Computational Model for Simulating Drug-Induced Arrhythmia Sensitivity of Human iPSC-derived Cardiomyocytes

Abstract

A mathematical model describing the electrophysiology and ion handling of cardiomyocytes is a complement to experimental analysis predicting drug-induced proarrhythmic potential in humans as proposed by Comprehensive in vitro Proarrhythmia Assay (CiPA). While CiPA endorses the use of the OHara Rudy (ORd) model, which was developed to simulate electrophysiology of human adult ventricular cardiomyocytes (hAVCMs), to predict drug-induced proarrhythmias; the human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) was proposed for experimental verifications. The hiPSC-CMs, especially cultured in 2D culture dishes, are inherently different from hAVCMs exhibiting different ion channel density and an immature sarcoplasmic reticulum function. To reconcile this mismatch, we have developed a mathematical electrophysiology model of an hiPSC-CM by incorporating differences in gene expressions of ion channels, pumps and receptors in hiPSC-CMs against those found in hAVCMs. This model can be used to model any hiPSC-CM cell line where expression data has been obtained and replaces the background currents for K+ and Na+ in the ORd model with the known ultra-rapid K+ channel and hyperpolarization activated K+/Na+ channel currents. With this new model, three batches each from two different hiPSC-CM cell lines are compared to experimental data of action potential duration. This mathematical model recapitulates a ventricular-like action potential morphology with a Phase 2 plateau lasting a few hundred milliseconds. However, the resting membrane potential is not as depolarized (-65 to -70 mV) as that of hAVCM (-80 mV). The elevated resting membrane potential matches experimental data previously and is thought to keep rapid sodium channels from triggering membrane depolarization instead being replaced by an overexpression of L-Type Ca2+ channel current. This model is a key step in identifying the variability between different hiPSC-CM lines and even batches of the same line, opening the door to realizing analysis of patient specific preparations in the future.