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. METHODS AND 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.

Observations on the onset of torsade de pointes arrhythmias in the acquired long QT syndrome.

OBJECTIVE: Premature ectopic beats may create a specific sequence of events (e.g. short-long-short) preceding Torsade de Pointes arrhythmias (TdP) in the long QT syndrome. The relevance of this sequence for the initiation of TdP is not clear. In our dog model of TdP, interventricular dispersion (DeltaAPD=left-right ventricular monophasic action potential duration: APD) is associated with TdP, therefore we tested the hypothesis that the ectopic beats contributes to DeltaAPD. METHODS: In 17 anaesthetized dogs with chronic AV-block, which showed spontaneous TdP after class III medication, APD was analyzed to 1. quantitate the alterations due to (multiple) ectopic beats on the left and right APD (measured with endocardial catheters) and 2. compare the DeltaAPD prior to the occurrence of premature beats (steady state) in dogs with non-sudden onset of TdP (n=10) and sudden onset TdP (n=7). Three phases were distinguished: phase 1: steady state beats prior to ectopic beats, phase II: the beat(s) belonging to the dynamic phase, and phase III: the beat causing TdP. Because the coupling interval of premature beats in this condition often falls within the APD, the DeltaAPD(50) was validated as an alternative for the previously applied DeltaAPD(100) (r=0.51, P<0.01). RESULTS: In steady state (phase I) DeltaAPD(50) is longer in the sudden onset TdP (130+/-35 ms) as in the non-sudden onset TdP (65+/-40 ms). In the non-sudden TdP group the dynamic phase II contribute to the heterogeneity in APD, i.e. LV-APD increases more than RV-APD leading to a DeltaAPD(50) increase to 130+/-100 ms (P<0.01) just preceding TdP (phase III). CONCLUSION: The synergism between ectopic beats (short-long-short sequence) and DeltaAPD create the circumstances for TdP initiation.

Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium.

OBJECTIVE: The mechanism of acquired torsade-de-pointes arrhythmias (TdP) is not clear but is suggested to be based on several parameters including early afterdepolarizations (EADs) and/or dispersion of repolarization (delta APD). In our animal model of TdP (anaesthetized dogs with chronic AV block), we assessed the relevance of interventricular dispersion for the initiation of TdP. METHODS: In 24 experiments, multiple endocardial monophasic action potential (MAP) recordings were made at baseline, after d-sotalol (2 mg/kg), and after MgSO4 (100 mg/kg, n = 11) to measure regional differences in action potential duration (APD). Rate-dependent behavior of the interventricular delta APD (APD of left minus right ventricle) and intraventricular dispersion was studied under the different circumstances. RESULTS: Dogs with induction of TdP by d-sotalol and pacing (11/20 = 55%) had longer cycle lengths of idioventricular rhythm, longer QT-durations, increased presence of EADs (14/22 vs 5/18 MAPs, P < 0.05) and increased interventricular delta APD (135 +/- 55 vs 60 +/- 40 ms. P < 0.05) compared with non-inducible dogs. There were no differences in intraventricular dispersion. MgSO4 diminished delta APD (110 +/- 45 to 55 +/- 60 ms, P < 0.05) and prevented TdP (4/4). In contrast to intraventricular dispersion, interventricular delta APD is clearly bradycardia-dependent. CONCLUSIONS: Next to bradycardia, prolonged repolarization, and EADs, we propose that delta APD should be added to the relevant factors for the initiation of TdP. Interventricular dispersion is much larger than intraventricular dispersion and demonstrates a very strong bradycardia dependence.