MicroRNA Expression in Circulating Microvesicles Predicts Cardiovascular Events in Patients With Coronary Artery Disease

BACKGROUND Circulating microRNAs (miRNAs) are differentially regulated and selectively packaged in microvesicles (MVs). We evaluated whether circulating vascular and endothelial miRNAs in patients with stable coronary artery disease have prognostic value for the occurrence of cardiovascular (CV) events. METHODS AND RESULTS Ten miRNAs involved in the regulation of vascular performance-miR-126, miR-222, miR-let7d, miR-21, miR-20a, miR-27a, miR-92a, miR-17, miR-130, and miR-199a-were quantified in plasma and circulating MVs by reverse transcription polymerase chain reaction in 181 patients with stable coronary artery disease. The median duration of follow-up for major adverse CV event-free survival was 6.1 years (range: 6.0-6.4 years). Events occurred in 55 patients (31.3%). There was no significant association between CV events and plasma level of the selected miRNAs. In contrast, increased expression of miR-126 and miR-199a in circulating MVs was significantly associated with a lower major adverse CV event rate. In univariate analysis, above-median levels of miR-126 in circulating MVs were predictors of major adverse CV event-free survival (hazard ratio: 0.485 [95% CIAUTHOR: Is 95% CI correct?: 0.278 to 0.846]; P=0.007) and percutaneous coronary interventions (hazard ratio: 0.458 [95% CI: 0.222 to 0.945]; P=0.03). Likewise, an increased level of miR-199a in circulating MVs was associated with a reduced risk of major adverse CV events (hazard ratio: 0.518 [95% CI: 0.299 to 0.898]; P=0.01) and revascularization (hazard ratio: 0.439 [95% CI: 0.232 to 0.832]; P=0.01) in univariate analysis. miRNA expression analysis in plasma compartments revealed that miR-126 and miR-199a are present mainly in circulating MVs. MV-sorting experiments showed that endothelial cells and platelets were found to be the major cell sources of MVs containing miR-126 and miR-199a, respectively. CONCLUSION MVs containing miR-126 and miR-199a but not freely circulating miRNA expression predict the occurrence of CV events in patients with stable coronary artery disease.