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.