Therapeutic Strategies to Reduce TNF-αMediated Cardiac Contractile Depression Following Ischemia and Reperfusion

Recent evidence has implicated proinflammatory mediators such as TNF-αin the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum levels of TNF-α are increased after myocardial infarction and after cardiopulmonary bypass. Each of these represent clinically relevant instances of cardiac I/R injury. We and others have recently reported that TNF-αis produced by the heart following experimental I/R in animals and that TNF-αdirectly decreases animal and human myocardial contractility in a dose dependent fashion. Thus, strategies to reduce or neutralize myocardial TNF-αproduction should conceptually decrease myocardial contractile dysfunction following I/R. The purposes of this manuscript are: 1) to explore the clinical and experimental instances of I/R injury in which TNF-αis elevated, 2) to review the molecular mechanisms of TNF-αinduced contractile dysfunction, 3) to examine both experimental and clinical strategies of reducing myocardial TNF-αproduction, and 4) to determine the influence of reducing post-I/R TNF-αon cardiac contractile function in both animals and man.