Plasma Circulating Extracellular RNAs in Left Ventricular Remodeling Post-Myocardial Infarction

Despite substantial declines in mortality following myocardial infarction (MI), subsequent left ventricular remodeling (LVRm) remains a significant long-term complication. Extracellular small non-coding RNAs (exRNAs) have been associated with cardiac inflammation and fibrosis and we hypothesized that they are associated with post-MI LVRm phenotypes. RNA sequencing of exRNAs was performed on plasma samples from patients with “beneficial” (decrease LVESVI ≥ 20%, n = 11) and “adverse” (increase LVESVI ≥ 15%, n = 11) LVRm. Selected differentially expressed exRNAs were validated by RT-qPCR (n = 331) and analyzed for their association with LVRm determined by cardiac MRI. Principal components of exRNAs were associated with LVRm phenotypes post-MI; specifically, LV mass, LV ejection fraction, LV end systolic volume index, and fibrosis. We then investigated the temporal regulation and cellular origin of exRNAs in murine and cell models and found that: 1) plasma and tissue miRNA expression was temporally regulated; 2) the majority of the miRNAs were increased acutely in tissue and at sub-acute or chronic time-points in plasma; 3) miRNA expression was cell-specific; and 4) cardiomyocytes release a subset of the identified miRNAs packaged in exosomes into culture media in response to hypoxia/reoxygenation. In conclusion, we find that plasma exRNAs are temporally regulated and are associated with measures of post-MI LVRm.
Highlights • Plasma exRNA signatures were associated with post-MI remodeling as assessed by cardiac MRI. • Candidate exRNAs originated from different cell types, and were dynamically regulated in experimental models of ischemia. • Candidate exRNAs were predicted to regulate pathways of inflammation and fibrosis by bioinformatics analysis. Plasma RNA signatures are associated with heart remodeling following a myocardial infarction, and are predicted to regulate inflammation pathways. These extracellular RNAs are derived from different types of cells in the heart and are altered in the heart tissue as well as plasma in a mouse model of myocardial infarction, reflecting the complex and dynamic process of heart remodeling after myocardial infarction.