Abstract
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 (AP) were examined first, and three-dimensional (3D) body-surface ECG simulations were performed at free Cmax values of 1×, 5×, and 10×. In the single-cell and ECG simulations at 5× 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.
Highlights
The proarrhythmic effects of cardiac and non-cardiac drugs have comprised a major drug safety issue for the past 20 years (Zipes, 1987; De Ponti et al, 2002; Moro et al, 2010)
Human ventricular geometry was reconstructed from the computed tomography (CT) images obtained from the University of Ulsan Medical Center using a commercially available software Aquarius intuition (TeraRecon Inc., San Mateo, CA, United States)
When Cmax was increased from 1× to 10×, APD90 increased for all three drugs and all three cell types, with the exception of M cells, in the presence of dofetilide
Summary
The proarrhythmic effects of cardiac and non-cardiac drugs have comprised a major drug safety issue for the past 20 years (Zipes, 1987; De Ponti et al, 2002; Moro et al, 2010). The electrocardiogram (ECG) is an effective means of determining whether a drug is proarrhythmic. The CiPA comprises in silico simulation of several ion-channel assays and ECG studies to identify biomarkers of false-positive results of single hERG channel assays and thorough QT (TQT) studies (Darpo, 2010) performed according to the International Council for Harmonisation (ICH) S7B and E14 guidelines. There have been a large number of studies that investigated the effect of drugs on ECG using in silicon three-dimensional (3D) heart model. Zemzemi et al (2013) examined the effect of the block of ion channels on ECG parameters. Sahli Costabal et al (2019) investigated the critical drug concentration which induced torsade de pointes. There have been a large number of studies that investigated the effect of drugs on ECG using in silicon three-dimensional (3D) heart model. Zemzemi et al (2013) examined the effect of the block of ion channels on ECG parameters. Okada et al (2018) generated an arrhythmic hazard map under multiple ion channel blocks. Sahli Costabal et al (2019) investigated the critical drug concentration which induced torsade de pointes. Rivolta et al (2017) performed sensitivity analysis of JTpeak and T-wave morphology parameters
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