Circulating metabolites underlying cardiometabolic risk for cardiac dysfunction and heart failure in diverse populations

About This Grant

Abstract Heart failure (HF) is a common and morbid consequence of metabolic dysfunction (excess/ectopic adipose, insulin resistance). Social determinants of health (SDOH) contribute to excess metabolic and HF risk, and disproportionately impact the health of Black and Hispanic adults, although many survive to late-life free of CV disease. Critical barriers to the development of interventions to prevent HF include the limited knowledge of molecular pathways (a) that link excess and ectopic adiposity to cardiac dysfunction and (b) by which SDOH and resilience to such adversity influence susceptibility to CV disease. Our overall objective is to use metabolomics and genomics to identify biologic pathways linking metabolic dysfunction – and ectopic adiposity specifically - to the development of subclinical and clinical cardiac dysfunction; mediating the impact of adverse SDOH on HF risk; and characterizing biologic resilience to these outcomes in the presence of adverse SDOH. The central hypothesis is that large-scale metabolomic and genomic data in a multiethnic population will enable discovery of novel metabolic signatures of specific ectopic fat depots that are relevant to HF pathobiology and underlie SDOH-related risk for and resilience to cardiac dysfunction. The rationale is that identifying metabolites with causal effects on cardiac dysfunction and defining molecular mediators of CV resilience to adverse SDOH may yield new prevention targets especially relevant to diverse populations. This project will measure metabolomics (~1,000 serum metabolites), and leverages existing WES, rich CV phenotyping (serial cardiac MRI, rest-exercise echo), MRI-based quantification of total and regional adipose, and prospectively adjudicated HF in the multiethnic Dallas Heart Study to address the following aims: (1) Identify metabolites reflecting metabolic dysfunction that associate with progressive subclinical cardiac dysfunction and development of HF; (2) Define genetic determinants of HF- and cardiac function-related metabolites, and identify metabolites with possible causal effects on HF development; (3) Discover molecular pathways linking SDOH, and resilience to social adversity, to cardiac dysfunction. The unique contribution will be to identify metabolic pathways linking ectopic fat to cardiac impairment and HF, and underlying SDOH- related risk of and resilience to cardiac dysfunction in diverse populations. This contribution will be significant in helping to identify novel therapeutic targets to prevent of cardiac dysfunction that are tailored to disease mechanisms impacting these communities. These studies may therefore help to reduce the morbidity, mortality, and racial/ethnic disparities associated with HF. Innovative features include: (a) linking ectopic adipose to impaired cardiac reserve, longitudinal changes in cardiac function, and HFpEF not feasible in other cohorts; (b) focus on understudied populations to interrogate mechanisms by which SDOH influence disease susceptibility; and (c) integration of SDOH and psychosocial assessments to identify protective metabolites underlying cardiac resilience in the face of social adversity.