Ischemic heart disease and antioxidants: Mechanistic aspects of oxidative injury and its prevention

The disease state of myocardial ischemia results from a hypoperfusion-induced insufficiency of heart-muscle oxidative metabolism due to inadequate coronary circulation. Myocardial ischemia is an important, lifespan-limiting medical problem and a major economic health-care concern. Reperfusion, although avidly pursued in the clinic as essential to the ultimate survival of acutely ischemic heart muscle, may itself carry an injury component. Cardiac reperfusion injury appears to reflect, at least in part, an oxidant burden established upon reoxygenation of ischemic myocardium. Laboratory evidence demonstrates that oxidative stress to the heart-muscle cell (cardiomyocyte) can elicit the three known types of ischemia-reperfusion injury that directly affect the myocardium: arrhythmia, stunning, and infarction. The limited clinical occurrence of serious reperfusion arrhythmias has restricted the importance of antioxidants as antiarrhythmic agents against this form of myocardial ischemia-reperfusion damage. Despite the utmost clinical significance of lethal cardiomyocyte injury as a negative prognostic indicator for the ischemic heart-disease patient, inconsistent results of antioxidant interventions in reducing infarct size have somewhat tempered interest in antioxidant infarct trials. By contrast, the negative clinical consequences of stunning may indeed be preventable by utilizing antioxidants to help restore postischemic cardiac pump function. Several as yet unanswered questions remain regarding oxidative stress in the reperfused heart, its significance to cardiomyocyte damage, and its ability to elicit specific postischemic myocardial derangements. Targeted mechanistic studies are required to address these questions and to define the pathogenic role of oxidative stress (and, hence, the therapeutic potential of antioxidant intervention) in myocardial ischemia-reperfusion injury. The overall aim of current research in this area is to enable the cardiac surgeon/cardiologist to advance beyond the largely palliative drugs now available for management of the coronary heart-disease patient and attack directly the pathogenic determinants of heart-muscle ischemia-reperfusion injury. Optimal use of antioxidants may help address this important medical need.