A novel computational model of human iPSC-derived ventricular myocytes with improved L-type calcium current for application to Timothy syndrome

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), tailored to better recapitulate Ca 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 with nifedipine, Ca overload and DAD-mediated triggered activity, and the interplay between intracellular Ca 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 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.