Cardiovascular Risk Associated With Social Determinants of Health at Individual and Area Levels.

Importance: The benefit of adding social determinants of health (SDOH) when estimating atherosclerotic cardiovascular disease (ASCVD) risk is unclear. Objective: To examine the association of SDOH at both individual and area levels with ASCVD risks, and to assess if adding individual- and area-level SDOH to the pooled cohort equations (PCEs) or the Predicting Risk of CVD Events (PREVENT) equations improves the accuracy of risk estimates. Design, Setting, and Participants: This cohort study included participants data from 4 large US cohort studies. Eligible participants were aged 40 to 79 years without a history of ASCVD. Baseline data were collected from 1995 to 2007; median (IQR) follow-up was 13.0 (9.3-15.0) years. Data were analyzed from September 2023 to February 2024. Exposures: Individual- and area-level education, income, and employment status. Main outcomes and measures: ASCVD was defined as the composite outcome of nonfatal myocardial infarction, death from coronary heart disease, and fatal or nonfatal stroke. Results: A total of 26 316 participants were included (mean [SD] age, 61.0 [9.1] years; 15 494 women [58.9%]; 11 365 Black [43.2%], 703 Chinese American [2.7%], 1278 Hispanic [4.9%], and 12 970 White [49.3%]); 11 764 individuals (44.7%) had at least 1 adverse individual-level SDOH and 10 908 (41.5%) had at least 1 adverse area-level SDOH. A total of 2673 ASCVD events occurred during follow-up. SDOH were associated with increased risk of ASCVD at both the individual and area levels, including for low education (individual: hazard ratio [HR], 1.39 [95% CI, 1.25-1.55]; area: HR, 1.31 [95% CI, 1.20-1.42]), low income (individual: 1.35 [95% CI, 1.25-1.47]; area: HR, 1.28 [95% CI, 1.17-1.40]), and unemployment (individual: HR, 1.61 [95% CI, 1.24-2.10]; area: HR, 1.25 [95% CI, 1.14-1.37]). Adding area-level SDOH alone to the PCEs did not change model discrimination but modestly improved calibration. Furthermore, adding both individual- and area-level SDOH to the PCEs led to a modest improvement in both discrimination and calibration in non-Hispanic Black individuals (change in C index, 0.0051 [95% CI, 0.0011 to 0.0126]; change in scaled integrated Brier score [IBS], 0.396% [95% CI, 0.221% to 0.802%]), and improvement in calibration in White individuals (change in scaled IBS, 0.274% [95% CI, 0.095% to 0.665%]). Adding individual-level SDOH to the PREVENT plus area-level social deprivation index (SDI) equations did not improve discrimination but modestly improved calibration in White participants (change in scaled IBS, 0.182% [95% CI, 0.040% to 0.496%]), Black participants (0.187% [95% CI, 0.039% to 0.501%]), and women (0.289% [95% CI, 0.115% to 0.574%]). Conclusions and Relevance: In this cohort study, both individual- and area-level SDOH were associated with ASCVD risk; adding both individual- and area-level SDOH to the PCEs modestly improved discrimination and calibration for estimating ASCVD risk for Black individuals, and adding individual-level SDOH to PREVENT plus SDI also modestly improved calibration. These findings suggest that both individual- and area-level SDOH may be considered in future development of ASCVD risk assessment tools, particularly among Black individuals.

Neighborhoods and Cardiovascular Health: A Scientific Statement From the American Heart Association.

