Circulation, Vol 88, 1030-1044, Copyright © 1993 by American Heart Association
J Wang, GW Bourne, Z Wang, C Villemaire, M Talajic and S Nattel
BACKGROUND. Antiarrhythmic drugs are considered to terminate atrial
fibrillation by prolonging refractoriness, but direct experimental
evaluation of this concept has been limited. The atria are activated
rapidly during atrial fibrillation, and antiarrhythmic drugs are known to
have important rate-dependent actions. The potential role of such
properties in determining drug effects during atrial fibrillation has not
been evaluated. METHODS AND RESULTS. We evaluated the effects of
representative class Ia (procainamide), Ic (propafenone), and III (sotalol)
antiarrhythmic drugs on sustained cholinergic atrial fibrillation and
atrial electrophysiological properties in anesthetized, open-chest dogs.
Loading and maintenance doses were used to produce stable plasma
concentrations, and computer-based 112- electrode epicardial mapping was
used to study atrial conduction and activation during atrial fibrillation.
Clinically used doses of procainamide and propafenone terminated atrial
fibrillation in 13 of 13 (100%) and 7 of 10 (70%) dogs, respectively, but a
dose of sotalol (2 mg/kg IV) in the clinical range terminated atrial
fibrillation in only 2 of 8 (25%) dogs (P = .0005 vs procainamide, P = .08
vs propafenone). Procainamide and propafenone prevented atrial fibrillation
induction in 13 of 13 (100%) and 7 of 10 (70%) dogs, respectively, compared
with none of 8 dogs for 2 mg/kg sotalol (P < .0001 vs procainamide, P =
.004 vs propafenone). A larger dose of sotalol (cumulative dose, 8 mg/kg)
was uniformly effective in terminating atrial fibrillation and preventing
its induction. All drugs significantly increased atrial refractory period,
with effects that were use dependent for propafenone but reverse use
dependent for sotalol. Effective doses of all drugs significantly increased
the wavelength for reentry at rapid atrial rates in the presence of vagal
stimulation into the range observed under drug-free conditions in the
absence of vagal input. The inefficacy of clinical doses of sotalol was
explained by the reverse use dependence of its effects on refractoriness,
which resulted in reduced effects on wavelength at rapid rates. The effects
of propafenone on refractoriness were significantly increased at rapid
rates, contributing to its ability to increase wavelength and terminate
atrial fibrillation. Activation mapping showed that drugs terminated atrial
fibrillation by reducing the number and increasing the size of reentry
circuits, leading to termination by mechanisms related to block in the
remaining circuit(s). CONCLUSIONS. We conclude that antiarrhythmic drugs
terminate experimental atrial fibrillation by increasing the wavelength for
reentry at rapid rates, leading to a reduction in the number of functional
reentry circuits and, eventually, failure of reentrant excitation.
Use-dependent effects on refractoriness can limit (in the case of the
reverse use dependence of sotalol) or contribute (in the case of
propafenone) to antiarrhythmic drug efficacy against atrial fibrillation by
determining drug-induced changes in wavelength at rapid atrial rates.
ARTICLES
Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness
Department of Medicine, Montreal Heart Institute, Quebec, Canada.
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