Ischemia-Reperfusion Injury of the Heart: Moving forward with our Knowledge

Reperfusion of the ischemic myocardium by Percutaneous Coronary Interventions (PCIs) such as coronary bypass surgery, angioplasty and thrombolytic therapy is essential for the improvement in morbidity and mortality for patients who suffer from ischemic heart disease However, if the reperfusion is not instituted within a certain timeperiod of the ischemic insult, several cardiac complications including arrhythmias, impaired recovery of cardiac function and myocardial cell damage become evident Such abnormalities, defined as Ischemia-Reperfusion (I/R) injury, are also seen during cardiac transplantation. Thus, a great deal of research has been carried out to understand the mechanisms of I/R injury as well as to develop different interventions which may improve clinical outcome of patients with ischemic heart disease. Indeed, there have been considerable improvements in understanding the pathophysiologic processes underlying the I/R injury and multiple targets for the development of drug therapy have been identified In this regard, several preclinical studies have shown a great promise for different agents to exert beneficial effects on I/R injury; however, when these interventions were tested in clinical trials, the results were disappointing. Perhaps the failure of clinical trials with several cardioprotective agents may be related to the fact that the clinical investigations were concerned with the treatment of patients with I/R injury whereas the preclinical studies were carried out to determine the preventive effects of different drugs. Furthermore, the pre-clinical studies seem to be designed for preventing the impact of myocardial ischemia on the reperfusion-induced defects in the heart. It is therefore of critical importance to understand the pathophysiology of myocardial ischemia to gain insight into the mechanisms of reperfusion injury to the ischemic heart. This review is focused on the current knowledge of the pathophysiologic processes due to I/R injury with respect to changes in the metabolic processes, development of oxidative stress, generation of inflammation as well as structural damage to subcellular organelles. This article is also intended to describe the functional effects of I/R injury to emphasize its clinical manifestations. Attempts are also made to explore the therapeutic value of pharmacologic agents including inhibitors of cation channels and exchangers, antiplatelet agents, vasodilators, anti-inflammatory agents as well as protease inhibitors from the prevention and treatment viewpoints. In addition, the cardioprotection afforded by interventions such as pre-conditioning, post-ischemic conditioning and remote ischemic conditioning against I/R-induced abnormalities are discussed.