Abstract
OBJECTIVE: Given the elevated mortality in individuals with acute coronary syndrome and increased adiposity, delineating the molecular mechanisms underlying obesity-associated adverse cardiac remodeling is critical for the identification of novel pathophysiological biomarkers and potential therapeutic targets. Circulating extracellular RNAs (ex-RNAs) regulate important biological processes and can serve as biomarkers of disease. This study aims to discover circulating extracellular RNAs (ex-RNAs) that serve as biomarkers of obesity-associated adverse cardiac remodeling in ACS survivors. METHODS: We analyzed extracellular RNA (ex-RNA) profiles in 296 survivors of acute coronary syndrome enrolled in the Transitions, Risks, and Actions in Coronary Events - Center for Outcomes Research and Education (TRACE-CORE) cohort. A total of 317 ex-RNAs were quantified, selected a priori based on prior findings from a large population-based study. We employed a two-step, mechanism-driven approach to identify ex-RNAs associated with echocardiographic phenotypes, including left atrial (LA) dimension, LA volume index, left ventricular (LV) ejection fraction, LV mass, and LV end-diastolic volume, then tested the relations of these ex-RNAs with obesity. We performed further bioinformatics analysis of the gene ontology categories and molecular pathways associated with predicted miRNA targets. RESULTS: We identified 45 ex-RNAs associated with at least one echocardiographic phenotype, of which miR-1185-1-3p, miR-550a-3p, and miR-885-5p were also associated with prevalent obesity. Bioinformatic analysis of their predicted gene targets (n=1,930) revealed enrichment in key pathways related to inflammation, fibrosis, and cellular toxicity, including Wnt/β-catenin signaling, TGF-β signaling, and hypoxia-inducible factor (HIF) signaling. Targets such as DICER1, VEGF, and EPO were implicated. Gene ontology analysis further highlighted associations with angiogenesis, FGF signaling, and interleukin pathways. CONCLUSIONS: Among ACS survivors, we observed that miR-1185-1-3p, miR-550a-3p, and miR-885-5p were associated with both echocardiographic markers of adverse cardiac remodeling and elevated BMI. Relevance for patients: miR-1185-1-3p, miR-550a-3p, and miR-885-5p were associated with echocardiographic phenotypes and obesity and are potential biomarkers for adverse cardiac remodeling in obesity.