Plasma extracellular vesicle cargo microRNAs are associated with heart failure and cardiovascular death following acute coronary syndrome

BACKGROUND AND AIMS: Patients with acute coronary syndromes (ACS) are at risk for long-term sequelae related to adverse ventricular remodeling including heart failure (HF) and cardiovascular death. Circulating microRNAs (miRNAs) have the potential to serve as biomarkers associated with the pathogenesis of ventricular remodeling. This study aims to identify and characterize plasma miRNAs associated with HF and cardiovascular death. METHODS: The association between 21 candidate miRNAs and HF or cardiovascular death was evaluated in 4541 patients from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial using samples from the time of index hospitalization for ACS. Associations between each miRNA and the composite endpoint of hospitalization for HF or cardiovascular death (HHF/CVD) were estimated in Cox proportional hazards models. The top candidate miRNAs were validated in an independent cohort of patients hospitalized for ACS using complementary methods for isolation of extracellular RNA carriers. RESULTS: Over 12 months in MERLIN-TIMI 36, 313 individuals met the primary endpoint. In total, 11 miRNAs were associated with HHF/CVD. After adjustment for clinical factors and established biomarkers, miR-223-3p (hazard ratio 0.81 [95% confidence interval: 0.60-1.09], 0.62 [0.45-0.87], and 0.61 [0.43-0.85] for the 2nd, 3rd, and 4th quartiles, respectively) and miR-378c (0.96 [0.65-1.42], 1.14 [0.78-1.66], and 1.39 [0.97-1.98], for the 2nd, 3rd, and 4th quartiles, respectively) were independently associated with the risk of HHF/CVD. In an independent validation cohort of 27 patients hospitalized with ACS, we found that both miRNAs were identified in different RNA-carrying extracellular particles in plasma, including extracellular vesicles (EVs) and nonvesicular extracellular nanoparticles (NVEPs) including exomeres and supermeres. Both miR-223-3p and 378c were more enriched in small EVs (sEVs) compared to NVEPs. In concordance with the direction of the associations observed in MERLIN-TIMI 36 with HHF, the level of miR-223-3p in sEVs and exomeres was positively associated with left ventricular ejection fraction (LVEF) post-ACS while the level of miR-378c in sEVs was negatively associated with LVEF in the acute phase. CONCLUSION: Circulating miRNAs 223-3p and 378c were associated with the risk of HHF/CVD after adjustment for clinical factors and established cardiovascular biomarkers. Carrier-specific measurement of these miRNAs may emerge as novel minimally invasive biomarkers for post-ACS cardiac remodeling and shed light on potentially new targetable pathways.