ABSTRACT Heart failure (HF) affects more than 6 million American adults, and the estimated prevalence and cost of care is expected to increase markedly. HF is characterized by cardiac metabolic dysfunction, including impaired branched-chain amino acid (BCAA) catabolism, decreased fatty acid oxidation and depressed urea cycle function. With the advent of high-throughput metabolomics, scores of circulating metabolic signatures have been identified to assist clinical management of HF. Perturbations in myocardial energy metabolism are detectable in at-risk individuals prior to the development of HF, and may contribute to alterations in cardiac structure and function that underlie HF. However, the role of metabolic dysfunction in the changes of cardiac structure and function and its relationship to the development of HF has not been well studied, specifically among African and Hispanic Americans, the two largest minority groups in the U.S. who exhibit a disproportionate risk of HF. Our previous work and preliminary results support that serum metabolites, reflecting systemic metabolism and myocardial energetics, and their genetic determinants are associated with cardiac dysfunction and HF risk, in both consistent and divergent fashion across different ethnic groups. The goal of this study is to identify serum metabolic signatures along with their genetic determinants that contribute to cardiac dysfunction and HF risk in European Americans (EAs), African Americans (AAs) and Hispanic Americans (HAs). This proposed study will leverage the rich infrastructure of the Atherosclerosis Risk in Communities (ARIC) study and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), two prospective cohorts with unique resources encompassing metabolome profiles, genomic data, measures of cardiac structure/function, and HF follow-up. Our aims are: (1) to identify metabolic signatures associated with subclinical cardiac dysfunction and their association with progression of cardiac dysfunction and HF risk; and (2) to identify genetic determinants of metabolites related to subclinical cardiac dysfunction, and their association with cardiac dysfunction, its progression and HF risk. We will apply integrative approaches to identify potential causal genetic and metabolic markers implemented in HF etiology, and consider the potential for effect modification by race/ethnicity and sex. Our team is uniquely positioned, given our expertise in metabolome profiling, genomics, cardiac structure/function, HF adjudication, biostatistics and bioinformatics. The results of this research will enable continued scientific progress toward an understanding of HF pathophysiology, with direct implications for prevention and potential therapies.