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

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.