Abstract Body: 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.