Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs

Abstract

Atrial fibrillation (AF) induces electrical and ionic remodeling of the atria. We investigated whether AF-induced remodeling alters the electrophysiological and anti-fibrillatory effects of class I (flecainide) and class III (d-sotalol, ibutilide) anti-arrhythmic drugs. In 9 goats, the effects of flecainide (6 mg/kg) and d-sotalol (6 mg/kg) on atrial electrophysiology were measured both before and after 48 h of electrically induced AF. During a 1-h infusion period the atrial effective refractory period (AERP) and conduction velocity (CV) were measured both during slow and rapid pacing (interval 400 and 200 ms). In 8 other goats, the rate-dependent effects of ibutilide (0.12 mg/kg) on AERP were determined. The effects of flecainide on atrial conduction and refractoriness were not altered after 48 h of AF. At a dose of 6 mg/kg flecainide reduced the CV200 by 19+/-5% in normal atria and by 21+/-9% after 48 h of AF (p=0.20). The AERP200 was prolonged by 10+/-6% and 8+/-7%, respectively (p=0.40). In contrast, the effect of d-sotalol on atrial refractoriness was markedly diminished. During control d-sotalol prolonged the AERP400 by 17+/-6% compared to only 6+/-5% after 2 days of AF (p<0.01). Also ibutilide lost much of its class III effect on the AERP by electrical remodeling (from 15 to 5%; p<0.05). The loss of class III action was less pronounced at rapid heart rates. AF-induced atrial electrical remodeling in the goat did not modulate the action of flecainide on atrial conduction and refractoriness. In contrast, the class III effects of d-sotalol and ibutilide on the atria were strongly reduced after 2 days of AF. The prolongation of QT-duration was not affected.