Torsade de Pointes arrhythmias are a feared proarrhythmic effect of (
antiarrhythmic) drugs. In dogs with chronic complete
AV-block bradycardia-induced volume overload leads to
electrical remodeling, which includes increased susceptibility to drug-induced
Torsade de Pointes arrhythmias. The IKr channel blocker,
dofetilide (
Tikosyn, 0.025 mg/kg/5 min), and the less specific
ion channel blocker,
azimilide (5 mg/kg/5 min), were compared in nine anesthetized dogs at 4 and 6 weeks of
AV-block in a randomized cross-over design. Dosages were based on our own dose-dependence studies and on
anti-arrhythmic dosages reported in the literature. Monophasic action potential
catheters were placed endocardially in both the left and right ventricle to measure action potential duration, visualize early afterdepolarizations, and to assess interventricular dispersion of repolarization (i.e. left ventricular monophasic action potential duration (at 100%) minus right ventricular monophasic action potential duration (at 100%). Cycle length of idioventricular rhythm, QT-time and the occurrence of drug-induced
Torsade de Pointes arrhythmias were determined using the surface electrocardiogram (ECG). Before 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. Dissimilar lengthening of left ventricular and right ventricular monophasic action potential duration increased the interventricular dispersion significantly from 55 to 110 ms for both drugs. All dogs had early afterdepolarizations, while, in the majority, ectopic ventricular beats developed (
dofetilide 8/9 and
azimilide 7/9).
Torsade de Pointes arrhythmias incidence was comparable 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 arrhythmias.