From Laboratory Bench to Hospital Bedside: Can the Diabetic Heart be
Pre- and Post-conditioned?

Coronary heart disease (IHD) is set to become the leading world-wide cause of death by the year 2020. Acute myocardial infarction is a major cause of such mortality and the best hope of salvaging viable myocardium is rapid reperfusion of the ischaemic myocardium, by either thrombolysis or primary percutaneous coronary intervention (PCI). However, despite these effective reperfusion strategies, the long-term benefit is suboptimal in that only one-third of the life-years lost by myocardial infarction is regained by reperfusion. This may be as a consequence of potentially lethal reperfusion-induced injury. Treatment strategies which directly target the reperfusion phase could provide a novel approach to cardio-protection. Two such mechanical treatment strategies which may have significant consequences for the future management of acute myocardial infarction are the phenomenon of ischaemic pre and postconditioning. Preconditioning is achieved by short repetitive periods of coronary reperfusion and occlusion immediately prior to a lethal ischaemic insult and postconditioning is achieved by very short repetitive periods of coronary reperfusion and occlusion in the early minutes of revascularization. Importantly is now appreciated that a number of clinically available pharmcological agents can mimic the effects of pre and postconditioning. In addition to the above, co-morbidities such as diabetes can significantly influence the ability to protect the myocardium from ischaemic-reperfusion injury. Recent studies have identified a signalling pathway that is recruited at the time of reperfusion and which is central to the protection observed in both the normal & diabetic heart. This signalling pathway comprises the survival kinases PI3K-Akt and Erk1/2, components of what has been termed the “Reperfusion Injury Salvage Kinase” (RISK) pathway. In addition, and of equal importance, is the identification that a non-specific pore of the inner mitochondrial membrane called the mitochondrial permeability transition pore, (MPTP) whose opening in the first few minutes of myocardial reperfusion mediates cell death. Targeting and understanding the biological events occurring in the first few moments of reperfusion within the cell and at the mitochondrial level, is allowing us to identify new therapeutic ways to protect the myocardium from the consequences of lethal reperfusion-induced injury to the benefit of patients presenting with acute myocardial infarction. Targeting the mitochondrial permeability transition pore as a treatment for cardiac ischemia