Proteomics of Cardiovascular Risk: The Multiethnic Study of Atherosclerosis

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PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) remain the leading cause of mortality in the U.S. Despite improved therapies, the incidence of first ASCVD and HF events is still unacceptably high. Progress in preventing and managing these conditions will require a better understanding of their novel risk factors and biological pathways. Protein levels can serve as potent, specific, and modifiable biomarkers for ASCVD and HF risk, guide therapy and elucidate causal pathways. Large-scale proteomic technology has become available to scan 4,993 distinct proteins simultaneously in just 0.15 ml of plasma, using modified aptamers as binding reagents. The overarching goal of this proposal is to apply large-scale proteomics to patients who are free of cardiovascular disease (CVD) to improve incident ASCVD and HF risk prediction and increase understanding of the biological pathways and mechanisms underlying the development of these diseases. We will conduct the proteomic investigation in MESA, a well-characterized, racially diverse cohort of 6814 persons without CVD at baseline, recruited between 2000 and 2002. Now >15 years out from the initial study visit, >800 cardiovascular events have accumulated, providing an opportunity for ASCVD and HF risk modeling. MESA was conceived with the primary goal to study “progression of subclinical to clinical CVD, with coronary artery calcification (CAC) as a subclinical measure of ASCVD and cardiac MR (CMR) as a subclinical measure of HF. Thus, in addition to modeling of ASCVD and HF clinical outcomes, we will devise proteomic risk scores for the development of subclinical ASCVD and HF and for their conversion to clinical events. We will conduct proteomic studies at three study visits that span 10 years, to delineate longitudinal proteomic risk trajectories and create “live” mutable risk scores. Lastly, in an exploratory aim, we will leverage MESA’s near equal representation of men and women and its racial diversity by testing for any heterogeneity of proteomic risk scores and biological pathways associated with ASCVD and HF, according to sex and by race. Models for ASCVD and HF risk will be developed within MESA and then externally validated in the Atherosclerosis Risk in Communities (ARIC) cohort. In sum, our Aims are to assay the concentrations of 4,993 plasma proteins in 6,043 MESA participants at 3 study visits spanning 10 years to: 1) improve the risk prediction of incident ASCVD and HF outcomes and earlier subclinical disease, 2) inform the biological pathways of incident ASCVD and HF outcomes and subclinical disease, 3) inform sex and racial differences in the biology and propensity to develop ASCVD and HF, and 4) validate key findings in the ARIC cohort.