title: Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias.
abstract: 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.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Van Opstal
authors.forename: J D
authors.initials: JD
authors.lastname: Leunissen
authors.forename: H J
authors.initials: HJ
authors.lastname: Wellens
authors.forename: M A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004285:Dogs; D006327:Heart Block; D006827:Hydantoins; D007093:Imidazoles / Q000009:adverse effects*; D048289:Imidazolidines; D010627:Phenethylamines / Q000009:adverse effects*; D010879:Piperazines / Q000009:adverse effects*; D013449:Sulfonamides / Q000009:adverse effects*; D016171:Torsades de Pointes / Q000139:chemically induced*; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D013449:Sulfonamides; C086123:azimilide; C063533:dofetilide