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

Abstract

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 Ca²⁺ transient duration (CTD₉₀) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na⁺ (I_Na), L-type Ca²⁺ (I_CaL), and rapid delayed rectifying K⁺ (I_Kr) currents was quantified. Finally, we compared the drug-induced effects on CTD₉₀ against the corresponding in vitro experiments. Results: The observed CTD₉₀ 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% CTD₉₀ 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_Kr. Paci2020 and Kernik2019 showed only repolarization failure, while Koivumäki2018 also displayed early and delayed afterdepolarizations. The spontaneous activity was suppressed by Na⁺ blockers and by drugs with similar effects on I_CaL and I_Kr in Koivumäki2018 and Paci2020, while only by strong I_CaL blockers, e.g. nisoldipine, in Kernik2019. These results were confirmed by the sensitivity analysis. Conclusion: To conclude, The CTD₉₀ 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.

Keywords: action potential; calcium transient; drug test; human stem cell-derived cardiomyocyte; in silico modeling; sensitivity analysis.