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Cardiovascular Research 2001 50(1):75-84; doi:10.1016/S0008-6363(00)00320-5
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

The class III antiarrhythmic drugs dofetilide and sotalol prevent AF induction by atrial premature complexes at doses that fail to terminate AF

Katayoun Derakhchana,b, Christine Villemaireb, Mario Talajicb and Stanley Nattela,b,*

aDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
bResearch Center and Department of Medicine, Montreal Heart Institute and University of Montreal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8

* Corresponding author. Tel.: +1-514-376-3330; fax: +1-514-376-1355 nattel{at}icm.umontreal.ca

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 S2 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 S2 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 S2-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 S2. 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.

KEYWORDS Antiarrhythmic agents; Arrhythmia (mechanisms); Supraventricular arrhythmia


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