Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias

Torsade de Pointes arrhythmias are a feared proarrhythmic effect of (antiar rhythmic) drugs. In dogs with chronic complete AV-block bradycardia-induced volume overload leads to electrical remodeling, which includes increased s usceptibility to drug-induced Torsade de Pointes arrhythmias. The IKr chann el blocker, dofetilide (Tikosyn(TM), 0.025 mg/kg/5 min), and the less speci fic ion channel blocker, azimilide (5 mg/kg/5 min), were compared in nine a nesthetized dogs at 4 and 6 weeks of AV-block in a randomized cross-over de sign. Dosages were based on our own dose-dependence studies and on anti-arr hythmic dosages reported in the literature. Monophasic action potential cat heters were placed endocardially in both the left and right ventricle to me asure action potential duration, visualize early afterdepolarizations, and to assess interventricular dispersion of repolarization (i.e. left ventricu lar monophasic action potential duration (at 100%) minus right ventricular monophasic action potential duration (at 100%). Cycle length of idioventric ular rhythm, QT-time and the occurrence of drug-induced Torsade de Pointes arrhythmias were determined using the surface electrocardiogram (ECG). Befo re drug administration, the electrophysiological parameters were identical at 4 and 6 weeks. Both azimilide and dofetilide increased monophasic action potential duration, cycle length of idioventricular rhythm, and QT-time. D issimilar lengthening of left ventricular and right ventricular monophasic action potential duration increased the interventricular dispersion signifi cantly from 55 to 110 ms for both drugs. All dogs had early afterdepolariza tions, while, in the majority, ectopic ventricular beats developed (dofetil ide 8/9 and azimilide 7/9). Torsade de Pointes arrhythmias incidence was co mparable for dofetilide (6/9) and azimilide (5/9). In conclusion, azimilide and dofetilide show similar electrophysiological and proarrhythmic effects in our canine model with a high incidence of Torsade de Pointes arrhythmia s. (C) 2001 Elsevier Science B.V. All rights reserved.