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This study aims to examine whether greater frequency of depressive symptoms associates with increased risk of incident heart failure (HF).Depressive symptoms associate with adverse prognosis in patients with prevalent HF. Their association with incident HF is less studied, particularly in low-income and minority individuals.We studied 23,937 Black or White Southern Community Cohort Study participants (median age: 53 years, 70% Black, 64% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services coverage. Cox models adjusted for traditional HF risk factors, socioeconomic and behavioral factors, social support, and antidepressant medications were used to quantify the association between depressive symptoms assessed at enrollment via the Center for Epidemiologic Studies Depression Scale (CESD-10) and incident HF ascertained from Centers for Medicare and Medicaid Services International Classification of Diseases-9th Revision (ICD-9) (code: 428.x) and ICD-10 (codes: I50, I110) codes through December 31, 2016.The median CESD-10 score was 9 (IQR: 5 to 13). Over a median 11-year follow-up, 6,081 (25%) participants developed HF. The strongest correlates of CESD-10 score were antidepressant medication use, age, and socioeconomic factors, rather than traditional HF risk factors. Greater frequency of depressive symptoms associated with increased incident HF risk (per 8-U higher CESD-10 HR: 1.04; 95% CI: 1.00 to 1.09; P = 0.038) without variation by race or sex. The association between depressive symptoms and incident HF varied by antidepressant use (interaction-P = 0.03) with increased risk among individuals not taking antidepressants.In this high-risk, low-income, cohort of predominantly Black participants, greater frequency of depressive symptoms significantly associates with higher risk of incident HF.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 ( APOL1 ) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01–1.21]; P =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05–1.36; P =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01–1.29l; P =0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. Conclusions: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

Introduction: Reproductive factors might have an effect on the development of heart failure (HF). Early age at menopause has been linked with increased risk of cardiovascular disease; however, there is limited evidence on the relationship between early menopause and HF. Hypothesis: We assessed the hypothesis that earlier age at menopause is associated with increased risk of incident HF among women in the southeastern United States. Methods: The Southern Community Cohort Study enrolled ~86,000 low-income black and white adults in 12 southeastern states (2002-2009). Participants for this analysis were 11,948 women who were postmenopausal at enrollment, had no history of HF, and were using Centers for Medicare or Medicaid Services (CMS). HF events were ascertained using International Classification of Diseases , Ninth Revision, codes 428.x via linkage of the cohort with CMS Research Identifiable Files through December 31, 2016. Early menopause was defined as self-reported age at menopause less than 45 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed from multivariable Cox regression models, overall and by race, adjusting for demographic, lifestyle, and reproductive factors, including reason for menopause. Results: At baseline, median age was 58 years and 65% of participants were black. Among women with early menopause, 76% (n=4,836) had menopause due to hysterectomy or oophorectomy. In women with later menopause, 74% (n=4,102) reported natural menopause. During a median follow-up of 9.5 years (interquartile range 6.0-11.8), 3,808 incident HF events occurred. Compared to women with later onset of menopause, those with early menopause had increased HF risk (HR: 1.13, 95% CI: 1.04-1.23). Risk of HF associated with early menopause differed between white and black women (p-value for interaction: 0.02). In stratified analyses, white women with early menopause had an increased risk of HF compared to those with later onset of menopause (HR: 1.26, 95% CI: 1.11-1.43), although there was no association between early age at menopause and risk of HF in black women (HR: 1.07, 95% CI: 0.98-1.18). Conclusions: In conclusion, in this largely low-income population, early menopause is associated with an increased risk of developing HF and associations differ by race. Women with early menopause represent a potential target population for future interventions aimed to decrease risk of HF and cardiovascular risk factors.

Introduction: Approximately 10-20% of treated hypertensive patients have apparent treatment-resistant hypertension (ATRH), which is associated with adverse cardiovascular outcomes. Our goal was to develop a prediction model for ATRH that combines clinical data and a genetic risk score (GRS) for ATRH. Methods: Study participants were 232,925 patients with hypertension (HTN) enrolled in the Million Veteran Program receiving care at the VA from 2004 to 2017. 21% were black and 6% were women. Incident ATRH was defined as failure to achieve outpatient blood pressure (BP) Results: Over a 13.5-year follow-up, 20,536 and 2,247 incident ATRH cases were observed in the training and test data. In the training data, the clinical model had reasonable discriminant ability (C=0.706) and good calibration (Brier score = 0.085). Age, diabetes, and SBP were the strongest predictors of ATRH. In the test dataset, a 1-IQR increase in the GRS was associated with a 10% (95%CI: 1.04-1.17) higher odds of ATRH. In the test dataset, the LR χ 2 , C-statistic and Brier score for the clinical model were 1075, 0.705 and 0.077 respectively. In the GRS-enriched model, these values were 1107, 0.708 and 0.077. The net reclassification improvement was 1.5% (95% CI: 0.3-2.8, p=0.02). The GRS-enriched model had excellent calibration with an optimism-corrected calibration slope of 0.95. Conclusion: Augmenting a clinical prediction model for ATRH with a GRS comprising GWAS-significant SNPs improved model fit but not discriminant ability. Future work will evaluate whether models incorporating polygenic risk scores with a larger number of variants may refine ATRH risk prediction and stratification and evaluate race-specific performance.