The neighborhoods where individuals reside shape environmental exposures, access to resources, and opportunities. The inequitable distribution of resources and opportunities across neighborhoods perpetuates and exacerbates cardiovascular health inequities. Thus, interventions that address the neighborhood environment could reduce the inequitable burden of cardiovascular disease in disenfranchised populations. The objective of this scientific statement is to provide a roadmap illustrating how current knowledge regarding the effects of neighborhoods on cardiovascular disease can be used to develop and implement effective interventions to improve cardiovascular health at the population, health system, community, and individual levels. PubMed/Medline, CINAHL, Cochrane Library reviews, and ClinicalTrials.gov were used to identify observational studies and interventions examining or targeting neighborhood conditions in relation to cardiovascular health. The scientific statement summarizes how neighborhoods have been incorporated into the actions of health care systems, interventions in community settings, and policies and interventions that involve modifying the neighborhood environment. This scientific statement presents promising findings that can be expanded and implemented more broadly and identifies methodological challenges in designing studies to evaluate important neighborhood-related policies and interventions. Last, this scientific statement offers recommendations for areas that merit further research to promote a deeper understanding of the contributions of neighborhoods to cardiovascular health and health inequities and to stimulate the development of more effective interventions.

Role of Sex in the Association of Socioeconomic Status With Cardiovascular Health in Black Americans: The Jackson Heart Study.

BACKGROUND: Socioeconomic status (SES) is associated with cardiovascular health (CVH). Potential differences by sex in this association remain incompletely understood in Black Americans, where SES disparities are posited to be partially responsible for cardiovascular inequities. The association of SES measures (income, education, occupation, and insurance) with CVH scores was examined in the Jackson Heart Study. METHODS AND RESULTS: American Heart Association CVH components (non-high-density-lipoprotein cholesterol, blood pressure, diet, tobacco use, physical activity, sleep, glycemia, and body mass index) were scored cross-sectionally at baseline (scale: 0-100). Differences in CVH and 95% CIs (Estimate, 95% CI) were calculated using linear regression, adjusting for age, sex, and discrimination. Heterogeneity by sex was assessed. Participants had a mean age of 54.8 years (SD 12.6 years), and 65% were women. Lower income, education, occupation (non-management/professional versus management/professional occupations), and insurance status (uninsured, Medicaid, Veterans Affairs, or Medicare versus private insurance) were associated with lower CVH scores (all P<0.01). There was heterogeneity by sex, with greater magnitude of associations of SES measures with CVH in women versus men. The lowest education level (high school) was associated with 8.8-point lower (95% CI: -10.2 to -7.3) and 5.4-point lower (95% CI: -7.2 to -3.6) CVH scores in women and men, respectively (interaction P=0.003). The lowest (<25 000) versus highest level of income (≥$75 000) was associated with a greater reduction in CVH scores in women than men (interaction P=0.1142). CONCLUSIONS: Among Black Americans, measures of SES were associated with CVH, with a greater magnitude in women compared with men for education and income. Interventions aimed to address CVH through SES should consider the role of sex.

Predicting incident cardiovascular disease among African-American adults: A deep learning approach to evaluate social determinants of health in the Jackson heart study.

The present study sought to leverage machine learning approaches to determine whether social determinants of health improve prediction of incident cardiovascular disease (CVD). Participants in the Jackson Heart study with no history of CVD at baseline were followed over a 10-year period to determine first CVD events (i.e., coronary heart disease, stroke, heart failure). Three modeling algorithms (i.e., Deep Neural Network, Random Survival Forest, Penalized Cox Proportional Hazards) were used to evaluate three feature sets (i.e., demographics and standard/biobehavioral CVD risk factors [FS1], FS1 combined with psychosocial and socioeconomic CVD risk factors [FS2], and FS2 combined with environmental features [FS3]) as predictors of 10-year CVD risk. Contrary to hypothesis, overall predictive accuracy did not improve when adding social determinants of health. However, social determinants of health comprised eight of the top 15 predictors of first CVD events. The social determinates of health indicators included four socioeconomic factors (insurance status and types), one psychosocial factor (discrimination burden), and three environmental factors (density of outdoor physical activity resources, including instructional and water activities; modified retail food environment index excluding alcohol; and favorable food stores). Findings suggest that whereas understanding biological determinants may identify who is currently at risk for developing CVD and in need of secondary prevention, understanding upstream social determinants of CVD risk could guide primary prevention efforts by identifying where and how policy and community-level interventions could be targeted to facilitate changes in individual health behaviors.

Social Networks and Cardiovascular Disease Events in the Jackson Heart Study.

