Protection and repair of the ischemic heart

Abstract

This thesis aimed to elucidate and advance strategies for cardioprotection and cardiac repair, translate preclinical findings towards future clinical studies and optimize the translational research process for IHD. So far, many cardioprotective strategies against reperfusion injury could not be successfully replicated in clinical studies, despite promising results in experimental studies. Failure to translate these promising findings could be the consequence of several factors, such as lack of testing in a large animal model, administration of the drug at a clinically irrelevant timepoint (i.e. prior to induction of ischemia) or fundamental differences in reperfusion injury in humans compared to laboratory animals. Fortunately, evidence in favor of reperfusion injury in humans is present rendering it a promising target to reduce cardiomyocyte loss.38 We designed a dose-optimizing study in pigs to investigate a clinically applicable treatment protocol. The outcome is presented in Chapter 3, showing for the first time that necrostatin-1 is also effective at reducing infarct size in a large animal model of I/R injury. Hence, these findings support the rationale to continue work on necrostatin-1. In particular, it is imperative that future work focuses on pharmacokinetics and safety profile as a prerequisite to advance towards a first-in-man clinical trial. The presence and growth factor mediated recruitment and activation of eCSCs in chapter 6 identify IGF-1 and HGF as one of many possible combinations of cardiotrophic factors to stimulate endogenous cardiac repair. Future work should investigate and identify key mediators to activate and bring about a robust regenerative response in the heart. In particular, cellular senescence in eldery patients that could impair this regenerative response should be studied to ensure that rejuvenation of eCSCs would lead to more effective regenerative therapy. As shown in chapter 6, biomaterials can facilitate local delivery of biologics and most importantly, can increase the effectiveness of new cardioregenerative therapies. It is imperative that ongoing development of biomaterials such as the UPy-gel system is aimed at increasing the tunability of its growth factor release and its biodegradation in vivo. 217 In summary, cardioprotection and cell based cardiac repair both represent unique and exciting research fields which should not be viewed as direct competitors but rather can act as adjuvant therapies that collectively provide new treatment options for patients that endure the burden of IHD. As the first phase III trials are currently underway in both research areas, cardioprotection and cell based therapy could provide new options for IHD patients in the foreseeable future.