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Oscillations of Cardiac Wave Length and Proarrhythmia

Hondeghem, LM and Dumotier, Berengere and Traebert, Martin (2010) Oscillations of Cardiac Wave Length and Proarrhythmia. Naunyn-Schmiedeberg Archives of Pharmacology.

Abstract

Purpose: Drug-induced 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.
Methods: 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.
Results: 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 and 450 ms), to then sharply decline with further
APD prolongation, until TdP 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.
Conclusions: Torsade de pointes can occur at normal, prolonged and shortened APD, so that QT prolongation
is an incomplete predictor of torsadogenicity. Torsade de pointes cannot only result from disturbances
of repolarization, but also from disturbances of conduction.

Item Type: Article
Additional Information: correspondence author external
Keywords: Proarrhythmia, Torsade de pointes, QT prolongation, Disturbances of conduction, Disturbances of repolarization.
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3397

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