Myocardial infarction with non-obstructive coronary artery disease (MINOCA) is a common problem in women, occurring in 5-20% of MIs. Several contributory mechanisms have been proposed, including coronary plaque rupture, plaque erosion, coronary embolism, spasm, and hypercoagulability, all of which may be partly mediated by platelet activity. Pathological and clinical studies consistently demonstrate that platelets are a major culprit in the pathogenesis of MI. We and others have shown that women have a particularly hyperactive platelet activity profile. Moreover, women report higher levels of stress than men and stress has been reported to further increase platelet activity.In addition to the well-known function of platelets in atherosclerosis and thrombosis, platelets play an important role in inflammation, immune activation, and vascular health. Because platelets are anuclear, transcriptional profiling provides a novel window on gene expression that precedes acute events, without the confounding possibility that the event itself has provoked new gene transcription. We propose a complementary set of studies to fully evaluate the mechanistic role of platelets in women with different phenotypes of cardiovascular disease, including MINOCA, MI with obstructive coronary artery disease (MI-CAD), and age- and race- matched stable women found to have non-obstructive coronary arteries at cardiac catheterization (Cath-NOCA). The array of studies will include platelet activity measurements, coding and non-coding RNA profiles, and investigation of the role of platelets as effector cells regulating endothelial cell, smooth muscle cell, monocyte, and macrophage activity in vitro. The study hypotheses are that women with MINOCA have (1) a heightened platelet activity profile, (2) differentially expressed platelet derived coding and noncoding RNA and microRNA, and (3) platelets more likely to upregulate inflammatory, thrombogenic, and adhesive gene expression and activity in various cell types, versus Cath-NOCA.This study will provide novel data to address existing gaps in knowledge regarding the mechanism of MI with and without obstructive CAD in women. Collectively, this work will facilitate the understanding of platelet transcriptomics, activity and signaling in MINOCA and provide insights into the role of platelets as disease mediators as well as potential diagnostic and therapeutic targets.
|Program type||Strategically Focused Research Network|
|Effective start/end date||04/01/2016 → 03/31/2020|