic stroke included male gender, fetal distress, emergent cesarean delivery, prematurity, and postmaturity but not birth weight. When entered into a multivariate model, fetal distress and postmaturity continued to be independent predictors. CONCLUSIONS: Fetal distress is an independent predictor of perinatal hemorrhagic stroke, perhaps suggesting a prenatal event. Postmaturity also predicts perinatal hemorrhagic stroke, an association not explained by large birth weight in our study.
Authors: Armstrong-Wells J; Johnston SC; Wu YW; Sidney S; Fullerton HJ
Pediatrics. 2009 Mar;123(3):823-8.
Risk factors for end-stage renal disease: 25-year follow-up
BACKGROUND: Few cohort studies have focused on risk factors for end-stage renal disease (ESRD). This investigation evaluated the prognostic value of several potential novel risk factors for ESRD after considering established risk factors. METHODS: We studied 177 570 individuals from a large integrated health care delivery system in northern California who volunteered for health checkups between June 1, 1964, and August 31, 1973. Initiation of ESRD treatment was ascertained using US Renal Data System registry data through December 31, 2000. RESULTS: A total of 842 cases of ESRD were observed during 5 275 957 person-years of follow-up. This comprehensive evaluation confirmed the importance of established risk factors, including the following: male sex, older age, proteinuria, diabetes mellitus, lower educational attainment, and African American race, as well as higher blood pressure, body mass index, and serum creatinine level. The 2 most potent risk factors were proteinuria and excess weight. For proteinuria, the adjusted hazard ratios (HRs) were 7.90 (95% confidence interval [CI], 5.35-11.67) for 3 to 4+ on urine dipstick, 3.59 (2.82-4.57) for 1 to 2+ on urine dipstick, and 2.37 (1.79-3.14) for trace vs negative on urine dipstick. For excess weight, the HRs were 4.39 (95% CI, 3.38-5.70) for class 2 to class 3 obesity, 3.11 (2.51-3.84) for class 1 obesity, and 1.65 (1.39-1.97) for overweight vs normal weight. Furthermore, several independent novel risk factors for ESRD were identified, including lower hemoglobin level (1.33 [1.08-1.63] for lowest vs highest quartile), higher serum uric acid level (2.14 [1.65-2.77] for highest vs lowest quartile), self-reported history of nocturia (1.36 [1.17-1.58]), and family history of kidney disease (HR, 1.40 [95% CI, 1.02-1.90]). CONCLUSIONS: We confirmed the importance of established ESRD risk factors in this large cohort with broad sex and racial/ethnic representation. Lower hemoglobin level, higher serum uric acid level, self-reported history of nocturia, and family history of kidney disease are independent risk factors for ESRD.
Authors: Hsu CY; Iribarren C; McCulloch CE; Darbinian J; Go AS
Arch Intern Med. 2009 Feb 23;169(4):342-50.
Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop
The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.
Authors: Benjamin EJ; Go AS; Wyse DG; et al.
Circulation. 2009 Feb 3;119(4):606-18.
The importance of cerebral aneurysms in childhood hemorrhagic stroke: a population-based study
BACKGROUND AND PURPOSE: Prior population-based studies of pediatric hemorrhagic stroke (HS) had too few incident cases to assess predictors of cerebral aneurysms, a HS etiology that requires urgent intervention. METHODS: We performed a retrospective cohort study of HS (intracerebral, subarachnoid [SAH], and intraventricular hemorrhage) using the population of all children <20 years of age enrolled in a large Northern Californian healthcare plan (January 1993 to December 2003). Cases were identified through electronic searches and confirmed through independent chart review by 2 neurologists with adjudication by a third; traumatic hemorrhages were excluded. Logistic regression was used to examine potential predictors of underlying aneurysm. RESULTS: Within a cohort of 2.3 million children followed for a mean of 3.5 years, we identified 116 cases of spontaneous HS (overall incidence, 1.4 per 100000 person-years). Cerebral aneurysms were identified in 15 (13%) of HS cases. Among 21 children with pure SAH, 57% were found to have an underlying aneurysm compared with only 2% of 58 children with pure intracerebral hemorrhage and 5% of 37 children with a mixed pattern of hemorrhage (intracerebral hemorrhage and SAH). Independent predictors of an underlying aneurysm included pure SAH (OR, 76; 95% CI, 9 to 657; P<0.001) and late adolescent age (15 to 19 years versus younger age groups; OR, 6.4; 95% CI, 1.0 to 40; P=0.047). CONCLUSIONS: Cerebral aneurysms cause the majority of spontaneous SAH in children and account for more than 10% of childhood HS overall. Children, and particularly teenagers, presenting with spontaneous SAH should be promptly evaluated with cerebrovascular imaging.
Authors: Jordan LC; Johnston SC; Wu YW; Sidney S; Fullerton HJ
Stroke. 2009 Feb;40(2):400-5. Epub 2008 Nov 20.
Prospective evidence that lactation protects against cardiovascular disease in women
Authors: Gunderson EP
Am J Obstet Gynecol. 2009 Feb;200(2):119-20.
Prevalence and progression of subclinical atherosclerosis in younger adults with low short-term but high lifetime estimated risk for cardiovascular disease: the coronary artery risk development in young adults study and multi-ethnic study of atherosclerosis
BACKGROUND: We hypothesized that individuals with low 10-year but high lifetime cardiovascular disease risk would have a greater burden of subclinical atherosclerosis than those with low 10-year but low lifetime risk. METHODS AND RESULTS: We included 2988 individuals < or = 50 years of age at examination year 15 from the Coronary Artery Risk Development in Young Adults (CARDIA) study and 1076 individuals < or = 50 of age at study entry from the Multi-Ethnic Study of Atherosclerosis (MESA). The 10-year risk and lifetime risk for cardiovascular disease were estimated for each participant, permitting stratification into 3 groups: low 10-year (<10%)/low lifetime (<39%) risk, low 10-year (<10%)/high lifetime risk (> or = 39%), and high 10-year risk (> or = 10%) or diagnosed diabetes mellitus. Baseline levels and change in levels of subclinical atherosclerosis (coronary artery calcium or carotid intima-media thickness) were compared across risk strata. Among participants with low 10-year risk (91% of all participants) in CARDIA, those with a high lifetime risk compared with low lifetime risk had significantly greater common (0.83 versus 0.80 mm in men; 0.79 versus 0.75 mm in women) and internal (0.85 versus 0.80 mm in men; 0.80 versus 0.76 mm in women) carotid intima-media thickness, higher coronary artery calcium prevalence (16.6% versus 9.8% in men; 7.1% versus 2.3% in women), and significantly greater incidence of coronary artery calcium progression (22.3% versus 15.4% in men; 8.7% versus 5.3% in women). Similar results were observed in MESA. CONCLUSIONS: Individuals with low 10-year but high lifetime risk have a greater subclinical disease burden and greater incidence of atherosclerotic progression compared with individuals with low 10-year and low lifetime risk, even at younger ages.
Authors: Berry JD; Liu K; Folsom AR; Lewis CE; Carr JJ; Polak JF; Shea S; Sidney S; O'Leary DH; Chan C; Lloyd-Jones DM
Circulation. 2009 Jan 27;119(3):382-9. Epub 2009 Jan 12.
Birthplace and mortality among insured Latinos: the paradox revisited
OBJECTIVES: We investigated the Latino paradox in a managed care setting and examined the role of birthplace. METHODS: We evaluated 133,155 non-Latino Whites and 5,237 Latinos (36% born in the United States, 34% in Central and South America, 21% in Mexico, and 8% in the Caribbean Islands) who were enrolled in an integrated healthcare delivery system in northern California. Baseline data were from 1964-1973, and the median followup was 34 years. Main outcome measures were cause-specific and all-cause mortality. RESULTS: In fully-adjusted analyses, and compared with non-Latino Whites, the risk of death from circulatory causes was significantly lower among US-born Latinos (hazard ratio [HR] .79, 95% confidence interval [CI] .66-.93), among Central and South America-born Latinos (HR .76, 95% CI .63-.91), and Caribbean-born Latinos (HR .66, 95% CI .47-0.93). Risk of death by malignant neoplasms was significantly lower among US-born Latinos (HR .68, 95% CI .56-.83). Risk of respiratory death was significantly lower among Central and South America-born Latinos (HR .50, 95% CI .32-.80). All-cause mortality risk was significantly decreased in US-born Latinos (HR .79, 95% CI .71-.87), Central and South America-born Latinos (HR .81, 95% CI .73-.90), and Caribbean-born Latinos (HR .76, 95% CI .63-.93) but not in Mexico-born Latinos. CONCLUSIONS: In our managed care setting, the Latino paradox phenomenon varied by birthplace; it was more evident among US-born Latinos. This subgroup experienced lower circulatory, cancer, and all-cause mortality than did non-Latino Whites, despite higher prevalences of current smoking, obesity, and asymptomatic hyperglycemia.
Authors: Iribarren C; Darbinian JA; Fireman BH; Burchard EG
Ethn Dis. 2009 Spring;19(2):185-91.
Characterizing the admixed African ancestry of African Americans
BACKGROUND: Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin. RESULTS: From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans. CONCLUSIONS: These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.
Authors: Zakharia F; Go AS; Iribarren C; Risch N; Tang H; et al.
Genome Biol. 2009;10(12):R141. Epub 2009 Dec 22.
Disparities in stroke rehabilitation: results of a study in an integrated health system in northern California
OBJECTIVE: To determine whether there are disparities in postacute stroke rehabilitation based on type of stroke, race/ethnicity, sex/gender, age, socioeconomic status, geographic region, or service area referral patterns in a large integrated health system with multiple levels of care. DESIGN: Cohort study tracking rehabilitation services for 365 days after acute hospitalization for a first stroke. SETTING: The Northern California Kaiser Permanente Health System (approximately 3.3 million membership population) PARTICIPANTS: A total of 11,119 patients hospitalized for acute stroke from 1996 to 2003. The cohort includes patients discharged from acute care after a stroke. Postacute care rehabilitation services were evaluated according to the level of care ever-received within the 365 days after discharge from acute care, including inpatient rehabilitation hospital (IRH), skilled nursing facility (SNF), home health and outpatient, or no rehabilitation services. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Service delivery. RESULTS: Patients discharged to an IRH had longer lengths of stay in acute care. Patients with hemorrhagic stroke were less likely to be treated in an IRH. Patients whose highest level of rehabilitation was SNF were older and more likely to be women. After adjusting for age and other covariates, women were less likely to go to an IRH than men. Asian and black patients were more likely than white patients to be treated in an IRH or SNF. Also more likely to go to an IRH were patients from higher socioeconomic groups, from urban areas, and from geographic areas close to the regional rehabilitation hospital. CONCLUSIONS: These results suggest variation in care delivery and extent of postacute care based on differences in patient demographics and geographic factors. Results also varied over time. Some minority populations in this cohort appeared to be more likely to receive IRH care, possibly because of disease severity, family support systems, cultural factors, or differences in referral patterns.
Authors: Sandel ME; Wang H; Terdiman J; Hoffman JM; Ciol MA; Sidney S; Quesenberry C; Lu Q; Chan L
PM R. 2009 Jan;1(1):29-40. Epub 2009 Jan 9.
Common variants in interleukin-1-Beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation
BACKGROUND: Polymorphisms in the proinflammatory cytokine interleukin (IL)-1beta gene have been associated with systemic atherogenesis, thrombosis and rupture. The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in IL-1beta and intracranial hemorrhage (ICH) in the natural course of brain arteriovenous malformation (BAVM) patients. METHOD: Two IL-1beta promoter SNPs (-511C–>T, -31T–>C) and 1 synonymous coding SNP in exon 5 at +3953C–>T (Phe) were genotyped in 410 BAVM patients. We performed a survival analysis of time to subsequent ICH, censoring cases at first treatment, death or last follow-up. A Cox regression analysis was performed to obtain hazard ratios (HRs) for genotypes adjusted for age, sex, Caucasian race/ethnicity and hemorrhagic presentation. RESULTS: Subjects with the -31 CC genotype (HR = 2.7; 95% CI 1.1-6.6; p = 0.029) or the -511 TT genotype (HR = 2.6; 95% CI 1.1-6.5; p = 0.039) had a greater risk of subsequent ICH compared with reference genotypes, adjusting for covariates. The +3953C–>T SNP was not significantly associated with an increased ICH risk (p = 0.22). The IL-1beta promoter polymorphisms were also associated with BAVM susceptibility among a subset of 235 BAVM cases and 255 healthy controls of Caucasian race/ethnicity (p < 0.001). CONCLUSION: IL-1beta promoter polymorphisms were associated with an increased risk of ICH in BAVM clinical course and with BAVM susceptibility. These results suggest that inflammatory pathways, including the IL-1beta cytokine, may play an important role in ICH.
Authors: Kim H; Zaroff JG; Young WL; et al.
Cerebrovasc Dis. 2009;27(2):176-82. Epub 2008 Dec 18.
Peroxisome proliferator-activated receptor gamma polymorphisms and coronary heart disease
Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor gamma (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96-12.27], P = .058, 3.41 [0.95-12.22], P = .060 and 5.10 [0.99-26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99 [0.92-1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99-1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20-2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed.
Authors: Dallongeville J; Iribarren C; Go AS; Meirhaeghe A; et al.
PPAR Res. 2009;2009:543746. Epub 2009 Dec 1.
Occupational exposures and the risk of COPD: dusty trades revisited
BACKGROUND: The contribution of occupational exposures to chronic obstructive pulmonary disease (COPD) and, in particular, their potential interaction with cigarette smoking remains underappreciated. METHODS: Data from the FLOW study of 1202 subjects with COPD (of which 742 had disease classified as stage II or above by Global Obstructive Lung Disease (GOLD) criteria) and 302 referent subjects matched by age, sex and race recruited from a large managed care organisation were analysed. Occupational exposures were assessed using two methods: self-reported exposure to vapours, gas, dust or fumes on the longest held job (VGDF) and a job exposure matrix (JEM) for probability of exposure based on occupation. Multivariate analysis was used to control for age, sex, race and smoking history. The odds ratio (OR) and adjusted population attributable fraction (PAF) associated with occupational exposure were calculated. RESULTS: VGDF exposure was associated with an increased risk of COPD (OR 2.11; 95% CI 1.59 to 2.82) and a PAF of 31% (95% CI 22% to 39%). The risk associated with high probability of workplace exposure by JEM was similar (OR 2.27; 95% CI 1.46 to 3.52), although the PAF was lower (13%; 95% CI 8% to 18%). These estimates were not substantively different when the analysis was limited to COPD GOLD stage II or above. Joint exposure to both smoking and occupational factors markedly increased the risk of COPD (OR 14.1; 95% CI 9.33 to 21.2). CONCLUSIONS: Workplace exposures are strongly associated with an increased risk of COPD. On a population level, prevention of both smoking and occupational exposure, and especially both together, is needed to prevent the global burden of disease.
Authors: Blanc PD; Iribarren C; Trupin L; Earnest G; Katz PP; Balmes J; Sidney S; Eisner MD
Thorax. 2009 Jan;64(1):6-12. Epub 2008 Aug 4.
Fifteen-year longitudinal trends in walking patterns and their impact on weight change
BACKGROUND: Although walking is the most popular leisure-time activity for adults, few long-term, longitudinal studies have examined the association between walking, an affordable and accessible form of physical activity, and weight gain. OBJECTIVE: The objective was to evaluate the association between changes in leisure-time walking and weight gain over a 15-y period. DESIGN: Prospective data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study of 4,995 men and women aged 18-30 y at baseline (1985-1986) from 4 US cities and reexamined 2, 5, 7, 10, and 15 y later. Sex-stratified, repeated-measures, conditional regression modeling with data from all 6 examination periods (n = 23,633 observations) was used to examine associations between walking and annualized 15-y weight change, with control for 15-y nonwalking physical activity, baseline weight (and their interaction), marital status, education, smoking, calorie intake, and baseline age, race, and field center. RESULTS: Mean (+/- SE) baseline weights were 77.0 +/- 0.3 kg (men) and 66.2 +/- 0.3 kg (women), weight gain was approximately 1 kg/y, and the mean duration of walking at baseline was <15 min/d. After accounting for nonwalking physical activity, calorie intake, and other covariates, we found a substantial association between walking and annualized weight change; the greatest association was for those with a larger baseline weight. For example, for women at the 75th percentile of baseline weight, 0.5 h of walking/d was associated with 8 kg less weight gain over 15 y compared with women with no leisure time walking. CONCLUSION: Walking throughout adulthood may attenuate the long-term weight gain that occurs in most adults.
Authors: Gordon-Larsen P; Hou N; Sidney S; Sternfeld B; Lewis CE; Jacobs DR Jr; Popkin BM
Am J Clin Nutr. 2009 Jan;89(1):19-26. Epub 2008 Dec 3.
The impact of SHS exposure on health status and exacerbations among patients with COPD
Secondhand smoke (SHS) is a major contributor to indoor air pollution. Because it contains respiratory irritants, it may adversely influence the clinical course of persons with chronic obstructive pulmonary disease (COPD). We used data from nonsmoking members of the FLOW cohort of COPD (n = 809) to elucidate the impact of SHS exposure on health status and exacerbations (requiring emergency department visits or hospitalization). SHS exposure was measured by a validated survey instrument (hours of exposure during the past week). Physical health status was measured by the SF-12 Physical Component Summary Score and disease-specific health-related quality of life (HRQL) by the Airways Questionnaire 20-R. Health care utilization for COPD was determined from Kaiser Permanente Northern California computerized databases. Compared to no SHS exposure, higher level SHS exposure was associated with poorer physical health status (mean score decrement -1.78 points; 95% confidence interval [CI] -3.48 to -0.074 points) after controlling for potential confounders. Higher level SHS exposure was also related to poorer disease-specific HRQL (mean score increment 0.63; 95% CI 0.016 to 1.25) and less distance walked during the Six-Minute Walk test (mean decrement -50 feet; 95% CI -102 to 1.9). Both lower level and higher level SHS exposure was related to increased risk of emergency department (ED) visits (hazard ratio [HR] 1.40; 95% CI 0.96 to 2.05 and HR 1.41; 95% CI 0.94 to 2.13). Lower level and higher level SHS exposure were associated with a greater risk of hospital-based care for COPD, which was a composite endpoint of either ED visits or hospitalizations for COPD (HR 1.52; 95% CI 1.06 to 2.18 and HR 1.40; 95% CI 0.94 to 2.10, respectively). In conclusion, SHS was associated with poorer health status and a greater risk of COPD exacerbation. COPD patients may comprise a vulnerable population for the health effects of SHS.
