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.
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.
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.
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.
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 smal