Multiple protective pathways against reperfusion injury: a SAFE path without Aktion?

Acute myocardial infarction is a burden disease that affects the population in developed countries and is also of increasing concern to developing countries. Coronary heart disease afflicts about 1.2 million Americans [1] every year and it is also the number one killer in some regions of South Africa [2]. Following acute coronary occlusion, with threat of myocardial infarction, current cardiological practice is that rapid reperfusion, with the use of coronary angioplasty or thrombolysis, is required to save the ischaemic cells from dying. Although beneficial, reperfusion is paradoxically associated with cellular damage by activation of deleterious signalling cascades to cause a substantial number ofmyocytes to die. It is considered that reperfusion injury accounts for up to 50% of thefinal size of the infarct [3]. Intensive laboratory research is devoted to finding additional strategies limiting the amount of dying cells. A large number of molecules, such as adenosine, bradykinin or insulin, have proved to be efficient in animal models but, so far, the translation to humans is not obvious and very few clinical trials have been successful (Table 1) (see review [4]). One explanation for this may be that sudden occlusion performed in healthy coronary arteries from animal models may differ from an unhealthy artery in the human situation. Also, most of the drugs tested in animal models were given prior to or during the ischaemic insult and, therefore, cannot be applied clinically in the context of coronary occlusion. However, the discovery in 2003 of the phenomenon called ischaemic postconditioning [5], whereby a succession of brief ischaemic episodes at the onset of reperfusion reduces the infarct size, offers better clinical application and it has proved, both in animals and humans, that intervention from the time of reperfusion may be enough to limit reperfusion damage [5–7]. As a consequence, a switch in the focus of basic science research occurred after 2003, so that most of the protective drugs now being studied are given at reperfusion.