Proteomic and Genomic Discovery of Targets for Atrial Cardiopathy-Related Cardiovascular Outcomes

ABSTRACT Atrial fibrillation (AF) is a common arrhythmia associated with serious consequences. Recent evidence suggests that much of the morbidity attributed to AF may be caused by underlying abnormalities in the structure and function of the left atrium, known as atrial cardiopathy. Among individuals free of AF at baseline, measures of atrial cardiopathy are independently associated with incident cardiovascular disease. Additionally, atrial cardiopathy is a potent prognostic marker in higher-risk patients with established cardiovascular disease. However, our limited understanding of the molecular mechanisms that link atrial cardiopathy with clinical disease is a major obstacle to developing new therapies. We propose to use proteomics and genomic methods in diverse primary and secondary prevention populations to improve our understanding of the etiology of atrial cardiopathy-related cardiovascular diseases, and to identify novel proteins that may be causal risk factors for these complications. The primary prevention study population includes participants of four NHLBI-funded prospective cohort studies who met criteria for atrial cardiopathy and were free of clinically recognized cardiovascular disease. In these cohorts, we will leverage existing data on proteomics, atrial cardiopathy, and potential confounding factors at the same study visit, and adjudicated cardiovascular events during follow-up. The secondary prevention study population includes participants of the ARCADIA trial, all of whom experienced a recent cryptogenic stroke and had evidence of atrial cardiopathy. This trial randomized patients to aspirin or apixaban and conducted adjudication of recurrent stroke events during follow up. In ARCADIA, we will conduct new proteomic profiling to measure levels of ~5,400 proteins using pre-randomization blood samples. The primary outcomes for this study are AF, ischemic stroke, and heart failure. We will conduct longitudinal analyses of individual proteins and study outcomes separately in these primary and secondary prevention study populations, which include over 30% Black participants. Genomic data will be used to select strong genetic determinants for Mendelian randomization experiments, which will evaluate whether significant protein associations with study outcomes are likely to be causal. For key proteins, we will conduct mass spectrometry validation and develop targeted immunoassays to facilitate additional clinical research. The rigorous approach described in this application will help to accelerate the discovery of novel etiologic factors and potential therapeutic targets for cardiovascular disease prevention.