title: Electrophysiologic profile of dronedarone on the ventricular level:  beneficial effect on postrepolarization refractoriness in the presence of rapid phase 3 repolarization.
abstract: 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.
  
  
  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 μM; 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 μM), +56 milliseconds (100 μM); 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.
authors.affiliation: Division of Clinical and Experimental Electrophysiology, Department of Cardiology and Angiology, Hospital of Westfälische Wilhelms University, Münster, Germany. milbergp@uni-muenster.de
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.forename: Timo
authors.initials: T
authors.lastname: Uphaus
authors.forename: Dennis
authors.initials: D
authors.lastname: Kaiser
authors.forename: Nani
authors.initials: N
authors.lastname: Osada
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000638:Amiodarone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000077764:Dronedarone; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced; D010477:Perfusion; D011817:Rabbits; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D013015:Sotalol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D013015:Sotalol; D000077764:Dronedarone; D000638:Amiodarone