Comparison of the Simulated Response of Three in Silico Human Stem Cell-Derived Cardiomyocytes Models and in Vitro Data Under 15 Drug Actions
Michelangelo Paci, Jussi T. Koivumäki, Hua Rong Lu, David J. Gallacher, Elisa Passini, Blanca Rodríguez
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 Ca 2+ transient duration (CTD 90 ) and occurrence of arrhythmic events. Then, the sensitivity of each model to different degrees of blockage of Na + (I Na ), L-type Ca 2+ (I CaL ), and rapid delayed rectifying K + (I Kr ) currents was quantified. Finally, we compared the drug-induced effects on CTD 90 against the corresponding in vitro experiments. Results: The observed CTD 90 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 90 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 CTD 90 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.