Background Cardiovascular disease (CVD) disproportionately affects Black adults. Greater social networks (SNs), or social connectedness, may lower the risk of CVD events. This study determined the association of SNs and incident CVD and tested mediation by depressive symptoms, hypertension control, and diabetes control. Methods and Results We used the Social Network Index at exam 1 (2000-2004) to develop a continuous standardized SN score and binary categories (high versus low) among participants in the Jackson Heart Study (n=4686; mean age, 54.8 years). Surveillance of coronary heart disease, stroke, and heart failure events occurred after exam 1 (2005 for HF) until 2016. Using Cox proportional hazards regression, we estimated the association of SNs and CVD events by sex and tested the mediation of depressive symptoms, hypertension control, and diabetes control. Models adjusted for age, education, health behaviors, CVD comorbidities, and depressive symptoms. Among women, the SN score was associated with a lower hazard of stroke, coronary heart disease, and heart failure after full adjustment (hazard ratio [HR], 0.78 [95% CI, 0.64-0.95]; HR, 0.79 [95% CI, 0.71-0.88]; and HR, 0.78 [95% CI, 0.66-0.92], respectively). SN scores were also associated with a lower hazard of coronary heart disease in men (HR, 0.84 [95% CI, 0.75-0.94]) after full adjustment. High versus low SNs were associated with a lower hazard of coronary heart disease and heart failure among women after full adjustment. There was no evidence of mediation by depressive symptoms, diabetes control, and hypertension control. Conclusions Higher SNs may lower the risk of CVD events, especially in women.

Neighborhood factors and survival to old age: The Jackson Heart Study.

Few studies have evaluated environmental factors that predict survival to old age. Our study included 913 African American participants in the Jackson Heart Study (JHS) who resided in the tri-county area of the Jackson, MS metropolitan area and were 65-80 years at baseline. Participants were followed from 2000 through 2019 for the outcome of survival to 85 years old. We evaluated each of the following census tract-level measures of the social/physical environment as exposures: socioeconomic status, cohesion, violence, disorder, healthy food stores, residential land use, and walkability. We assessed mediation by physical activity and chronic conditions. As a complementary ecologic analysis, we used census-tract data to examine factors associated with a greater life expectancy. A total of 501 (55%) JHS participants survived to age 85 years or older. Higher social cohesion and greater residential land use were modestly associated with survival to old age (risk difference = 25%, 95% CI: 0-49%; and 4%, 95% CI: 1-7%, respectively). These neighborhood effects were modestly mediated through leisure time physical activity; additionally, social cohesion was mediated through home and yard activity. In our ecologic analysis, a greater percentage of homeowners and a greater proportion of people living in partnered families were associated with higher census-tract level life expectancy. African American older adults living in residential neighborhoods or neighborhoods with high social cohesion were more likely to survive to old age.

Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma.

Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.

Examining the Relationship Between Multilevel Resilience Resources and Cardiovascular Disease Incidence, Overall and by Psychosocial Risks, Among Participants in the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study.

We examined relationships between resilience resources (optimism, social support, and neighborhood social cohesion) and cardiovascular disease (CVD) incidence and assessed potential effect-measure modification by psychosocial risk factors (e.g., stress, depression) among adults without CVD in 3 cohort studies (2000-2018): the Jackson Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study. We fitted adjusted Cox models accounting for within-neighborhood clustering while censoring at dropout or non-CVD death. We assessed for effect-measure modification by psychosocial risks. In secondary analyses, we estimated standardized risk ratios using inverse-probability-weighted Aalen-Johansen estimators to account for confounding, dropout, and competing risks (non-CVD deaths) and obtained 95% confidence intervals (CIs) using cluster bootstrapping. For high and medium (versus low) optimism (n = 6,243), adjusted hazard ratios (HRs) for incident CVD were 0.94 (95% CI: 0.78, 1.13) and 0.90 (95% CI: 0.75, 1.07), respectively. Corresponding HRs were 0.88 (95% CI: 0.74, 1.04) and 0.92 (95% CI: 0.79, 1.06) for social support (n = 7,729) and 1.10 (95% CI: 0.94, 1.29) and 0.99 (95% CI: 0.85, 1.16) for social cohesion (n = 7,557), respectively. Some psychosocial risks modified CVD HRs. Secondary analyses yielded similar findings. For optimism and social support, an inverse relationship was frequently most compatible with the data, but a positive relationship was also compatible. For neighborhood social cohesion, positive and null relationships were most compatible. Thus, specific resilience resources may be potential intervention targets, especially among certain subgroups.

