Abstract 68: Metabolomic Profiles of Cardiac Structure and Function and Their Associations with Incident Heart Failure in Multi-Ethnic Populations

Abstract

Introduction: Metabolic dysregulation is associated with heart failure (HF). However, comprehensive evaluation of the effect of circulating metabolites on cardiac function, a critical measure for predicting HF risk and prognosis, in multi-ethnic populations remains limited. Objectives: We aim to identify circulating metabolites associated with cardiac function and HF risk in multi-ethnic populations. Methods: We evaluated 21,638 HF-free participants (57% non-White, 57% women) from seven studies, who had contemporaneous circulating metabolite and echocardiography (echo) measures. We used linear regressions (within study) to evaluate the cross-sectional associations between metabolites and cardiac structure/function traits, adjusting for clinical risk factors. Random-effect meta-analyses were performed to produce overall estimates. Cox proportional hazard regression was used to examine the association of echo-related metabolites with incident HF, and its subsets, HF with reduced and preserved ejection fraction (HFrEF, HFpEF). Results: Of 1,027 analyzed metabolites in relation to 42 echo measures, 604 were significantly associated with 28 echo measures (FDR <0.05), including cardiac structure and left and right ventricular function traits. In the prospective analyses, 156, 59, and 73 metabolites showed a significant association with incident HF, HFrEF, and HFpEF, with an average hazard change of 21%, 13%, and 32% per SD difference in metabolite level. Many identified metabolites showed consistent effects across echo measures and HF risk (Figure). High levels of acisoga, an end-product of polyamine metabolism and a potential biomarker for HF, were associated with greater left atrial size and HFpEF risk; high levels of homoarginine, an amino acid with anti-inflammatory properties, were associated with low left ventricular mass and a lower risk for HFrEF and HFpEF. Some metabolites demonstrated divergent effects-high levels of glycerol, a precursor for the synthesis of triacylglycerols and phospholipids, were associated with low left ventricular mass yet a high risk of HFrEF. Conclusions: Metabolomic profiling revealed distinct and mostly consistent associations between circulating metabolites, cardiac structure/function, and incident HF in multi-ethnic populations. Our findings provide insights into the metabolic pathways underlying cardiac remodeling and HF pathogenesis, and raise the possibility that novel metabolites may inform HF risk stratification.