Authors: Eisner MD; Iribarren C; Yelin EH; Sidney S; Katz PP; Sanchez G; Blanc PD
Int J Chron Obstruct Pulmon Dis. 2009;4:169-76. Epub 2009 May 7.
Chronic kidney disease in United States Hispanics: a growing public health problem
Hispanics are the fastest growing minority group in the United States. The incidence of end-stage renal disease (ESRD) in Hispanics is higher than non-Hispanic Whites and Hispanics with chronic kidney disease (CKD) are at increased risk for kidney failure. Likely contributing factors to this burden of disease include diabetes and metabolic syndrome, both are common among Hispanics. Access to health care, quality of care, and barriers due to language, health literacy and acculturation may also play a role. Despite the importance of this public health problem, only limited data exist about Hispanics with CKD. We review the epidemiology of CKD in US Hispanics, identify the factors that may be responsible for this growing health problem, and suggest gaps in our understanding which are suitable for future investigation.
Authors: Lora CM; Daviglus ML; Kusek JW; Porter A; Ricardo AC; Go AS; Lash JP
Ethn Dis. 2009 Autumn;19(4):466-72.
Short sleep duration and incident coronary artery calcification
CONTEXT: Coronary artery calcification is a subclinical predictor of coronary heart disease. Recent studies have found that sleep duration is correlated with established risk factors for calcification including glucose regulation, blood pressure, sex, age, education, and body mass index. OBJECTIVE: To determine whether objective and subjective measures of sleep duration and quality are associated with incidence of calcification over 5 years and whether calcification risk factors mediate the association. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort of home monitoring in a healthy middle-aged population of 495 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort Chicago site (black and white men and women aged 35-47 years at year 15 of the study in 2000-2001 with follow-up data at year 20 in 2005-2006). Potential confounders (age, sex, race, education, apnea risk, smoking status) and mediators (lipids, blood pressure, body mass index, diabetes, inflammatory markers, alcohol consumption, depression, hostility, self-reported medical conditions) were measured at both baseline and follow-up. Sleep metrics (wrist actigraphy measured duration and fragmentation, daytime sleepiness, overall quality, self-reported duration) were examined for association with incident calcification. Participants had no detectable calcification at baseline. MAIN OUTCOME MEASURE: Coronary artery calcification was measured by computed tomography in 2000-2001 and 2005-2006 and incidence of new calcification over that time was the primary outcome. RESULTS: Five-year calcification incidence was 12.3% (n = 61). Longer measured sleep duration was significantly associated with reduced calcification incidence (adjusted odds ratio, 0.67 per hour [95% confidence interval, 0.49-0.91 per hour]; P = .01). No potential mediators appreciably altered the magnitude or significance of sleep (adjusted odds ratio estimates ranged from 0.64 to 0.68 per sleep hour; maximum P = .02). Alternative sleep metrics were not significantly associated with calcification. CONCLUSION: Longer measured sleep is associated with lower calcification incidence independent of examined potential mediators and confounders.
Authors: King CR; Knutson KL; Rathouz PJ; Sidney S; Liu K; Lauderdale DS
JAMA. 2008 Dec 24;300(24):2859-66.
Comparative effectiveness of different beta-adrenergic antagonists on mortality among adults with heart failure in clinical practice
BACKGROUND: Randomized trials have demonstrated the efficacy of selected beta-blockers in systolic heart failure, but the comparative effectiveness of different beta-blockers in practice is poorly understood. METHODS: We compared mortality associated with different beta-blockers following hospitalization for heart failure between 2001 and 2003. Longitudinal exposure to beta-blockers was ascertained from pharmacy databases. Patient characteristics and other medication use were identified from administrative, hospitalization, outpatient, and pharmacy databases. Death was identified from administrative, state mortality, and Social Security Administration databases. Multivariate Cox regression was used to examine the association between different beta-blockers and death. RESULTS: Among 11 326 adults surviving a hospitalization for heart failure, 7976 received beta-blockers (atenolol, 38.5%; metoprolol tartrate, 43.2%; carvedilol, 11.6%; and other, 6.7%) during follow-up. The rate (per 100 person-years) of death during the 12 months after discharge varied by exposure and type of beta-blocker (atenolol, 20.1; metoprolol tartrate, 22.8; carvedilol, 17.7; and no beta-blockers, 37.0). After adjustment for confounders and the propensity to receive carvedilol, the risk of death compared with atenolol was higher for metoprolol tartrate (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.01-1.34) and no beta-blockers (HR, 1.63; 95% CI, 1.44-1.84) but was not significantly different for carvedilol (HR, 1.16; 95% CI, 0.92-1.44). CONCLUSIONS: Compared with atenolol, the adjusted risks of death were slightly higher with shorter-acting metoprolol tartrate but did not significantly differ for carvedilol in adults with heart failure. Our results should be interpreted cautiously and they suggest the need for randomized trials within real-world settings comparing a broader spectrum of beta-blockers for heart failure.
Authors: Go AS; Yang J; Gurwitz JH; Hsu J; Lane K; Platt R
Arch Intern Med. 2008 Dec 8;168(22):2415-21.
Long-term blood pressure changes measured from before to after pregnancy relative to nonparous women
OBJECTIVE: To prospectively examine whether blood pressure changes persist after pregnancy among women of reproductive age. METHODS: This was a prospective, population-based, observational cohort of 2,304 (1,167 black, 1,137 white) women (aged 18-30 years) who were free of hypertension at baseline (1985-1986) and reexamined up to six times at 2, 5, 7, 10, or 20 years later (2005-2006). We obtained standardized blood pressure measurements before and after pregnancies and categorized women into time-dependent groups by the cumulative number of births since baseline within each time interval (zero births [referent]; one interim birth and two or more interim births; nonhypertensive pregnancies). The study assessed differences in systolic and diastolic blood pressures among interim birth groups using multivariable, repeated measures linear regression models stratified by baseline parity (nulliparous and parous), adjusted for time, age, race, baseline covariates (blood pressure, body mass index, education, and oral contraceptive use), and follow-up covariates (smoking, antihypertensive medications, oral contraceptive use, and weight gain). RESULTS: Among nulliparas at baseline, mean (95% confidence interval) fully adjusted systolic and diastolic blood pressures (mm Hg), respectively, were lower by -2.06 (-2.72 to -1.41) and -1.50 (-2.08 to -0.92) after one interim birth, and lower by -1.89 (-2.63 to -1.15) and -1.29 (-1.96 to -0.63) after two or more interim births compared with no births (all P<.001). Among women already parous at baseline, adjusted mean blood pressure changes did not differ by number of subsequent births. CONCLUSION: A first birth is accompanied by persistent lowering of blood pressure from preconception to years after delivery. Although the biologic mechanism is unclear, pregnancy may create enduring alterations in vascular endothelial function. LEVEL OF EVIDENCE: II.
Authors: Gunderson EP; Chiang V; Lewis CE; Catov J; Quesenberry CP Jr; Sidney S; Wei GS; Ness R
Obstet Gynecol. 2008 Dec;112(6):1294-302.
Calcium plus vitamin D supplementation and the risk of breast cancer
BACKGROUND: Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships. METHODS: Postmenopausal women (N = 36 282) who were enrolled in a Women’s Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D(3). Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided. RESULTS: Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (P(trend) = .20). CONCLUSIONS: Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.
Authors: Chlebowski RT; Khandekar J; Women's Health Initiative Investigators; et al.
J Natl Cancer Inst. 2008 Nov 19;100(22):1581-91. Epub 2008 Nov 11.
The Cardiovascular Research Network: a new paradigm for cardiovascular quality and outcomes research
BACKGROUND: A clear need exists for a more systematic understanding of the epidemiology, diagnosis, and management of cardiovascular diseases. More robust data are also needed on how well clinical trials are translated into contemporary community practice and the associated resource use, costs, and outcomes. METHODS AND RESULTS: The National Heart, Lung, and Blood Institute recently established the Cardiovascular Research Network, which represents a new paradigm to evaluate the epidemiology, quality of care, and outcomes of cardiovascular disease and to conduct future clinical trials using a community-based model. The network includes 15 geographically distributed health plans with dedicated research centers, National Heart, Lung, and Blood Institute representatives, and an external collaboration and advisory committee. Cardiovascular research network sites bring complementary content and methodological expertise and a diverse population of approximately 11 million individuals treated through various health care delivery models. Each site’s rich electronic databases (eg, sociodemographic characteristics, inpatient and outpatient diagnoses and procedures, pharmacy, laboratory, and cost data) are being mapped to create a standardized virtual data warehouse to facilitate rapid and efficient large-scale research studies. Initial projects focus on (1) hypertension recognition and management, (2) quality and outcomes of warfarin therapy, and (3) use, outcomes, and costs of implantable cardioverter defibrillators. CONCLUSIONS: The Cardiovascular Research Network represents a new paradigm in the approach to cardiovascular quality of care and outcomes research among community-based populations. Its unique ability to characterize longitudinally large, diverse populations will yield novel insights into contemporary disease and risk factor surveillance, management, outcomes, and costs. The Cardiovascular Research Network aims to become the national research partner of choice for efforts to improve the prevention, diagnosis, treatment, and outcomes of cardiovascular diseases.
Authors: Go AS; Gurwitz JH; et al.
Circ Cardiovasc Qual Outcomes. 2008 Nov;1(2):138-47.
Higher ABCD2 score predicts patients most likely to have true transient ischemic attack
BACKGROUND AND PURPOSE: Some patients diagnosed with transient ischemic attack (TIA) in the emergency department may actually have alternative diagnoses such as seizure, migraine, or other nonvascular spells. The ABCD2 score has been shown to predict subsequent risk of stroke in patients with TIA diagnosed by emergency physicians, but perhaps high ABCD2 scores simply separate those patients with true TIA from those with alternative diagnoses. We investigated this hypothesis in a cohort of patients with TIA identified in the emergency department whose records were reviewed by an expert neurologist. METHODS: Among patients diagnosed by emergency physicians with TIA in 16 hospitals in the Kaiser-Permanente Medical Care Plan over a 1-year period ending February 1998 (before publication of prediction rules), an expert neurologist reviewed all records for those in which the diagnosis of TIA was considered questionable by a medical records analyst and determined whether the spell was likely to represent a true TIA. Subsequent strokes within 90 days were identified. ABCD2 scores were calculated for all patients and 2-sided Cochrane-Armitage trend tests were used to assess subsequent risk of stroke. RESULTS: Of the 713 patients reviewed by the expert neurologist, 642 (90%) were judged to likely have experienced a true TIA. Ninety-day stroke risk was 24% (95% CI, 20% to 27%) in the group judged to have experienced a true TIA and 1.4% (0% to 7.6%) in the group judged to not have a true TIA (P<0.0001). ABCD(2) scores were higher in those judged to have a true TIA compared with others (P=0.0001). In the group judged to have a true TIA, 90-day stroke risk increased as ABCD2 score increased (P<0.0001); there was no relationship between ABCD2 score and stroke risk in those judged unlikely to have had a TIA (P=0.73). CONCLUSIONS: Among patients diagnosed by emergency department physicians with TIA, higher ABCD2 score was associated with a greater likelihood that the diagnosis was confirmed on expert review. The predictive power of the ABCD2 model is therefore partially explained by identification of those patients likely to have experienced a true TIA, an important aspect of the score when used by nonneurologists. However, higher ABCD2 scores still remained predictive of 90-day stroke rate in the group of patients judged to have a true TIA by an expert neurologist.
Authors: Josephson SA; Sidney S; Pham TN; Bernstein AL; Johnston SC
Stroke. 2008 Nov;39(11):3096-8. Epub 2008 Aug 7.
Racial differences in self-reported infertility and risk factors for infertility in a cohort of black and white women: the CARDIA Women’s Study
OBJECTIVE: To determine racial differences in self-reported infertility and in risk factors for infertility in a cohort of black and white women. DESIGN: A cross-sectional analysis of data from the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective, epidemiologic investigation of the determinants and evolution of cardiovascular risk factors among black and white young adults and from the ancillary CARDIA Women’s Study (CWS). SETTING: Population-based sample from four US communities (Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA). PATIENT(S): Women aged 33-44 years who had complete data (n = 764). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Self-report of ever having unprotected sexual intercourse for at least 12 months without becoming pregnant. RESULT(S): Among nonsurgically sterile women, blacks had a twofold increased odds (95% confidence interval [CI] 1.3-3.1) of infertility compared with whites after adjustment for socioeconomic position (education and ability to pay for basics), correlates of pregnancy intent (marital status and hormonal contraceptive use), and risk factors for infertility (age, smoking, T, fibroid presence, and ovarian volume). The corresponding odds ratio among all women was 1.5 (95% CI 1.0-2.2). Difficulty paying for basics and ovarian volume were associated with infertility among black but not white women. CONCLUSION(S): In this population-based sample, black women were more likely to have experienced infertility. This disparity is not explained by common risk factors for infertility, such as smoking and obesity, and among nonsurgically sterile women, it is not explained by gynecologic risk factors such as fibroids and ovarian volume.
Authors: Wellons MF; Lewis CE; Schwartz SM; Gunderson EP; Schreiner PJ; Sternfeld B; Richman J; Sites CK; Siscovick DS
Fertil Steril. 2008 Nov;90(5):1640-8. Epub 2008 Mar 5.
Incidental pulmonary nodules on cardiac computed tomography: prognosis and use
BACKGROUND: Small asymptomatic lung nodules are found frequently in the course of cardiac computed tomography (CT) scanning. However, the utility of assessing and reporting incidental findings in healthy, asymptomatic subjects is unknown. METHODS: The sample comprised 1023 60- to 69-year-old subjects free of clinical cardiovascular disease and cancer who participated in the Atherosclerotic Disease, VAscular functioN and genetiC Epidemiology Study. All subjects underwent cardiac CT for determination of coronary calcium between 2001 and 2004, and the first 459 subjects were assessed for incidental pulmonary findings. We used health plan clinical databases to ascertain 24-month health care use and clinical outcomes. RESULTS: Noncalcified pulmonary nodules were reported in 81 of 459 subjects (18%). Chest CT was performed on 78% of participants in the 24 months after notification, compared with 2.5% in the previous 24 months. Chest x-ray use increased from 28% to 49%. The mean number of chest CT scans per subject was 1.3 (range, 0-5). Although no malignant lesions were diagnosed in the group who had pulmonary findings read, 1 lung cancer case was diagnosed in the group who did not have lung findings read. Among the 63 participants followed up by CT, the original lesion was not identified in 22 participants (35%), the lesion had decreased or remained stable in 39 participants (62%), and there was interval growth in 2 participants (3%). CONCLUSION: Reporting noncalcified pulmonary nodules resulted in substantial rescanning that overwhelmingly revealed resolution or stability of pulmonary nodules, arguing for benign processes.
Authors: Iribarren C; Hlatky MA; Chandra M; Fair JM; Rubin GD; Go AS; Burt JR; Fortmann SP
Am J Med. 2008 Nov;121(11):989-96.
Central obesity and increased risk of dementia more than three decades later
BACKGROUND: Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later. METHODS: A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted. RESULTS: A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33-3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58-2.35). Those with high SAD (>25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98-3.81) vs those with low SAD (<25 cm) and normal BMI (18.5-24.9 kg/m(2)), whereas those both obese (BMI >30 kg/m(2)) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI, 2.85-4.55). CONCLUSIONS: Central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities. Fifty percent of adults have central obesity; therefore, mechanisms linking central obesity to dementia need to be unveiled.
Authors: Whitmer RA; Gustafson DR; Barrett-Connor E; Haan MN; Gunderson EP; Yaffe K
Neurology. 2008 Sep 30;71(14):1057-64. Epub 2008 Mar 26.
Epidemiology of acute infections among patients with chronic kidney disease
The objectives of this review were (1) to review recent literature on the rates, risk factors, and outcomes of infections in patients who had chronic kidney disease (CKD) and did or did not require renal replacement therapy; (2) to review literature on the efficacy and use of selected vaccines for patients with CKD; and (3) to outline a research framework for examining key issues regarding infections in patients with CKD. Infection-related hospitalizations contribute substantially to excess morbidity and mortality in patients with ESRD, and infection is the second leading cause of death in this population. Patients who have CKD and do not require renal replacement therapy seem to be at higher risk for infection compared with patients without CKD; however, data about patients who have CKD and do not require dialysis therapy are very limited. Numerous factors potentially predispose patients with CKD to infection: advanced age, presence of coexisting illnesses, vaccine hyporesponsiveness, immunosuppressive therapy, uremia, dialysis access, and the dialysis procedure. Targeted vaccination seems to have variable efficacy in the setting of CKD and is generally underused in this population. In conclusion, infection is a primary issue when caring for patients who receive maintenance dialysis. Very limited data exist about the rates, risk factors, and outcomes of infection in patients who have CKD and do not require dialysis. Future research is needed to delineate accurately the epidemiology of infections in these populations and to develop effective preventive strategies across the spectrum of CKD severity.
Authors: Dalrymple LS; Go AS
Clin J Am Soc Nephrol. 2008 Sep;3(5):1487-93. Epub 2008 Jul 23.
Creating a research data network for cardiovascular disease: the CVRN
Authors: Magid DJ; Gurwitz JH; Rumsfeld JS; Go AS
Expert Rev Cardiovasc Ther. 2008 Sep;6(8):1043-5.
Alcohol and hypertension: a review
In recent decades alcohol use has joined other correlates of hypertension (HTN), such as obesity and salt intake, as a major research focus about HTN risk factors. In cross-sectional and prospective epidemiologic studies, higher blood pressure (BP) has consistently been found among persons reporting usual daily intake of three standard-sized drinks or more. Although definitive mechanisms have not been established, several aspects of the data, including short and intermediate term experiments, suggest a causal relationship. Heavier drinking may, in fact, be the commonest cause of reversible HTN, and reduction of heavy alcohol intake plays an important public health role in HTN management. Additional to the mechanism, unresolved issues about the alcohol-BP relationship include whether there is a threshold dosage of alcohol for association with HTN, the sequelae of alcohol-associated HTN and the roles of interactions with gender, ethnicity, other lifestyle traits, drinking pattern, and choice of beverage. This article reviews these areas and includes new data about the beverage choice aspect.
