Modelling effects of sotalol on T-wave morphology

Abstract

The QT interval has well-documented shortcomings as a predictor of Torsades de Pointes (TdP) and recent studies have shown that T-wave morphology might provide insight into drug effects on ventricular repolarisation. In this paper, we investigate the underlying mechanisms of the effects of sotalol, a known anti-arrhythmic drug, on T-wave morphology as seen in the surface electrocardiogram (ECG). Analysis of clinical ECG data from a controlled study shows that sotalol alters T-wave morphology, resulting in particular in a decrease in T-wave amplitude. Our multi-scale modelling approach uses a Markov formulation to represent sotalolpsilas interaction with the rapid delayed rectifier potassium channel current (IKr), validated using experimental data. The ion channel model is then incorporated into a human ventricular cell model, which is then used in a 1D fibre model with transmural heterogeneities to simulate a pseudo-ECG. The simulation results show sotalol-induced changes in IKr cause rate and dose-dependent increase in action potential duration (APD) and in transmural APD heterogeneities, which result in a decrease of T-wave amplitude and an increase in T-wave dispersion in the pseudo-ECG signal. Thus, our modelling study is able to explain the ionic mechanisms underlying the main sotalol-induced changes in clinical T-wave morphology.