Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve

Figures

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  Figure 1. Single myocyte and PV sleeve geometry used in these EMI model simulations. A: The upper illustration shows the surface of a single myocyte within the PV sleeve, and the lower illustration shows the full finite element mesh of the myocyte. In the mesh, each cell is represented by about 85 nodes, of which approximately 80 are located on the membrane or at the intercalated discs. B and C: Illustration of a cylinder of myocytes making up the PV sleeve. Each cell is shaped as illustrated in Panel A. The figure in Panel B also illustrates the stimulation protocol used in the simulations performed to investigate excitability, and the figure in Panel C illustrates the stimulation protocol used to investigate re-entry. Note that to improve the visibility, the cylinders in Panels B and C are not shown to scale.

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  Figure 2. Action potentials (left) and [\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {Ca}^{2+}$$\end{document}Ca2+] transients (right) for the LA and PV versions of our base model obtained at steady-state in response to a 1 Hz stimulus train.

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  Figure 3. Membrane currents during an action potential in the LA and PV versions of the base model. Definitions and mathematical specifications for each of these currents are provided in the Supplementary Information.

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  Figure 4. Action potential duration (APD) and effective refractory period (ERP) restitution curves for the LA and PV base models. For the APD restitution curve, the APD90 value is computed for a number of different diastolic interval (DI) values. The diastolic interval is defined as the time between the time point when the membrane potential has returned to 90% repolarization in the previous action potential (resulting from an S1 stimulation) to the time the next stimulation (S2) is applied. To compute the ERP restitution, a third stimulation (S3) is applied for each S2 DI. This S3 stimulation (lasting for 3 ms and of an amplitude about twice as large as was needed to generate an action potential from rest) is applied at progressively shorter time intervals after the S2 stimulation and the ERP is defined as the longest S2S3 interval that failed to capture60.

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  Figure 5. Effects of selected mutations on the AP and maximal upstroke velocity in single myocyte simulations of the LA and PV versions of our membrane model. The black lines and bars refer to WT, and the red lines and bars refer to the mutant cases. Note that the c.932delC mutation (in connexin 43) is not included here because the c.932delC mutation does not affect any of the parameters of the membrane models. However, it can have a significant effect on intercellular coupling, CV and arrhythmogenic substrate in the multicellular (syncytium) simulations.

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  Figure 6. Excitability analysis for WT, and for the N588K, A545P, and E299V mutations. Intracellular potential of myocytes in the PV sleeve is illustrated at four different times (rows) for each mutation (columns). In all cases a regenerative AP was generated and propagated around the tissue cylinder. The stimulus intensity (applied to 2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\times$$\end{document}×2 cells for 2 ms) required to initiate the propagating action potential in each case is provided in the title for each mutation. Note that to improve the visibility, the transversal axis of the myocytes has been stretched by a factor of 20.

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  Figure 7. Excitability analysis for WT, and for the E375X, A130V, and c.932delC mutations. This presentation format is the same as that of Fig. 6.

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  Figure 8. EMI-based multicellular simulations of electrical propagation and re-entry in the cylinder segment of the PV sleeve tissue. We use the simulation protocol described in the “Re-entry” section for investigating re-entry. Data are illustrated for WT, and the N588K, A545P, and E299V mutations (columns). Specifically, we show the intracellular potential of the cells in the PV sleeve at five different times after stimulation (rows). Note that to improve the visual resolution, the transversal axis of the myocytes has again been stretched by a factor of 20.

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  Figure 9. EMI-based multicellular simulations for WT, and for the E375X, A130V, and c.932delC mutations. The format of the figure is analogous to that of Fig. 8.