Authors: Klatsky AL; Gunderson E
J Am Soc Hypertens. 2008 Sep-Oct;2(5):307-17. Epub 2008 Jun 24.
Cardiology clinical trial participation in community-based healthcare systems: obstacles and opportunities
BACKGROUND: The objective of our study was to examine cardiologists’ and organizational leaders’ interest in clinical trial participation and perceived barriers and facilitators to participation within ten diverse non-profit healthcare delivery systems. Trials play a pivotal role in advancing knowledge about the safety and efficacy of cardiovascular interventions and tests. Although cardiovascular trials successfully enroll patients, recruitment challenges persist. Community-based health systems could be an important source of participants and investigators, but little is known about community cardiologists’ experiences with trials. METHODS: We interviewed 25 cardiology and administrative leaders and mailed questionnaires to all 280 cardiologists at 10 U.S. healthcare organizations. RESULTS: The survey received a 73% response rate. While 60% of respondents had not participated in any trials in the past year, nearly 75% wanted greater participation. Cardiologists reported positive attitudes toward trial participation; more than half agreed that trials were their first choice of therapy for patients, if available. Almost all leaders described their organizations as valuing research but not necessarily trials. Major barriers to participation were lack of physician time and insufficient skilled research nurses. CONCLUSIONS: Cardiologists have considerable interest in trial participation. Major obstacles to increased participation are lack of time and effective infrastructure to support trials. These results suggest that community-based health systems are a rich source for cardiovascular research but additional funding and infrastructure are needed to leverage this resource.
Authors: Somkin CP; Altschuler A; Ackerson L; Tolsma D; Rolnick SJ; Yood R; Weaver WD; Von Worley A; Hornbrook M; Magid DJ; Go AS
Contemp Clin Trials. 2008 Sep;29(5):646-53. Epub 2008 Mar 4.
COPD as a systemic disease: impact on physical functional limitations
PURPOSE: Although chronic obstructive pulmonary disease (COPD) has a major impact on physical health, the specific impact of COPD on physical functional limitations has not been characterized clearly. We aimed to elucidate the physical functional limitations that are directly attributable to COPD compared to a matched referent group without the condition. METHODS: We used the Function, Living, Outcomes, and Work (FLOW) cohort study of adults with COPD (n=1202) and referent subjects matched by age, sex, and race (n=302) to study the impact of COPD on the risk of a broad array of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery [SPPB]), submaximal exercise performance (Six Minute Walk Test [SMWT]), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multivariate analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking. RESULTS: COPD was associated with poorer lower extremity function (mean SPPB score decrement for COPD vs referent -1.0 points; 95% CI, -1.25 to -0.73 pts) and less distance walked during the SMWT (-334 feet; 95% CI, -384 to -282 ft). COPD also was associated with weaker muscle strength in every muscle group tested, including both the upper and lower extremities (P<.0001 in all cases) and with a greater risk of self-reported functional limitation (OR 6.4; 95% CI, 3.7 to 10.9). CONCLUSIONS: A broad array of physical functional limitations were specifically attributable to COPD. COPD affects a multitude of body systems remote from the lung.
Authors: Eisner MD; Blanc PD; Yelin EH; Sidney S; Katz PP; Ackerson L; Lathon P; Tolstykh I; Omachi T; Byl N; Iribarren C
Am J Med. 2008 Sep;121(9):789-96.
Breast-feeding and diabetes: long-term impact on mothers and their infants
In the general population, breast-feeding is associated with a reduced risk of the offspring being overweight later in life by 22% to 24% across the age spectrum, from preschool children to adults. There is a dose-response gradient with increasing duration of breast-feeding, and lowest risk with prolonged, exclusive breast-feeding. Breast-feeding has been shown to slow infant growth up to 2 years of age. By contrast, the scientific evidence is inconclusive about whether breast-feeding protects against the onset of overweight and subsequent development of type 2 diabetes among offspring whose mothers had diabetes during pregnancy. Moreover, evidence is insufficient to determine if lactation protects against development of type 2 diabetes later in life in women with a diabetes history during pregnancy. Given the paucity of the evidence and equivocal findings about the long-term effects of breast-feeding on future health of women with diabetes during pregnancy and their infants, further research is recommended.
Authors: Gunderson EP
Curr Diab Rep. 2008 Aug;8(4):279-86.
Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study
A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.
Authors: Assimes TL; Iribarren C; Go AS; Risch N; Quertermous T; et al.
Hum Mol Genet. 2008 Aug 1;17(15):2320-8. Epub 2008 Apr 28.
Risk factors for death in adults with severe asthma
BACKGROUND: Mortality risk in adult asthma is poorly understood, especially the interplay among race, disease severity, and health care access. OBJECTIVE: To examine mortality risk factors in adult asthma. METHODS: In a prospective cohort study of 865 adults with severe asthma in a closed-panel managed care organization, we used structured interviews to evaluate baseline sociodemographics, asthma history, and health status. Patients were followed up until death or the end of the study (mean, 2 years). We used Cox proportional hazards regression to evaluate the impact of sociodemographics, cigarette smoking, and validated measures of perceived asthma control, physical health status, and severity of asthma on the risk of death. RESULTS: We confirmed 123 deaths (mortality rate, 6.7 per 100 person-years). In an analysis adjusted for sociodemographics and tobacco history, higher severity-of-asthma scores (hazard ratio [HR], 1.11 per 0.5-SD increase in severity-of-asthma score; 95% confidence interval [CI], 1.01-1.23) and lower perceived asthma control scores (HR, 0.91 per 0.5-SD increase in perceived asthma control score; 95% CI, 0.83-0.99) were each associated with risk of all-cause mortality. In the same adjusted analysis, African American race was not associated with increased mortality risk relative to white race (HR, 0.64; 95% CI, 0.36-1.14). CONCLUSIONS: In a large managed care organization in which access to care is unlikely to vary widely, greater severity-of-asthma scores and poorer perceived asthma control scores are each associated with increased mortality risk in adults with severe asthma, but African American patients are not at increased risk for death relative to white patients.
Authors: Omachi TA; Iribarren C; Sarkar U; Tolstykh I; Yelin EH; Katz PP; Blanc PD; Eisner MD
Ann Allergy Asthma Immunol. 2008 Aug;101(2):130-6.
Low-fat dietary pattern and risk of treated diabetes mellitus in postmenopausal women: the Women’s Health Initiative randomized controlled dietary modification trial
BACKGROUND: Decreased fat intake with weight loss and increased exercise may reduce the risk of diabetes mellitus in persons with impaired glucose tolerance. This study was undertaken to assess the effects of a low-fat dietary pattern on incidence of treated diabetes among generally healthy postmenopausal women. METHODS: A randomized controlled trial was conducted at 40 US clinical centers from 1993 to 2005, including 48,835 postmenopausal women aged 50 to 79 years. Women were randomly assigned to a usual-diet comparison group (n = 29,294 [60.0%]) or an intervention group with a 20% low-fat dietary pattern with increased vegetables, fruits, and grains (n = 19,541 [40.0%]). Self-reported incident diabetes treated with oral agents or insulin was assessed. RESULTS: Incident treated diabetes was reported by 1303 intervention participants (7.1%) and 2039 comparison participants (7.4%) (hazard ratio, 0.96; 95% confidence interval, 0.90-1.03; P = .25). Weight loss occurred in the intervention group, with a difference between intervention and comparison groups of 1.9 kg after 7.5 years (P < .001). Subgroup analysis suggested that greater decreases in percentage of energy from total fat reduced diabetes risk (P for trend = .04), which was not statistically significant after adjusting for weight loss. CONCLUSIONS: A low-fat dietary pattern among generally healthy postmenopausal women showed no evidence of reducing diabetes risk after 8.1 years. Trends toward reduced incidence were greater with greater decreases in total fat intake and weight loss. Weight loss, rather than macronutrient composition, may be the dominant predictor of reduced risk of diabetes.
Authors: Tinker LF; Larson J; Women's Health Initiative; et al.
Arch Intern Med. 2008 Jul 28;168(14):1500-11.
Prehypertension during young adulthood and coronary calcium later in life
BACKGROUND: High blood pressure in middle age is a well-established risk factor for cardiovascular disease, but the consequences of low-level elevations during young adulthood are unknown. OBJECTIVE: To measure the association between prehypertension exposure before age 35 years and coronary calcium later in life. DESIGN: Prospective cohort study. SETTING: Four communities in the United States. PARTICIPANTS: Black and white men and women age 18 to 30 years recruited for the CARDIA (Coronary Artery Risk Development in Young Adults) Study in 1985 through 1986 who were without hypertension before age 35 years. MEASUREMENTS: Blood pressure trajectories for each participant were estimated by using measurements from 7 examinations over the course of 20 years. Cumulative exposure to blood pressure in the prehypertension range (systolic blood pressure of 120 to 139 mm Hg, or diastolic blood pressure of 80 to 89 mm Hg) from age 20 to 35 years was calculated in units of mm Hg-years (similar to pack-years of tobacco exposure) and related to the presence of coronary calcium measured at each participant’s last examination (mean age, 44 years [SD, 4]). RESULTS: Among 3560 participants, the 635 (18%) who developed prehypertension before age 35 years were more often black, male, overweight, and of lower socioeconomic status. Exposure to prehypertension before age 35 years, especially systolic prehypertension, showed a graded association with coronary calcium later in life (coronary calcium prevalence of 15%, 24%, and 38% for 0, 1 to 30, and >30 mm Hg-years of exposure, respectively; P < 0.001). This association remained strong after adjustment for blood pressure elevation after age 35 years and other coronary risk factors and participant characteristics. LIMITATION: Coronary calcium, although a strong predictor of future coronary heart disease, is not a clinical outcome. CONCLUSION: Prehypertension during young adulthood is common and is associated with coronary atherosclerosis 20 years later. Keeping systolic pressure below 120 mm Hg before age 35 years may provide important health benefits later in life.
Authors: Pletcher MJ; Bibbins-Domingo K; Lewis CE; Wei GS; Sidney S; Carr JJ; Vittinghoff E; McCulloch CE; Hulley SB
Ann Intern Med. 2008 Jul 15;149(2):91-9.
Chronic conditions and mortality among the oldest old
OBJECTIVES: We sought to determine whether chronic conditions and functional limitations are equally predictive of mortality among older adults. METHODS: Participants in the 1998 wave of the Health and Retirement Study (N=19430) were divided into groups by decades of age, and their vital status in 2004 was determined. We used multivariate Cox regression to determine the ability of chronic conditions and functional limitations to predict mortality. RESULTS: As age increased, the ability of chronic conditions to predict mortality declined rapidly, whereas the ability of functional limitations to predict mortality declined more slowly. In younger participants (aged 50-59 years), chronic conditions were stronger predictors of death than were functional limitations (Harrell C statistic 0.78 vs. 0.73; P=.001). In older participants (aged 90-99 years), functional limitations were stronger predictors of death than were chronic conditions (Harrell C statistic 0.67 vs. 0.61; P=.004). CONCLUSIONS: The importance of chronic conditions as a predictor of death declined rapidly with increasing age. Therefore, risk-adjustment models that only consider comorbidities when comparing mortality rates across providers may be inadequate for adults older than 80 years.
Authors: Lee SJ; Go AS; Lindquist K; Bertenthal D; Covinsky KE
Am J Public Health. 2008 Jul;98(7):1209-14. Epub 2008 May 29.
Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation
BACKGROUND: Circulating levels of acute phase reactant proteins such as plasma C-reactive protein (CRP) are likely influenced by multiple genes regulating the innate immune response. METHODS AND RESULTS: We screened a set of 16 inflammation-related genes for association with CRP in a large population-based study of healthy young adults (n=1627). Results were validated in 2 independent studies (n=1208 and n=4310), including a pooled analysis of all 3 studies. In the pooled analysis, the minor allele of IL1RN 1018 (rs4251961) within the gene encoding interleukin (IL)-1 receptor antagonist (IL-1RA) was significantly associated with higher mean plasma log(CRP) level (P<1 x 10(-4)). The same IL1RN 1018 allele was associated with higher mean plasma log(IL-6) levels (P=0.004). In the pooled analysis, the minor allele of IL1RN 13888 (rs2232354) was associated with higher fibrinogen, (P=0.001). The IL1RN 1018 and 13888 variant alleles tag a clade of IL1RN haplotypes linked to allele 1 of an 86-bp VNTR polymorphism. We confirmed that the IL1RN 1018 variant (rs4251961) was associated with decreased cellular IL-1RA production ex vivo. CONCLUSIONS: Common functional polymorphisms of the IL1RN gene are associated with several markers of systemic inflammation.
Authors: Reiner AP; Walston JD; Jarvik GP; et al.
Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):1407-12. Epub 2008 May 1.
The risk of acute renal failure in patients with chronic kidney disease
Few studies have defined how the risk of hospital-acquired acute renal failure varies with the level of estimated glomerular filtration rate (GFR). It is also not clear whether common factors such as diabetes mellitus, hypertension and proteinuria increase the risk of nosocomial acute renal failure independent of GFR. To determine this we compared 1,746 hospitalized adult members of Kaiser Permanente Northern California who developed dialysis-requiring acute renal failure with 600,820 hospitalized members who did not. Patient GFR was estimated from the most recent outpatient serum creatinine measurement prior to admission. The adjusted odds ratios were significantly and progressively elevated from 1.95 to 40.07 for stage 3 through stage 5 patients (not yet on maintenance dialysis) compared to patients with estimated GFR in the stage 1 and 2 range. Similar associations were seen after controlling for inpatient risk factors. Pre-admission baseline diabetes mellitus, diagnosed hypertension and known proteinuria were also independent risk factors for acute kidney failure. Our study shows that the propensity to develop in-hospital acute kidney failure is another complication of chronic kidney disease whose risk markedly increases even in the upper half of stage 3 estimated GFR. Several common risk factors for chronic kidney disease also increase the peril of nosocomial acute kidney failure.
Authors: Hsu CY; Ordonez JD; Chertow GM; Fan D; McCulloch CE; Go AS
Kidney Int. 2008 Jul;74(1):101-7. Epub 2008 Apr 2.
Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation
BACKGROUND AND PURPOSE: More than a dozen schemes for stratifying stroke risk in patients with nonvalvular atrial fibrillation have been published. Differences among these schemes lead to inconsistent stroke risk estimates for many atrial fibrillation patients, resulting in confusion among clinicians and nonuniform use of anticoagulation. METHODS: Twelve published schemes stratifying stroke risk in patients with nonvalvular atrial fibrillation are analyzed, and observed stroke rates in independent test cohorts are compared with predicted risk status. RESULTS: Seven schemes were based directly on event-rate analyses, whereas 5 resulted from expert consensus. Four considered only clinical features, whereas 7 schemes included echocardiographic variables. The number of variables per scheme ranged from 4 to 8 (median, 6). The most frequently included features were previous stroke/TIA (100% of schemes), patient age (83%), hypertension (83%), and diabetes (83%), and 8 additional variables were included in >/=1 schemes. Based on published test cohorts, all 8 tested schemes stratified stroke risk, but the absolute stroke rates varied widely. Observed rates for those categorized as low risk ranged from 0% to 2.3% per year and those categorized as high risk ranged from 2.5% to 7.9% per year. When applied to the same cohorts, the fractions of patients categorized by the different schemes as low risk varied from 9% to 49% and those categorized by the different schemes as high-risk varied from 11% to 77%. CONCLUSIONS: There are substantial, clinically relevant differences among published schemes designed to stratify stroke risk in patients with atrial fibrillation. Additional research to identify an optimum scheme for primary prevention and subsequent standardization of recommendations may lead to more uniform selection of patients for anticoagulant prophylaxsis.
Authors: Stroke Risk in Atrial Fibrillation Working Group
Stroke. 2008 Jun;39(6):1901-10. Epub 2008 Apr 17.
Changes over 14 years in androgenicity and body mass index in a biracial cohort of reproductive-age women
BACKGROUND: Body mass index (BMI) is directly related to testosterone (total T and free T) and inversely to SHBG cross-sectionally, but little is known about how changes in body fat and androgen markers affect each other over time. METHODS: Participants included 969 White and Black women from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, who were ages 18-30 at entry into the study and were pre- or perimenopausal 16 yr later at the time of the CARDIA Women’s Study (CWS). Total T and SHBG were assayed from specimens drawn at the CWS examination and stored serum from the yr 2 and 10 CARDIA exams. Free T was calculated based on total T and SHBG. BMI and waist circumference were measured at yr 2, 10, and 16. RESULTS: Despite clinically significant increases in BMI and waist circumference, total T and free T tended to decline, whereas SHBG remained relatively constant. BMI and waist circumference were directly correlated with free T and inversely correlated with SHBG in cross-sectional analyses. In longitudinal, multivariable analyses, an annualized increase in BMI was inversely related to a concurrent annualized decrease in SHBG (beta = -0.79 ng/dl, and se = 0.22 in Blacks; beta = -1.07 ng/dl; and se = 0.31 in Whites). However, early increases in BMI were not related to later decreases in SHBG. CONCLUSION: Increases in adiposity are closely tied to decreases in SHBG, but changes in BMI and SHBG may occur concurrently rather than sequentially.
Authors: Sternfeld B; Quesenberry CP Jr; Siscovick DS; et al.
J Clin Endocrinol Metab. 2008 Jun;93(6):2158-65. Epub 2008 Mar 11.
Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
This chapter about antithrombotic therapy in atrial fibrillation (AF) is part of the American College of Chest Physicians Evidence-Based Guidelines Clinical Practice Guidelines (8th Edition). Grade 1 recommendations indicate that most patients would make the same choice and Grade 2 suggests that individual patient’s values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following (all vitamin K antagonist [VKA] recommendations have a target international normalized ratio [INR] of 2.5; range 2.0-3.0, unless otherwise noted). In patients with AF, including those with paroxysmal AF, who have had a prior ischemic stroke, transient ischemic attack (TIA), or systemic embolism, we recommend long-term anticoagulation with an oral VKA, such as warfarin, because of the high risk of future ischemic stroke faced by this set of patients (Grade 1A). In patients with AF, including those with paroxysmal AF, who have two or more of the risk factors for future ischemic stroke listed immediately below, we recommend long-term anticoagulation with an oral VKA (Grade 1A). Two or more of the following risk factors apply: age >75 years, history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function and/or heart failure. In patients with AF, including those with paroxysmal AF, with only one of the risk factors listed immediately above, we recommend long-term antithrombotic therapy (Grade 1A), either as anticoagulation with an oral VKA, such as warfarin (Grade 1A), or as aspirin, at a dose of 75-325 mg/d (Grade 1B). In these patients at intermediate risk of ischemic stroke we suggest a VKA rather than aspirin (Grade 2A). In patients with AF, including those with paroxysmal AF, age < or =75 years and with none of the other risk factors listed above, we recommend long-term aspirin therapy at a dose of 75-325 mg/d (Grade 1B), because of their low risk of ischemic stroke. For patients with atrial flutter, we recommend that antithrombotic therapy decisions follow the same risk-based recommendations as for AF (Grade 1C). For patients with AF and mitral stenosis, we recommend long-term anticoagulation with an oral VKA (Grade 1B). For patients with AF and prosthetic heart valves we recommend long-term anticoagulation with an oral VKA at an intensity appropriate for the specific type of prosthesis (Grade 1B). See CHEST 2008; 133(suppl):593S-629S. For patients with AF of > or =48 h or of unknown duration for whom pharmacologic or electrical cardioversion is planned, we recommend anticoagulation with an oral VKA, such as warfarin, for 3 weeks before elective cardioversion and for at least 4 weeks after sinus rhythm has been maintained (Grade 1C). For patients with AF of > or = 48 h or of unknown duration undergoing pharmacological or electrical cardioversion, we also recommend either immediate anticoagulation with unfractionated IV heparin, or low-molecular-weight heparin (LMWH), or at least 5 days of warfarin by the time of cardioversion (achieving an INR of 2.0-3.0) as well as a screening multiplane transesophageal echocardiography (TEE). If no thrombus is seen, cardioversion is successful, and sinus rhythm is maintained, we recommend anticoagulation for at least 4 weeks. If a thrombus is seen on TEE, then cardioversion should be postponed and anticoagulation should be continued indefinitely. We recommend obtaining a repeat TEE before attempting later cardioversion (Grade 1B addressing the equivalence of TEE-guided vs non-TEE-guided cardioversion). For patients with AF of known duration <48 h, we suggest cardioversion without prolonged anticoagulation (Grade 2C). However, in patients without contraindications to anticoagulation, we suggest beginning IV heparin or LMWH at presentation (Grade 2C).
Authors: Singer DE; Albers GW; Dalen JE; Fang MC; Go AS; Halperin JL; Lip GY; Manning WJ; American College of Chest Physicians
Chest. 2008 Jun;133(6 Suppl):546S-592S.
Cardiac autonomic control and the effects of age, race, and sex: the CARDIA study
BACKGROUND: Stratification variables of age, race, and sex figure prominently in the assessment of cardiovascular disease risk. Similarly, cardiac autonomic regulation, measured by RR interval variability (RRV), is associated with risk. The relationship among these variables is unclear. METHODS: We examined the cross-sectional relationship between RRV and age, race, and sex in 757 subjects from the NHLBI-funded Coronary Artery Disease in Young Adults (CARDIA) Study. RESULTS: Age was a significant determinant of RRV, despite the narrow range (33-47): participants aged 33-39 years had had greater levels of HF power, LF power, and standard deviation (SD) of RR intervals than did those aged 40-47 years. There was no age effect for the LF/HF ratio. Compared to whites, blacks had lower levels of LF power, SD, and lower LF/HF. Blacks and whites did not differ in HF power. Finally, compared to men, women had lower levels of LF power, SD, and LF/HF but did not differ in HF power. CONCLUSIONS: Data from the CARDIA study suggest that in adults in the 33-47 year age range, indices of RRV were greater in younger compared to older subjects, in men compared to women and in whites compared to blacks. These findings are broadly consistent with those of other large studies examining relationships between RRV and age, sex, and race. However, patterns of associations between RRV and these stratification variables are not entirely consistent with an underlying autonomic physiology linked to cardioprotection.
Authors: Sloan RP; Huang MH; McCreath H; Sidney S; Liu K; Dale Williams O; Seeman T
Auton Neurosci. 2008 May 30;139(1-2):78-85. Epub 2008 Mar 4.
The associations of regional adipose tissue with lipid and lipoprotein levels in HIV-infected men
BACKGROUND: HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional adipose tissue depots and lipid levels is not defined. METHODS: The association of magnetic resonance imaging-measured visceral adipose tissue (VAT) and regional subcutaneous adipose tissue (SAT) volume with fasting lipid parameters was analyzed by multivariable linear regression in 737 HIV-infected and 145 control men from the study of Fat Redistribution and Metabolic Change in HIV Infection. RESULTS: HIV-infected men had higher median triglycerides (170 mg/dL vs. 107 mg/dL; P < 0.0001), lower high-density lipoprotein cholesterol (HDL-C; 38 mg/dL vs. 46 mg/dL; P < 0.0001), and lower low-density lipoprotein cholesterol (LDL-C; 105 mg/dL vs. 125 mg/dL; P < 0.0001) than controls. After adjustment, greater VAT was associated with higher triglycerides and lower HDL-C in HIV-infected and control men, whereas greater leg SAT was associated with lower triglycerides in HIV-infected men with a similar trend in controls. More upper trunk SAT was associated with higher LDL-C and lower HDL-C in controls, whereas more lower trunk SAT was associated with higher triglycerides in controls. After adjustment, HIV infection remained strongly associated (P < 0.0001) with higher triglycerides (+76%, 95% confidence interval [CI]: 53 to 103), lower LDL-C (-19%, 95% CI: -25 to -12), and lower HDL-C (-18%, 95% CI: -22 to -12). CONCLUSIONS: HIV-infected men are more likely than controls to have higher triglycerides and lower HDL-C, which promote atherosclerosis, but also lower LDL-C. Less leg SAT and more VAT are important factors associated with high triglycerides and low HDL-C in HIV-infected men. The reduced leg SAT in HIV-infected men with lipoatrophy places them at increased risk for proatherogenic dyslipidemia.
Authors: Wohl D; Scherzer R; Heymsfield S; Simberkoff M; Sidney S; Bacchetti P; Grunfeld C; FRAM Study Investigators
J Acquir Immune Defic Syndr. 2008 May 1;48(1):44-52.
Regional adipose tissue and lipid and lipoprotein levels in HIV-infected women
BACKGROUND: HIV infection and antiretroviral therapy are associated with dyslipidemia, but the association between regional body fat and lipid levels is not well described. METHODS: Multivariable linear regression analyzed the association between magnetic resonance imaging-measured regional adipose tissue and fasting lipids in 284 HIV-infected and 129 control women. RESULTS: Among African Americans, HIV-infected women had higher triglyceride (116 vs. 83 mg/dL; P < 0.001), similar high-density lipoprotein (HDL; 52 vs. 50 mg/dL; P = 0.60), and lower low-density lipoprotein (LDL; 99 vs. 118 mg/dL; P = 0.008) levels than controls. Among whites, HIV-infected women had higher triglyceride (141 vs. 78 mg/dL; P < 0.001), lower HDL (46 vs. 57 mg/dL; P < 0.001), and slightly lower LDL (100 vs. 107 mg/dL; P = 0.059) levels than controls. After adjustment for demographic and lifestyle factors, the highest tertile of visceral adipose tissue (VAT) was associated with higher triglyceride (+85%, 95% confidence interval [CI]: 55 to 121) and lower HDL (-9%, 95% CI: -18 to 0) levels in HIV-infected women; the highest tertile of leg subcutaneous adipose tissue (SAT) was associated with lower triglyceride levels in HIV-infected women (-28%, 95% CI: -41 to -11) and controls (-39%, 95% CI: -5 to -18). After further adjustment for adipose tissue, HIV infection remained associated with higher triglyceride (+40%, 95% CI: 21 to 63) and lower LDL (-17%, 95% CI: -26 to -8) levels, whereas HIV infection remained associated with lower HDL levels (-21%, 95% CI: -29 to -12) in whites but not in African Americans (+8%, 95% CI: -2 to 19). CONCLUSIONS: HIV-infected white women are more likely to have proatherogenic lipid profiles than HIV-infected African American women. Less leg SAT and more VAT are important factors associated with adverse lipid levels. HIV-infected women may be at particular risk for dyslipidemia because of the risk for HIV-associated lipoatrophy.
Authors: Currier J; Scherzer R; Bacchetti P; Heymsfield S; Lee D; Sidney S; Tien PC; Fat Redistribution and Metabolic Changes in HIV Infection Study Investigators
J Acquir Immune Defic Syndr. 2008 May 1;48(1):35-43.
Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care
Authors: Kitzmiller JL; Gunderson EP; Kirkman MS; et al.
Diabetes Care. 2008 May;31(5):1060-79.
Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease
Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
Authors: Assimes TL; Knowles JW; Priest JR; Basu A; Volcik KA; Southwick A; Tabor HK; Hartiala J; Allayee H; Grove ML; Tabibiazar R; Sidney S; Fortmann SP; Go A; Hlatky M; Iribarren C; Boerwinkle E; Myers R; Risch N; Quertermous T
Hum Genet. 2008 May;123(4):399-408. Epub 2008 Mar 28.
A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease
OBJECTIVE: Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD). METHODS AND RESULTS: We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9). CONCLUSIONS: A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.
Authors: Assimes TL; Go AS; Iribarren C; Risch N; Quertermous T; et al.
Atherosclerosis. 2008 May;198(1):136-44. Epub 2007 Oct 23.
Pulmonary function and the risk of functional limitation in chronic obstructive pulmonary disease
The authors’ objective was to analyze the impact of respiratory impairment on the risk of physical functional limitations among adults with chronic obstructive pulmonary disease (COPD). They hypothesized that greater pulmonary function decrement would result in a broad array of physical functional limitations involving organ systems remote from the lung, a key step in the pathway leading to overall disability. The authors used baseline data from the Function, Living, Outcomes, and Work (FLOW) study, a prospective cohort study of adults with COPD recruited from northern California in 2005-2007. They studied the impact of pulmonary function impairment on the risk of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery), submaximal exercise performance (6-Minute Walk Test), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multiple variable analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking. Greater pulmonary function impairment, as evidenced by lower forced expiratory volume in 1 second (FEV(1)), was associated with poorer Short Physical Performance Battery scores and less distance walked during the 6-Minute Walk Test. Lower forced expiratory volume in 1 second was also associated with weaker muscle strength and with a greater risk of self-reported functional limitation (p < 0.05). In conclusion, pulmonary function impairment is associated with multiple manifestations of physical functional limitation among COPD patients. Longitudinal follow-up can delineate the impact of these functional limitations on the prospective risk of disability, guiding preventive strategies that could attenuate the disablement process.
Authors: Eisner MD; Iribarren C; Yelin EH; Sidney S; Katz PP; Ackerson L; Lathon P; Tolstykh I; Omachi T; Byl N; Blanc PD
Am J Epidemiol. 2008 May 1;167(9):1090-101. Epub 2008 Mar 14.
Childbearing may increase visceral adipose tissue independent of overall increase in body fat
OBJECTIVE: To examine whether childbearing is associated with increased visceral adiposity and whether the increase is proportionally larger than other depots. METHODS AND PROCEDURES: This prospective study examined changes in adiposity assessed via computed tomography (CT) and dual-energy X-ray absorptiometry among 122 premenopausal women (50 black, 72 white) examined in 1995-1996 and again in 2000-2001. During the 5-year interval, 14 women had one interim birth and 108 had no interim births. Multiple linear regression models estimated mean (95% confidence interval (CI)) 5-year changes in anthropometric and adiposity measures by interim births adjusted for age, race, and changes in total and subcutaneous adiposity. RESULTS: We found no significant differences between one interim birth and no interim births for 5-year changes in weight, BMI, total body fat, subcutaneous adipose tissue, or total abdominal adipose tissue. Visceral adipose tissue increased by 40 and 14% above initial levels for 1 birth and 0 birth groups, respectively. Having 1 birth vs. 0 births was associated with a greater increase in visceral adipose tissue of 18.0 cm2 (4.8, 31.2), P<0.01; gain of 27.1 cm2 (14.5, 39.7) vs. 9.2 cm2 (4.8, 13.6), and a borderline greater increase in waist girth of 2.3 cm (0, 4.5), P=0.05; gain of 6.3 cm (4.1, 8.5) vs. 4.0 cm (3.2, 4.8), controlling for gain in total body fat and covariates. DISCUSSION: Pregnancy may be associated with preferential accumulation of adipose tissue in the visceral compartment for similar gains in total body fat. Further investigation is needed to confirm these findings and determine whether excess visceral fat deposition with pregnancy adversely affects metabolic risk profiles among women.
Authors: Gunderson EP; Sternfeld B; Wellons MF; Whitmer RA; Chiang V; Quesenberry CP Jr; Lewis CE; Sidney S
Obesity (Silver Spring). 2008 May;16(5):1078-84. Epub 2008 Mar 6.
Incidental findings on cardiac multidetector row computed tomography among healthy older adults: prevalence and clinical correlates
BACKGROUND: With the widespread use of cardiac multidetector row computed tomography (MDCT), the issue of incidental findings is receiving increasing attention. Our objectives were to evaluate the prevalence of incidental findings discovered during cardiac MDCT scanning and to identify clinical variables associated with incidental findings. METHODS: This cross-sectional analysis involved a population-based sample recruited from an integrated health care delivery system in Northern California as part of the Atherosclerotic Disease, Vascular Function and Genetic Epidemiology (ADVANCE) Study. Healthy men and women aged 60 to 69 years without diagnosed cardiovascular disease underwent cardiac MDCT for the detection and quantification of coronary artery calcification. The images were prospectively evaluated for incidental findings. RESULTS: A total of 459 participants underwent MDCT scanning, and the overall prevalence of any incidental finding was 41%. Of the 459 participants, 105 (23%) had at least 1 incidental finding that was recommended for clinical or radiological follow-up examination, the most common of which was single or multiple pulmonary nodules (18%). Participants with and without incidental findings had comparable baseline demographics and selected clinical variables, although there were significantly fewer men and a significantly lower prevalence of the metabolic syndrome in those with incidental findings. CONCLUSIONS: Incidental findings, especially pulmonary nodules, are common in cardiac MDCT performed to assess coronary artery calcification in older healthy adults. The net risks and benefits of looking for noncardiac abnormalities during cardiac MDCT should be rigorously evaluated.
Authors: Burt JR; Iribarren C; Fair JM; Norton LC; Mahbouba M; Rubin GD; Hlatky MA; Go AS; Fortmann SP; Atherosclerotic Disease VFaGEAS
Arch Intern Med. 2008 Apr 14;168(7):756-61.
How accurate is CT angiography in evaluating intracranial atherosclerotic disease?
BACKGROUND AND PURPOSE: Digital subtraction angiography (DSA) is regarded as the gold standard in assessing degree of stenosis in intracranial vessels. However, it is invasive and can only be carried out at specialized centers. We sought to compare CT angiography (CTA) to DSA for detection and measurement of stenosis in large intracranial arteries.METHODS: We identified all subjects admitted with ischemic stroke or transient ischemic attack and with CTA and DSA studies of good quality completed within 30 days of each other between April 2000 and May 2006 at a single medical center. Two readers blinded to clinical information reviewed each CTA and DSA independently. Each reader located and measured stenosis of 15 prespecified large intracranial arterial segments per study at the same level of magnification. These stenotic lesions were most likely atherosclerotic in etiology. All measurements were made with Wiha digiMax 6" digital calipers. The degree of stenosis was calculated using the published method for the Warfarin-Aspirin Symptomatic Intracranial Disease study. All disagreements of greater than 10% were reviewed by a third reader who decided between the 2 prior measurements. Segments were excluded from analyses if they were judged to be congenitally hypoplastic or seen only through collaterals or cross-filling. Intraclass correlation, sensitivity, and specificity were calculated using DSA as the reference standard.RESULTS: Forty-one pairs of CTA and DSAs from 41 patients were reviewed. CTAs were completed within 28 days before 13 days after DSA, with a median of 1 day. A total of 475 pairs of major intracranial arterial segment were analyzed. Intraclass correlation between degree of stenosis based on CTA and DSA for all segments was 0.98 (P=0.001). CTA detected large arterial occlusion with 100% sensitivity and specificity. For detection of >or=50% stenosis, CTA had 97.1% sensitivity and 99.5% specificity. To detect all lesions >or=50% as determined by DSA, the cut off point on CTA appeared to be at >or=30%, with a false-positive rate of 2.4%.CONCLUSIONS: Compared to DSA, CTA has high sensitivity and specificity for detecting >or=50% stenosis of large intracranial arterial segments. CTA is minimally invasive and may be a useful screening tool for intracranial arterial disease and occlusion.
Authors: Nguyen-Huynh MN1; Wintermark M; English J; Lam J; Vittinghoff E; Smith WS; Johnston SC;
Stroke. 2008 Apr;39(4):1184-8. doi: 10.1161/STROKEAHA.107.502906. Epub 2008 Feb 21.
Short sleep duration in infancy and risk of childhood overweight
OBJECTIVE: To examine the extent to which infant sleep duration is associated with overweight at age 3 years. DESIGN: Longitudinal survey. SETTING: Multisite group practice in Massachusetts. PARTICIPANTS: Nine hundred fifteen children in Project Viva, a prospective cohort. Main Exposure At children’s ages 6 months, 1 year, and 2 years, mothers reported the number of hours their children slept in a 24-hour period, from which we calculated a weighted average of daily sleep. MAIN OUTCOME MEASURES: We used multivariate regression analyses to predict the independent effects of sleep duration (< 12 h/d vs > or = 12 h/d) on body mass index (BMI) (calculated as the weight in kilograms divided by the height in meters squared) z score, the sum of subscapular and triceps skinfold thicknesses, and overweight (BMI for age and sex > or = 95th percentile) at age 3 years. RESULTS: The children’s mean (SD) duration of daily sleep was 12.3 (1.1) hours. At age 3 years, 83 children (9%) were overweight; the mean (SD) BMI z score and sum of subscapular and triceps skinfold thicknesses were 0.44 (1.03) and 16.66 (4.06) mm, respectively. After adjusting for maternal education, income, prepregnancy BMI, marital status, smoking history, and breastfeeding duration and child’s race/ethnicity, birth weight, 6-month weight-for-length z score, daily television viewing, and daily participation in active play, we found that infant sleep of less than 12 h/d was associated with a higher BMI z score (beta, 0.16; 95% confidence interval, 0.02-0.29), higher sum of subscapular and triceps skinfold thicknesses (beta, 0.79 mm; 95% confidence interval, 0.18-1.40), and increased odds of overweight (odds ratio, 2.04; 95% confidence interval, 1.07-3.91). CONCLUSION: Daily sleep duration of less than 12 hours during infancy appears to be a risk factor for overweight and adiposity in preschool-aged children.
