title: Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome.
abstract: BACKGROUND
  Amiodarone is an effective antiarrhythmic drug rarely associated with torsade de pointes arrhythmias (TdP). The noniodinated compound dronedarone could resemble amiodarone and be devoid of the adverse effects. In the dog with chronic complete atrioventricular (AV) block (CAVB) and acquired long-QT syndrome, the electrophysiological and proarrhythmic properties of the drugs were compared after 4 weeks of oral treatment.
  
  
  RESULTS
  Amiodarone (n=7, 40 mg. kg(-1). d(-1)) and dronedarone (n=8, 20 mg/kg BID) were started at 6 weeks of CAVB (baseline). Six dogs served as controls. Surface ECGs and endocardially placed monophasic action potential catheters in the left (LV) and right (RV) ventricles were recorded to assess QTc time, action potential duration (APD), interventricular dispersion (DeltaAPD=LV APD minus RV APD), early afterdepolarizations (EADs), ectopic beats, and TdP. Both amiodarone (+21%) and dronedarone (+31%) increased QTc time. Amiodarone showed no increase in DeltaAPD in 4 of 7 dogs, whereas dronedarone augmented DeltaAPD in 7 of 8 animals. After dronedarone, TdP occurred in 4 of 8 dogs with the highest DeltaAPD (105+/-20 ms). TdP was never seen with amiodarone, not even in the dogs that had DeltaAPD values comparable to those with dronedarone. Furthermore, a difference existed in EADs and ectopic activity incidence (dronedarone 3 of 8; amiodarone 0 of 7), which was also seen during an epinephrine challenge.
  
  
  CONCLUSIONS
  In the CAVB dog model, both amiodarone and dronedarone prolong QT time (class III effect). The absence of TdP with amiodarone seems to be related to homogeneous APD lengthening in the majority of dogs and the lack of EADs and/or ventricular ectopic beats in all.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands. m.vos@cardio.azm.nl
authors.forename: J M
authors.initials: JM
authors.lastname: van Opstal
authors.forename: M
authors.initials: M
authors.lastname: Schoenmakers
authors.forename: S C
authors.initials: SC
authors.lastname: Verduyn
authors.forename: S H
authors.initials: SH
authors.lastname: de Groot
authors.forename: J D
authors.initials: JD
authors.lastname: Leunissen
authors.forename: F F
authors.initials: FF
authors.lastname: van Der Hulst
authors.forename: M M
authors.initials: MM
authors.lastname: Molenschot
authors.forename: H J
authors.initials: HJ
authors.lastname: Wellens
authors.forename: M A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000638:Amiodarone / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D006328:Cardiac Catheterization; D004195:Disease Models, Animal; D004285:Dogs; D000077764:Dronedarone; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006327:Heart Block / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008133:Long QT Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014851:Wakefulness
chemical_list: D000889:Anti-Arrhythmia Agents; D014662:Vasoconstrictor Agents; D000077764:Dronedarone; D000638:Amiodarone; D004837:Epinephrine