Prospective Study on Circulating MicroRNAs and Risk of Myocardial Infarction

List of Authors: Anna Zampetaki*, Peter Willeit*, Lindsey Tilling, Ignat Drozdov, Agnes Mayr, Siegfried Weger, Ajay Shah, Chantal Boulanger, Johann Willeit, Philip J. Chowienczyk, Stefan Kiechl, Manuel Mayr(* equal contribution)

Objectives
We sought to explore the association between baseline levels of microRNAs (miRNAs) (1995) and incident myocardial infarction (1995-2005) in the Bruneck cohort and determine their cellular origin.

Background
Circulating miRNAs are emerging as potential biomarkers. We have previously identified a miRNA signature for type 2 diabetes in the general population.

Methods
A total of nineteen candidate miRNAs were quantified by real time polymerase chain reactions in 820 participants.

Results
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). Upon addition of the three miRNAs to a base model of the Framingham Risk Score for hard coronary heart disease as an endpoint, the net reclassification improvement (NRI) was 16.86 [-1.99 – 35.71] % (P=0.080). The integrated discrimination improvement (IDI) was 0.047 [0.005 – 0.089] (P=0.029). To determine the cellular origin of these miRNAs associated with cardiovascular risk, healthy volunteers were subject to limb ischaemia-reperfusion generated by thigh cuff inflation and plasma miRNA changes were analysed at baseline, at 10 min, 1h, 5h, 2 days and 7 days. Computational analysis using the temporal clustering by affinity propagation algorithm 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.

Conclusions
In subjects with subsequent myocardial infarction differential co-expression patterns of circulating miRNAs occur around endothelial-enriched miR-126 with platelets being a major contributor to this miRNA signature.

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