Authors: Taveras EM; Rifas-Shiman SL; Oken E; Gunderson EP; Gillman MW
Arch Pediatr Adolesc Med. 2008 Apr;162(4):305-11.
Community-level social capital and recurrence of acute coronary syndrome
Social capital has been shown to be associated with reduced mortality due to cardiovascular disease. Our aim was to determine the association of time-varying community-level social capital (CSC) with recurrence of acute coronary syndrome using a retrospective cohort study design. A total of 34,752 men and women were identified, aged 30-85 years, who were hospitalized for acute coronary syndrome between January 1, 1998 and December 31, 2002 in Kaiser Permanente Northern California, USA, an integrated health care delivery system. The primary outcome was recurrent non-fatal or fatal acute coronary syndrome; median follow-up was 19 months. We estimated random-effects, three-level Cox proportional hazard models adjusting for sex, age, race/ethnicity, comorbidities, medication use, and revascularization procedures at level 1, median household income for the census block-group at level 2, and income inequality, racial/ethnic concentration, penetration of health maintenance organizations, and CSC at level 3. Our measure of CSC was the previously validated Petris Social Capital Index (PSCI). We found that a one-standard deviation increase in the PSCI, after adjusting for the above covariates, was significantly associated with decreased recurrence of acute coronary syndrome only for those living in areas where block-group level median household income was below the grand median compared to those living in areas where block-group level median household income was at the grand median or above. These results suggest that community-level social capital may be negatively associated with recurrence of acute coronary syndrome among lower-income individuals.
Authors: Scheffler RM; Brown TT; Syme L; Kawachi I; Tolstykh I; Iribarren C
Soc Sci Med. 2008 Apr;66(7):1603-13. Epub 2008 Jan 28.
Impaired coronary vasodilation by magnetic resonance angiography is associated with advanced coronary artery calcification
OBJECTIVES: This study evaluated the hypothesis that impaired nitroglycerin (NTG)-induced coronary vasodilation is associated with advanced coronary atherosclerosis in asymptomatic older patients. BACKGROUND: Atherosclerosis is associated with both structural and functional abnormalities of the vessel wall. Noninvasive functional measures of subclinical coronary atherosclerosis may help characterize high-risk subjects and guide preventive therapy. METHODS: A total of 236 older patients (age 60 to 72 years, 33% female) without a history of cardiovascular disease were studied. Nitroglycerin-induced coronary vasodilation was measured by magnetic resonance angiography (MRA). Cross-sectional images of the right coronary artery were acquired before and 5 min after 0.4-mg sublingual NTG using a gated, breath-held spiral coronary MRA sequence (0.7-mm resolution). Quantitative analysis of the increase in cross-sectional area was performed in the 90% of patients (n = 212) with adequate image quality. Quantitation of coronary artery calcification (CAC) was performed by multidetector computed tomography using the Agatston method. RESULTS: Forty patients (19%) had advanced CAC (> or =400). Coronary vasodilation to NTG was significantly impaired (p = 0.02) in patients with advanced CAC (median [interquartile range] = 15.9% [4.2% to 28.0%] vs. 21.5% [9.6% to 36.6%] for CAC <400). Importantly, NTG-induced coronary vasodilation remained independently associated with advanced CAC after multivariate analysis incorporating risk factors (p = 0.02) and other potential confounders (p = 0.04). There was no significant difference in coronary vasodilation between men and women, but few women (n = 3) had advanced CAC. CONCLUSIONS: Impaired NTG-induced coronary vasodilation by MRA is associated with advanced coronary atherosclerosis in a community-based cohort of older asymptomatic subjects. Coronary MRA may provide a noninvasive functional assessment of subclinical coronary atherosclerosis.
Authors: Terashima M; Nguyen PK; Rubin GD; Iribarren C; Courtney BK; Go AS; Fortmann SP; McConnell MV
JACC Cardiovasc Imaging. 2008 Mar;1(2):167-73.
Bone mineral density changes during the menopause transition in a multiethnic cohort of women
CONTEXT: Rates of bone loss across the menopause transition and factors associated with variation in menopausal bone loss are poorly understood. OBJECTIVE: Our objective was to assess rates of bone loss at each stage of the transition and examine major factors that modify those rates. DESIGN, SETTING, AND PARTICIPANTS: We conducted a longitudinal cohort study of 1902 African-American, Caucasian, Chinese, or Japanese women participating in The Study of Women’s Health Across the Nation. Women were pre- or early perimenopausal at baseline. OUTCOME MEASURE: We assessed bone mineral density (BMD) of the lumbar spine and total hip across a maximum of six annual visits. RESULTS: There was little change in BMD during the pre- or early perimenopause. BMD declined substantially in the late perimenopause, with an average loss of 0.018 and 0.010 g/cm2.yr from the spine and hip, respectively (P<0.001 for both). In the postmenopause, rates of loss from the spine and hip were 0.022 and 0.013 g/cm2.yr, respectively (P<0.001 for both). During the late peri- and postmenopause, bone loss was approximately 35-55% slower in women in the top vs. the bottom tertile of body weight. Apparent ethnic differences in rates of spine bone loss were largely explained by differences in body weight. CONCLUSIONS: Bone loss accelerates substantially in the late perimenopause and continues at a similar pace in the first postmenopausal years. Body weight is a major determinant of the rate of menopausal BMD loss, whereas ethnicity, per se, is not. Healthcare providers should consider this information when deciding when to screen women for osteoporosis.
Authors: Finkelstein JS; Brockwell SE; Mehta V; Greendale GA; Sowers MR; Ettinger B; Lo JC; Johnston JM; Cauley JA; Danielson ME; Neer RM
J Clin Endocrinol Metab. 2008 Mar;93(3):861-8. Epub 2007 Dec 26.
Factors associated with the decision to hospitalize patients after transient ischemic attack before publication of prediction rules
BACKGROUND AND PURPOSE: One important criterion for hospitalizing patients after transient ischemic attack (TIA) is the short-term risk of stroke. Before publication of prediction rules for stroke after TIA, physician judgment was required to make a decision about hospitalization. We sought to identify factors associated with the decision to admit patients with TIA from the emergency department (ED) and to see whether those at highest risk of stroke were selected for admission. METHODS: All patients diagnosed with TIA in the ED of 16 hospitals in the Kaiser-Permanente Medical Care Plan over a 1-year period before publication of prediction rules were included (n=1707). Risk of subsequent stroke was stratified according to a validated prediction rule (ABCD(2) score), and the decision to admit was correlated with these risk scores. Factors associated with admission in univariate analysis were included in a logistic regression model. RESULTS: Overall, 243 patients with TIA (14%) were admitted. Admission weakly correlated with the ABCD(2) score (rank biserial R(2)=0.036; 10.0% at low 2-day risk of stroke admitted versus 20.3% at high risk). Seven variables were independently associated with a decision to admit after TIA: prior TIA, speech impairment, weakness, gait disturbance, history of atrial fibrillation, symptoms on arrival to ED, and use of ticlopidine. CONCLUSIONS: In this cohort of patients with TIA, the decision to admit was weakly correlated with risk of subsequent stroke as measured by the ABCD(2) score, and several risk factors for stroke were not important for the decision to admit. Before publication of prediction rules for stroke after TIA, physicians were not identifying the majority of patients at highest risk of stroke for admission.
Authors: Josephson SA; Sidney S; Pham TN; Bernstein AL; Johnston SC
Stroke. 2008 Feb;39(2):411-3. Epub 2007 Dec 20.
Stroke prevention in atrial fibrillation: another step sideways
Authors: Go AS; Singer DE
Lancet. 2008 Jan 26;371(9609):278-80.
Association of fewer hours of sleep at 6 months postpartum with substantial weight retention at 1 year postpartum
Shorter sleep duration is linked to obesity, coronary artery disease, and diabetes. Whether sleep deprivation during the postpartum period affects maternal postpartum weight retention remains unknown. This study examined the association of sleep at 6 months postpartum with substantial postpartum weight retention (SPPWR), defined as 5 kg or more above pregravid weight at 1 year postpartum. The authors selected 940 participants in Project Viva who enrolled during early pregnancy from 1999 to 2002. Logistic regression models estimated odds ratios of SPPWR for sleep categories, controlling for sociodemographic, prenatal, and behavioral attributes. Of the 940 women, 124 (13%) developed SPPWR. Sleep distributions were as follows: 114 (12%) women slept < or =5 hours/day, 280 (30%) slept 6 hours/day, 321 (34%) slept 7 hours/day, and 225 (24%) slept > or =8 hours/day. Adjusted odds ratios of SPPWR were 3.13 (95% confidence interval (CI): 1.42, 6.94) for < or =5 hours/day, 0.99 (95% CI: 0.50, 1.97) for 6 hours/day, and 0.94 (95% CI: 0.50, 1.78) for > or =8 hours/day versus 7 hours/day (p = 0.012). The adjusted odds ratio for SPPWR of 2.05 (95% CI: 1.11, 3.78) was twofold greater (p = 0.02) for a decrease in versus no change in sleep at 1 year postpartum. Sleeping < or =5 hours/day at 6 months postpartum was strongly associated with retaining > or =5 kg at 1 year postpartum. Interventions to prevent postpartum obesity should consider strategies to attain optimal maternal sleep duration.
Authors: Gunderson EP; Rifas-Shiman SL; Oken E; Rich-Edwards JW; Kleinman KP; Taveras EM; Gillman MW
Am J Epidemiol. 2008 Jan 15;167(2):178-87. Epub 2007 Oct 29.
Effect of race/ethnicity on the efficacy of warfarin: potential implications for prevention of stroke in patients with atrial fibrillation
Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. It affects approximately 6% of persons over 65 years of age and is independently associated with a 4- to 5-fold higher risk of ischaemic stroke and a 2-fold higher risk of death. Randomized controlled trials have shown that treatment with adjusted-dose oral vitamin K antagonists (primarily warfarin with a target international normalized ratio [INR] of 2.0-3.0) reduces the relative risk of ischaemic stroke by two-thirds (an approximately 3% reduction in annual absolute risk), but is associated with a 0.2% excess annual absolute risk of intracranial haemorrhage (ICH). However, in ‘real world’ studies, the risk reductions in ischaemic stroke with warfarin have been significantly lower (25-50% relative risk reduction) than in selected trial samples. Moreover, more than 90% of patients enrolled in the sentinel trials were White/European. This raises the question of whether the beneficial results of warfarin can be extrapolated to persons of colour. Important differences in stroke risk profile and responsiveness to warfarin exist across racial/ethnic groups, such that one cannot assume a priori that there is a net benefit of warfarin therapy for AF patients of all racial/ethnic groups.Among patients with ischaemic stroke, AF is more likely to be implicated as the cause of stroke in the White population than in other racial/ethnic groups. Furthermore, AF may be a stronger predictor of ischaemic stroke among the White population than in Black or Hispanic/Latino populations. Approximately one-third of strokes in AF patients are noncardioembolic. Warfarin has been shown to be ineffective in preventing recurrent noncardioembolic strokes. Many persons of colour with AF have other risk factors that predispose them to noncardioembolic stroke, which may partially explain why warfarin has been reported to be less efficacious in preventing strokes in non-White patients with AF, even after adjustment for co-morbidities and anticoagulation monitoring. Notably, the background incidence of ICH is higher in Black, Hispanic and Asian patients than in White patients. Any greater than expected increases in bleeding secondary to anticoagulation may potentially offset any benefit gained from cardioembolic stroke reduction, although this has not been fully resolved.Finally, there are racial/ethnic differences in the prevalence of certain polymorphisms in genes that influence warfarin pharmacokinetics and pharmacodynamics (e.g. cytochrome P450 2C9 and vitamin K epoxide reductase). The Asian population generally appear to require the lowest daily dose of warfarin to maintain a given INR target, with the White population requiring an intermediate daily dose and the Black population requiring the highest daily dose. These differences must be taken into account when administering warfarin in order to minimize the risk of under- or over-anticoagulation.In summary, warfarin is highly effective in preventing ischaemic strokes in White patients with AF at a modestly higher risk of ICH. Whether the same net clinical benefit extends to persons of colour is unproven. Given the rapidly changing demographic nationally and internationally, additional research is needed to resolve this important question.
Authors: Shen AY; Chen W; Yao JF; Brar SS; Wang X; Go AS
CNS Drugs. 2008;22(10):815-25.
Longitudinal association of serum carotenoids and tocopherols with hostility: the CARDIA Study
Hostility is a personality trait associated with increased risk of coronary heart disease. No study has reported the association between hostility and antioxidants, which may be mediators for atherosclerosis. CARDIA (Coronary Artery Risk Development in Young Adults) Study participants were 3,579 men and women 18-30 years of age in 1985-1986. Serum carotenoids and tocopherols were measured at years 0 and 7, and hostility was measured at years 0 and 5. Analysis of covariance was used to test for covariate-adjusted differences in serum carotenoids and tocopherols across quartiles of hostility. After adjustment for age, gender, race, serum lipids, and baseline of the dependent variable, the mean carotenoid values at year 7 of the lowest and highest quartiles of hostility score at year 0 were 3.9 and 3.3 microg/liter for alpha-carotene (p < 0.001), 9.1 and 8.0 microg/liter for beta-cryptoxanthin (p < 0.001), and 50.6 and 46.8 microg/liter for the sum of four carotenoids (p < 0.001). Hostility scores at year 0 were unrelated to year 7 lycopene and tocopherols. In contrast, neither year 0 carotenoids nor tocopherols predicted the hostility score at year 5. High hostility predicted future low levels of some serum carotenoids, which may help to explain the association of hostility and cardiovascular risk observed in other epidemiologic studies.
Authors: Ohira T; Hozawa A; Iribarren C; Daviglus ML; Matthews KA; Gross MD; Jacobs DR Jr
Am J Epidemiol. 2008 Jan 1;167(1):42-50. Epub 2007 Oct 10.
Population stratification in a case-control study of brain arteriovenous malformation in Latinos
BACKGROUND: Genetic association studies conducted in admixed populations may be confounded by population stratification resulting in spurious associations. The purpose of this pilot study was to determine the presence and effect of population stratification in a case-control study of brain arteriovenous malformation (BAVM). METHODS: We tested 83 ancestry informative markers in BAVM cases and healthy controls of self-reported Latino race/ethnicity (n = 294). Individual ancestry estimates (IAE) were obtained using the Structure program, assuming 3 underlying subpopulations. Summary chi(2) tests comparing genotype frequency of ancestry informative markers were used to detect stratification and IAE were included as covariates in logistic regression analysis to account for differences in genetic background. RESULTS: Admixture estimates for Latinos (overall 47% native American, 45% European and 8% African ancestry) revealed heterogeneity between individuals within ancestral groups. The summary chi(2) test was significant (p = 0.005), suggesting ancestral differences between cases and controls. Furthermore, genetic ancestry was associated with frequency differences in a promoter variant in the IL-6 gene (IL-6 -174G>C). On average, subjects with the IL6 -174 GG genotype had 6% greater Native American ancestry (p = 0.023). Age- and sex-adjusted risk of BAVM associated with the IL-6 -174 GG genotype was 1.85 (95% CI 0.99-3.48, p = 0.055), and further adjustments for IAE yielded an OR of 1.96 (95% CI 1.03-3.72, p = 0.039). CONCLUSION: The IL-6 -174G>C polymorphism was associated with increased risk of BAVM among Latinos after accounting for differences in ancestral background. These results suggest subtle, negative confounding and illustrate the importance of addressing population stratification in case-control studies conducted in admixed populations.
Authors: Kim H; Hysi PG; Pawlikowska L; Choudhry S; Gonzalez Burchard E; Kwok PY; Sidney S; McCulloch CE; Young WL
Neuroepidemiology. 2008;31(4):224-8. Epub 2008 Oct 7.
Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLR1) with CAD
BACKGROUND: The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in OLR1 are associated with clinically significant CAD in the Atherosclerotic Disease, VAscular FuNction, & Geneti C Epidemiology (ADVANCE) study. METHODS: ADVANCE is a population-based case-control study of subjects receiving care within Kaiser Permanente of Northern California including a subset of participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We first resequenced the promoter, exonic, and splice site regions of OLR1 and then genotyped four single nucleotide polymorphisms (SNPs), including a non-synonymous SNP (rs11053646, Lys167Asn) as well as an intronic SNP (rs3736232) previously associated with CAD. RESULTS: In 1,809 cases with clinical CAD and 1,734 controls, the minor allele of the coding SNP was nominally associated with a lower odds ratio (OR) of CAD across all ethnic groups studied (minimally adjusted OR 0.8, P = 0.007; fully adjusted OR 0.8, P = 0.01). The intronic SNP was nominally associated with an increased risk of CAD (minimally adjusted OR 1.12, p = 0.03; fully adjusted OR 1.13, P = 0.03). However, these associations were not replicated in over 13,200 individuals (including 1,470 cases) in the Atherosclerosis Risk in Communities (ARIC) study. CONCLUSION: Our results do not support the presence of an association between selected common SNPs in OLR1 and the risk of clinical CAD.
Authors: Knowles JW; Go A; Iribarren C; Risch N; Quertermous T; et al.
BMC Med Genet. 2008 Apr 2;9:23.
