Simulated drug-induced CTD90 changes in three in silico hSC-CM models were qualitatively consistent with in vitro data but showed smaller magnitudes (e.g., +6% to +17% vs +42% for sparfloxacin).
In silico hSC-CM models show qualitatively consistent but quantitatively smaller responses to drug-induced CTD90 changes compared to in vitro data, highlighting variability in model construction.
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.
Paci et al. (2021) studied this question. 15 drugs (e.g., sparfloxacin) vs. in vitro data was evaluated on Ca 2+ transient duration (CTD 90) and occurrence of arrhythmic events. Simulated drug-induced CTD90 changes in three in silico hSC-CM models were qualitatively consistent with in vitro data but showed smaller magnitudes (e.g., +6% to +17% vs +42% for sparfloxacin).