Objectives The purpose of this study was to examine race- and sex-based variation in the associations between modifiable risk factors and incident heart failure (HF) among the SCCS (Southern Community Cohort Study) participants. Background Low-income individuals in the southeastern United States have high HF incidence rates, but relative contributions of risk factors to HF are understudied in this population. Methods We studied 27,078 black or white SCCS participants (mean age: 56 years, 69% black, 63% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services. The presence of hypertension, diabetes mellitus, physical underactivity, high body mass index, smoking, high cholesterol, and poor diet was assessed at enrollment. Incident HF was ascertained using International Classification of Diseases-9th revision, codes 428.x in Centers for Medicare and Medicaid Services data through December 31, 2010. Individual risk and population attributable risk for HF for each risk factor were quantified using multivariable Cox models. Results During a median (25th, 75th percentile) 5.2 (3.1, 6.7) years, 4,341 (16%) participants developed HF. Hypertension and diabetes were associated with greatest HF risk, whereas hypertension contributed the greatest population attributable risk, 31.8% (95% confidence interval: 27.3 to 36.0). In black participants, only hypertension and diabetes associated with HF risk; in white participants, smoking and high body mass index also associated with HF risk. Physical underactivity was a risk factor only in white women. Conclusions In this high-risk, low-income cohort, contributions of risk factors to HF varied, particularly by race. To reduce the population burden of HF, interventions tailored for specific race and sex groups may be warranted.

Background The myocardial contraction fraction (MCF: stroke volume to myocardial volume) is a volumetric measure of left ventricular myocardial shortening. We examined the relationship of MCF, measured by cardiac magnetic resonance imaging (cMRI), to incident cardiovascular (CV) events within the Multi-Ethnic Study of Atherosclerosis (MESA). Methods Participants (n = 5000, aged 45–84 years) underwent cMRI. Primary outcome: CVD events (myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease: CHD death, and stroke death). Secondary outcomes: CHD and heart failure (HF) events. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for outcomes. Results There were 299 incident CVD, 188 CHD, and 151 HF events over 10.2 years. The lowest MCF quartile was associated with an increased risk for incident CVD [HR 2.42, CI: 1.58–3.72], CHD [HR 2.32, CI: 1.36–3.96] and HF events [HR 1.99, CI: 1.15–3.44]. In a model adjusted for demographics, CV risk factors, antihypertensive and lipid-lowering medication use, each standard deviation decrease in MCF was associated with incident CVD [HR 1.42, CI: 1.23–1.64], CHD [HR 1.40, CI: 1.17–1.67] and HF [HR 1.58, CI: 1.30–1.94]. In a subgroup analysis of participants with preserved ejection fraction and without left ventricular hypertrophy, the lowest MCF quartile and each standard deviation decrease in MCF was also associated with an increased risk for incident CVD in fully-adjusted analyses. Conclusions MCF is a novel measure that can be measured using cMRI. In this multi-ethnic cohort, MCF is a measure that can be used to predict incident CVD events.

