Three-Dimensional Heart Model-Based Screening of Proarrhythmic Potential by in silico Simulation of Action Potential and Electrocardiograms

The proarrhythmic risk is a major concern in drug development. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative has proposed the JTpeak interval on electrocardiograms (ECGs) and qNet, an in silico metric, as new biomarkers that may overcome the limitations of the hERG assay and QT interval. In this study, we simulated body-surface ECGs from patch-clamp data using realistic models of the ventricles and torso to explore their suitability as new in silico biomarkers for cardiac safety. We tested seven drugs in this study: dofetilide (high proarrhythmic risk), ranolazine, verapamil (QT increasing, but safe), bepridil, cisapride, mexiletine, and diltiazem. Human ventricular geometry was reconstructed from computed tomography (CT) images, and a Purkinje fiber network was mapped onto the endocardial surface. The electrical wave propagation in the ventricles was obtained by solving a reaction-diffusion equation using finite-element methods. The body-surface ECG data were calculated using a torso model that included the ventricles. The effects of the drugs were incorporated in the model by partly blocking the appropriate ion channels. The effects of the drugs on single-cell action potential were examined first, and three-dimensional (3D) body-surface ECG simulations were performed at free Cmax values of 1x, 5x, and 10x. In the single-cell and ECG simulations at 5x Cmax, dofetilide, but not verapamil or ranolazine, caused arrhythmia. However, the non-increasing JTpeak caused by verapamil and ranolazine that has been observed in humans was not reproduced in our simulation. Our results demonstrate the potential of 3D body-surface ECG simulation as a biomarker for evaluation of the proarrhythmic risk of candidate drugs.