Proteomic profiling to identify mechanisms of susceptibility and resilience to cardiac dysfunction in Black Americans

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

Heart failure (HF) and atrial fibrillation (AF) are common and differentially burden Black Americans. Social determinants of health (SDOH) also disproportionately impact Black Americans and contribute to an excess of cardiovascular (CV) events, although many Black Americans survive to late-life free of CV disease. Critical barriers to the development of interventions to prevent HF and AF include the limited knowledge of disease pathobiology and of the molecular pathways by which SDOH and resilience to such adversity influence susceptibility to CV disease. The objective of this proposal is to use proteomics and genomics to identify biologic pathways that are responsible for the development of subclinical and clinical cardiac dysfunction, that mediate the impact of SDOH on HF and AF risk, and that characterize biologic resilience to these outcomes despite adverse SDOH. The central hypothesis is that integrated analysis of proteomic and genomic data in a Black American population will enable discovery of novel inflammation- and fibrosis-related proteins relevant to HF and AF development, and identify biologic pathways underlying SDOH-related risk for and resilience to these CV conditions. The rationale is that identifying proteins with causal effects on cardiac dysfunction and defining molecular mediators of CV resilience to adverse SDOH may yield new therapeutic targets that are especially relevant to Black populations. This project leverages proteomics (~3,000 plasma proteins) measured 20 years apart, existing genomic data, rich CV phenotyping (echo, ambulatory arrhythmia monitoring), and prospectively adjudicated events in the largest prospective CV cohort of Black Americans - the Jackson Heart Study - to address the following aims: (1) Define proteins and protein networks associated with clinical and subclinical cardiac dysfunction; (2) Identify proteins and protein networks associated with atrial fibrillation and subclinical arrhythmia; (3) Identify molecular pathways linking SDOH, and resilience to adverse SDOH, to cardiac function and arrhythmia in Black adults. The unique contribution of this project will be to identify biologic mechanisms responsible for risk of and resilience to HF and AF in Black Americans. This contribution will be significant because it will identify novel therapeutic targets for the prevention of cardiac dysfunction tailored to disease mechanisms impacting Black Americans. These studies will therefore help to reduce the morbidity, mortality, and racial disparity associated with HF and AF. Innovative features include: (a) integration of repeated-measure proteomics and genomics to identify potentially causal proteins for cardiac dysfunction and arrhythmia among Black Americans; (b) focus on an understudied population with excess burden of CVD to interrogate mechanisms by which SDOH influence disease susceptibility; and (c) integration of SDOH and psychosocial assessments to identify protective proteins underlying cardiac resilience in the face of social adversity. Expected outcomes include advancing understanding of the biology of resilience and discovery of therapeutic targets relevant to Black Americans.