Precision Cardiovascular Diseases Phenotyping and Pathophysiological Pathways in the CARRS Cohort (Precision-CARRS)

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PROJECT SUMMARY / ABSTRACT (Overall) Precision-CARRS will revolutionize the cardiovascular disease (CVD) prevention and care paradigm from imprecise prediction with focus on late stage disease to personalized and precise prediction with improved understanding of early-stage disease to maintain cardiovascular health. Atherosclerotic CVD (ASCVD) and heart failure (HF) phenotypes are heterogeneous and result from complex interactions between immutable genetic factors and mutable forces operating at environmental (e.g., ambient air quality), individual (e.g., health behaviors, social influence), and molecular (e, g, proteins, 'omics) levels. South Asians are an understudied population at high CVD risk even at young ages, at low body weight, and in the absence of traditional risk factors. We will leverage substantial matched resources, and also build upon the NHLBI- funded CARRS cohort, a representative sample of n=21,864 South Asians aged ≥ 20 years, with ongoing follow-up for clinical ASCVD risk factors, clinical disease, and mortality. The cohort has high retention (>95% have at least one follow-up) and a biorepository of 360,000 stored samples. We will add detailed subclinical and clinical CVD phenotyping, repeated measures of targeted protein markers and untargeted multi-omics, and real-time assessment of health behaviors. By extending follow-up by an additional 5 years, we will accrue 176,536 person-years of follow up, >1,000 incident ASCVD, and nearly >900 cases of clinical HF (Stages C/D). Enabled by precise mapping of CVD at the granular level of subclinical and clinical phenotypes, we will investigate the epidemiology and causes of CVD along both ASCVD and HF pathways. Three complementary cores (Administrative and Field Coordination; CVD Phenotyping; and Data Management and Analysis) will support four interconnected projects, one of which is led by an early-stage investigator (ESI). All four project examine common subclinical and clinical endpoints from synergistic vantage points: traditional risk factors and targeted protein-based pathophysiological pathways (Project 1), the impact of air pollution and mediating mechanisms (Project 2), molecular signals and mechanisms through integrative untargeted multi-omics (Project 3), and socio-behavioral influences on CVD risk and outcomes studied via spousal dyads (Project 4, ESI). Precision-CARRS will unravel the natural history, pathophysiology, and causal factors of vascular and myocardial disease and pave the way for precision CVD diagnostics, prevention, and care for South Asians–who represent one fifth of humanity and are a rapidly growing sub- population in the US. In summary, Precision-CARRS is designed to be a powerful platform to understand the natural history of CVD in an understudied high-risk population and to spur future innovative scientific collaborations with other CVD longitudinal cohorts in the US and globally.