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

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.

Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials.

BACKGROUND AND PURPOSE: Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential. EXPERIMENTAL APPROACH: We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC(50) value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions. KEY RESULTS: Introducing a 50% hERG-channel current block results in 8% prolongation of the APD(90) and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD(90) is not affected. CONCLUSIONS AND IMPLICATIONS: Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.