A novel computational model of human iPSC-derived ventricular myocytes with improved L-type calcium current for application to Timothy syndrome

Figures

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  Fig. 1. Simulated ionic currents during the steady-state action potential in the novel ventricular hiPSC-CM model. Top row: membrane potential trace at steady-state pacing (800 s). Subsequent panels (left to right, top to bottom) show the time courses of the main transmembrane ionic currents underlying the action potential: fast sodium current (I\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_\text {Na}$$\end{document}), funny current (I\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_\text {f}$$\end{document}), L-type Ca2+ current (I\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_\text {CaL}$$\end{document}), transient outward K+ current…

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  Fig. 2. Validation of the novel wild-type hiPSC-CM model against experimental recordings. (a,b) Representative experimental action potential (AP) traces recorded from two different wild-type (WT) hiPSC-derived cardiomyocytes. (c) Simulated APs obtained from the novel WT hiPSC-CM model at steady-state spontaneous activity. (d,e) Experimental recordings showing simultaneous membrane voltage (blue) and Ca2+ transients (magenta) from two WT hiPSC-CMs. (f) Simulated membrane potential and corresponding Ca2+ transient traces from the model. (g) Comparison of quantitative electrophysiological biomarkers between experiment and simulation. Box plots represent the distribution of experimental measurements obtained from 8 WT hiPSC-CM cells (red line: mean; whiskers: ±SD), while simulated model outputs are shown as blue dots. Biomarkers include: cycle length (CL), AP duration at 90% repolarization (TR90), AP triangulation, maximum diastolic potential (MDP), AP amplitude (APA), CaT time to peak, full duration at half maximum (CaT FDHM), time to 90% CaT decay, and CaT decay time constant.

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  Fig. 3. Ionic currents underlying the steady-state action potential in the Timothy Syndrome (TS) hiPSC-CM model. Top row: membrane potential. Remaining panels (left to right, top to bottom): fast sodium current (I\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_\text {Na}$$\end{document}), funny current (I\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_\text {f}$$\end{document}), L-type Ca2+ current (I\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$_\text {CaL}$$\end{document}), transient outward potassium current (I\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}…

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  Fig. 4. Validation of the Timothy Syndrome (TS) hiPSC-CM model against experimental recordings. (a) Representative experimental action potential (AP) trace recorded from a TS patient–derived hiPSC-CM. (b) Simulated steady-state spontaneous APs (last three beats) generated by the TS hiPSC-CM model. (c) Quantitative comparison of AP biomarkers between experiment and simulation. Box plots show the distribution of experimental data obtained from 10 TS hiPSC-CM cells (red line: mean; whiskers: ±SD). Model outputs are overlaid as blue symbols. Biomarkers include: cycle length (CL), AP duration at 90% repolarization (TR90), AP triangulation, maximum diastolic potential (MDP), and AP amplitude (APA).

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  Fig. 5. Comparison between wild-type (WT) and Timothy Syndrome (TS) hiPSC-CM models and experimental data. (a,b) Experimental (a) and simulated (b) action potentials (APs) from WT hiPSC-CMs, showing three spontaneous beats at steady state. (c,d) Experimental (c) and simulated (d) APs from TS hiPSC-CMs. (e) Comparison between WT (blue) and TS (red) models: top to bottom panels show membrane voltage (Vm), L-type Ca2+ current (ICaL), cytosolic Ca2+ transient (CaT), and sarcoplasmic reticulum Ca2+ concentration ([Ca2+]SR). (f) Quantification of key biomarkers in WT and TS models: action potential duration at 90% repolarization (TR90), peak Ca2+ transient amplitude (CaT peak), and diastolic sarcoplasmic Ca2+ concentration ([Ca2+]SR).

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  Fig. 6. Simulation of nifedipine effects on the wild-type hiPSC-CM model under spontaneous and paced conditions. Top panels show membrane voltage (Vm) traces; bottom panels show the corresponding L-type Ca2+ current (ICaL). Left column: last spontaneous beat at steady state under control conditions and with increasing nifedipine concentrations (3, 10, 30, 50, and 70 nM). Right column: action potentials and ICaL recorded during pacing at 1.5 Hz for the same drug concentrations. The simulations demonstrate a dose-dependent reduction of ICaL amplitude and progressive shortening of action potential duration.

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  Fig. 7. Sensitivity analysis of action potential and Ca2+ transient biomarkers across different hiPSC-CM models. (a) Overlay of the last spontaneous beat from all valid models (blue traces) compared to the corresponding reference model (magenta) for: the Paci2020 model (top left), the novel wild-type hiPSC-CM model (top right), the Timothy Syndrome hiPSC-CM model (bottom left), and the wild-type hiPSC-CM model under 50 nM nifedipine (bottom right). (b) Heatmaps of the sensitivity matrix \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\textbf{B}$$\end{document} for each model. Rows represent AP and Ca2+ transient biomarkers, while columns represent model parameters. Each cell shows the normalized linear regression coefficient, reflecting the influence of a given parameter on a specific biomarker. Red indicates positive correlation, blue negative correlation, and white denotes no substantial effect.