Tumor necrosis factor alpha, rapid ventricular tachyarrhythmias, and infarct size in canine models of myocardial infarction.

Etanercept (2 mg/kg), a TNFalpha sequestrant, was administered 24 hours and 1 hour before LAD coronary artery ligation to examine the role of TNFalpha on lethal ventricular tachyarrhythmias and myocardial necrosis. Dogs treated with etanercept had decreased very rapid (>360 bpm) ventricular triplets (6 +/- 1/h, n = 8) 2 to 24 hours following coronary artery ligation compared with saline (21 +/- 6/h, n = 10, P < 0.05). This was concordant with 8-fold salvage of beta-adrenergic receptor kinase 1 (betaARK) activity compared with control (33.8 +/- 7.2% versus 4.3 +/- 2.2% of unoperated control tissue, P < 0.01, n = 5). Salvage of betaARK occurred without change in the thickness of the epicardial tissue overlying the infarct. In dogs pretreated with etanercept before a 2-hour occlusion/4-hour reperfusion of the LAD coronary artery, infarct mass decreased by 61% (% area at risk) and 55% (% left ventricular mass) in the etanercept group (n = 8) compared with saline (n = 9, P < 0.05). This was concordant with an etanercept-mediated six-fold decrease in leukocyte accumulation within ischemically injured myocardium. TNFalpha antagonism decreases malignant ventricular tachyarrhythmias and may relate to partial protection of normal betaARK-mediated desensitization of beta-adrenergic receptors. TNFalpha sequestration also decreases infarct size in an occlusion/reperfusion model of myocardial ischemia.