Historical Redlining, Socioeconomic Distress, and Risk of Heart Failure Among Medicare Beneficiaries.

BACKGROUND: The association of historical redlining policies, a marker of structural racism, with contemporary heart failure (HF) risk among White and Black individuals is not well established. METHODS: We aimed to evaluate the association of redlining with the risk of HF among White and Black Medicare beneficiaries. Zip code-level redlining was determined by the proportion of historically redlined areas using the Mapping Inequality Project within each zip code. The association between higher zip code redlining proportion (quartile 4 versus quartiles 1-3) and HF risk were assessed separately among White and Black Medicare beneficiaries using generalized linear mixed models adjusted for potential confounders, including measures of the zip code-level Social Deprivation Index. RESULTS: A total of 2 388 955 Medicare beneficiaries (Black n=801 452; White n=1 587 503; mean age, 71 years; men, 44.6%) were included. Among Black beneficiaries, living in zip codes with higher redlining proportion (quartile 4 versus quartiles 1-3) was associated with increased risk of HF after adjusting for age, sex, and comorbidities (risk ratio, 1.08 [95% CI, 1.04-1.12]; P<0.001). This association remained significant after further adjustment for area-level Social Deprivation Index (risk ratio, 1.04 [95% CI, 1.002-1.08]; P=0.04). A significant interaction was observed between redlining proportion and Social Deprivation Index (Pinteraction<0.01) such that higher redlining proportion was significantly associated with HF risk only among socioeconomically distressed regions (above the median Social Deprivation Index). Among White beneficiaries, redlining was associated with a lower risk of HF after adjustment for age, sex, and comorbidities (risk ratio, 0.94 [95% CI, 0.89-0.99]; P=0.02). CONCLUSIONS: Historical redlining is associated with an increased risk of HF among Black patients. Contemporary zip code-level social determinants of health modify the relationship between redlining and HF risk, with the strongest relationship between redlining and HF observed in the most socioeconomically disadvantaged communities.

Adiposity, aldosterone and plasma renin activity among African Americans: The Jackson Heart Study.

Objective: To analyze associations between adiposity and the renin-angiotensin-aldosterone system (RAAS) in a large African American (AA) cohort. Methods: Cross-sectional associations of adiposity (body mass index [BMI], waist circumference [WC], waist:height ratio, waist:hip ratio, leptin, adiponectin, leptin:adiponectin ratio [LAR], subcutaneous [SAT] and visceral adipose tissue [VAT], and liver attenuation [LA]) with aldosterone, plasma renin activity (renin), and aldosterone:renin ratio (ARR) were assessed in the Jackson Heart Study using adjusted linear regression models. Results: A 1-SD higher BMI was associated with a 4.8 % higher aldosterone, 9.4 % higher renin, and 5.0 % lower ARR (all p < 0.05). Log-leptin had the largest magnitude of association with renin (30.2 % higher) and ARR (9.6 % lower), while the strongest association of aldosterone existed for log-LAR (15.3 % higher) (all 1-SD, p < 0.05). SAT was only associated with renin. VAT was associated with higher aldosterone, renin, and ARR. Liver fat was associated with aldosterone and renin, but not ARR. Associations of WC, BMI, and SAT with aldosterone were greater in men while the association with VAT was greater in women (p-interactions < 0.05). Conclusion: Multiple measures of adiposity are associated with the RAAS in AAs. Further studies should examine the role of RAAS in obesity-driven cardiometabolic diseases.