Background and aims Consumption of polyunsaturated fatty acids (PUFA), especially the n3-series, may protect against cardiovascular disease (CVD), but recent randomized studies have failed to demonstrate these benefits. One of the prevailing hypotheses is that PUFA intake may not confer benefits beyond those provided by statins, but studies comparing statin users to non-users with regard to effects of PUFA are lacking. Methods and results Black and white men and women (n = 69,559) in the Southern Community Cohort Study were studied. Cox regression models adjusting for age, sex, race, BMI, recruitment site, education, income, smoking, diabetes, and dietary variables were used. Results At baseline the mean ± SD age was 52 ± 9 years, 60% of participants were women, 54% had hypertension and 16% used statins. We observed modest inverse associations between n3-PUFA and n6-PUFA intake with mortality among non-statin users but not among statin users. In adjusted analyses, the HRs (95% CIs) for all-cause mortality (6,396 deaths over a median of 6.4 years) comparing the highest to the lowest quintile were 0.90 (0.82–1.00) for n3-PUFA and 0.80 (0.70–0.92) for n6-PUFA among non-statin users, whereas they were 1.06 (0.87–1.28) and 0.96 (0.78–1.19) for n3-PUFA and n6-PUFA, respectively, among statin users. Conclusions Our results suggest potential benefits of PUFA consumption on mortality which are only apparent in the absence of statin therapy. It seems prudent to consider the potential benefit of PUFA consumption in the primary prevention of CVD among patients who are not candidates for statin therapy but are at increased risk for CVD and mortality.

Background Cardiac rehabilitation (CR) is underutilized in the United States, with fewer than 20% of eligible patients participating in CR programs. Individual socioeconomic status is associated with CR utilization, but data regarding neighborhood characteristics and CR are sparse. We investigated the association of neighborhood socioeconomic context with CR participation in the SCCS (Southern Community Cohort Study). Methods and Results The SCCS is a prospective cohort study of 84 569 adults in the southeastern United States from 2002 to 2009, 52 117 of whom have Medicare or Medicaid claims. Using these data, we identified participants with hospitalizations for myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery and ascertained their CR utilization. Neighborhood socioeconomic context was assessed using a neighborhood deprivation index derived from 11 census‐tract level variables. We analyzed the association of CR utilization with neighborhood deprivation after adjusting for individual socioeconomic status. A total of 4096 SCCS participants (55% female, 57% black) with claims data were eligible for CR. CR utilization was low, with 340 subjects (8%) participating in CR programs. Study participants residing in the most deprived communities (highest quintile of neighborhood deprivation) were less than half as likely to initiate CR (odds ratio 0.42, 95% confidence interval, 0.27–0.66, P P Conclusions Lower neighborhood socioeconomic context was associated with decreased CR participation independent of individual socioeconomic status. These data invite research on interventions to increase CR access in deprived communities.

Background Recent data suggest that neighborhood socioeconomic environment predicts heart failure (HF) hospital readmissions. We investigated whether neighborhood deprivation predicts risk of incident HF beyond individual socioeconomic status in a low-income population. Methods and Results Participants were 27 078 whites and blacks recruited during 2002 to 2009 in the SCCS (Southern Community Cohort Study), who had no history of HF and were using Centers for Medicare or Medicaid Services. Incident HF diagnoses through December 31, 2010, were ascertained using International Classification of Diseases , Ninth Revision, codes 428.x via linkage with Centers for Medicare or Medicaid Services research files. Participant residential information was geocoded and census tract determined by a spatial join to the US Census Bureau TIGER/Line Shapefiles. The neighborhood deprivation index was constructed using principal components analysis based on census tract-level socioeconomic variables. Cox models with Huber–White cluster sandwich estimator of variance were used to investigate the association between neighborhood deprivation index and HF risk. The study sample was predominantly middle aged (mean, 55.5 years), black (69%), female (63%), low income (70% earned 50% of participants lived in the most deprived neighborhoods (third neighborhood deprivation index tertile). Over median follow-up of 5.2 years, 4300 participants were diagnosed with HF. After adjustment for demographic, lifestyle, and clinical factors, a 1 interquartile increase in neighborhood deprivation index was associated with a 12% increase in risk of HF (hazard ratio, 1.12; 95% confidence interval, 1.07–1.18), and 4.8% of the variance in HF risk (intraclass correlation coefficient, 4.8; 95% confidence interval, 3.6–6.4) was explained by neighborhood deprivation. Conclusions In this low-income population, scant neighborhood resources compound the risk of HF above and beyond individual socioeconomic status and traditional cardiovascular risk factors. Improvements in community resources may be a significant axis for curbing the burden of HF.

Background— There is a paucity of data on heart failure (HF) incidence among low-income and minority populations. Our objective was to investigate HF incidence and post-HF survival by race and sex among low-income adults in the southeastern United States. Methods and Results— Participants were 27 078 white and black men and women enrolled during 2002 to 2009 in the SCCS (Southern Community Cohort Study) who had no history of HF and were receiving Centers for Medicare and Medicaid Services. Incident HF diagnoses through December 31, 2010 were ascertained using International Classification of Diseases 9th Revision codes 428.x via linkage with Centers for Medicare and Medicaid Services research files. Most participants were black (68.8%), women (62.6%), and earned Conclusions— In this low-income population, HF incidence was higher for all race–sex groups than previously reported in other cohorts. The SCCS is a unique resource to investigate determinants of HF risk in a segment of the population underrepresented in other existing cohorts.

