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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.

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