Computational study of the excitation of human induced pluripotent stem cell‐derived cardiomyocytes

Abstract Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) have proven to be a revolutionary advance for tissue engineering, disease modelling, and drug testing and discovery. Computational modelling enables detailed electrophysiological analysis that is otherwise difficult or impossible to achieve under strictly experimental settings. Action potential characteristics of hiPSC‐CMs measured in our lab at four different pacing rates were used to modify the computational Kernik–Clancy hiPSC‐CM model. The modified model was used to compare the excitation of single hiPSC‐CMs with a model of single human ventricular cardiomyocytes (hV‐CMs) under varying conditions, including stimulation at different strengths, rates and pulse durations. Furthermore, the physiological stimulation of hiPSC‐CMs or hV‐CMs embedded within a tissue strand involves a biphasic waveform during which time excitatory currents (particularly I Na , but also I CaT and I CaL for hiPSC‐CMs and I NaL and I CaL for hV‐CMs) are activated during both phases of the waveform. I Na in particular activated more slowly and with diminished amplitude under conditions of increasing pacing rate or increasing intracellular resistance. Lastly, histograms characterizing the relative amounts of excitatory currents in a population of hiPSC‐CMs become broader with increasing levels of I Na block, with I CaT and I CaL working in tandem to excite cells where I Na has failed to activate. In general, hiPSC‐CMs were found to be more excitable from rest compared with hV‐CMs owing to their more depolarized resting potential and intrinsic automaticity despite a lower sodium channel density. Such a mismatch should be taken into consideration for applications using these cells, particularly for cardiac repair.