Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression following ischemia and reperfusion

Recent evidence has implicated proinflammatory mediators such as TNF-alpha in the pathophysiology of ischemia-reperfusion (I/R) injury, Clinically, se rum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Each of these represent clinically relevant instan ces of cardiac I/R injury. Mie and others have recently reported that TNF-a lpha is produced by the heart following experimental I/R in animals and tha t TNF-alpha directly decreases animal and human myocardial contractility in a dose dependent fashion. Thus. strategies to reduce or neutralize myocard ial TNF-alpha production should conceptually decrease myocardial contractil e dysfunction following I/R, The purposes of this manuscript are: 1) to exp lore the clinical and experimental instances of IIR injury in which TNF-alp ha is elevated, 2) to review the molecular mechanisms of TNF-alpha induced contractile dysfunction. 3) to examine both experimental and clinical strat egies of reducing myocardial TNF-alpha production, and 4) to determine the influence of reducing post-I/R TNF-alpha on cardiac contractile function in both animals and man, (C) 1999 Academic Press.