Optimization of an in silico cardiac cell model for proarrhythmia risk assessment

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a regulatory paradigm proposed to replace the ICH S7B and E14 guidelines for assessing drug-induced proarrhythmia. Under CiPA, drug effects on multiple cardiac ion channels will be measured in vitro and integrated into an in silico model of the adult human ventricular cell, based on the O'Hara-Rudy (ORd) model. However, the ORd model does not accurately represent certain ionic currents known to be critical in triggering drug-induced arrhythmias, such as the late sodium current (I
_NaL
). The goal of the present study is to systematically assess and improve the simulation of the main depolarizing and repolarizing ionic currents (the inward rectifying potassium currents, L-type calcium current and I
_NaL
) in the ORd model. We present a new model with scaled conductances calculated by fitting to O'Hara et al. in vitro human cardiomyocyte channel blocking experiments using a genetic algorithm, which improves discrepancies of the original model. The modified model particularly improves the effect of INaL block on action potential prolongation, an important determinant of proarrhythmia risk in the context of CiPA.