Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone.
BACKGROUND
The basis of the unique effectiveness of amiodarone for atrial fibrillation (AF) is poorly understood. The present study tested the hypothesis that amiodarone blocks electrical remodeling induced by atrial tachycardia.


RESULTS
Mongrel dogs were subjected to atrial tachycardia (400 bpm for 7 days) in the absence and presence of therapy with amiodarone, the class III cardiac antiarrhythmic drug dofetilide, or the class I agent flecainide begun 3 days before the onset of tachypacing and maintained until a final electrophysiological study. AF vulnerability (percentage of sites with AF induction by single premature extrastimuli), mean AF duration, atrial effective refractory period (ERP), and conduction velocity were compared among these dogs and in unpaced dogs in the absence or presence of treatment with the same agents. Only amiodarone prevented promotion of AF duration and vulnerability by atrial tachycardia. Furthermore, only amiodarone eliminated tachycardia-induced ERP abbreviation and loss of ERP rate adaptation while obviating L-type Ca2+-current alpha1c-subunit downregulation as determined by Western blot. In an additional series of dogs monitored with repeated electrophysiological studies, amiodarone administered after the induction of atrial tachycardia remodeling reversed remodeling within several days, despite continued atrial tachypacing during amiodarone therapy.


CONCLUSIONS
Amiodarone is uniquely effective against AF promotion by atrial tachycardia remodeling in this experimental model and prevents electrophysiological and biochemical consequences of remodeling. Amiodarone also reversed remodeling established by 4 days of atrial tachycardia. The inhibition of atrial tachycardia remodeling may therefore contribute to the superior efficacy of amiodarone in AF.
Shinagawa
Kaori
K
Research Center and Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
Shiroshita-Takeshita
Akiko
A
Schram
Gernot
G
Nattel
Stanley
S
D000638:Amiodarone / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D004285:Dogs; D004562:Electrocardiography; D004594:Electrophysiology; D005424:Flecainide / Q000494:pharmacology / Q000627:therapeutic use; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010627:Phenethylamines / Q000494:pharmacology / Q000627:therapeutic use; D012032:Refractory Period, Electrophysiological; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013610:Tachycardia / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D010627:Phenethylamines; D013449:Sulfonamides; D005424:Flecainide; D000638:Amiodarone; C063533:dofetilide