Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness.

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.