The pharmacological response of ischemia-related atrial fibrillation in dogs: Evidence for substrate-specific efficacy

Abstract

Acute atrial ischemia produces a substrate for atrial fibrillation (AF) maintenance, but the response of this substrate to antiarrhythmic-drugs has not been defined. The present study assessed the effects of class 1-4 antiarrhythmic-drugs on the electrophysiological consequences of acute atrial ischemia, and compared effects in ischemic AF with those in vagal AF. Isolated atrial ischemia was created by ligating a right coronary artery branch perfusing the right atrial free wall. Experiments were performed in dogs treated with loading and maintenance doses of flecainide (class 1; n=5), nadolol (class 2, n=7), dofetilide (class 3, n=5), or diltiazem (class 4, n=7) prior to coronary artery occlusion. Dogs subjected to coronary occlusion without pre-treatment (n=10) served as controls. Coronary artery occlusion substantially increased AF duration, e.g. from 7+/-4 s (pre-ischemic baseline) to 876+/-245 s at 3 h of ischemia, and caused substantial ischemic zone conduction slowing. Diltiazem and nadolol prevented AF promotion (AF durations 12+/-8 s and 4+/-1 s at 3 h of ischemia respectively; each p<0.001 vs control) and suppressed ischemic conduction slowing. Flecainide and dofetilide failed to prevent ischemia-induced AF promotion (e.g. AF duration at 3-hour ischemia 779+/-417 and 801+/-414 respectively, p=NS vs control) and failed to alter ischemia-induced conduction slowing. A different pattern of response occurred with vagal AF: flecainide was highly effective in reducing vagal AF duration; dofetilide, diltiazem, and nadolol were ineffective. Beta-blockade and Ca(2+) antagonism suppress the arrhythmic consequences of acute atrial ischemia, whereas Na(+) channel or K(+)-channel block are ineffective. These results are relevant to understanding the effects of different classes of antiarrhythmic-drugs on AF occurring in coronary disease patients.