Health-related characteristics and preferred methods of receiving health education according to dominant language among Latinos aged 25 to 64 in a large Northern California health plan
BACKGROUND: Latinos are a fast growing segment of the U.S. health care population. Acculturation factors, including English fluency, result in an ethnic group heterogeneous with regard to SES, health practices, and health education needs. This study examined how demographic and health-related characteristics of Spanish-dominant (SD), Bilingual (BIL), and English-dominant (ED) Latino men and women aged 25-64 differed among members of a large Northern California health plan. METHODS: This observational study was based on data from cohorts of 171 SD (requiring an interpreter), 181 BIL, and 734 ED Latinos aged 25-64 who responded to random sample health plan member surveys conducted 2005-2006. Language groups were compared separately by gender on education, income, behavioral health risks (smoking, obesity, exercise frequency, dietary practices, health beliefs), health status (overall health and emotional health, diabetes, hypertension, high cholesterol, heartburn/acid reflux, back pain, depression), computer and Internet access, and health education modality preferences. RESULTS: Compared with ED Latinos, higher percentages of the SD and BIL groups had very low educational attainment and low income. While groups were similar in prevalence of diabetes, hypertension, and high cholesterol, SD were less likely than ED Latinos to rate overall health and emotional well-being as good, very good, or excellent and more likely to report heartburn and back pain (women only). The groups were similar with regard to smoking and obesity, but among women, SD were more likely to be physically inactive than ED, and BIL were less likely than SD and ED groups to eat <3 servings of fruit/vegetables per day. SD and BIL of both genders were significantly less likely than ED Latinos to believe that health practices had a large impact on health. Compared to ED men and women, SD and BIL Latinos had significantly lower Internet and computer access. As a result, SD Latinos had a greater preference for lower technology health education modalities such as videos and taped phone messages. CONCLUSION: There are important differences among Latinos of different English language proficiency with regard to education, income, health status, health behaviors, IT access, and health education modality preferences that ought to be considered when planning and implementing health programs for this growing segment of the U.S. population.
Authors: Gordon NP; Iribarren C
BMC Public Health. 2008 Sep 9;8:305.
Do plasma biomarkers of coagulation and fibrinolysis differ between patients who have experienced an acute myocardial infarction versus stable exertional angina?
BACKGROUND: Circulating concentrations of proteins associated with coagulation and fibrinolysis may differ between individuals with coronary artery disease (CAD) who develop an acute myocardial infarction (AMI) rather than stable exertional angina. METHODS: We compared plasma concentrations of fibrinogen, d-dimer, tissue-type plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1) between patients whose first clinical manifestation of CAD was an AMI (n = 198) rather than stable exertional angina (n = 199). We also compared plasma concentrations of these proteins between patients with symptomatic CAD (either AMI or stable angina; n = 397) and healthy, control subjects (n = 197) to confirm the sensitivity of these assays to detect epidemiologic associations. RESULTS: At a median of 15 weeks after presentation, patients with AMI had slightly higher d-dimer concentrations than patients with stable angina (P = .057), but were not significantly different in other markers. By contrast, fibrinogen, d-dimer, and tissue-type plasminogen activator were significantly higher (P < .001) and PAI-1 lower in patients with CAD than in healthy control subjects. After statistical adjustment for clinical covariates, cardiac risk factors, medications, and other confounders, fibrinogen, d-dimer, and PAI-1 remained significantly associated with CAD. CONCLUSION: Selected plasma markers of coagulation and fibrinolysis did not distinguish patients presenting with AMI from those with stable exertional angina.
Authors: Itakura H; Sobel BE; Boothroyd D; Leung LL; Iribarren C; Go AS; Fortmann SP; Quertermous T; Hlatky MA; Atherosclerotic Disease VFaGEAAS
Am Heart J. 2007 Dec;154(6):1059-64.
Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction
BACKGROUND: Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis. METHODS: We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina. RESULTS: An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively). CONCLUSIONS: Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.
Authors: Knowles JW; Wang H; Itakura H; Southwick A; Myers RM; Iribarren C; Fortmann SP; Go AS; Quertermous T; Hlatky MA
Am Heart J. 2007 Dec;154(6):1052-8.
Matrix metalloproteinase circulating levels, genetic polymorphisms, and susceptibility to acute myocardial infarction among patients with coronary artery disease
OBJECTIVE: The aim of this study was to assess systematic differences between patients with acute myocardial infarction (MI) and patients with stable angina in matrix metalloproteinase (MMP) circulating levels and genetic polymorphisms. METHODS: We identified adults in a large integrated health care delivery system whose initial clinical presentation of coronary disease was either an acute MI or stable exertional angina. A total of 909 patients with acute MI, 466 patients with stable angina, and 1023 healthy older control subjects were genotyped. Serum levels of pro-MMP1, MMP2, MMP3, MMP9, and MMP10 were measured in 199 randomly selected patients from each group. RESULTS: At a median of 15 weeks after initial clinical presentation, higher circulating levels of MMP2 and MMP9 were independently associated with acute MI after statistical adjustment for conventional risk factors, hs-CRP levels, and cardiac medications. By contrast, none of the polymorphisms in MMP1, MMP2, MMP3, MMP9, or MMP10 was significantly associated with either acute MI compared with angina, or with coronary disease compared with controls. CONCLUSIONS: Circulating levels of MMP2 and MMP9 are independently associated with development of an acute MI rather than stable angina as the initial clinical presentation of coronary artery disease.
Authors: Hlatky MA; Ashley E; Quertermous T; Boothroyd DB; Ridker P; Southwick A; Myers RM; Iribarren C; Fortmann SP; Go AS; Atherosclerotic Disease VFaGEAS
Am Heart J. 2007 Dec;154(6):1043-51.
Polymorphisms in hypoxia inducible factor 1 and the initial clinical presentation of coronary disease
BACKGROUND: Only some patients with coronary artery disease (CAD) develop acute myocardial infarction (MI), and emerging evidence suggests vulnerability to MI varies systematically among patients and may have a genetic component. The goal of this study was to assess whether polymorphisms in genes encoding elements of pathways mediating the response to ischemia affect vulnerability to MI among patients with underlying CAD. METHODS: We prospectively identified patients at the time of their initial clinical presentation of CAD who had either an acute MI or stable exertional angina. We collected clinical data and genotyped 34 polymorphisms in 6 genes (ANGPT1, HIF1A, THBS1, VEGFA, VEGFC, VEGFR2). RESULTS: The 909 patients with acute MI were significantly more likely than the 466 patients with stable angina to be male, current smokers, and hypertensive, and less likely to be taking beta-blockers or statins. Three polymorphisms in HIF1A (Pro582Ser, rs11549465; rs1087314; and Thr418Ile, rs41508050) were significantly more common in patients who presented with stable exertional angina rather than acute MI, even after statistical adjustment for cardiac risk factors and medications. The HIF-mediated transcriptional activity was significantly lower when HIF1A null fibroblasts were transfected with variant HIF1A alleles than with wild-type HIF1A alleles. CONCLUSIONS: Polymorphisms in HIF1A were associated with development of stable exertional angina rather than acute MI as the initial clinical presentation of CAD.
Authors: Hlatky MA; Iribarren C; Go AS; et al.
Am Heart J. 2007 Dec;154(6):1035-42. Epub 2007 Sep 18.
A 20-year prospective study of childbearing and incidence of diabetes in young women, controlling for glycemia before conception: the Coronary Artery Risk Development in Young Adults (CARDIA) Study
OBJECTIVE: We sought to determine whether childbearing increases incidence of type 2 diabetes after accounting for preconception glycemia and gestational glucose intolerance. RESEARCH DESIGN AND METHODS: A prospective, biracial cohort was examined up to five times during 1985-2006 in the multicenter, U.S. population-based Coronary Artery Risk Development in Young Adults Study. The analysis included 2,408 women (1,226 black and 1,182 white) aged 18-30 years who were free of diabetes and had a fasting plasma glucose (FPG) <126 mg/dl at baseline. Incident diabetes was diagnosed by self-report, diabetes medication use, FPG >or=126 mg/dl, and/or plasma glucose >or=200 mg/dl after a 2-h oral glucose load. Time-dependent interim birth groups were those with zero and those with one or more births with or without gestational diabetes mellitus (GDM), stratified by baseline parity. Complementary log-log models estimated relative hazards of incident diabetes by interim births adjusted for age, race, family history of diabetes, and baseline covariates (FPG, BMI, education, smoking, and physical activity). RESULTS: Of 193 incident diabetes cases in 42,782 person-years (4.5 cases/1,000 person-years), 84 (44%) had one or more interim births. Among nulliparas at baseline, incident rates per 1,000 person-years were 3.2 (95% CI 2.4-4.1) for those with no births, 2.9 (1.8-3.9) for one or more births without GDM, and 18.4 (10.9-25.9) for one or more births with GDM; adjusted relative hazards (95% CI) were 0.9 (0.6-1.4) for one or more births without GDM and 3.8 (2.2-6.6) for one or more births with GDM versus no births. CONCLUSIONS: Childbearing did not elevate diabetes incidence among those with normal glucose tolerance during pregnancy (without GDM). GDM conferred the highest risk of developing diabetes independent of family history of diabetes and preconception glycemia and obesity.
Authors: Gunderson EP; Lewis CE; Tsai AL; Chiang V; Carnethon M; Quesenberry CP Jr; Sidney S
Diabetes. 2007 Dec;56(12):2990-6. Epub 2007 Sep 26.
Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease
Serum inflammatory markers correlate with outcome and response to therapy in subjects with cardiovascular disease. However, current individual markers lack specificity for the diagnosis of coronary artery disease (CAD). We hypothesize that a multimarker proteomic approach measuring serum levels of vascular derived inflammatory biomarkers could reveal a ‘signature of disease’ that can serve as a highly accurate method to assess for the presence of coronary atherosclerosis. We simultaneously measured serum levels of seven chemokines [CXCL10 (IP-10), CCL11 (eotaxin), CCL3 (MIP1 alpha), CCL2 (MCP1), CCL8 (MCP2), CCL7 (MCP3), and CCL13 (MCP4)] in 48 subjects with clinically significant CAD (‘cases’) and 44 controls from the ADVANCE Study. We applied three classification algorithms to identify the combination of variables that would best predict case-control status and assessed the diagnostic performance of these models with receiver operating characteristic (ROC) curves. The serum levels of six chemokines were significantly higher in cases compared with controls (P < 0.05). All three classification algorithms entered three chemokines in their final model, and only logistic regression selected clinical variables. Logistic regression produced the highest ROC of the three algorithms (AUC = 0.95; SE = 0.03), which was markedly better than the AUC for the logistic regression model of traditional risk factors of CAD without (AUC = 0.67; SE = 0.06) or with CRP (AUC = 0.68; SE = 0.06). A combination of serum levels of multiple chemokines identifies subjects with clinically significant atherosclerotic heart disease with a very high degree of accuracy. These results need to be replicated in larger cross-sectional studies and their prognostic value explored.
Authors: Ardigo D; Assimes TL; Fortmann SP; Go AS; Hlatky M; Hytopoulos E; Iribarren C; Tsao PS; Tabibiazar R; Quertermous T; ADVANCE Investigators
Physiol Genomics. 2007 Nov 14;31(3):402-9. Epub 2007 Aug 14.
Patient sex and quality of ED care for patients with myocardial infarction
OBJECTIVE: The aim of the study was to assess the quality of care between male and female emergency department (ED) patients with acute myocardial infarction (AMI). METHODS: A 2-year retrospective cohort study of 2215 patients with AMI presenting immediately to 5 EDs from July 1, 2000, through June 30, 2002 was conducted. Data on patient characteristics, clinical presentation, and ED processes of care were obtained from chart and electrocardiogram reviews. Multivariable regression models were used to assess the independent association between sex and the ED administration of aspirin, beta-blockers, and reperfusion therapy to eligible patients with AMI. RESULTS: There were 849 women and 1366 men in the study. Female patients were older than male patients (74.3 years for women vs 66.8 years for men, P < .001). Among ideal patients, women were less likely than men to receive aspirin (76.3% of women vs 81.3% of men, P < .01), beta-blockers (51.7% of women vs 61.4% of men, P < .01), and reperfusion therapy (64.0% of women vs 72.8% of men, P < .05). However, after adjustment for age, there was no longer a significant relationship between sex and the use of aspirin (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.95-1.03), beta-blockers (OR, 0.94; 95% CI, 0.82-1.04), or reperfusion therapy (OR, 1.01; 95% CI, 0.89-1.09). In models adjusting for additional demographic, clinical, and hospital characteristics, there remained no association between sex and the processes of care. CONCLUSION: Women with AMI treated in the ED have a lower likelihood of receiving aspirin, beta-blocker, and reperfusion therapy. However, this association appears to be explained by the age difference between men and women with AMI. Although there are no apparent sex disparities in care, ED AMI management remains suboptimal for both sexes.
Authors: Vinson DR; Go AS; Rumsfeld JS; et al.
Am J Emerg Med. 2007 Nov;25(9):996-1003.
Glycemic response to newly initiated diabetes therapies
OBJECTIVE: The glycemic response to antihyperglycemic therapies for type 2 diabetes has been thoroughly evaluated in randomized controlled trials, but inadequately studied in real-world settings. STUDY DESIGN: We studied glycemic response among 15 126 type 2 diabetic patients who initiated any single new antihyperglycemic agent (metformin, sulfonylureas, thiazolidinediones, or insulin added to medical nutrition therapy or to existing diabetes therapies) during 1999-2000 within Kaiser Permanente of Northern California, an integrated healthcare delivery system. METHODS: Pre-post (3-12 months after initiation) change in glycosylated hemoglobin (A1C) was analyzed using ANCOVA (analysis of covariance) models adjusted for baseline A1C, concurrent (ongoing) antihyperglycemic therapy, demographics, health behaviors, medication adherence, clinical factors, and processes of care. RESULTS: Mean A1C was 9.01% (95% confidence interval [CI] 8.98%-9.04%) before therapy initiation and 7.87% (95% CI 7.85%-7.90%) 3 to 12 months after initiation (mean A1C reduction 1.14 percentage points; 95% CI 1.11-1.17). Overall, 30.2% (95% CI 29.2%-31.1%) of patients achieved glycemic target (A1C < 7%). Although baseline disease severity and concurrent therapies differed greatly across therapeutic classes, after adjustment for these baseline clinical characteristics, no significant differences were noted in glucose-lowering effect across therapeutic classes. Treatment effects did not differ by age, race, diabetes duration, obesity, or level of renal function. CONCLUSIONS: Metformin, sulfonylures, thiazolidinediones, and insulin were equally effective in improving glucose control. Nonetheless, most patients failed to achieve the glycemic target. Findings suggest that, to keep up with progressive worsening of glycemic control, patients and providers must commit to earlier, more aggressive therapy intensification, triggered promptly after A1C exceeds the recommended glycemic target.
Authors: Karter AJ; Moffet HH; Liu J; Parker MM; Ahmed AT; Go AS; Selby JV
Am J Manag Care. 2007 Nov;13(11):598-606.
Recurrent hemorrhagic stroke in children: a population-based cohort study
BACKGROUND AND PURPOSE: Although hemorrhagic strokes (HS) account for half of all strokes in children, rates and predictors of recurrent HS have not been studied. METHODS: We collected data on all documented cases of HS (intracerebral hemorrhage, subarachnoid hemorrhage, and intraventricular hemorrhage, except neonatal intraventricular hemorrhage), among 2.3 million children (<20 years) enrolled in a Northern Californian health maintenance organization from January 1993 to December 2004. Using Kaplan-Meier survival analyses censoring at death or loss to follow-up, we determined rates of recurrent HS. Log rank tests were used for bivariate comparisons. RESULTS: Among 116 children with atraumatic incident HS followed for a mean of 4.2 years, 11 had a recurrent HS at a median of 3.1 months (range 7 days to 5.7 years), yielding an overall 5-year cumulative recurrence rate (CRR) of 10% (95% CI, 58% to 18%). Sixty-four percent of recurrences were within the first 6 months. Whereas children with idiopathic HS (n=29) had no recurrences, children with structural lesions (vascular malformations or tumors) had a 5-year cumulative recurrence rate of 13% (95% CI, 7% to 25%; 9 recurrences among 71 children; P<0.05 compared with idiopathic). Children with medical etiologies (eg, thrombocytopenia, hypertension) had a 5-year cumulative recurrence rate of 13% (95% CI, 3% to 41%; 2 recurrences among 16 children), but the recurrences were within the first week. CONCLUSIONS: Overall, 1 in 10 children with HS experienced a recurrence within 5 years, despite available therapies. Whereas idiopathic HS rarely recurred, and HS due to medical etiologies tended to recur acutely, children with structural lesions had a high and prolonged risk for recurrence.
Authors: Fullerton HJ; Wu YW; Sidney S; Johnston SC
Stroke. 2007 Oct;38(10):2658-62. Epub 2007 Aug 30.
GFR, body mass index, and low high-density lipoprotein concentration in adults with and without CKD
BACKGROUND: Low high-density lipoprotein (HDL) cholesterol level is common in patients with chronic kidney disease, but associations between severity of chronic kidney disease, obesity, and HDL level have not been well defined. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Within a large integrated health care delivery system, we identified all adult individuals without diabetes who had measured kidney function (estimated glomerular filtration rate [eGFR]), body mass index (BMI), and HDL level, but no substantial proteinuria, confounding medications, or prior renal replacement therapy. PREDICTORS: The primary predictors for our analyses were eGFR and BMI. OUTCOMES: Low HDL cholesterol level was the outcome. We performed multivariable logistic regression to investigate whether the relationship between BMI and low HDL level (men, <40 mg/dL; women, <50 mg/dL) varied as a function of eGFR. RESULTS: Of 380,207 individuals who met cohort entry criteria, there were 26,089 (7%) with chronic kidney disease by eGFR level. Compared with eGFR of 60 mL/min/1.73 m(2) or greater, lower eGFR category (in mL/min/1.73 m(2)) was associated with an increased adjusted odds of low HDL level independent of BMI and other confounders. However, there was a significant interaction between eGFR and BMI (P < 0.001). In separate models stratified by eGFR category (>or=60, 45 to 59, and 30 to 44 mL/min/1.73 m(2)), greater BMI was associated with a graded increased adjusted odds of low HDL level in each eGFR category, but this relationship was attenuated in patients with lower eGFR. LIMITATIONS: Information for undiagnosed diabetes and proteinuria was unavailable. CONCLUSIONS: Decreased eGFR is independently associated with greater odds of having a low HDL level. Across a spectrum of eGFR, greater BMI was associated with lower HDL level, but the magnitude of this association was diminished at lower eGFR, suggesting that other factors may also contribute to low HDL levels in patients with advanced chronic kidney disease.
