ANTITUMOR NECROSIS FACTOR-ALPHA IMPROVES MYOCARDIAL RECOVERY AFTER ISCHEMIA AND REPERFUSION

Objectives. This study sought to assess the importance of locally rele ased or paracrine myocardial tumor necrosis factor alpha (TNF-alpha) i n the evolution of postischemic myocardial dysfunction and to use immu nohistochemical studies to localize TNF-alpha within the myocardium. B ackground. TNF alpha is implicated as a systemic mediator in the devel opment of myocardial ischemia-reperfusion injury by promoting leukocyt e myocardial infiltration, and it has been shown to originate from non cardiac peripheral mononuclear cells. We have recently documented in a blood-free environment the release of TNF-alpha from the ischemic-rep erfused myocardium. Methods. Isolated rat hearts undergoing 1 h of glo bal cardioplegia-induced ischemia and 30 min of reperfusion mere inves tigated with use of the modified Langendorff model. Hearts were random ly divided into three subgroups: group A, control group; and groups B and C, isolated hearts receiving cardioplegic solution containing mono clonal hamster antimurine TNF-alpha antibodies (group B) or hamster Ig G (group C). Results. Significant amounts of TNF-alpha were detected i n group A and group C effluent on 1 min of reperfusion (752 +/- 212 an d 958 +/- 409 pmol/ml, respectively). However, in group B, TNF-alpha,v as below detectable levels. In this group, postischemic left ventricul ar peak systolic pressures, first derivative of the rise in left ventr icular pressure (dP/dt(max)), pressure-time integral, coronary flow an d O-2 consumption improved (analysis of variance [ANOVA] p < 0.0001 fo r all variables) compared with values in groups A and C; creatine kina se levels decreased (p < 0.005); and myocardial structure was preserve d. Immunohistochemical staining localized TNF-alpha to cardiac myocyte s and to endothelial cells. Conclusions. Anti-TNF-alpha neutralizes lo cal TNF-alpha release from cardiac myocytes after ischemia and improve s myocardial recovery during reperfusion, indicating that postischemic paracrine TNF-alpha release plays an active role in myocardial dysfun ction. (C) 1997 by the American College of Cardiology.