“Early” Class III Drugs for the Treatment of Atrial Fibrillation

Abstract

Background— Currently available antiarrhythmic drugs are only moderately effective against atrial fibrillation (AF) and may cause ventricular proarrhythmia. AVE0118 is a blocker of atrium-specific early K + currents ( I Kur / I to ). Methods and Results— Effects of intravenous AVE0118 and dofetilide on atrial effective refractory period (AERP) and inducibility of AF were measured before and after 48-hours of AF-induced electrical remodeling in the goat. During persistent AF (53±19 days), the cardioversion efficacy and effects on atrial wavelength of AVE0118, dofetilide, and ibutilide were evaluated. QT durations were measured during atrial pacing and persistent AF. After 48 hours of AF, the effect of dofetilide on AERP was reduced, and induction of AF was not prevented. In contrast, the class III action of AVE0118 was enhanced, and AF inducibility decreased from 100% to 32% ( P <0.001). At 1, 3, and 10 mg · kg −1 · h −1 , AVE0118 terminated persistent AF in 1 of 8, 3 of 8, and 5 of 8 goats, respectively. Dofetilide and ibutilide terminated AF in 1 of 5 and 2 of 7 goats. AVE0118 0.5, 1.5, and 5 mg/kg prolonged the AERP during AF and increased the fibrillation wavelength from 6.7±0.6 to 8.5±0.5, 9.7±0.5, and 11.2±0.9 cm ( P <0.01). Whereas dofetilide and ibutilide prolonged QT duration, AVE0118 had no appreciable effect. Conclusions— AVE0118 markedly prolongs the AERP during AF without affecting QT duration. Cardioversion of AF was due to an ≈2-fold increase in fibrillation wavelength. Atrium-selective class III drugs like AVE0118 may be a promising new option for safe and effective cardioversion of AF.