Fig. 4.

Simulation results for the population of Trovato2020 models, including calibration (A-C), validation (D), and investigation of EAD and DAD inducibility (E-F). A) Results of the first calibration step, based on AP biomarkers. AP traces are shown for the baseline model (red), the discarded models (grey), and the accepted models (blue), compared against experimental traces from Dataset II (green). B) Results of the second calibration step, based on APD₉₀ rate-dependence. C) Results of the third calibration step, based on I_CaL modulation of APD₉₀. D) Comparison of APs with the experimentally-calibrated population of Trovato2020 models against experimental data from Dataset III. Boxplots represent the APD₉₀ distribution at 1 Hz (left) and 2 Hz (right) in control conditions (blue) and with Dofetilide 100 nM (pink). Simulation results with the baseline model are reported as a red star, while experimental data are shown as green squares. On each box, the central mark is the median of the population, box limits are the 25th and 75th percentiles, and whiskers extend to the most extreme data points not considered outliers, plotted individually as separate crosses. E) Top panel: Simulated AP traces for the EADs protocol, including the baseline model (black), models not displaying EADs (blue), and models displaying EADs (pink). The baseline model is shown in black. Bottom panel: Distribution of the scaling factors of the ionic current conductances varied in the population of models, highlighting the differences between the two groups of models. F) Top panel: Simulated AP traces for the DADs protocol, including the baseline model (black), models not displaying DADs (blue), models displaying DADs (pink), and models displaying triggered APs (green). Bottom panel: distribution of the scaling factors of the ionic current conductances varied in the population, highlighting the differences between the three groups of models. Boxplot description as in D. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)