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Introduction: Measures of cardiac structure and function provide important diagnostic and prognostic information for heart failure (HF). Few studies have assessed the associations of circulating metabolites with cardiac structure and function. Hypothesis: We hypothesize that circulating metabolites that reflect aging process are associated with cardiac structure and function measures and incident HF. Methods: Participants from the Atherosclerosis Risk in Communities (ARIC) study visit 5 and the Hispanic Community Health Study / Study of Latinos (HCHS/SOL) study visit 1 who had serum metabolite measures but not prevalent HF were included. Linear regressions were used to examine the associations of metabolites with ten cardiac structure and function variables adjusting for clinical risk factors in each race and study strata, followed by random-effect meta-analyses. The Cox regression was applied to examine the relationship between those identified metabolites and incident HF post visit 5 in ARIC. Results: Among 589 analyzed metabolites, 179 were associated with cardiac structure or function measures in 706 Blacks, 3,358 Whites, and 1,380 Hispanics (FDR < 0.05). Forty-one metabolites were related to two or more measures, where 22 were associated with incident HF (308 HF cases, p Conclusions: We identified multiple metabolites associated with cardiac structure and function measures in multi-ethnic populations, highlighting metabolic pathways in aging and their impact on HF.

Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine intercontinental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra-platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension.

Introduction: Heart Failure (HF) has shared genetic architecture with its risk factors, including atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). The risk prediction performance of polygenic risk scores (PRS) for those HF risk factors and HF itself over an established risk equation warrants investigation. Methods: Within the Atherosclerosis Risk in Communities (ARIC) study, six PRSs were constructed for AF, BMI, CHD, SBP, T2D, and HF by summing the product of pre-computed weights from genome-wide association studies and SNP allele dosages in European and African Americans separately. The association between PRSs and incident HF was assessed using cox proportional hazard models, and the 10-, 20-, and 30-year risk prediction performance of PRS over the ARIC HF risk equation was assessed using C-statistics. Associations between AF PRS and HF subtypes, echocardiographic measures, and 4,877 proteins were examined. Results: Over 30 years follow-up, 1,922 (22%) and 735 (29%) HF cases developed in 8,624 European (mean age=54.2, 52% female) and 2,525 African (mean age=53.3, 61% female) Americans. The PRSs for AF and HF were associated with incident HF in both European and African Americans (P-4 ). Protein analyses revealed that 61 proteins were associated with AF PRS, where NT-proBNP and Coagulation factor X showed the strongest positive and negative associations respectively. Conclusions: The PRS of AF was associated with incident HF, and had significant incremental value over an established HF risk prediction equation. These findings suggest that PRS may be useful in identifying individuals with high risk of HF.

IMPORTANCE: Cardiometabolic disease is responsible for decreased longevity and poorer cardiovascular outcomes in the modern era. Metabolite profiling provides a specific measure of global metabolic function to examine specific metabolic mechanisms and pathways of cardiometabolic disease beyond its clinical definitions. OBJECTIVES: To define a molecular basis for cardiometabolic stress and assess its association with cardiovascular prognosis. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational cohort study was conducted in a population-based setting across 2 geographically distinct centers (Boston Puerto Rican Health Study [BPRHS], an ongoing study of individuals enrolled between June 1, 2004, and October 31, 2009; and Atherosclerosis Risk in Communities [ARIC] study, whose participants were originally sampled between November 24, 1986, and February 10, 1990, and followed up through December 31, 2017). Participants in the BPRHS were 668 Puerto Rican individuals with metabolite profiling living in Massachusetts, and participants in the ARIC study were 2152 individuals with metabolite profiling and long-term follow-up for mortality and cardiovascular outcomes. Statistical analysis was performed from October 1, 2018, to March 13, 2020. EXPOSURE: The primary exposure was metabolite profiles across both cohorts. MAIN OUTCOMES AND MEASURES: Outcomes included associations with multisystem cardiometabolic stress and all-cause mortality and incident coronary heart disease (in the ARIC study). RESULTS: Participants in the BPRHS (N = 668; 491 women; mean [SD] age, 57.0 [7.4] years; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 32.0 [6.5]) had higher prevalent cardiometabolic risk relative to those in the ARIC study (N = 2152; 599 African American individuals; 1213 women; mean [SD] age, 54.3 [5.7] years; mean [SD] body mass index, 28.0 [5.5]). Multisystem cardiometabolic stress was defined for 668 Puerto Rican individuals in the BPRHS as a multidimensional composite of hypothalamic-adrenal axis activity, sympathetic activation, blood pressure, proatherogenic dyslipidemia, insulin resistance, visceral adiposity, and inflammation. A total of 260 metabolites associated with cardiometabolic stress were identified in the BPRHS, involving known and novel pathways of cardiometabolic disease (eg, amino acid metabolism, oxidative stress, and inflammation). A parsimonious metabolite-based score associated with cardiometabolic stress in the BPRHS was subsequently created; this score was applied to shared metabolites in the ARIC study, demonstrating significant associations with coronary heart disease and all-cause mortality after multivariable adjustment at a 30-year horizon (per SD increase in metabolomic score: hazard ratio, 1.14; 95% CI, 1.00-1.31; P = .045 for coronary heart disease; and hazard ratio, 1.15; 95% CI, 1.07-1.24; P