Myocardial postconditioning: reperfusion injury revisited

CORONARY HEART DISEASE is the leading cause of death in the Western world and represents one of the major burdens on healthcare systems today. Targeting those strategies that limit the damage sustained as a result of a lethal ischemic insult has been a major goal for many years. One of these strategies, termed ischemic preconditioning, in which brief nonlethal episodes of ischemia protect the myocardium before a subsequent prolonged ischemic insult, has received an enormous amount of interest over the past two decades. This phenomenon is recognized as the most powerful endogenous cardioprotective mechanism known, and many pharmacological preconditioning mimetics have been described since (45). However, ischemic preconditioning has its limitations in that the preconditioning mimetic must be applied before the index ischemic event, which in the clinical setting of acute myocardial infarction is unpredictable and impractical. Although preconditioning has given us invaluable information regarding cellular adaptation to stress, cell signaling, and viability, it in itself has failed to find a clinical niche. However, based on our understanding of the mechanisms associated with preconditioning, this has allowed us to revisit and focus on other cardioprotective strategies. The prerequisite for rescuing viable myocardium and reducing the mortality and morbidity as a consequence of an acute myocardial infarction is the early restitution of coronary flow, i.e., reperfusion, after the ischemic event by such means as thromobolytic drugs, primary coronary angioplasty, or coronary bypass graft surgery. Because the onset of reperfusion is more predictable and is under the control of the operator, the period surrounding the reestablishment of coronary flow is a more attractive window of opportunity for protection from the consequences of both the ischemia and reperfusion-induced injury (32). Novel cardioprotective strategies, which protect the myocardium from the detrimental effects of ischemiareperfusion injury, may therefore be applied as adjunctive therapy to current reperfusion strategies. However, reperfusion is not a completely benign process and can induce myocyte death, a phenomenon known as lethal reperfusion injury (8), which is now known to involve the processes of necrosis and apoptosis (11, 25). The concept of reperfusion-induced injury is controversial, being initially supported by most groups but then falling out of vogue (35). More recently, however, based on new hypotheses and a better understanding of cellular signaling, it seems that the concept has now returned full circle with the advent of pharmacological agents that have been shown to reduce myocardial cell death when given during the initial stages of reperfusion (44). One such novel strategy targeting the reperfusion phase is the phenomenon known as ischemic postconditioning, which was first introduced in 2002 by Vinten-Johansen’s group (3). This phenomenon, in which the application of transient brief interruptions to reperfusion by ischemic episodes results in reduced myocardial injury, has led to renewed interest in the development of protective maneuvers to combat the effects of lethal reperfusion injury. More recent studies (40, 43) have demonstrated that ischemic postconditioning activates cellular prosurvival cascades such as the phosphatidylinositol 3-kinase (PI3K)-Akt and MEK 1/2-ERK pathways via downstream mediators such as endothelial nitric oxide (NO) synthase (eNOS) and p70S6K and that by inhibiting these pathways, the protective effects of ischemic postconditioning are abolished (see Fig. 1). However, ischemic postconditioning, as discussed below, is likely to represent a form of modified reperfusion that paradoxically has been known for a number of years to be beneficial to the ischemic myocardium.