Simulating Drug-Induced Effects on the Heart: From Ion Channel to Body Surface Electrocardiogram

Abstract

[EN] The electrocardiogram (ECG) is widely used as a clinical tool for the evaluation of cardiac conditions caused by drugs, mutations and diseases. However, the ionic basis underlying changes in the ECG are often unclear. In the present study, we present a computational model of the human ECG capable of representing drug-induced effects from the ionic to the surface potential level. Bidomain simulations are conducted to simulate the electrophysiological activity of the heart and extracellular potentials in the whole body. Membrane kinetics are represented by the most recent version of a human action potential model, modified to include representation of HERG block by dofetilide, a known class III anti-arrhythmic drug with potential pro-arrhythmic effects. Simulation results are presented showing how dofetilide administration results in the prolongation of the action potential duration in the ventricles and the QT interval measured on the surface of the thorax, in agreement with clinical results. The state-of-the-art tools and methodologies presented here could be useful in the investigation and assessment of drug cardiotoxicity and can also be extended to the investigation of the effect of mutations or disease on the ECG.