The role of muscle-enriched microRNAs as markers of failed myocardial reperfusion

Abstract

The advent of primary percutaneous coronary intervention (PPCI) for the treatment of ST-elevation myocardial infarction (STEMI) has significantly reduced mortality rates in this population. However, coronary artery disease remains a leading cause of morbidity and death worldwide. This may be a consequence of inadequate myocardial reperfusion despite reestablishment of coronary artery patency following PPCI. Failed myocardial reperfusion is associated with worse prognosis but usually passes undetected, as current diagnostic methods are not routinely available. The aim of my PhD was to investigate the plasmatic kinetics of muscle-enriched micro ribonucleic acids (microRNAs) following PPCI as well as their association with cardiac damage, function and the phenomenon of failed myocardial reperfusion. Firstly, I retrospectively analysed the prognostic importance of cardiac troponins, which are established markers of myocardial injury, in a large cohort (n = 4,914) of STEMI patients treated with PPCI. Troponin levels routinely measured at 12 hours post-reperfusion were not associated with mortality, highlighting the need for identification of new prognostic markers in this population. To overcome methodological issues for microRNA quantification in plasma samples from STEMI patients, I validated an endogenous microRNA (miR-425-5p) as a control for realtime polymerase chain reaction (RT-qPCR) data normalisation. Subsequent microRNA screening and kinetics analyses revealed that the muscle-enriched miR-1 and miR-133b are rapidly released into the circulation following PPCI, reaching an initial peak at 30min and a second peak at 90min post-PCI. The presence of a second peak seemed to be associated with a higher index of microvascular resistance, a surrogate marker of failed myocardial reperfusion. In addition, miR-1 and miR-133b levels at 30min and 90min post-PPCI were associated with microvascular obstruction measured by cardiac MRI, another parameter of unsuccessful myocardial reperfusion. Finally, miR-1 and miR-133b levels were significantly elevated in a subgroup of STEMI patients with larger infarcts and worse left ventricular function and remodelling 3 months after PPCI. These findings suggest a potential new role for muscle-enriched microRNAs as tools for early identification of failed myocardial reperfusion and prognostic stratification in STEMI patients.