Beat-to-Beat Variability of Repolarization Determines Proarrhythmic Outcome in Dogs Susceptible to Drug-Induced Torsades de Pointes

Beat-To-Beat Variability of Repolarization Determines Proarrhythmic Outcome in Dogs Susceptible to Drug-Induced Torsades de Pointes Morten B. Thomsen, Paul G. A. Volders, Jet D. M. Beekman, Jørgen Matz, Marc A. Vos In dogs with chronic atrioventricular block, we investigated the association between drug-induced QT interval prolongation, beat-to-beat variability of repolarization (BVR) duration, and torsades de pointes arrhythmia. The non-cardiovascular, IKr-blocking drug sertindole was used to reproducibly induce proarrhythmia. To suppress the induced arrhythmia, we employed 3 different interventions, all of which did not affect the prolonged QT interval. With all interventions, BVR was decreased alongside successful antiarrhythmic treatment. The BVR duration is superior to QT interval prolongation in the prediction and prevention of drug-induced torsades de pointes arrhythmia in this experimental model. We investigated whether increasing or decreasing beat-to-beat variability of repolarization (BVR) would change drug-induced proarrhythmic outcome accordingly. Increased variability of repolarization has been suggested as a prelude to proarrhythmic circumstances in experimental and clinical situations. The non-cardiovascular, IKr-blocking drug sertindole was administered to anesthetized dogs with chronic atrioventricular block. Three interventions were used to prevent or suppress sertindole-induced torsades de pointes (TdP). Supratherapeutic doses of sertindole (1.0 mg/kg intravenously) induced TdP in 10 of 13 dogs whereas 0.2 mg/kg induced no TdP, despite increases in QT intervals by both doses. The BVR, quantified as short-term variability (STV) from Poincaré plots, was the only parameter that predicted TdP outcome (1.0 mg/kg sertindole: 2.3 ± 0.7 ms to 5.1 ± 2.1 ms, p < 0.05; 0.2 mg/kg sertindole: 2.3 ± 0.8 ms to 3.2 ± 1.1 ms, p= NS). Interventions: 1) KCl, intravenous, reduced the incidence of sertindole-induced TdP from 6 of 7 to 1 of 7 dogs (p