Gupta, Deepak K.

Introduction: Greater religiosity, or degree of involvement in religious activities, associates with better CV health profiles. Yet, studies of the association between religiosity and incident CV events have yielded mixed results. The southeastern US is characterized by strong religious practice but has among the highest rates of incident heart failure (HF). The relationship between religiosity and incident HF is not well characterized, particularly among low-income populations. Methods: We studied 23,893 Black or White Southern Community Cohort Study participants (median age 53 years, 70% Black, 64% women, 70% annual household income <$15k) without prevalent HF or CAD at enrollment (2002-2009). Religiosity, defined by religious service attendance, was ascertained at enrollment via a single item adapted from the Duke University Religion Index. Incident HF was determined using Centers for Medicare and Medicaid Services Research Identifiable Files (ICD-9/-10 codes 428.x or I50, I110) through December 31, 2016. We quantified the association of religious attendance with incident HF via Cox models adjusted for demographics, HF risk factors (HTN, HLD, DM, BMI, CVA), health behaviors (smoking, alcohol, physical activity, DASH diet), socioeconomic (income, education, employment, neighborhood deprivation, rurality) and psychosocial factors (marital status, social support, depressive symptoms, anti-depressant use). Results: Religious service attendance was common: >1/week (24%), 1/week (27%), <1/week (33%), and never (15%). Participants attending >1/week were more likely to be older and female, had relatively higher SES and more comorbidities, but better health behaviors and psychosocial support. HF developed in 6081 participants (25%; median 10-yr follow-up). Adjusting for demographics and HF risk factors, attendance >1/week associated with lower HF risk (HR 0.88 [0.82,0.94] and HR 0.92 [0.84,1.00] compared to <1/week or never, respectively). Attendance 1/week compared to <1/week showed similar association (HR 0.91 [0.85, 0.97]). Further adjustment for health behaviors, socioeconomic and psychosocial factors attenuated the association to non-significance. There was no interaction between religiosity and race. Conclusion: Greater frequency of religious service attendance associated with lower incident HF risk adjusting for demographics and HF risk factors; however, this association attenuated with adjustment for health behaviors, socioeconomic and psychosocial factors.

BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code–based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code–based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.

Introduction: Through degradation of the cardio- and renal-protective second messenger cyclic GMP, phosphodiesterase-9 (PDE9) excess may contribute to cardiomyocyte hypertrophy, fibrosis, and renal dysfunction, common features in heart failure with preserved ejection fraction (HFpEF) development and progression. Hypothesis: Selective PDE9 inhibition with IMR-687 mitigates an adverse cardiac and renal phenotype in mouse models of HFpEF. Methods: Cardiac and renal responses to IMR-687 (60 mg/kg, 100 mg/kg) compared with vehicle were examined over 6-8 weeks in 3 adult male mouse models of HFpEF (1.5 mg/kg/d angiotensin-II infusion [ang-II]; uninephrectomy + 0.30 ug/h d-aldosterone infusion + 1% NaCl drinking water [neph-aldo]; and db/db [db]). Phenotyping included wheat germ agglutinin staining for cardiomyocyte cross-sectional area (CSA); RT-PCR for myocardial PDE9, natriuretic peptide, inflammatory and fibrosis marker transcript abundances; ELISA for plasma natriuretic peptides; and urinary albumin to creatinine ratio (UACR). Results: IMR-687 reduced median cardiomyocyte size (CSA) by 54, 58, and 35% compared with vehicle in the ang-II, neph-aldo, and db models, respectively; p < 0.003 for all. Myocardial PDE9, NPPA, NPPB, COL3A1, and IL-1β expression were decreased by IMR-687 in all models (Table). Median plasma BNP levels (pg/mL) were lower in IMR-687 vs. vehicle treated mice in all models (ang-II: 2376 vs. 5757; neph-aldo: 1216 vs. 1860; db: 830 vs. 1216); p < 0.007 for all, with similar findings for ANP (Table). UACR was lower in IMR-687 compared with vehicle treated mice in all models (Table). Heart rate and blood pressure did not differ between IMR-687 and vehicle treated mice. Conclusion: Selective PDE9 inhibition with IMR-687 was effective for prevention and treatment of cardiac hypertrophy and renal dysfunction in 3 different preclinical models of HFpEF. IMR-687 may be a promising candidate therapy for testing in clinical trials of human HFpEF.

Objective Natriuretic peptides (NPs) are hormones with cardioprotective effects. NP levels vary by race; however, the pathophysiological consequences of lower NP levels are not well understood. We aimed to quantify the association between NPs and endothelial function as measured by flow-mediated dilation (FMD) and the contribution of NP levels to racial differences in endothelial function. Methods In this cross-sectional study of 2938 Multi-Ethnic Study of Atherosclerosis participants (34% Caucasian, 20% African-American, 20% Asian-American and 26% Hispanic) without cardiovascular disease at baseline, multivariable linear regression models were used to examine the association between serum N-terminal pro-B-type NP (NT-proBNP) and natural log-transformed FMD. We also tested whether NT-proBNP mediated the relationship between race and FMD using the product of coefficients method. Results Among African-American and Chinese-American individuals, lower NT-proBNP levels were associated with lower FMD, β=0.06 (95% CI: 0.03 to 0.09; p<0.001) and β=0.06 (95% CI: 0.02 to 0.09; p=0.002), respectively. Non-significant associations between NT-proBNP and FMD were found in Hispanic and Caucasian individuals. In multivariable models, endothelial function differed by race, with African-American individuals having the lowest FMD compared with Caucasians, p<0.001. Racial differences in FMD among African-Americans and Chinese-Americans were mediated in part by NT-proBNP levels (African-Americans, mediation effect: −0.03(95% CI: −0.05 to −0.01); Chinese-Americans, mediation effect: −0.03(95% CI: −0.05 to −0.01)). Conclusions Lower NP levels are associated with worse endothelial function among African-Americans and Chinese-Americans. A relative NP deficiency in some racial/ethnic groups may contribute to differences in vascular function.