The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs.
OBJECTIVE
The electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the I(Kr) -blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility.


METHODS
Our 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed.


RESULTS
During normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation.


CONCLUSIONS
In the canine CAVB model, ventricular remodelling and I(Kr) block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide-induced TdP.
Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
T R G
TR
Stams
V J A
VJ
Bourgonje
H D M
HD
Beekman
M
M
Schoenmakers
R
R
van der Nagel
P
P
Oosterhoff
J M
JM
van Opstal
M A
MA
Vos
D000818:Animals; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000517:prevention & control; D064752:Atrial Remodeling / Q000187:drug effects; D054537:Atrioventricular Block / Q000503:physiopathology*; D016208:Databases, Factual; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004285:Dogs; D042241:Early Diagnosis; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015203:Reproducibility of Results; D013449:Sulfonamides; D016171:Torsades de Pointes / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide
Torsade de Pointes; cardiac safety pharmacology; chronic AV-block dog; dofetilide; electromechanical window; electrophysiology; ventricular remodelling