Abstract
BACKGROUND AND PURPOSE: To date, proposed in silico models for preclinical cardiac safety testing are limited in their predictability and usability. We previously reported a multi-scale heart simulation that accurately predicts arrhythmogenic risk for benchmark drugs. EXPERIMENTAL APPROACH: We created a comprehensive hazard map of drug-induced arrhythmia based on the electrocardiogram (ECG) waveforms simulated under wide range of drug effects using the multi-scale heart simulator described here, implemented with cell models of human cardiac electrophysiology. KEY RESULTS: A total of 9075 electrocardiograms constitute the five-dimensional hazard map, with coordinates representing the extent of the block of each of the five ionic currents (rapid delayed rectifier potassium current (I(Kr) ), fast (I(Na) ) and late (I(Na,L) ) components of the sodium current, L-type calcium current (I(Ca,L) ) and slow delayed rectifier current (I(Ks) )), involved in arrhythmogenesis. Results of the evaluation of arrhythmogenic risk based on this hazard map agreed well with the risk assessments reported in the literature. ECG databases also suggested that the interval between the J-point and the T-wave peak is a superior index of arrhythmogenicity when compared to the QT interval due to its ability to characterize the multi-channel effects compared with QT interval. CONCLUSION AND IMPLICATIONS: Because concentration-dependent effects on electrocardiograms of any drug can be traced on this map based on in vitro current assay data, its arrhythmogenic risk can be evaluated without performing costly and potentially risky human electrophysiological assays. Hence, the map serves as a novel tool for use in pharmaceutical research and development.