Unresolved issues in myocardial reperfusion injury.

While the basic pathobiology of myocardial ischemic injury and reperfusion has been determined over the last 50 years, there are important, unresolved, or at least not completely elucidated, issues in the field. These include the relative contributions of different modes of cell injury and death to evolving myocardial infarcts; interactions of phenomena produced by reperfusion, including stunning and preconditioning; and potential new approaches for successfully combining adjuvant therapy with coronary artery opening. A model of myocardial ischemic and reperfusion injury is proposed involving the potential expression of apoptotic and oncotic pathways in the same perturbed cardiomyocytes. Promising new cardioprotective strategies for reducing lethal reperfusion injury are discussed, including ischemic postconditioning, activators of the reperfusion injury salvage kinase (RISK) pathway, inhibitors of protein kinase c-delta, and inhibitors of the mitochondrial membrane permeability transition pore (PTP). Major outstanding clinical challenges are also discussed, including the development of clinical care systems that can routinely deliver very timely coronary opening and reperfusion, perhaps combined with adjuvant therapy, and the development of strategies to retard adverse remodeling and congestive heart failure in patients with significant myocardial infarction and scarring, perhaps by refinements in stem cell therapy.