Background: Numerous prospective studies suggest inverse associations between intake of polyunsaturated fatty acids (PUFA) and cardiovascular outcomes. However, recent randomized studies have failed to demonstrate these benefits. One of the prevailing hypotheses is that the beneficial effects of PUFA may now be masked by the widespread use of statins, which lower lipids and blood pressure and are potent modulators of cardiovascular risk. Hypothesis: We tested the hypothesis that the association between PUFA and hypertension varies by statin use. Methods and Results: We conducted a cross-sectional analysis based on 74,658 black and white men and women in the Southern Community Cohort Study. Intake of PUFA was assessed by a food-frequency questionnaire, while history of diagnosed hypertension and statin use were self-reported. The mean±SD age was 52±9 years, body mass index was 30±8 kg/m 2 , and energy intake from PUFA was 8.0±1.8%. Sixty percent of the participants were women and 68% were African Americans. Hypertension (55%), statin use (16%), smoking (40%) and alcohol use (55%) were common in this cohort. In an adjusted logistic model with hypertension as the dependent variable, there was no interaction between PUFA intake and statin therapy ( P =0.13), whereas a significant inverse association was evident between PUFA intake and hypertension among non-statin users ( P for trend = 0.03) but not among statin users ( P for trend = 0.36) ( Table ). Conclusion: In conclusion, these results support a beneficial effect of PUFA consumption on hypertension, which is only apparent in the absence of statin therapy. These findings underscore the need to stratify by statin therapy when randomizing participants to cardiovascular interventions and support the notion that PUFA may be important in cardiovascular risk reduction in patients where statin therapy is not an option.

Background: Persons with diabetes mellitus (DM) have altered cardiac structure and function, which increases heart failure (HF) risk. Myocardial contraction fraction (MCF) is an echocardiographic global measure of fractional shortening recently applied to cardiac MRI. We sought to determine if MCF differed by DM status and if MCF predicts HF in the Multi-Ethnic Study of Atherosclerosis, a cohort which enrolled ethnically diverse adults aged 45-84 who were free of clinical CVD. Methods: Analyses included 4991 with MRI data for whom DM status could be ascertained. Left ventricle (LV) volumes and mass (LVM) were calculated by the summation of disks method from cine short axis images. Ejection fraction (EF) is defined as LV stroke volume (SV) / end diastolic luminal volume. MCF is defined as LV SV/ end diastolic myocardial volume. DM was defined as using hypoglycemic drugs or a fasting glucose>125mg/dl. Linear regression was utilized for cross sectional analyses of the association between MCF and DM status, adjusting for age, gender, race/ethnicity, BMI, systolic BP, BP drugs, and smoking. Cox proportional hazards modeling was used to compare MCF, EF and LV mass quartiles as predictors of HF, adjusting for the above variables and DM. Results: At baseline the mean age was 61.5 (SD 10), 52% were female, 39% white, and 61% minorities; 13% had impaired fasting glucose (IFG) and 12% DM. The table indicates LV measurements. After adjustment, DM status remained associated with a lower MCF (IFG -0.02, 95% CI -0.03,-0.01; DM -0.032, 95%CI -0.04, -0.02). There were 96 incident HF events. Compared to the 4 th quartile, the 1 st MCF quartile was associated with HF (adjusted HR 2.2; 95%CI 1.13, 4.43) as was 1 st EF quartile (adjusted HR 2.9; 95%CI 1.6, 5.2) and 4 th quartile LVM (adjusted HR 5.4; 95%CI 2.2, 13.2). Among those with DM, 39% were in the 1 st MCF quartile, compared to 27% in the 1 st EF and 33% in the 4 th LVM quartile. Conclusions: Incident HF is predicted by MCF. MCF may be a more sensitive marker for diabetic cardiomyopathy than EF or LVM. Ventricular Measures by Diabetes Status Glucose Category Parameter Normal 100-125 mg/dl Diabetes p-value MCF 0.66 (0.14) 0.61 (0.14) 0.59 (0.14) EF, % 69 (7) 69 (8) 68 (9) 0.11 SV (ml) 87 (20) 86 (19) 86 (19) 0.05 LMV (g) 142 (38) 153 (41) 157 (43) Mean (Std Dev)