REPRODUCIBLE INDUCTION OF EARLY AFTERDEPOLARIZATIONS AND TORSADE-DE-POINTES ARRHYTHMIAS BY D-SOTALOL AND PACING IN DOGS WITH CHRONIC ATRIOVENTRICULAR-BLOCK

It has been well established that antiarrhythmic drugs can also have p roarrhythmic effects such as torsade de pointes (TdP) arrhythmias. It was the purpose of this study to create an animal model with a high in cidence of reproducible TdP that occurs under clinically relevant circ umstances. Experiments were performed in anesthetized dogs that had be en in chronic atrioventricular block for 9+/-6 weeks. TdP inducibility was attempted using different pacing modes before and after the admin istration of 2 mg/kg d-sotalol. In some experiments, endocardial monop hasic action potentials were recorded. d-Sotalol increased the cycle l ength of the idioventricular rhythm (1475+/-460 to 1730+/-570 ms, P<.0 1) and the QT time (390+/-65 to 480+/-85 ms, P<.01). In 10% of the exp eriments, spontaneous TdP occurred after d-sotalol. The incidence of p acing-dependent TdP was 52% (P<.01). In the inducible group, the cycle length of idioventricular rhythm and QT time were significantly longe r despite equal percentage increases in these parameters after d-sotal ol in both groups. The pacing modes consisting of more than one freque ncy change had a higher TdP induction rate (P<.05). Reproducibility of TdP induction (three times or more using the same pacing train) remai ned present for approximately 60 minutes after d-sotalol and was great er than 90% within the same animal over weeks. TdP induction was relat ed to the presence of early afterdepolarizations on the monophasic act ion potential recordings: five of six in the inducible group versus tw o of six in the nonresponders. Inducibility could be further increased to 89% when a second bolus of d-sotalol was administered to noninduci ble dogs. On the other hand, decreasing QT time by faster basic pacing or administration of isoproterenol, or MgSO4 prevented TdP induction. This effect of MgSO4 coincided with the disappearance of early afterd epolarizations. Our animal model shows a high incidence of reproducibl e acquired TdP arrhythmias, allowing study of the mechanism and treatm ent of TdP. TdP induction was related to the combination of a slow ven tricular rate, the prolongation of QT time, a sudden induced rate chan ge that often required two or more cycle length changes, and the prese nce of early afterdepolarizations.