Systemic Markers of Lung Function and Forced Expiratory Volume in 1 Second Decline across Diverse Cohorts.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery ß = 0.0561, Q = 4.05 × 10-10; ß = 0.0421, Q = 1.12 × 10-3; and ß = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; ß = -4.3 ml/yr, Q = 0.049; ß = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

Cumulative socioeconomic status and incident type 2 diabetes among African American adults from the Jackson heart study.

Background: The cumulative socioeconomic status (SES) model posits that childhood and adult experiences accumulate to influence disease risk. While individual SES indicators such as education and income are independently associated with incident type 2 diabetes (T2D), the association of cumulative SES and incident T2D is unclear, especially in African American adults. Methods: We utilized cohort data of African American participants (n = 3681, mean age 52.6 years) enrolled in the Jackson Heart Study from 2000 to 2013 free of T2D or cardiovascular disease at baseline (2000-2004). Cumulative SES scores at baseline were derived using six SES indicators (education, wealth, income, occupation, employment status, and mother's education) categorized as low, middle, and high. Incident T2D was defined at exam 2 (2005-2008) or exam 3 (2009-2013) based on fasting glucose ≥126 mg/dL, HbA1c ≥ 6.5, reported diabetic medication use, or self-reported physician diagnosis. Proportional hazards regression, allowing for interval censoring, was used to estimate the association between cumulative SES and incident T2D (hazard ratio(HR), 95% confidence interval (CI)) after adjustment for covariates. Sex and age differences were tested using interaction terms. Results: There were 544 incident T2D cases. The association between low (versus high) cumulative SES and incident T2D was not significant (HR 1.04 [95% CI 0.85, 1.28]) and did not differ by sex (p value for interaction>0.05). However, there were differences by (age p value for interaction = 0.0052 for middle-aged adults and 0.0186 for older adults). Low (versus high) cumulative SES was associated a greater hazard of incident T2D among those 20-46 years (HR 1.12 [95% CI 1.03, 1.21]), 47-59 years (HR 1.25 [95% CI 1.06, 1.47]) and those 60-93 years (HR 1.39 [95% CI 1.09, 1.78]) after adjustment for sex and family history of diabetes. Associations attenuated after adding behavioral and lifestyle risk factors. Conclusion: The association of low cumulative SES and incident T2D differed by age, which may suggest interventionist should consider impacts of SES on T2D by age.

Social integration and risk of mortality among African-Americans: the Jackson heart study.

OBJECTIVE: Evidence suggests that greater social integration is related to lower mortality rates. However, studies among African-Americans are limited. We examined whether higher social integration was associated with lower mortality in 5306 African-Americans from the Jackson Heart Study, who completed the Berkman-Syme Social Network Index in 2000-2004 and were followed until 2018. METHODS: We estimated hazard ratios (HR) of mortality by categories of the Social Network Index (i.e., high social isolation, moderate social isolation [reference group], moderate social integration, high social integration) using Cox proportional hazard models. Covariates included baseline sociodemographics, depressive symptoms, health conditions, and health behaviors. RESULTS: Compared with moderate isolation, moderate integration was associated with an 11% lower mortality rate (HR = 0.89, 95% confidence interval [CI] 0.77, 1.03), and high integration was associated with a 25% lower mortality rate (HR = 0.75, 95% CI 0.64, 0.87), controlling for sociodemographics and depressive symptoms; compared with moderate isolation, high isolation was related to a 34% higher mortality rate (HR = 1.34, 95% CI 1.00, 1.79). Further adjustment of potential mediators (health conditions and health behaviors) only slightly attenuated HRs (e.g., HRmoderate integration = 0.90, 95% CI 0.78, 1.05; HRhigh integration = 0.77, 95% CI 0.66, 0.89). CONCLUSION: Social integration may be a psychosocial health asset with future work needed to identify biobehavioral processes underlying observed associations with mortality among African-Americans.

The association of perceived discrimination with dementia risk in Black older adults.

