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


RESULTS
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.


CONCLUSIONS
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.
Rivard
Lena
L
Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Canada.
Sinno
Hani
H
Shiroshita-Takeshita
Akiko
A
Schram
Gernot
G
Leung
Tack-Ki
TK
Nattel
Stanley
S
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000209:etiology / Q000517:prevention & control*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D003327:Coronary Disease / Q000150:complications / Q000188:drug therapy*; D004110:Diltiazem / Q000627:therapeutic use; D004285:Dogs; D004558:Electric Stimulation; D005424:Flecainide / Q000627:therapeutic use*; D023421:Models, Animal; D009248:Nadolol / Q000627:therapeutic use; D010627:Phenethylamines / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000627:therapeutic use; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D014630:Vagus Nerve
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D009248:Nadolol; D004110:Diltiazem; D005424:Flecainide; C063533:dofetilide