Myocardial infarction : early diagnosis and cardioprotective strategies

Abstract

In this thesis, we have investigated novel diagnostic and cardioprotective strategies to limit myocardial cell death and improve cardiac function after myocardial infarction. We demonstrated a new way to speed up the diagnosis of acute MI by using very small pieces of RNA (microRNAs). Using these microRNAs, diagnosis was established much earlier and faster than with the current standard biomarker, cardiac troponin. Next, we investigated the role of two genes that showed an increased expression pattern following MI. The role of microRNA-223, a microRNA known to be involved in inflammation, was examined together with its modulation in vivo as well as the role of Wnt signalling and its cell-specific activation pattern after MI. Based on the knowledge obtained from our studies, we believe that therapeutic modulation these two genes can only work when targeting a specific cell type during the right period after MI. In addition, we compared the characteristics and therapeutic efficacy of human versus porcine MSC as these cells are an attractive source for stem cell therapy after MI. We have demonstrated that pMSCs have comparable characteristics and functionality with hMSCs, making reliable extrapolation of future pre-clinical pMSC studies into a clinical setting very well possible. Finally, we investigated the role of a novel compound, Necrostatin-1 (Nec-1), capable of inhibiting the execution of programmed necrosis. Using this compound, we showed that administration of Nec-1 in a model of ischemia-reperfusion reduced infarct size and improved long-term cardiac function in mice as well as in pigs.Taken together, our data show that there is a large window of opportunity to improve clinical outcome after myocardial infarction, mainly by improving early diagnosis and application of promising cardioprotective strategies