Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome.
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.
van Opstal
J M
JM
Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands. m.vos@cardio.azm.nl
Schoenmakers
M
M
Verduyn
S C
SC
de Groot
S H
SH
Leunissen
J D
JD
van Der Hulst
F F
FF
Molenschot
M M
MM
Wellens
H J
HJ
Vos
M A
MA
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
D000889:Anti-Arrhythmia Agents; D014662:Vasoconstrictor Agents; D000077764:Dronedarone; D000638:Amiodarone; D004837:Epinephrine