INTRODUCTION: Non-Hispanic Black, compared to non-Hispanic White, older adults are at increased risk for dementia. This may be due partly to greater exposure to psychosocial stressors, such as discrimination; however, few studies have examined this association. METHODS: We examined the association of perceived discrimination (e.g., everyday, lifetime, and discrimination burden) with dementia risk in 1583 Black adults co-enrolled in the Atherosclerosis Risk in Communities (ARIC) Study and the Jackson Heart Study (JHS). Perceived discrimination (defined continuously and using tertiles) was assessed at JHS Exam 1 (2000-2004; mean age ± SD:66.2 ± 5.5) and related to dementia risk through ARIC visit 6 (2017) using covariate-adjusted Cox proportional hazards models. RESULTS: Associations of perceived everyday, lifetime, and burden of discrimination with dementia risk were not supported in age-adjusted models or demographic- and cardiovascular health-adjusted models. Results were similar across sex, income, and education. DISCUSSION: In this sample, associations between perceived discrimination and dementia risk were not supported. HIGHLIGHTS: In Black older adults perceived discrimination not associated with dementia risk. Younger age and greater education linked to greater perceived discrimination. Older age and less education among factors associated with dementia risk. Factors increasing exposure to discrimination (education) are also neuroprotective.

The role of aldosterone and ideal cardiovascular health in incident cardiovascular disease: The Jackson heart study.

Background: Higher levels of ideal cardiovascular health (ICH) are associated with lower levels of aldosterone and incidence of cardiovascular disease (CVD). However, the degree to which aldosterone mediates the association between ICH and CVD incidence has not been explored. Thus, we investigated the mediational role of aldosterone in the association of 5 components of ICH (cholesterol, body mass index (BMI), physical activity, diet and smoking) with incident CVD and the mediational role of blood pressure (BP) and glucose in the association of aldosterone with incident CVD in a cohort of African Americans (AA). Methods: The Jackson Heart Study is a prospective cohort of AAs adults with data on CVD outcomes. Aldosterone, ICH metrics and baseline characteristics were collected at exam 1 (2000-2004). ICH score was developed by summing 5 ICH metrics (smoking, dietary intake, physical activity, BMI, and total cholesterol) and grouped into two categories (0-2 and ≥3 metrics). Incident CVD was defined as stroke, coronary heart disease, or heart failure. Cox proportional hazard regression models were used to model the association of categorical ICH score with incident CVD. The R Package Mediation was utilized to examine: 1) The mediational role of aldosterone in the association of ICH with incident CVD and 2) The mediational role of blood pressure and glucose in the association of aldosterone with incident CVD. Results: Among 3,274 individuals (mean age: 54±12.4 years, 65% female), there were 368 cases of incident CVD over a median of 12.7 years. The risk of incident CVD was 46% lower (HR: 0.54; 95%CI 0.36, 0.80) in those with ≥3 ICH metrics at baseline compared to 0-2. Aldosterone mediated 5.4% (p = 0.006) of the effect of ICH on incident CVD. A 1-unit increase in log-aldosterone was associated with a 38% higher risk of incident CVD (HR 1.38, 95%CI: 1.19, 1.61) with BP and glucose mediating 25.6% (p<0.001) and 4.8% (p = 0.048), respectively. Conclusion: Aldosterone partially mediates the association of ICH with incident CVD and both blood pressure and glucose partially mediate the association of aldosterone with incident CVD, emphasizing the potential importance of aldosterone and ICH in risk of CVD among AAs.

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.

N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genomic associations of four plasma N-acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2351 individuals from the Jackson Heart Study. We find that plasma levels of specific N-acyl amino acids are associated with cardiometabolic disease endpoints independent of free amino acid plasma levels and in patterns according to the amino acid head group. By integrating whole genome sequencing data with N-acyl amino acid levels, we identify that the genetic determinants of N-acyl amino acid levels also cluster according to the amino acid head group. Furthermore, we identify the CYP4F2 locus as a genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels in human plasma. In experimental studies, we demonstrate that CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids. These studies provide a structural framework for understanding the regulation and disease associations of N-acyl amino acids in humans and identify that the diversity of this lipid signaling family can be significantly expanded through CYP4F-mediated ω-hydroxylation.

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.

