Abstract 17100: MicroRNAs and Risk of Myocardial Infarction: Prospective Results from the Bruneck Study

Abstract

Background: Circulating microRNAs (miRNAs) are emerging as promising biomarkers in cardiovascular diseases. We have previously identified a miRNA signature for type 2 diabetes in the general population (Zampetaki et al, Circ Res, 2010).

Objective: Our aim was to investigate the association between baseline levels of miRNAs (1995) and incident myocardial infarction (1995-2005) in the Bruneck cohort, determine their cellular origin and explore their role in the pathogenesis of the disease.

Methods and Results: Following RNA extraction, a total of nineteen circulating miRNAs were quantified by real time polymerase chain reactions in 820 participants. In multivariable Cox regression analysis, three miRNAs were consistently and significantly related with incident myocardial infarction: miR-126 showed a positive association (multivariable hazard ratio 2.69 [95%CI 1.45-5.01], P=0.002) while miR-223 and miR-197 were inversely associated with disease risk (multivariable hazard ratio 0.47 [95% CI 0.29-0.75], P=0.002, and 0.56 [95% CI 0.32-0.96], P=0.036). To determine their cellular origin, healthy volunteers underwent limb ischaemia-reperfusion generated by thigh cuff inflation. Plasma miRNA changes were analysed at baseline, at 10 min, 1h, 5h, 2 days and 7 days. Computational analysis using the temporal clustering identified six distinct miRNA clusters. One cluster included all miRNAs associated with risk of future myocardial infarction. It was characterized by early (1h) and sustained activation (7 days) post ischaemia-reperfusion injury and consisted of miRNAs predominantly expressed in platelets. Furthermore, proteomics revealed that overexpression of the precursor of miR-126 reduced endothelial secretion of plasminogen-activator inhibitor-1, the key inhibitor of endogenous fibrinolysis.

Conclusions: This study highlights the importance of platelets as a major contributor to the circulating miRNA pool. In subjects with subsequent myocardial infarction differential co-expression patterns of miRNAs occur around endothelial-enriched miR-126 with a potential link to fibrinolysis.