Authors: Lo JC; Go AS; Chandra M; Fan D; Kaysen GA
Am J Kidney Dis. 2007 Oct;50(4):552-8.
Effect of race on asthma management and outcomes in a large, integrated managed care organization
BACKGROUND: Morbidity from asthma disproportionately affects black people. Whether this excess morbidity is fully explained by differences in asthma severity, access to care, or socioeconomic status (SES) is unknown. METHODS: We assessed whether there were racial disparities in asthma management and outcomes in a managed care organization that provides uniform access to health care and then determined to what degree these disparities were explained by differences in SES, asthma severity, and asthma management. We prospectively studied 678 patients from a large, integrated health care delivery system. Patients who had been hospitalized for asthma were interviewed after discharge to ascertain information about asthma history, health status, and SES. Small-area socioeconomic data were ascertained by means of geocoding and linkage to the US Census 2000. Patients were followed up for subsequent emergency department (ED) visits or hospitalizations (median follow-up, 1.9 years). RESULTS: Black race was associated with a higher risk of ED visits (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.39-2.66) and hospitalizations (HR, 1.89; 95% CI, 1.30-2.76). This finding persisted after adjusting for SES and differences in asthma therapy (adjusted HR for ED visits, 1.73; 95% CI, 1.07-2.81; and adjusted HR for hospitalizations, 2.01; 95% CI, 1.33-3.02). CONCLUSIONS: Even in a health care setting that provides uniform access to care, black race was associated with worse asthma outcomes, including a greater risk of ED visits and hospitalizations. This association was not explained by differences in SES, asthma severity, or asthma therapy. These findings suggest that genetic differences may underlie these racial disparities.
Authors: Erickson SE; Iribarren C; Tolstykh IV; Blanc PD; Eisner MD
Arch Intern Med. 2007 Sep 24;167(17):1846-52.
Ethnic differences in coronary artery calcium in a healthy cohort aged 60 to 69 years
Measurement of coronary artery calcium (CAC) has been proposed as a screening tool, but CAC levels may differ according to race and gender. Racial/ethnic and gender distributions of CAC were examined in a randomly selected cohort of 60- to 69-year-old healthy subjects. Demographic, race/ethnicity (R/E), and clinical characteristics and assessment of CAC were collected. There were 723 white/European, 105 African-American, 73 Hispanic, and 67 East Asian subjects (597 men, 369 women) included in this analysis. Men had a significantly higher prevalence of any CAC (score>10) than women (76% vs 41%; p<0.0001). For men, the unadjusted odds of having any CAC was 2.2 (95% confidence interval [CI] 1.3 to 3.8) for whites compared with African-Americans. For women, CAC scores were not significantly different across ethnic groups. After adjustment for coronary risk factors, African-American and East Asian R/E remained associated with a lower prevalence of CAC in men (adjusted odds ratios [ORs] 0.33 and 0.47, respectively), as well as older age (OR 1.2, 95% CI 1.1 to 1.3), known hyperlipidemia (OR 1.7, 95% CI 1.1 to 2.7), and history of hypertension (OR 2.2, 95% CI 1.4 to 3.3). In women, Asian R/E (OR 2.5, 95% CI 1.1 to 5.7), history of smoking (adjusted OR 2.8, 95% CI 1.3 to 6.1), and known hyperlipidemia (adjusted OR 2.0, 95% CI 1.3 to 3.1) were associated with a higher prevalence of CAC independent of other risk factors. In conclusion, our data indicate that the presence of CAC varied significantly across selected race/ethnic groups independent of traditional cardiovascular risk factors.
Authors: Fair JM; Kiazand A; Varady A; Mahbouba M; Norton L; Rubin GD; Iribarren C; Go AS; Hlatky MA; Fortmann SP
Am J Cardiol. 2007 Sep 15;100(6):981-5. Epub 2007 Jul 2.
Racial/Ethnic differences in longitudinal risk of intracranial hemorrhage in brain arteriovenous malformation patients
BACKGROUND AND PURPOSE: Race/ethnicity is associated with overall incidence of intracranial hemorrhage (ICH), but its impact in patients with brain arteriovenous malformation is unknown. We evaluated whether race/ethnicity was a risk factor for ICH in the natural course in a large, multiethnic cohort of patients with brain arteriovenous malformation followed longitudinally. METHODS: Data were collected prospectively for patients with brain arteriovenous malformation evaluated at the University of California, San Francisco (n=436) and retrospectively through databases and chart review in the 20 hospitals of the Kaiser Permanente Medical Care Program (n=1028). Multivariate Cox regression was performed to assess the influence of race/ethnicity on subsequent ICH, adjusting for risk factors. Cases were censored at first treatment, loss to follow-up, or death. RESULTS: Average follow up was 4.7+/-8.0 years for Kaiser Permanente Medical Care Program patients and 2.8+/-7.3 years for University of California, San Francisco patients with no difference in time to ICH between cohorts (log rank P=0.57). The annualized 5-year ICH rate was 2.1% (3.7% for ruptured at presentation; 1.4% for unruptured). Initial ICH presentation (hazard ratio: 3.0, 95% CI: 1.9 to 4.9, P<0.001) and Hispanic race/ethnicity (hazard ratio: 1.9, 95% CI: 1.1 to 3.3, P=0.02) were independent predictors of ICH, adjusting for age, gender, cohort, and a cohort-age interaction. The ICH risk for Hispanics versus whites increased to 3.1 (95% CI: 1.3 to 7.4, P=0.013) after further adjusting for arteriovenous malformation size and deep venous drainage in a subset of cases with complete data. Similar trends were observed for blacks (hazard ratio: 2.1, 95% CI: 0.9 to 4.8, P=0.09) and Asians (hazard ratio: 2.4, 95% CI: 0.8 to 7.1, P=0.11), although nonsignificant. CONCLUSIONS: This study reports the first description of race/ethnic differences in brain arteriovenous malformation, with Hispanics at an increased risk of subsequent ICH compared with whites.
Authors: Kim H; McCulloch CE; UCSF BAVM Study Project; et al.
Stroke. 2007 Sep;38(9):2430-7. Epub 2007 Aug 2.
Traditional and novel risk factors for clinically diagnosed abdominal aortic aneurysm: the Kaiser multiphasic health checkup cohort study
BACKGROUND: Identification of risk factors for and early diagnosis of clinically significant abdominal aortic aneurysm (AAA) before rupture is vital to optimize outcomes in these patients. Our aim was to examine traditional and three novel potential risk factors (abdominal obesity, white blood cell count, and kidney function) for abdominal aortic aneurysm (AAA, comprising discharge diagnosis or surgical repair) in a large multiethnic population. METHODS: Cohort study (N =104,813) conducted at an integrated health care delivery system in northern California. RESULTS: After a median of 13 years, 605 AAA events (490 in men and 115 in women; 91 [15%] fatal) were observed. In multivariable analysis, factors significantly associated with risk of clinically detected AAA included male gender, older age, black race (inversely), low educational attainment, cigarette smoking (with dose-response relation), height, treated and untreated hypertension, high total serum cholesterol, elevated white blood cell count, known coronary artery disease, history of intermittent claudication, and reduced kidney function. A significant Asian race by gender interaction was found such that Asian race had a (borderline significant) protective association with AAA in men but not in women. CONCLUSIONS: Our findings confirm that major atherosclerotic risk factors, except for diabetes and obesity, are also prospectively related to AAA and suggest that elevated white blood cell count and reduced kidney function may improve risk stratification for clinically relevant AAA.
Authors: Iribarren C; Darbinian JA; Go AS; Fireman BH; Lee CD; Grey DP
Ann Epidemiol. 2007 Sep;17(9):669-78. Epub 2007 May 18.
Comparative effectiveness of beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with heart failure
Placebo-controlled randomized trials have demonstrated the efficacy of selected beta blockers on outcomes in chronic heart failure (HF), but the relative effectiveness of different beta blockers in usual clinical care is poorly understood. We compared 12-month risk of rehospitalization for HF associated with receipt of different beta blockers in 7,883 adults hospitalized for HF within 2 large health plans between January 1, 2001 and December 31, 2002. Beta-blocker use was ascertained from electronic pharmacy databases and readmissions within 12 months were identified from hospital discharge databases. Extended Cox regression was used to examine the association between receipt of different beta blockers and risk of readmission for HF after adjustment for potential confounders. During follow-up, there were 3,234 person-years of exposure to beta blockers (39.3% atenolol, 42.0% metoprolol tartrate, 12.3% carvedilol, and 6.4% other). Crude 12-month rates of readmissions for HF were high overall (42.6 per 100 person-years). After adjustment for potential confounders, cumulative exposure to each beta blocker, and propensity to receive carvedilol compared with atenolol, adjusted risks of readmission were not significantly different for metoprolol tartrate (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.05) or for carvedilol (adjusted hazard ratio 0.92, 95% confidence interval 0.74 to 1.14). In conclusion, in a contemporary cohort of high-risk patients hospitalized with HF, we found that adjusted risks of rehospitalization for HF within 12 months were not significantly different in patients receiving atenolol, shorter-acting metoprolol tartrate, or carvedilol.
Authors: Go AS; Yang J; Gurwitz JH; Hsu J; Lane K; Platt R
Am J Cardiol. 2007 Aug 15;100(4):690-6. Epub 2007 Jun 26.
Death and disability from warfarin-associated intracranial and extracranial hemorrhages
OBJECTIVES: Little is known about the outcomes of patients who have hemorrhagic complications while receiving warfarin therapy. We examined the rates of death and disability resulting from warfarin-associated intracranial and extracranial hemorrhages in a large cohort of patients with atrial fibrillation. METHODS: We assembled a cohort of 13,559 adults with nonvalvular atrial fibrillation and identified patients hospitalized for warfarin-associated intracranial and major extracranial hemorrhage. Data on functional disability at discharge and 30-day mortality were obtained from a review of medical charts and state death certificates. The relative odds of 30-day mortality by hemorrhage type were calculated using multivariable logistic regression. RESULTS: We identified 72 intracranial and 98 major extracranial hemorrhages occurring in more than 15,300 person-years of warfarin exposure. At hospital discharge, 76% of patients with intracranial hemorrhage had severe disability or died, compared with only 3% of those with major extracranial hemorrhage. Of the 40 deaths from warfarin-associated hemorrhage that occurred within 30 days, 35 (88%) were from intracranial hemorrhage. Compared with extracranial hemorrhages, intracranial events were strongly associated with 30-day mortality (odds ratio 20.8 [95% confidence interval, 6.0-72]) even after adjusting for age, sex, anticoagulation intensity on admission, and other coexisting illnesses. CONCLUSIONS: Among anticoagulated patients with atrial fibrillation, intracranial hemorrhages caused approximately 90% of the deaths from warfarin-associated hemorrhage and the majority of disability among survivors. When considering anticoagulation, patients and clinicians need to weigh the risk of intracranial hemorrhage far more than the risk of all major hemorrhages.
Authors: Fang MC; Go AS; Chang Y; Hylek EM; Henault LE; Jensvold NG; Singer DE
Am J Med. 2007 Aug;120(8):700-5. Epub 2007 May 24.
The metabolic syndrome is no better than its components
The usefulness of the metabolic syndrome is subject of debate. A central issue from the epidemiological perspective is whether the syndrome predicts cardiovascular disease above and beyond its individual components. In this paper, the current evidence regarding this matter is reviewed, and the conclusion of two recent studies is that there is no added predictive value of the syndrome when the individual components are in the model. Rather than perpetuate an arbitrary concept and create another disease entity, attention should be redirected to the individual components and, in particular, to the ”driving” condition whose downstream consequences are serious in terms of morbidity and mortality: central or visceral obesity.
Authors: Iribarren C
Minerva Cardioangiol. 2007 Aug;55(4):487-9.
Clinical utility of the Stanford brief activity survey in men and women with early-onset coronary artery disease
PURPOSE: To determine the utility of the Stanford Brief Activity Survey (SBAS) as a quick screening tool in a clinical population, where no other measure of physical activity was available. METHODS: The SBAS was administered to 500 younger cases in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study, a case-control genetic association study, between December 2001 and January 2004. Younger cases in the ADVANCE study included men (<46 years old) and women (<56 years old) diagnosed with early-onset coronary artery disease. Frequency distributions of the SBAS and associations between SBAS activity categories and selected cardiovascular disease risk factors by sex were calculated. RESULTS: Subjects were 45.9 +/- 6.4 years old, 68% married, 61% women, 51% white, and 21% college graduates. Clinical diagnoses for early-onset coronary artery disease included 61% myocardial infarction, 23% coronary revascularization procedure, and 16% angina pectoris. In women, associations between all cardiovascular disease risk factors examined across SBAS categories were statistically significant (P trend < .01). In men, the associations across SBAS categories were statistically significant (P trend < .01), except for body mass index (P trend = .065). Adjustment for body mass index, age, ethnicity, and education with interactions by sex did not change the results. CONCLUSION: Subjects in the higher SBAS activity categories had more favorable cardiovascular disease risk profiles than did their less active counterparts, regardless of sex. The SBAS can be recommended for use in clinical populations providing immediate feedback on current physical activity level.
Authors: Taylor-Piliae RE; Haskell WL; Iribarren C; Norton LC; Mahbouba MH; Fair JM; Hlatky MA; Go AS; Fortmann SP
J Cardiopulm Rehabil Prev. 2007 Jul-Aug;27(4):227-32.
Abdominal obesity and coronary artery calcification in young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study
BACKGROUND: Whether abdominal obesity is related to coronary artery calcification (CAC) is not known. OBJECTIVE: We investigated the relations of waist girth and waist-hip ratio (WHR) to CAC in 2951 African American and white young adults from the Coronary Artery Risk Development in Young Adults Study. DESIGN: The present study was a cross-sectional and observational cohort study. Using standardized protocols, we measured CAC in 2001-2002 by using computed tomography and measured waist and hip girths in 1985-1986 (baseline), 1995-1996 (year 10), and 2001-2002 (year 15, waist girth only). CAC was classified as present or absent, whereas waist girth and WHR were placed in sex-specific tertiles. RESULTS: After adjustment for age, sex, race, clinical center, physical activity, cigarette smoking, education, and alcohol intake, baseline waist girth and WHR were directly associated with a higher prevalence of CAC 15 y later (P for trend < 0.001 for both). The odds ratios (ORs) for CAC in the highest versus lowest tertiles of waist girth and WHR were 1.9 (95% CI: 1.36, 2.65) and 1.7 (1.23, 2.41), respectively. Waist girth and WHR at year 10 and waist girth at year 15 similarly predicted CAC. These associations persisted after additional adjustment for systolic blood pressure, fasting insulin concentrations, diabetes, and antihypertensive medication use but became nonsignificant after additional adjustment for blood lipids. CONCLUSIONS: Abdominal obesity measured by waist girth or WHR is associated with early atherosclerosis as measured by the presence of CAC in African American and white young adults. This is consistent with an involvement of visceral fat in the occurrence of coronary artery calcium in young adults.
Authors: Lee CD; Jacobs DR Jr; Schreiner PJ; Iribarren C; Hankinson A
Am J Clin Nutr. 2007 Jul;86(1):48-54.
Breastfeeding after gestational diabetes pregnancy: subsequent obesity and type 2 diabetes in women and their offspring
Authors: Gunderson EP
Diabetes Care. 2007 Jul;30 Suppl 2:S161-8.
Community-based incidence of acute renal failure
There is limited information about the true incidence of acute renal failure (ARF). Most studies could not quantify disease frequency in the general population as they are hospital-based and confounded by variations in threshold and the rate of hospitalization. Earlier studies relied on diagnostic codes to identify non-dialysis requiring ARF. These underestimated disease incidence since the codes have low sensitivity. Here we quantified the incidence of non-dialysis and dialysis-requiring ARF among members of a large integrated health care delivery system – Kaiser Permanente of Northern California. Non-dialysis requiring ARF was identified using changes in inpatient serum creatinine values. Between 1996 and 2003, the incidence of non-dialysis requiring ARF increased from 322.7 to 522.4 whereas that of dialysis-requiring ARF increased from 19.5 to 29.5 per 100,000 person-years. ARF was more common in men and among the elderly, although those aged 80 years or more were less likely to receive acute dialysis treatment. We conclude that the use of serum creatinine measurements to identify cases of non-dialysis requiring ARF resulted in much higher estimates of disease incidence compared with previous studies. Both dialysis-requiring and non-dialysis requiring ARFs are becoming more common. Our data underscore the public health importance of ARF.
Authors: Hsu CY; McCulloch CE; Fan D; Ordonez JD; Chertow GM; Go AS
Kidney Int. 2007 Jul;72(2):208-12. Epub 2007 May 16.
Genetic ancestry, population sub-structure, and cardiovascular disease-related traits among African-American participants in the CARDIA Study
African-American populations are genetically admixed. Studies performed among unrelated individuals from ethnically admixed populations may be both vulnerable to confounding by population stratification, but offer an opportunity for efficiently mapping complex traits through admixture linkage disequilibrium. By typing 42 ancestry-informative markers and estimating genetic ancestry, we assessed genetic admixture and heterogeneity among African-American participants in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. We also assessed associations between individual genetic ancestry and several quantitative and binary traits related to cardiovascular risk. We found evidence of population sub-structure and excess inter-marker linkage disequilibrium, consistent with recent admixture. The estimated group admixture proportions were 78.1% African and 22.9% European, but differed according to geographic region. In multiple regression models, African ancestry was significantly associated with decreased total cholesterol, decreased LDL-cholesterol, and decreased triglycerides, and also with increased risk of insulin resistance. These observed associations between African ancestry and several lipid traits are consistent with the general tendency of individuals of African descent to have healthier lipid profiles compared to European-Americans. There was no association between genetic ancestry and hypertension, BMI, waist circumference, CRP level, or coronary artery calcification. These results demonstrate the potential for confounding of genetic associations with some cardiovascular disease-related traits in large studies involving US African-Americans.
Authors: Reiner AP; Carlson CS; Ziv E; Iribarren C; Jaquish CE; Nickerson DA
Hum Genet. 2007 Jun;121(5):565-75. Epub 2007 Mar 14.
