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.
Yu
Xichun
X
Endocrinology and the Cardiac Arrhythmia Research Institute, Department of Medicine, University of Oklahoma Health Sciences Center and VAMC, Oklahoma City, Oklahoma 73104, USA.
Patterson
Eugene
E
Huang
Shijun
S
Garrett
Marion W
MW
Kem
David C
DC
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents; D015153:Blotting, Western; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000187:drug effects; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D000068800:Etanercept; D006439:Hemodynamics / Q000187:drug effects; D007074:Immunoglobulin G / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D051552:beta-Adrenergic Receptor Kinases
D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D000068800:Etanercept