title: Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias.
abstract: OBJECTIVE
  Interaction between dronedarone and digitalis has been discussed as a possible cause for increased mortality in the presence of dronedarone observed in the PALLAS trial. The aim of this study was to assess possible proarrhythmic effects of dronedarone in combination with digitalis in an experimental whole heart model.
  
  
  RESULTS
  Twenty-six female rabbits underwent chronic oral treatment with dronedarone (50 mg/kg/day for 6 weeks). Twenty-four rabbits received placebo. Heart failure was induced by rapid ventricular pacing. Sham-operated rabbits received a right-ventricular pacing lead but were not paced. Thereafter, hearts were isolated and Langendorff-perfused. Monophasic action potentials and a 12 lead electrocardiogram showed a dose-dependent decrease of QT interval, APD90, effective refractory periods, and postrepolarization refractoriness in control hearts and dronedarone-pretreated hearts after application of ouabain (0.1 and 0.2 µM). After acute application of ouabain, ventricular fibrillation (VF) was inducible by programmed ventricular stimulation in 6 of 12 untreated sham hearts (38 episodes) as compared with 7 of 11 dronedarone-pretreated sham hearts (76 episodes). In untreated failing hearts, 6 of 12 hearts were inducible (47 episodes) as compared with 7 of 15 hearts dronedarone-pretreated failing hearts (93 episodes).
  
  
  CONCLUSIONS
  In this study, ouabain treatment resulted in an increased ventricular vulnerability in chronically dronedarone-pretreated control and failing hearts. Ouabain led to a significant abbreviation of ventricular repolarization. This was more marked in dronedarone-pretreated hearts and resulted in an elevated incidence of VF. This may help to interpret the results of the PALLAS trial.
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany gerrit.frommeyer@ukmuenster.de.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Frommeyer
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Milberg
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schulze Grotthoff
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Dechering
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Kochhäuser
authors.affiliation: Division of Cardiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Clinic of Exotic Pets, Reptiles, Exotic and Feral Birds, University of Hanover, Hanover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Fehr
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.affiliation: Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckardt
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects; D004071:Digitalis Glycosides / Q000008:administration & dosage* / Q000009:adverse effects*; D000077764:Dronedarone; D004347:Drug Interactions; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D011817:Rabbits; D014693:Ventricular Fibrillation / Q000139:chemically induced* / Q000175:diagnosis / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D004071:Digitalis Glycosides; D000077764:Dronedarone; D000638:Amiodarone
keywords: Digitalis; Dronedarone; Ouabain; Post-repolarization refractoriness; Therapeutic safety; Ventricular fibrillation