Good News for Experimental Concept but Bad News for Clinically Effective Therapy

Although it is widely accepted from experimental studies that timely reperfusion limits myocardial infarct size, reperfusion by itself may not achieve the greatest possible effect. In a clinical setting, reperfusion, whether by thrombolytic therapy or emergency coronary angioplasty, never can be achieved instantaneously. Thus, adjunctive therapy, which could either slow ischemic metabolism and cellular injury pending successful reperfusion or protect myocytes against undesired, potentially lethal effects of reperfusion (“lethal reperfusion injury”), should have added clinical benefit for limiting infarct size. Moreover, it would be possible to treat patients at high risk of infarction prophylactically if a safe and effective cardioprotective agent could be developed. Several endogenous mechanisms or exogenous interventions are known to both slow the rate of ischemic metabolism and delay the onset of lethal myocyte injury. For example, the speed at which ischemic cell injury occurs is markedly temperature-dependent. Hypothermia substantially slows ischemic metabolism and the onset of lethal myocyte injury.1 This approach is commonly used in cardiac surgical procedures requiring a cessation of myocardial blood flow to slow ischemic injury and thereby prolong the tolerable period of ischemia. Studies in several animal species have shown that exposing myocardium to ≥1 short (5- to 15-minute) episodes of ischemia (“ischemic preconditioning”) slows energy metabolism and delays the onset of myocardial necrosis in a subsequent prolonged period of ischemia.2 3 Although the mechanism is not completely established, there is considerable evidence that the effect requires activation of ≥1 signaling pathways, the end effect of which is enhanced opening of ATP-dependent potassium (KATP) channels.3 Calcium channel blockers also generally have had cardioprotective, infarct-limiting effects in studies based on an animal model in which infarcts were induced by relatively short periods of ischemia (40 to 90 minutes) followed by reperfusion.4 5 6 Thus, calcium antagonists delay but …