Electrophysiologic Profile of Dronedarone on the Ventricular Level: Beneficial Effect on Postrepolarization Refractoriness in the Presence of Rapid Phase 3 Repolarization

Background: Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model. Methods and Results: Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg.kg(-1).d(-1)) and amiodarone (A; n = 20; 50 mg.kg(-1).d(-1)). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50-100 mu M; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: + 24 milliseconds, A: + 28 milliseconds, S: + 35 milliseconds (50 mu M), + 56 milliseconds (100 mu M); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = + 12 milliseconds; A = + 14 milliseconds; S = + 25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A. Conclusions: Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.