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.

A bilayer model of human atria: mathematical background, construction, and assessment.

AIMS: Atrial numerical modelling has generally represented the organ as either a surface or tissue with thickness. While surface models have significant computational advantages over tissue models, they cannot fully capture propagation patterns seen in vivo, such as dissociation of activity between endo- and epicardium. We introduce an intermediate representation, a bilayer model of the human atria, which is capable of recreating recorded activation patterns. METHODS AND RESULTS: We simultaneously solved two surface monodomain problems by formalizing an optimization method to set a coupling term between them. Two different asymptotically equivalent numerical implementations of the model are presented. We then built a geometrically and electrophysiologically detailed model of the human atria based on CT data, including two layers of fibre directions, major muscle bundles, and discrete atrial coupling. We adjusted parameters to recreate clinically measured activation times. Activation was compared with a monolayer model. Activation was fit to the physiological range measured over the entire atria. The crista terminalis and pectinate muscles were important for local right atrial activation, but did not significantly affect total activation time. Propagation in the bilayer model was similar to that of a monolayer, but with noticeable difference, due to three-dimensional propagation where fibre direction changed abruptly across the wall, resulting in a slight dissociation of activity. CONCLUSION: Atrial structure plays the dominant role in determining activation. A bilayer model is able to take into account transmural heterogeneities, while maintaining the low computational load associated with surface models.