Improvement of QT analysis for Evaluating the Proarrhythmic Risk of Drug: The Importance of Spatial and Temporal Dispersion of Repolarization

Cardiac arrhythmias, in particular life-threatening Torsades de Pointes (TdP) are serious adverse effects associated with a number of pharmaceuticals belonging to different classes. It is therefore critical to have reliable biomarkers for assessing this risk during pre-clinical testing of new compounds. Prolongation of cardiac action potential and consequently of the QT interval of the ECG is generally considered as indicative of a risk of arrhythmia. Evaluation of drug effects on QT in preclinical studies is therefore requested by ICH (International Conference on Harmonization) guideline (S7B). However there is now growing evidence that the prolongation of mean QT interval is not an accurate indicator of the risk of arrhythmia and that other parameters of cardiac repolarization are more predictive. They include instability of action potential duration and increase in transmural heterogeneity of myocardial repolarization (spatial variability), which can be investigated in specific in vitro tests. We have conducted a number of experiments in dogs for evaluating the ECG correlates of both markers in studies testing the effects of isoproterenol, cisapride, astemizole and hypokaliemia, which are known to be associated with a proarrhythmic risk. Instability of action potential duration is associated with an increase in the beat-to-beat (temporal) variability of the QT interval that is evaluated by calculating the coefficient of variation of this parameter or by plotting QT from each beat versus QT of previous beat. Spatial variability of repolarization correlates with changes in the morphology of the T wave, in particular increase in the interval between the peak and the end of the T wave and notching of this wave. In these experiments, we have therefore established a simple method for in vivo assessment of spatial and temporal variability of cardiac repolarization, which may help in the evaluation the pro-arrhythmic risk of drugs.