Circulating extracellular RNAs, myocardial remodeling, and elevated BMI in patients with acute coronary syndrome

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.

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.

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.

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.