Targeting cell death in the reperfused heart: pharmacological approaches for cardioprotection

During acute myocardial infarction and in the reperfused heart, loss of cardiomyocytes is mostly caused by apoptosis and necrosis. As apoptosis was considered as the only form of regulated cell death for many years, initial studies investigating cardiomyocyte cell death mainly focused on direct inhibition of apoptosis. However, it has become clear that ischemic conditioning protocols--the application of alternating periods of non-lethal ischemia and reperfusion--can reduce necrotic cell death in the reperfused heart. Research on the signal-transduction pathways responsible for this phenomenon resulted in the discovery of many pharmacological targets to limit cell death after reperfusion, in which the activation of survival kinases and inhibition of mitochondrial permeability transition pore (MPTP) play an important role. Very recently, a regulated form of necrotic cell death (called 'necroptosis') was identified together with potential pharmacological inhibitors, which may also protect the myocardium from lethal reperfusion injury. This review highlights the role of apoptosis and necrosis in the reperfused hearts, including its execution and regulation and the emerging role of programmed necrosis (necroptosis). Furthermore, we will focus on the results of pharmacological interventions in experimental studies as well as relevant proof-of-concept clinical trials trying to limit apoptosis, necrosis and necroptosis in the reperfused heart. Although the list of cardioprotective compounds is promising, large multi-centre clinical trials, with enough statistical power, will be necessary to determine whether they can improve clinical outcome and can be applied in patients as adjuvant therapy next to reperfusion.