N-acyl amino acids are a large family of circulating lipid metabolites that modulate energy expenditure and fat mass in rodents. However, little is known about the regulation and potential cardiometabolic functions of N-acyl amino acids in humans. Here, we analyze the cardiometabolic phenotype associations and genetic regulation of four plasma N-fatty acyl amino acids (N-oleoyl-leucine, N-oleoyl-phenylalanine, N-oleoyl-serine, and N-oleoyl-glycine) in 2,351 individuals from the Jackson Heart Study. N-oleoyl-leucine and N-oleoyl-phenylalanine were positively associated with traits related to energy balance, including body mass index, waist circumference, and subcutaneous adipose tissue. In addition, we identify the CYP4F2 locus as a human-specific genetic determinant of plasma N-oleoyl-leucine and N-oleoyl-phenylalanine levels. In vitro, CYP4F2-mediated hydroxylation of N-oleoyl-leucine and N-oleoyl-phenylalanine results in metabolic diversification and production of many previously unknown lipid metabolites with varying characteristics of the fatty acid tail group, including several that structurally resemble fatty acid hydroxy fatty acids (FAHFAs). By contrast, FAAH-regulated N-oleoyl-glycine and N-oleoyl-serine were inversely associated with traits related to glucose and lipid homeostasis. These data uncover a human-specific enzymatic node for the metabolism of a subset of N-fatty acyl amino acids and establish a framework for understanding the cardiometabolic roles of individual N-fatty acyl amino acids in humans.

Social Networks and Cardiovascular Disease Events in the Jackson Heart Study.

Background: Cardiovascular disease (CVD) disproportionately affects African American adults. Greater social networks (SN), or social connectedness, may lower the risk of CVD events. Objective: Determine the association of SN and incident CVD and test mediation by depressive symptoms, hypertension control and diabetes control. Methods: We used the Social Network Index (SNI) at exam 1 (2000-2004) to develop a continuous standardized SN score and binary categories (high vs. low) among participants in the Jackson Heart Study (n=5252, mean age=54.8 years). Surveillance of coronary heart disease (CHD), stroke, and heart failure (HF) events occurred after exam 1 (2005 for HF) until 2016. Using Cox proportional hazards regression, we estimated the association of SN and CVD events by sex and tested the mediation of depressive symptoms, hypertension control and diabetes control. Models adjusted for age, education, health behaviors, and CVD co-morbidities. Results: Among women, the SN score was associated with a lower risk of CHD and HF after full adjustment (HR 0.78, 95% CI 0.68, 0.89 and HR 0.78, 95% CI 0.63, 0.95, respectively), but the association with stroke attenuated after adjustment for co-morbidities (HR 95% CI 0.88 95% CI 0.67, 1.14). SN scores were also associated with CHD in men (HR 0.84, 95% CI 0.70, 0.99) after full adjustment. High vs. low SN was associated with CHD in men and women, but not after adjustment for co-morbidities. There was no evidence of mediation by depressive symptoms, diabetes control, and hypertension control. Conclusion: Higher SN may lower the risk of CVD events, especially in women.

The role of aldosterone and ideal cardiovascular health in incident diabetes: The Jackson Heart Study.

