Electromechanical modelling and simulation of hiPSC-derived cardiac cell cultures

Numerous drugs had to be removed from the market because of their potential to induce the life-threatening ventricular tachyarrhythmia Torsades de Pointes (TdP). To prevent potentially torsadogenic drugs to enter the market, a detailed safety assessment in drug development is of utmost importance. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative has been founded in order to develop a mechanistic-based approach for TdP risk predictions in safety assessments. Central component is a mathematical model of cardiomyocyte electrophysiology that is used to predict the TdP risk based on an electrophysiological biomarker. Then, unanticipated drug effects are evaluated in human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) cultures before the evaluation continues in humans in the phase 1 clinical trials. The action potential triggers mechanical contraction through the mechanisms of excitation-contraction coupling but the mechanics has widely been neglected in studies dealing with TdP risk prediction.

This thesis describes the development of a mathematical model of the electromechanics in hiPSC-derived cell cultures. In the first study, it was applied to investigate whether the TdP risk of drugs can also be predicted using mechanical biomarkers. To this end, the mathematical model was fitted to experiments with the novel FLEXcyte96 technology that has been developed to analyse the contraction-relaxation cycle in hiPSC-derived cell cultures. Ten drugs of the CiPA reference set with known TdP risk were considered in the study and mechanical drug effects were analysed by twelve biomarkers of the contraction-relaxation cycle. Three biomarkers were found that could differentiate the drugs by their known TdP risk and are suggested to be further examined in studies with a larger number of drugs.

To improve the translation of hiPSC-CMs studies to humans, it is required to engineer hiPSC-derived cardiac cell cultures that resemble regions of the undiseased and diseased human heart as good as possible. The heart is not only made up by cardiomyocytes but also by a large number of cardiac fibroblasts. Cardiac fibroblasts are able to modify cardiac electrophysiology but this has not yet been studied comprehensively in hiPSC-derived cardiac cell cultures. In the second study, the effects of human induced pluripotent stem cell-derived cardiac fibroblasts (hiPSC-CFs) on hiPSC-CM electrophysiology were investigated in two-dimensional co-cultures. This was done based on microelectrode array (MEA) experiments and using the mathematical model that was fitted to these experiments. The observed electrophysiological effects were in wide agreement with those found in animal cell cultures and demonstrate the capability of hiPSC-derived cardiac fibroblasts to modify hiPSC-CM electrophysiology in co-cultures. In addition, it was found that modifications of the electrophysiology are associated with modifications of the contraction-relaxation cycle.


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