The class III antiarrhythmic drugs dofetilide and sotalol prevent AF induction by atrial premature complexes at doses that fail to terminate AF.
BACKGROUND
Clinical trials suggest that sotalol and dofetilide are much more effective in preventing atrial fibrillation (AF) than in terminating it. This study evaluated potential mechanisms of discordant sotalol and dofetilide effects on AF termination vs. prevention.


METHODS
We applied 240-electrode epicardial mapping and programmed stimulation in a vagotonic dog model of AF before and after dofetilide or sotalol.


RESULTS
Under control conditions, sustained AF could be induced by single S(2) extrastimuli that caused unidirectional block and macroreentry. Sotalol (2 mg/kg) and dofetilide (0.04 mg/kg) failed to terminate AF in any dog, but prevented AF induction by S(2) stimuli in 19/22 (86%) and 4/5 (80%) of animals, respectively. With sotalol and dofetilide, unidirectional block still occurred, but wavefront reentry failed. The prevention of S(2)-induced reentry was related to large increases in the effective refractory period (ERP) at a BCL of 1000 ms, leading to ERPs that exceeded the conduction delay following S(2). Reverse use-dependent effects resulted in smaller ERP increases at BCLs closer to the AF cycle length. Although the number of zones of reactivation per cycle during sustained AF were decreased by sotalol and dofetilide, the changes were small and insufficient to terminate AF.


CONCLUSIONS
Sotalol and dofetilide prevent AF initiation by premature depolarizations at doses that fail to terminate vagotonic AF, by increasing ERP at the basic cycle length beyond the associated conduction delay that leads to reentry.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
K
K
Derakhchan
C
C
Villemaire
M
M
Talajic
S
S
Nattel
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D018880:Atrial Premature Complexes / Q000150:complications*; D004285:Dogs; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D004594:Electrophysiology; D006329:Heart Conduction System / Q000187:drug effects; D010627:Phenethylamines / Q000627:therapeutic use*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; D013015:Sotalol; C063533:dofetilide