Objective: In electrically remodeled atria the effect of blockers of the delayed rectifier K+ current I(Kr) on repolarization is reduced, whereas the efficacy of 'early' class III drugs (I(Kur)/I(to)/I(Kach) blockers) is enhanced. We evaluated the electrophysiological and antifibrillatory effects of AVE0118, dofetilide, and ibutilide (alone and in combination) on persistent atrial fibrillation (AF) in the goat.
Methods and results: The effects of separate and combined administration of AVE0118, dofetilide, and ibutilide were determined before and after 48 h of AF. AVE0118 alone markedly prolonged the atrial refractory period (400 ms cycle length) (AERP400) before and after 48 h of AF. The prolongation of AERP(400) by dofetilide and ibutilide, respectively, was reduced by AF from 22+/-2 to 7+/-2 ms (p<0.01) and 25+/-5 to 5+/-2 ms (p=0.01). Pre-treatment with AVE0118 restored the prolongation of AERP400 by dofetilide or ibutilide (to 20+/-3 and 30+/-6 ms; p<0.01). This effect was atrial specific since the QT-interval was not changed. The antifibrillatory action was evaluated in 10 goats that were in persistent AF for 57+/-7 days. Dofetilide (20 microg/kg/h) or ibutilide (4 mg/h) alone restored sinus rhythm in only 20% of the animals. AVE0118 (1, 3 and 10 mg/kg/h) [DOSAGE ERROR CORRECTED] terminated AF in 11, 30, and 60%, respectively. Additional infusion of I(Kr) blockers caused an additional number of cardioversions, resulting in a final cardioversion rate of 56, 80, and 100%, respectively. AVE0118 alone prolonged the AF cycle length (AFCL) while the conduction velocity during AF (CV(AF)) remained unchanged (70+/-1 vs. 68+/-2 cm/s; p=0.3). Addition of dofetilide or ibutilide caused a synergistic increase in AFCL and a slight increase in CV(AF) to 74+/-1 cm/s (p<0.001). The length of the reentrant trajectories increased from 7.6+/-0.3 (control) to 11.6+/-0.5 cm after AVE0118 alone (p<0.001) and 14.8+/-0.8 cm after addition of dofetilide or ibutilide (p<0.001).
Conclusions: In electrically remodeled atria, blockade of I(Kur)/I(to)/I(KAch) restored the class III action of I(Kr) blockers. Persistent AF could be effectively cardioverted by infusion of a combination of AVE0118 and dofetilide or ibutilide. This antifibrillatory action was associated with an almost twofold lengthening of the intra-atrial pathways for reentry.