Aims: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising experimental tool for translational heart research and drug development. However, their usability as a human adult cardiomyocyte model is limited by their functional immaturity. Our aim is to analyse quantitatively those characteristics and how they differ from adult CMs. Methods and Results: We have developed a novel in silico model with all essential functional electrophysiology and calcium handling features of hiPSC-CMs. Importantly, the virtual cell recapitulates the immature intracellular ion dynamics that are characteristic for hiPSC-CMs, as quantified based our in vitro imaging data. The strong “calcium clock” is a source for a dual function of excitation-contraction coupling in hiPSC-CMs: action potential and calcium transient morphology vary substantially depending on the activation sequence of underlying ionic currents and fluxes that is altered in spontaneous vs. paced mode. Furthermore, parallel simulations with hiPSC-CM and adult cardiomyocyte models demonstrate the central differences. Results indicate that hiPSC-CMs translate poorly the disease specific phenotypes of Brugada syndrome, long QT Syndrome and catecholaminergic polymorphic ventricular tachycardia, showing less robustness and greater tendency for arrhythmic events than adult CMs. Based on a comparative sensitivity analysis, hiPSC-CMs share some features with adult CMs, but are still functionally closer to prenatal CMs than adult CMs. A database analysis of 3000 hiPSC-CM model variants suggests that hiPSC-CMs recapitulate poorly fundamental physiological properties of adult CMs. Single modifications do not appear to solve this problem, which is mostly contributed by the immaturity of intracellular calcium handling. Conclusion: Our data indicates that translation of findings from hiPSC-CMs to human disease should be made with great caution. Furthermore, we established a mathematical platform that can be used to improve the translation from hiPSC-CMs to human, and to quantitatively evaluate hiPSC-CMs development towards more general and valuable model for human cardiac diseases.

Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca²⁺ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca²⁺ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca²⁺ dynamics: 1) the biphasic increment during the upstroke of the Ca²⁺ transient resulting from the delay between the peripheral and central SR Ca²⁺ release, and 2) the relative contribution of SL Ca²⁺ current and SR Ca²⁺ release to the Ca²⁺ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca²⁺ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca²⁺ release sites define the interface between Ca²⁺ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca²⁺ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na⁺ concentration. Finally, the results indicate that the SR Ca²⁺ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca²⁺ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes. In the human heart, the contraction of atrial and ventricular muscle cells is based largely on common mechanisms. There is, however, a fundamental difference in the cellular calcium dynamics that underlie the contractile function. Here, we have developed a computational model of the human atrial cell that convincingly reproduces the experimentally observed characteristics of the electrical activity and the cyclic fluctuations of the intracellular calcium concentration. With the model, we evaluate the relative roles of the most important cellular calcium transport mechanisms and their impact on the electrical behavior of the cell. Our simulations predict that the amount of calcium released from the cellular stores during each electrical cycle crucially regulates the excitability of the human atrial cell. Furthermore, the results indicate that the cellular sodium accumulation related to faster heart rates is one of the main mechanisms driving the adaptation of cardiac electrical activity. Finally, we conclude that the presented model also provides a useful framework for future studies of human atrial cells.