Anti–Tumor Necrosis Factor-Alph Improves Myocardial Recovery After Ischemi and Reperfusion

Objectives. This study sought to assess the importance of locally released or paracrine myocardial tumor necrosis factor-alph (TNF-alpha) in the evolution of postischemic myocardial dysfunction and to use immunohistochemical studies to localize TNF-alph within the myocardium. Background. TNF-alph is implicated as systemic mediator in the development of myocardial ischemia–reperfusion injury by promoting leukocyte myocardial infiltration, and it has been shown to originate from noncardiac peripheral mononuclear cells. We have recently documented in blood-free environment the release of TNF-alph from the ischemic-reperfused myocardium. Methods. Isolated rat hearts undergoing 1 h of global cardioplegia-induced ischemi and 30 min of reperfusion were investigated with use of the modified Langendorff model. Hearts were randomly divided into three subgroups: group A, control group; and groups B and C, isolated hearts receiving cardioplegic solution containing monoclonal hamster antimurine TNF-alph antibodies (group B) or hamster IgG (group C). Results. Significant amounts of TNF-alph were detected in group and group C effluent on 1 min of reperfusion (752 ± 212 and 958 ± 409 pmol/ml, respectively). However, in group B, TNF-alph was below detectable levels. In this group, postischemic left ventricular peak systolic pressures, first derivative of the rise in left ventricular pressure (dP/dtmax), pressure-time integral, coronary flow and O2 consumption improved (analysis of variance [ANOVA] p < 0.0001 for all variables) compared with values in groups and C; creatine kinase levels decreased (p < 0.005); and myocardial structure was preserved. Immunohistochemical staining localized TNF-alph to cardiac myocytes and to endothelial cells. Conclusions. Anti–TNF-alph neutralizes local TNF-alph release from cardiac myocytes after ischemi and improves myocardial recovery during reperfusion, indicating that postischemic paracrine TNF-alph release plays an active role in myocardial dysfunction.