Background: Greater attainment of ideal cardiovascular health (ICH) and lower serum aldosterone are associated with lower diabetes risk. Higher levels of ICH are associated with lower aldosterone. The mediational role of aldosterone in the association of ICH with incident diabetes remains unexplored. Thus, we examined the mediational role of aldosterone in the association of 5 ICH components (smoking, diet, physical activity, body mass index [BMI], and cholesterol) with incident diabetes. Additionally, we investigated the mediational role of glucose and blood pressure (BP) in the association of aldosterone with incident diabetes in an African American (AA) cohort. Methods: We conducted a prospective cohort analysis among AA adults, aged 21-94 years, in the Jackson Heart Study. Data on ICH, aldosterone, and cardiometabolic risk factors were collected at exam 1 (2000-2004). Diabetes (fasting glucose ≥ 126 mg/dL, physician diagnosis, use of diabetes drugs, or glycated hemoglobin ≥ 6.5%) was assessed at exams 1 through 3 (2009-2012). ICH metrics were defined by American Heart Association 2020 goals for smoking, dietary intake, physical activity, BMI, total cholesterol, BP and glucose. The number of ICH metrics attained at exam 1, excluding BP and fasting glucose, were summed (0-2, vs. 3+). R Package Mediation was used to examine: 1) The mediational role of aldosterone in the association of ICH with incident diabetes; and 2) the mediational role of BP and glucose in the association of aldosterone with incident diabetes. Results: Among 2,791 participants (mean age: 53±12, 65% female) over a median of 7.5 years, there were 497 incident diabetes cases. Risk of incident diabetes was 37% (HR: 0.63, 95%CI: 0.47, 0.84) lower in 3+ ICH category compared to 0-2 ICH category. Aldosterone mediated 6.98% (95% CI: 1.8%, 18.0%) of the direct effect of ICH on incident diabetes. A 1-unit increase in log-aldosterone was associated with a 44% higher risk of diabetes (HR 1.44, 95%CI 1.25-1.64). BP and glucose mediated 16.3% (95% CI: 7.0%, 31.0%) and 19.7% (95% CI: 6.5%, 34.0%) of the association of aldosterone with incident diabetes, respectively. Conclusion: Aldosterone is a mediator of the association of ICH with incident diabetes, whereas BP and glucose are mediators of the association of aldosterone with incident diabetes, emphasizing the importance of the renin-angiotensin-aldosterone system and ICH in lowering risk of diabetes in AA populations.

Measures of Food Inadequacy and Cardiovascular Disease Risk in Black Individuals in the US From the Jackson Heart Study.

Importance: Food insecurity disproportionately affects Black individuals in the US. Its association with coronary heart disease (CHD), heart failure (HF), and stroke is unclear. Objective: To evaluate the associations of economic food insecurity and proximity with unhealthy food options with risk of incident CHD, HF, and stroke and the role of diet quality and stress. Design, Setting, and Participants: This cohort study was a time-to-event analysis of 3024 Black adult participants in the Jackson Heart Study (JHS) without prevalent cardiovascular disease (CVD) at visit 1 (2000-2004). Data analysis was conducted from September 1, 2020, to November 30, 2021. Exposures: Economic food insecurity, defined as receiving food stamps or self-reported not enough money for groceries, and high frequency of unfavorable food stores (>2.5 unfavorable food stores [fast food restaurants, convenience stores] within 1 mile). Main Outcomes and Measures: The main outcomes were incident CVD including incident CHD, stroke, and HF with preserved ejection fraction and with reduced ejection fraction (HFrEF). During a median follow-up of 13.8 (IQR, 12.8-14.6) years, the associations of measures of food inadequacy with incident CVD (CHD, stroke, and HF) were assessed using multivariable Cox proportional hazards regression models. Results: Among the 3024 study participants, the mean (SD) age was 54 (12) years, 1987 (66%) were women, 630 (21%) were economically food insecure, and 50% (by definition) had more than 2.5 unfavorable food stores within 1 mile. In analyses adjusted for cardiovascular risk and socioeconomic factors, economic food insecurity was associated with higher risk of incident CHD (hazard ratio [HR], 1.76; 95% CI, 1.06-2.91) and incident HFrEF (HR, 2.07; 95% CI, 1.16-3.70), but not stroke. These associations persisted after further adjustment for diet quality and perceived stress. In addition, economic food insecurity was associated with higher high-sensitivity C-reactive protein and renin concentrations. High frequency of unfavorable food stores was not associated with CHD, HF, or stroke. Conclusions and Relevance: The findings of this cohort study suggest that economic food insecurity, but not proximity to unhealthy food options, was associated with risk of incident CHD and HFrEF independent of socioeconomic factors, traditional cardiovascular risk factors, diet quality, perceived stress, and other health behaviors. Economic food insecurity was also associated with markers of inflammation and neurohormonal activation. Economic food insecurity may be a promising potential target for the prevention of CVD.