Electromechanical modelling and simulation of human‐induced pluripotent stem cell‐derived cardiomyocytes predict drug‐induced contractility effects

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold promise in personalized medicine, particularly for cardiac diseases and human-data-based pharmacology studies. Assessing hiPSC-CM mechanics and their changes in response to drug action in silico enables more efficient drug testing. For such investigations, hiPSC-CMs also provide a versatile alternative to adult human cardiac tissue which is limited in availability for research. To enable in silico investigations of hiPSC-CM electrophysiology and contraction, we developed and evaluated two versions of hiPSC-CM electromechanical models with different maturation states. The models were based solely on human cardiomyocyte and hiPSC-CM data. The evaluation process involved comparing simulation outcomes with an extensive dataset of experimental data to ensure the reliability of the model within the context of hiPSC-CM pharmacology studies. The models uniquely incorporated the mechanical properties of hiPSC-CMs, providing insights into the mechanisms underlying their contractile behaviour. In our in silico studies, we simulated the effects of 64 different drugs, including those with previously untested inotropic effects. We demonstrated agreement between the simulation and experimental datasets, correctly identifying the inotropic effects of 41 out of 48 drugs. We also compared the effect of pharmacological agents with unknown inotropic effects and conducted novel experiments demonstrating agreement with simulation outcomes. Finally, using the models, we demonstrated the mechanisms of previously unrecognized rate-dependent inotropic effects of paliperidone. Altogether this study presents an in vitro - in silico framework which is evaluated against experimental data and allows for simulating drug-dependent electromechanical effects with high accuracy and prediction of rate-dependent inotropic effects. KEY POINTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are promising for drug testing and disease modelling, but current computer models that allow us to simulate hiPSC-CM behaviour lack human-specific mechanical properties. We developed and validated hiPSC-CM electromechanical models, allowing accurate simulations of contraction, calcium signalling and electrophysiology for two different maturation stages. Simulations with the new models correctly predicted inotropic effects for 41 out of 48 drugs and identified previously unknown effects of two drugs, later confirmed experimentally. Simulations revealed novel rate-dependent inotropic effects of paliperidone linked to calcium handling differences in paced versus non-paced cells. This in silico framework can enhance drug testing accuracy and understanding through mechanistic studies by integrating experimental data with computational predictions.