Passive smoke exposure trends and workplace policy in the Coronary Artery Risk Development in Young Adults (CARDIA) study (1985-2001)
OBJECTIVE: There has been reduced active smoking, decreased societal acceptance for smoking indoors, and changing smoking policy since the mid-1980s. We quantified passive smoke exposure trends and their relationship with workplace policy. METHOD: We studied 2504 CARDIA participants (Blacks and Whites, 18-30 years old when recruited in 1985-86 from four US cities, reexamination 2, 5, 7, 10, and 15 years later) who never reported current smoking and attended examinations at 10 or 15 years. RESULTS.: In non-smokers with a college degree (n=1581), total passive smoke exposure declined from 16.3 h/week in 1985/86 to 2.3 h/week in 2000/01. Less education tended to be associated with more exposure at all timepoints, for example, in high school or less (n=292) 22.2 h/week in 1985/86 to 8.5 h/week in 2000/01. Those who experienced an increase in the restrictiveness of self-reported workplace smoking policy from 1995/96 to 2000/01 were exposed to almost 3 h per week less passive smoke than those whose workplace policies became less restrictive in this time period. CONCLUSIONS: The increasing presence of restrictive workplace policies seemed to be a component of the substantial decline in self-reported passive smoke exposure since 1985.
Authors: Widome R; Jacobs DR Jr; Schreiner PJ; Iribarren C
Prev Med. 2007 Jun;44(6):490-5. Epub 2007 Feb 23.
Asthma drug use and the development of Churg-Strauss syndrome (CSS)
PURPOSE: Case reports suggest that leukotriene modifier use may be associated with the onset of Churg-Strauss syndrome (CSS). Using pooled data from two nested case-control studies, we examined the association between asthma drug use and the development of CSS. METHODS: The study was performed in three US managed care organizations and a US national health plan with chart access and complete electronic pharmacy data, with a covered population of 13.9 million. There were 47 cases of possible or definite CSS and 4700 asthma drug user controls identified between January 1, 1995 and December 31, 2002. We examined exposure to asthma drugs in cases and controls, including leukotriene modifiers (6 cases and 202 controls), in the two to 6 months prior to the onset of adjudicated CSS. RESULTS: While the crude association between use of leukotriene modifiers and CSS was strong (odds ratio (OR) 4.00, 95% confidence interval (CI): 1.49-10.60), in a multivariable analysis controlling for use of oral corticosteroids, inhaled corticosteroids, and number of categories of asthma drugs dispensed, there was no significant association (OR 1.32, 95% CI: 0.44-3.96). Use of inhaled and oral corticosteroids, evaluated as markers of asthma severity, were associated with CSS (OR 3.07, 95% CI: 1.34-7.03 and OR 5.36, 95% CI: 2.51-11.45, respectively). CONCLUSIONS: No association was found between CSS and leukotriene modifiers after controlling for asthma drug use However, it is not possible to rule out modest associations with asthma treatments given CSS is so rare and so highly correlated with asthma severity, suggesting further investigation is warranted.
Authors: Harrold LR; Go AS; Walker AM; et al.
Pharmacoepidemiol Drug Saf. 2007 Jun;16(6):620-6.
Early adult risk factor levels and subsequent coronary artery calcification: the CARDIA Study
OBJECTIVES: We sought to determine whether early adult levels of cardiovascular risk factors predict subsequent coronary artery calcium (CAC) better than concurrent or average 15-year levels and independent of a 15-year change in levels. BACKGROUND: Few studies have used multiple measures over the course of time to predict subclinical atherosclerosis. METHODS: African American and white adults, ages 18 to 30 years, in 4 U.S. cities were enrolled in the prospective CARDIA (Coronary Artery Risk Development in Young Adults) study from 1985 to 1986. Risk factors were measured at years 0, 2, 5, 7, 10, and 15, and CAC was assessed at year 15 (n = 3,043). RESULTS: Overall, 9.6% adults had any CAC, with a greater prevalence among men than women (15.0% vs. 5.1%), white than African American men (17.6% vs. 11.3%), and ages 40 to 45 years than 33 to 39 years (13.3% vs. 5.5%). Baseline levels predicted CAC presence (C = 0.79) equally as well as average 15-year levels (C = 0.79; p = 0.8262) and better than concurrent levels (C = 0.77; p = 0.019), despite a 15-year change in risk factor levels. Multivariate-adjusted odds ratios of having CAC by ages 33 to 45 years were 1.5 (95% confidence interval [CI] 1.3 to 1.7) per 10 cigarettes, 1.5 (95% CI 1.3 to 1.8) per 30 mg/dl low-density lipoprotein cholesterol, 1.3 (95% CI 1.1 to 1.5) per 10 mm Hg systolic blood pressure, and 1.2 (95% CI 1.1 to 1.4) per 15 mg/dl glucose at baseline. Young adults with above optimal risk factor levels at baseline were 2 to 3 times as likely to have CAC. CONCLUSIONS: Early adult levels of modifiable risk factors, albeit low, were equally or more informative about odds of CAC in middle age than subsequent levels. Earlier risk assessment and efforts to achieve and maintain optimal risk factor levels may be needed.
Authors: Loria CM; Liu K; Lewis CE; Hulley SB; Sidney S; Schreiner PJ; Williams OD; Bild DE; Detrano R
J Am Coll Cardiol. 2007 May 22;49(20):2013-20. Epub 2007 May 4.
Illicit drug use in young adults and subsequent decline in general health: the Coronary Artery Risk Development in Young Adults (CARDIA) Study
BACKGROUND: The long-term health consequences of drug use among healthy young adults in the general population are not well described. We assessed whether drug use predicted decline in general self-rated health (GSRH) in a community-based cohort, healthy at baseline. METHODS: A prospective cohort of 3124 young adults (20-32 years old) from four US cities, the Coronary Artery Risk Development in Young Adults Study, was followed from 1987/1988 to 2000/2001. All reported ‘Good’ or better GSRH at baseline, with reassessment in 2000/2001. Drug use in 1987/1988 was as follows: 812 participants were Never Users; 1554 Past Users Only; 503 Current Marijuana Users Only; 255 Current Hard Drug Users (e.g. cocaine, amphetamines, opiates). Analyses measured the association of drug use (1987/1988) with decline to ‘Fair’ or ‘Poor’ GSRH in 2000/2001, adjusting for biological and psychosocial covariates. RESULTS: Reporting health decline were: 7.2% of Never Users; 6.5%, Past Use Only; 7.0%, Current Marijuana Only; 12.6%, Current Hard Drugs (p<0.01). After multivariable adjustment, Current Hard Drug Use in 1987/1988 remained associated with health decline (Odds Ratio (OR), referent Never Use: 1.83, 95% confidence interval (CI) 1.07-3.12). The health decline associated with Current Hard Drugs appeared to be partly mediated by tobacco smoking in 2000/2001, which independently predicted health decline (OR 1.66, 95% CI 1.08-2.50) and weakened the apparent effect of Current Hard Drugs (OR 1.21, 95% CI 0.62-2.36). CONCLUSIONS: Hard drug use in healthy young adults, even when hard drug use stops, is associated with a subsequent decrease in general self-rated health that may be partially explained by persistent tobacco use.
Authors: Kertesz SG; Pletcher MJ; Safford M; Halanych J; Kirk K; Schumacher J; Sidney S; Kiefe CI
Drug Alcohol Depend. 2007 May 11;88(2-3):224-33. Epub 2006 Nov 29.
Asymmetric dimethyl-arginine and coronary artery calcification in young adults entering middle age: the CARDIA Study
BACKGROUND: Normal endothelial function depends on nitric oxide (NO) release by endothelial cells. Asymmetric dimethylarginine (ADMA), by competing with L-arginine, inhibits NO production and may lead to endothelial dysfunction and atherosclerotic development. Our aim was to ascertain the association between ADMA and coronary artery calcification (CAC), a marker of atherosclerotic coronary disease burden. DESIGN: A nested case-control study within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, an observational study among young adults residing in four US cities. METHODS: Participants were 263 white and black male and female cases with the presence of CAC and 263 sex and race-matched controls without evidence of CAC by computed tomography, 33-47 years old in 2000-2001. RESULTS: The median level (range) of ADMA was significantly higher in cases (0.55; 0.20-2.22 micromol/l) than in controls (0.53; 0.32-1.30 micromol/l; P=0.03). In conditional logistic regression adjusting for age, field center, educational attainment, smoking status, alcohol consumption, body mass index, waist circumference, hypertension, diabetes, low-density lipoprotein and high-density lipoprotein-cholesterol, triglycerides, renal function and C-reactive protein, the highest tertile of ADMA, compared with the lowest tertile, was associated with 1.80 (95% confidence interval 1.03-3.15) increased odds of the presence of any CAC. By linear regression, a significant independent relationship was also found between ADMA and the degree of CAC. CONCLUSION: These results support a role for ADMA as a biochemical marker of CAC.
Authors: Iribarren C; Husson G; Sydow K; Wang BY; Sidney S; Cooke JP
Eur J Cardiovasc Prev Rehabil. 2007 Apr;14(2):222-9.
Lactation and changes in maternal metabolic risk factors
OBJECTIVE: To examine the relationship between duration of lactation and changes in maternal metabolic risk factors. METHODS: This 3-year prospective study examined changes in metabolic risk factors among lactating women from preconception to postweaning and among nonlactating women from preconception to postdelivery, in comparison with nongravid women. Of 1,051 (490 black, 561 white) women who attended two consecutive study visits in years 7 (1992-1993) and 10 (1995-1996), 942 were nongravid and 109 had one interim birth. Of parous women, 48 (45%) did not lactate, and 61 (55%) lactated and weaned before year 10. The lactated and weaned women were subdivided by duration of lactation into less than 3 months and 3 months or more. Multiple linear regression models estimated mean 3-year changes in metabolic risk factors adjusted for age, race, parity, education, and behavioral covariates. RESULTS: Both parous women who did not lactate and parous women who lactated and weaned gained more weight (+5.6, +4.4 kg) and waist girth (+5.3, +4.9 cm) than nongravid women over the 3-year interval; P<.001. Low-density lipoprotein cholesterol (+6.7 mg/dL, P<.05) and fasting insulin (+2.6 microunits, P=.06) increased more for parous women who did not lactate than for nongravid and parous women who lactated and weaned. High-density lipoprotein cholesterol decrements for both parous women who did not lactate and parous women who lactated and weaned were 4.0 mg/dL greater than for nongravid women (P<.001). Among parous, lactated and weaned women, lactation for 3 months or longer was associated with a smaller decrement in high-density lipoprotein cholesterol (-1.3 mg/dL versus -7.3 mg/dL for less than 3 months; P<.01). CONCLUSION: Lactation may attenuate unfavorable metabolic risk factor changes that occur with pregnancy, with effects apparent after weaning. As a modifiable behavior, lactation may affect women's future risk of cardiovascular and metabolic diseases. LEVEL OF EVIDENCE: II.
Authors: Gunderson EP; Lewis CE; Wei GS; Whitmer RA; Quesenberry CP; Sidney S
Obstet Gynecol. 2007 Mar;109(3):729-38.
Risk of recurrent childhood arterial ischemic stroke in a population-based cohort: the importance of cerebrovascular imaging
OBJECTIVE: Few data exist regarding rates and predictors of recurrence after childhood arterial ischemic stroke. We sought to establish such rates within a large, multiethnic population and determine whether clinical vascular imaging predicts recurrence. PATIENTS AND METHODS: In a population-based cohort study, we collected data on all documented cases of arterial ischemic stroke among 2.3 million children (<20 years old) enrolled in a northern Californian managed care plan from January 1993 to December 2004. Perinatal strokes were those that occurred by 28 days of life. Data on cerebrovascular imaging (conventional or magnetic resonance angiography), including presence of vascular abnormalities, were abstracted from official radiology reports. We used Kaplan-Meier survival-analysis techniques to determine rates and predictors of recurrent stroke. RESULTS: Among 181 incident childhood stroke cases (84 perinatal; 97 later childhood), there were 16 recurrent strokes (1 after a perinatal stroke) at a median of 2.7 months. The 5-year cumulative recurrence rates were 1.2% after perinatal stroke and 19% after later childhood stroke. Of the 97 children with later childhood strokes, 52 received cerebrovascular imaging, predominantly magnetic resonance angiography (n = 36) and conventional angiography (n = 26). Although there were no recurrences among children with normal vascular imaging, children with a vascular abnormality had a 5-year cumulative recurrence rate of 66%. CONCLUSIONS: Strokes recur in one fifth of cases of later childhood arterial ischemic stroke but are rare after perinatal stroke. Among the later childhood cases, cerebrovascular imaging identifies those at highest risk for recurrence.
Authors: Fullerton HJ; Wu YW; Sidney S; Johnston SC
Pediatrics. 2007 Mar;119(3):495-501.
Patients with vascular calcifications are at increased risk of cardiovascular events: implications for risk factor management and further research
Authors: Iribarren C
J Intern Med. 2007 Mar;261(3):235-7.
RR interval variability is inversely related to inflammatory markers: the CARDIA study
Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the ‘cholinergic anti-inflammatory pathway.’ Stimulation of vagus nerve activity significantly inhibits cytokine levels in animal models, and cholinergic agents inhibit cytokine release by human macrophages. Moreover, when vagus nerve activity is decreased or absent, cytokines are overproduced. Atherosclerosis is an inflammatory disease characterized by elevated levels of CRP and IL-6, but the relationship between cardiac vagal activity and cytokine levels in healthy humans is not well understood. Here we measured RR interval variability, an index of cardiac vagal modulation, and CRP and IL-6 in 757 subjects participating in a subset of the year 15 data collection in the CARDIA study of the evolution of risk factors in young adults. Univariate analysis revealed that all indices of RRV were strongly and inversely related to IL-6 (log pg/mL b=-0.08 and -0.17 for HF and LF power, P<0.001 respectively) and CRP (log mg/L b=-0.14 and -0.26 for HF and LF power, P<0.001 respectively) levels. In the multivariate model including gender, race, age, smoking, physical activity, SBP, BMI, and disease, the inverse relationship between RRV and inflammatory markers, although slightly attenuated, remained significant. These findings are consistent with the hypothesis that diminished descending vagal anti-inflammatory signals can allow cytokine overproduction in humans.
Authors: Sloan RP; McCreath H; Tracey KJ; Sidney S; Liu K; Seeman T
Mol Med. 2007 Mar-Apr;13(3-4):178-84.
Calcium/vitamin D supplementation and cardiovascular events
BACKGROUND: Individuals with vascular or valvular calcification are at increased risk for coronary events, but the relationship between calcium consumption and cardiovascular events is uncertain. We evaluated the risk of coronary and cerebrovascular events in the Women’s Health Initiative randomized trial of calcium plus vitamin D supplementation. METHODS AND RESULTS: We randomized 36,282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo. Cardiovascular disease was a prespecified secondary efficacy outcome. During 7 years of follow-up, myocardial infarction or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). In subgroup analyses, women with higher total calcium intake (diet plus supplements) at baseline were not at higher risk for coronary events (P=0.91 for interaction) or stroke (P=0.14 for interaction) if assigned to active calcium/vitamin D. CONCLUSIONS: Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period.
Authors: Hsia J; Trevisan M; Women's Health Initiative Investigators; et al.
Circulation. 2007 Feb 20;115(7):846-54.
Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Authors: Rosamond W; Go A; American Heart Association Statistics Committee and Stroke Statistics Subcommittee; et al.
Circulation. 2007 Feb 6;115(5):e69-171. Epub 2006 Dec 28.
The association of heart rate recovery immediately after exercise with coronary artery calcium: the coronary artery risk development in young adults study
We tested whether slower heart rate recovery (HRR) following graded exercise treadmill testing (GXT) was associated with the presence of coronary artery calcium (CAC). Participants (n = 2,648) ages 18-30 years at baseline examination underwent GXT, followed by CAC screening 15 years later. Slow HRR was not associated with higher odds of testing positive (yes/no) for CAC at year 15 (OR = 0.99, p = 0.91 per standard deviation change in HRR). Slow HRR in young adulthood is not associated with the presence of CAC at middle age.
Authors: Kizilbash MA; Carnethon MR; Chan C; Jacobs DR Jr; Lloyd-Jones DM; Sidney S; Liu K
Clin Auton Res. 2007 Feb;17(1):46-9. Epub 2007 Jan 30.
Plasma leptin levels and coronary artery calcification in older adults
CONTEXT: Leptin is associated with adiposity and insulin resistance and may play a direct role in vascular calcification. It is unclear, however, whether leptin is an independent predictor of atherosclerotic burden. OBJECTIVE: The aim of this study was to examine the association between plasma leptin and coronary artery calcification (CAC) in an ethnically diverse cohort of older adult men and women free of clinical cardiovascular disease. DESIGN: This was a cross-sectional study with data collection between January 2002 and February 2004 as part of the ADVANCE Study. SETTING: The study was conducted at an integrated health care delivery system in Northern California. PARTICIPANTS: Participants included 949 men and women aged 60-69 yr old. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: The main outcome measure was CAC by multidetector row computed tomography. RESULTS: In ordinal logistic regression, plasma leptin levels were positively associated with extent of CAC independently of age, race/ethnicity, and smoking status in women (odds ratio of higher CAC for the sex-specific upper tertile vs. lower tertile = 1.81; 95% confidence interval, 1.10-3.00) but not in men (odds ratio = 1.29; 95% confidence interval = 0.89-1.86). However, this association was explained by metabolic risk factors and adiposity measures. CONCLUSIONS: Our findings support a role of leptin on vascular calcification in women but, in our sample of older adults, the association between leptin and CAC was not independent of other cardiac risk factors.
Authors: Iribarren C; Husson G; Go AS; Lo JC; Fair JM; Rubin GD; Hlatky MA; Fortmann SP
J Clin Endocrinol Metab. 2007 Feb;92(2):729-32. Epub 2006 Dec 5.
Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack
BACKGROUND: We aimed to validate two similar existing prognostic scores for early risk of stroke after transient ischaemic attack (TIA) and to derive and validate a unified score optimised for prediction of 2-day stroke risk to inform emergency management. METHODS: The California and ABCD scores were validated in four independent groups of patients (n=2893) diagnosed with TIA in emergency departments and clinics in defined populations in the USA and UK. Prognos