Abstract
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for modeling inherited arrhythmias, yet current in silico representations face limitations in Ca2+ handling. Here, we present a novel ventricular hiPSC-CM ionic model incorporating a Markovian formulation of the L-type Ca2+ current (I\(_\text {CaL}\)), tailored to better recapitulate Ca\(^{2+}\) dynamics and voltage-dependent inactivation. The model was calibrated against experimental data from hiPSC-CMs derived from a healthy individual and validated through a series of simulations relevant to both physiological and pathological conditions. These included pharmacological inhibition of I\(_\text {CaL}\) with nifedipine, Ca\(^{2+}\) overload and DAD-mediated triggered activity, and the interplay between intracellular Ca\(^{2+}\) cycling and membrane mechanisms in driving automaticity. Sensitivity analysis was used to generate a population of models capturing intercellular variability. In addition, the model was able to reproduce the effects of genetic mutations in the L-type Ca\(^{2+}\) channel, including those associated with Timothy Syndrome, providing an additional layer of validation. Overall, this computational framework offers a flexible and physiologically grounded tool for investigating the mechanisms of arrhythmogenesis in hiPSC-CMs and for supporting personalized medicine applications.
Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The full computational implementation of the model is publicly available in the CellML repository at https://models.cellml.org/workspace/d92/view. All other data supporting the findings of this study are available from the corresponding author upon reasonable request.”
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Acknowledgements
Authors are indebted to Ana Guío and the personnel of CNIC’s Pluripotent Stem Cell Technology Unit for their technical expertise regarding hiPSC culture and characterization.
Funding
This project was supported by the Italian Ministry of University and Research under Grant PRIN PNRR 2022, P2002B38NR (F.S., L.F.P.) and by the European High-Performance Computing Joint Undertaking (JU) EuroHPC under grants agreement No 955495 (MICROCARD) (F.S, L.F.P.). S.G.P. was funded by the European Research Council Grant ‘EU-Rhythmy’ ERC-ADG-2014-ID:669387 and by the Ministerio de Economía y Competitividad Grant PID2020-113484RB-I00. CNIC is supported by the Instituto de Salud Carlos III, the Ministerio de Ciencia, Innovación y Universidades and the ProCNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033).
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S.G.P., L.F.P. and D.J.S. designed the research. F.S. and A.T. produced the simulated data. C.M.P., J.K.S. and D.J.S. produced the experimental data. D.J.S. analyzed the experimental data. F.S., A.T., L.F.P., S.G.P., and D.J.S. wrote the manuscript. All authors have approved the final version of the manuscript.
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Simone, F., Trancuccio, A., Sochacki, J.K. et al. A novel computational model of human iPSC-derived ventricular myocytes with improved L-type calcium current for application to Timothy syndrome. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37707-4
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DOI: https://doi.org/10.1038/s41598-026-37707-4
