In-Silico Human Induced Pluripotent Stem Cell Derived Cardiomyocyte Electro-Mechanical Modelling and Simulation

Milda Folkmanaite, Xin Zhou, Francesca Margara, Manuela Zaccolo, Blanca Rodriguez
University of Oxford


INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) enable accessible human data-based cardiology studies. However, an immature hiPSC-CM electrophysiological and contractile phenotype hinders data translation to adult cardiomyocytes. In silico hiPSC-CM investigations could aid in hiPSC-CM data translation but most hiPSC-CM models do not feature a contractile element which limits their application for such studies. In the light of the growing use of hiPSC-CM, it is vital to enable investigations of hiPSC-CM-specific contractile features.

AIM: To address the need of hiPSC-CM model with integrated contractile element, we aim to develop an electromechanical hiPSC-CM computer model.

METHODS: We coupled a published hiPSC-CM electrophysiological model with a model of human adult cardiomyocyte contractile machinery by linking intracellular calcium and calcium-bound troponin dynamics. The established electromechanical hiPSC-CM model was calibrated using experimental hiPSC-CM active tension data and its simulated electromechanical biomarkers were also evaluated against experimental action potential and calcium transient data.

RESULTS: First, we test if the model successfully reproduces hiPSC-CM contractile phenotype. We compute active tension biomarkers and compare them with experimental data. Simulations show a peak twitch tension of 0.44 kPa which takes 201 ms to peak (TP) and 164 ms to achieve 50% relaxation (RT50), which all agree with the experimental hiPSC-CM values. Second, we demonstrate that calcium transient and action potential biomarkers with the electromechanical hiPSC-CM model remain within the experimentally established ranges. Finally, a comparison with human adult cardiomyocyte electromechanical models shows that TP is 14.9-25.6% and RT50 is 35.5-41% larger in simulations with hiPSC-CM model. This agrees with experimental data ranges demonstrating that models can capture relative differences between the cells which provides further confidence for their usability in future data translation.

CONCLUSION: Altogether, we present a new electromechanical hiPSC-CM model for comprehensive in silico hiPSC-CM-based studies, for mechanistic investigations and translation to adult cardiomyocytes behaviour.