In Silico Human Cardiomyocyte Action Potential Modeling: Exploring Ion Channel Input Combinations

Abstract

In silico modeling offers an opportunity to supplement and accelerate cardiac safety testing. With in silico modeling, computational simulation methods are used to predict electrophysiological interactions and pharmacological effects of novel drugs on critical physiological processes. The O'Hara-Rudy's model was developed to predict the response to different ion channel inhibition levels on cardiac action potential duration (APD) which is known to directly correlate with the QT interval. APD data at 30% 60% and 90% inhibition were derived from the model to delineate possible ventricular arrhythmia scenarios and the marginal contribution of each ion channel to the model. Action potential values were calculated for epicardial, myocardial, and endocardial cells, with action potential curve modeling. This study assessed cardiac ion channel inhibition data combinations to consider when undertaking in silico modeling of proarrhythmic effects as stipulated in the Comprehensive in Vitro Proarrhythmia Assay (CiPA). As expected, our data highlight the importance of the delayed rectifier potassium channel (I_Kr) as the most impactful channel for APD prolongation. The impact of the transient outward potassium channel (I_to) inhibition on APD was minimal while the inward rectifier (I_K1) and slow component of the delayed rectifier potassium channel (I_Ks) also had limited APD effects. In contrast, the contribution of fast sodium channel (I_Na) and/or L-type calcium channel (I_Ca) inhibition resulted in substantial APD alterations supporting the pharmacological relevance of in silico modeling using input from a limited number of cardiac ion channels including I_Kr, I_Na, and I_Ca, at least at an early stage of drug development.

Keywords: CiPA; O’Hara Rudy model; action potential duration; hERG; in silico; torsade de pointes.