Session S45.4

Modelling Effects of Sotalol on T-Wave Morphology

TP Brennan*, M Fink, B Rodriguez, LT Tarassenko

University of Oxford
Oxford, UK

The QT interval has well-documented shortcomings as a predictor of Torsades de Pointes (TdP). Heart rate corrected QT interval (QTc) prolongation has led to a significant number of drugs being withdrawn from development. Alternative biomarkers of drug-induced pro-arrhythmia effects, based on T-wave morphology, have been proposed. However the electrophysiology underpinning these changes is not clearly understood. The goal of this research is to combine signal analysis and mathematical modelling to investigate the effects of drugs on ventricular repolarisation. In this paper, we analyze the effects of Sotalol, a known anti-arrhythmic drug, on the T-wave morphology as seen in the standard 12-lead surface electrocardiogram (ECG). Analysis of clinical ECG data from a controlled study on the effects of Sotalol (n=6) shows that Sotalol has a prolonging effect on QTc (55 ± 7ms) and a triangulation effect on T-wave morphology with a decreased T-wave amplitude. The maximal QTc prolongation occurs 265 ± 35min after drug administration, whereas the maximal morphology effect occurs another 150 ± 32min later. To investigate the mechanisms behind these dynamics a Markov model was developed to model Sotalol's interaction with the rapid delayed rectifier potassium current (IKr), which plays a major role in ventricular repolarization and is also the target of class III anti-arrhythmic drugs, such as Sotalol. The current is encoded by the Human Ether-a-go-go Related Gene (HERG), which is readily blocked by non-cardiac drugs because of its unique structure and electrophysiological qualities. The model was subsequently integrated into the ten Tusscher (2006) human ventricular cell model to simulate the effect of Sotalol on action potential duration (APD) of endocardial, mid-myocardial and epicardial cells. Subsequently, a 1D model representing a transmural cardiac fibre was developed and the pseudo-ECG was computed for several Sotalol concentrations (0, 160 and 320mg Sotalol). The simulation results show that the 320mg increase in Sotalol concentration decreases the overall conductance of IKr by 35% over time, resulting in prolongation of APD in mid-myocardium and QTc of 50ms. Furthermore, the heterogeneities across the heart wall affect the T-wave morphology in the pseudo-ECG. Thus, the main findings from the clinical ECGs are repeated in modelling study.

(Abstract Control Number: 5)