In silico assessment of the effects of various compounds in MEA/hiPSC-CM assays: Modeling and numerical simulations

Abstract

We propose a mathematical approach for the analysis of drugs effects on the electrical activity of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) based on multi-electrode array (MEA) experiments. Our goal is to produce an in silico tool able to simulate drugs action in MEA/hiPSC-CM assays. The mathematical model takes into account the geometry of the MEA and the electrodes' properties. The electrical activity of the stem cells at the ion-channel level is governed by a system of ordinary differential equations (ODEs). The ODEs are coupled to the bidomain equations, describing the propagation of the electrical wave in the stem cells preparation. The field potential (FP) measured by the MEA is modeled by the extracellular potential of the bidomain equations. First, we propose a strategy allowing us to generate a field potential in good agreement with the experimental data. We show that we are able to reproduce realistic field potentials by introducing different scenarios of heterogeneity in the action potential. This heterogeneity reflects the differentiation atria/ventricles and the age of the cells. Second, we introduce a drug/ion channels interaction based on a pore block model. We conduct different simulations for five drugs (mexiletine, dofetilide, bepridil, ivabradine and BayK). We compare the simulation results with the field potential collected from experimental measurements. Different biomarkers computed on the FP are considered, including depolarization amplitude, repolarization delay, repolarization amplitude and depolarization-repolarization segment. The simulation results show that the model reflect properly the main effects of these drugs on the FP.

Keywords: Cardiac electrophysiology; Drug modeling; Field potential; MEA; hIPSC-CMs.