Comparison of the Simulated Response of Three in Silico Human Stem Cell-Derived Cardiomyocytes Models and in Vitro Data Under 15 Drug Actions

Abstract

<p>Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (Koivumäki2018, Kernik2019, and Paci2020) to simulated drug action, and compare simulation results against in vitro data for 15 drugs. Methods: First, simulations were conducted considering 15 drugs, using a simple pore-block model and experimental data for seven ion channels. Similarities and differences were analyzed in the in silico responses of the three models to drugs, in terms of Ca<sup>2+</sup> transient duration (CTD<sub>90</sub>) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na<sup>+</sup> (I<sub>Na</sub>), L-type Ca<sup>2+</sup> (I<sub>CaL</sub>), and rapid delayed rectifying K<sup>+</sup> (I<sub>Kr</sub>) currents was quantified. Finally, we compared the drug-induced effects on CTD<sub>90</sub> against the corresponding in vitro experiments. Results: The observed CTD<sub>90</sub> changes were overall consistent among the in silico models, all three showing changes of smaller magnitudes compared to the ones measured in vitro. For example, sparfloxacin 10 µM induced +42% CTD<sub>90</sub> prolongation in vitro, and +17% (Koivumäki2018), +6% (Kernik2019), and +9% (Paci2020) in silico. Different arrhythmic events were observed following drug application, mainly for drugs affecting I<sub>Kr</sub>. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na<sup>+</sup> blockers and by drugs with similar effects on I<sub>CaL</sub> and I<sub>Kr</sub> in Koivumäki2018 and Paci2020, while only by strong I<sub>CaL</sub> blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis. Conclusion: To conclude, The CTD<sub>90</sub> changes observed in silico are qualitatively consistent with our in vitro data, although our simulations show differences in drug responses across the hSC-CM models, which could stem from variability in the experimental data used in their construction.</p>