Abstract
Drug-induced action potential duration (APD) prolongation was first proposed to be antiarrhythmic, but is now widely presumed to be torsadogenic. To elucidate this paradox, we tested the effect of APD upon liability for torsade de pointes. In addition, torsadogenicity is commonly associated with disturbances of repolarization, but at least in theory, it could also result from disturbances of conduction. These possibilities were tested in female rabbit hearts. Dofetilide, ATX II, and sodium channel blockers that did not prolong the action potential duration were used to modulate the APD and induce disturbances of conduction and disturbances of repolarization. Torsadogenicity could be induced by dofetilide and ATX II starting at normal APD (210 ms), reaching a peak incidence around a doubling of APD (400 to 450 ms), to then sharply decline with further APD prolongation, until torsade de pointes disappeared above 725 ms. Early afterdepolarizations (EAD) were regular triggers for torsade de pointes; while most of the EADs occurred in the plateau range, their incidence declined with repolarization but their potential for torsadogenicity increased. Sodium channel blockers that shorten the APD, even when devoid of hERG blocking properties, can yield torsade de pointes. Torsade de pointes can occur at normal, prolonged, and shortened APD, so that QT prolongation is an incomplete predictor of torsadogenicity. Torsade de pointes can result not only from disturbances of repolarization but also from disturbances of conduction.
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Abbreviations
- APD:
-
Action potential duration
- λ :
-
CV × ERP
- CV:
-
Conduction velocity
- ERP:
-
Effective refractory period
- TdP:
-
Torsade de pointes
- VT:
-
Ventricular tachycardia
- VF:
-
Ventricular fibrillation
- TRIaD:
-
Triangulation Reverse use dependence, Instability and Dispersion
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Acknowledgments
The author wishes to thank Elisabeth Beck, Jessica Bigneron, and Bruno Hespel for their assistance with the experiments. Many thanks to Dr. Belardinelli of CV Therapeutics for the donation of the dofetilide. This work was supported by grants from HPC and Novartis, and the authors declare to have no conflict of interest.
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Hondeghem, L.M., Dumotier, B. & Traebert, M. Oscillations of cardiac wave length and proarrhythmia. Naunyn-Schmied Arch Pharmacol 382, 367–376 (2010). https://doi.org/10.1007/s00210-010-0549-y
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DOI: https://doi.org/10.1007/s00210-010-0549-y