Preconditioning

Benefits of Exercise Clinicians have learned about the beneficial effects of several factors that may prevent a myocardial infarction (MI), including avoidance of smoking; treatment of high blood pressure, diabetes, dyslipidemia, and obesity; and regular performance of exercise. This last factor is based on epidemiological observations such as a decrease in the incidence of MI in men who perform heavy work1,2; however, it is only in the last few years that the beneficial effect of exercise has obtained plausible explanations of its own, that is, apart from its effect on other risk factors. There are at least 3 distinct mechanisms for this benefit: (1) Improvement of endothelial function, thereby preventing atherosclerosis and coronary occlusion3; (2) prevention of remodeling after MI through the expression of oxidative metabolism–related genes4; and (3) delaying acute ischemic injury after a coronary occlusion by preconditioning. Since the discovery of ischemic preconditioning by Murry et al5 in 1986, studies have appeared in the literature searching for its mechanisms and for alternative ways to trigger it. The concept that 1 or 2 episodes of brief ischemia ( 5 minutes in duration each), induced a few minutes or a few hours (early preconditioning) or 24 to 72 hours (late preconditioning or second window) before a prolonged coronary occlusion, followed by reperfusion substantially decreases the speed of the ischemic injury and limits infarct size is firmly established in all animal species studied in the experimental laboratory.6 It is one of the most powerful means of protecting the myocardium with the exception of early reperfusion. Several lines of evidence in coronary patients suggest but do not prove that the human myocardium is also protected by ischemic preconditioning. For example, preinfarction angina is associated with a smaller infarct size; a lower incidence of congestive heart failure, shock, and ventricular arrhythmias; and decreased mortality.7–9 The ST-segment elevation observed during angioplasty decreases after subsequent occlusions,10 which suggests that each occlusion provides preconditioning for the ischemic effect of the next one. Protocols of ischemic preconditioning before coronary artery bypass grafting preserve ATP levels during the subsequent global ischemic period11 and decrease serum levels of troponin T, thereby suggesting a smaller infarct size.12 Finally, the progressive decrease in the magnitude of ischemia during several consecutive episodes of exercise in patients with demand angina (warm-up phenomenon) suggests the preconditioning effect of each episode.13 The protective effect of ischemic preconditioning can be reproduced by several drugs, thus avoiding the necessity of ischemic periods to induce it. Pharmacological preconditioning is potentially a strong therapeutic tool. For example, the opening of mitochondrial ATP-sensitive potassium channels appears to be an important mediator of ischemic preconditioning. The administration of a mitochondrial ATP-sensitive potassium channel opener before planned procedures that involve a potentially ischemic insult (such as coronary artery surgery or angioplasty in the presence of a non–