Platelet-activating factor antagonism: A new concept in the management of regional myocardial ischemia-reperfusion injury

Reperfusion therapies for treatment of myocardial infarction successfully reduce patient mortality; however, regional myocardial ischemia-reperfusion (RMIR) causes its own expression of cardiovascular dysfunction, including myocardial depression, hemodynamic instability, and dysrhythmias, which have increased patient mortality within the first 24 h after starting reperfusion therapy. Current evidence suggests that the release of oxygen-derived reactive substances and subsequent inflammatory mediators during ischemia-reperfusion contribute toward this injury. Platelet-activating factor (PAF), a mediator released during RMIR, has been emphasized by many investigators as playing a central role in causing RMIR injury. Similar cardiovascular dysfunctions that occur during RMIR, including myocardial depression, hemodynamic instability, and dysrhythmias, occur after administration of PAF and are ameliorated with PAF antagonists. Further, PAF antagonists have been shown to be cardioprotective and improve survival when administered before onset of reperfusion. A variety of phospholipid analogues, naturally derived compounds, and synthetic compounds have been developed that form the different classes of PAF antagonists, each with unique antagonizing properties. Several of these compounds have successfully passed safety and efficacy testing in humans; however, to date, no clinical trials have investigated the protective effects of PAF antagonists against RMIR injury. A current theory in the pathogenesis of RMIR injury considers the ischemic and necrotic portion of the myocardium and regional dysfunction due to tissue necrosis to be solely responsible for global cardiac dysfunction leading to hemodynamic instability and death. Evidence now suggests, however, that the global dysfunction is also due to the effect of inflammatory mediators such as PAF, thromboxanes, leukotrienes, and endothelins that are released during RMIR and are distributed throughout the heart on reperfusion. Antagonizing a central inflammatory mediator such as PAF, as adjunct treatment with currently used reperfusion therapies, improves cardiovascular function and survival in animals and should be introduced into clinical trials to investigate if similar protective effects can be provided in humans.