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PRECLINICAL STUDY

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

Morten B. Thomsen, PhD^_*,,2,_*, Paul G.A. Volders, MD, PhD^,1, Jet D.M. Beekman^_*, Jørgen Matz, PhD^,3 and Marc A. Vos, PhD^_*

^_* Department of Medical Physiology, Heart Lung Center Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
Center of Excellence, Cardiovascular Research, H. Lundbeck, Copenhagen, Denmark.

Manuscript received March 29, 2006; revised manuscript received May 4, 2006, accepted May 9, 2006.

^_* Reprint requests and correspondence: Dr. Marc A. Vos, Department of Medical Physiology, Yalelaan 50, NL 3584 CM Utrecht, the Netherlands. (Email: m.a.vos{at}umcutrecht.nl).

OBJECTIVES: We investigated whether increasing or decreasing beat-to-beat variability of repolarization (BVR) would change drug-induced proarrhythmic outcome accordingly.

BACKGROUND: Increased variability of repolarization has been suggested as a prelude to proarrhythmic circumstances in experimental and clinical situations.

METHODS: The non-cardiovascular, I_Kr-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).

RESULTS: 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 < 0.05) and prevented sertindole-related increase of STV: 3.0 ± 1.1 ms vs. 4.5 ± 1.3 ms (p < 0.05); 2) levcromakalim (I_K,ATP activator) reduced sertindole-induced TdP and decreased STV from 4.9 ± 2.1 ms to 2.6 ± 0.9 ms (p < 0.05); 3) steady-state ventricular pacing (60 beats/min) abolished sertindole-induced TdP and decreased STV from 4.9 ± 1.5 to 3.2 ± 1.0 (p < 0.05). Torsades de pointes reappeared upon return to non-paced idioventricular rhythm. None of the 3 interventions reduced the sertindole-induced prolonged QT interval.

CONCLUSIONS: Proarrhythmic intervention is related to an increase in BVR, whereas antiarrhythmic treatment is associated with a decrease in BVR. The BVR is superior to QT interval prolongation in the prediction and prevention of drug-induced TdP in this experimental model.

Abbreviations and Acronyms   BVR = beat-to-beat variability of repolarization   CAVB = chronic atrioventricular block   CL = cycle length   IVR = idioventricular rhythm   LV = left ventricle/ventricular   MAPD = monophasic action potential duration   QTc = heart rate–corrected QT intervals   RV = right ventricle/ventricular   STV = short-term variability   TdP = torsades de pointes   MAPD = interventricular dispersion of repolarization duration

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