Diffuse fibrosis and repolarization disorders explain ventricular arrhythmias in Brugada syndrome: a computational study

Figures

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  Figure 1. Comparison of simulated and experimental BrS AP. Left: simulated AP for different values of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0; arrows indicate the effects of stronger transient outward currents (i.e., lower values of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0); the inset zooms on the upstroke phase. Right: in vivo human epicardial monophasic APs33.

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  Figure 2. Different antidromic P2R modalities corresponding to different values of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0. For each situation, a propagating lost dome impulse in the BrS region (blue) depolarizes the healthy tissue (red). P2R is observed when the electrotonic currents from the healthy region to the BrS region cause a new excitation. (a) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0 = 0.43$$\end{document}dw0=0.43; P2R generates a delayed dome AP close to the healthy tissue, whereas farther from the healthy tissue a lost dome AP is followed by a new delayed dome AP. (b) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt}…

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  Figure 3. Different orthodromic P2R modalities corresponding to different values of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0. For each situation, a propagating healthy AP (red) depolarizes the BrS tissue (blue). P2R is observed when the electrotonic currents from the healthy region to the BrS region cause a new excitation. (a) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0 = 0.5$$\end{document}dw0=0.5; a delayed dome action potential propagates in the BrS region, therefore P2R is not possible. (b) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0 = 0.4$$\end{document}dw0=0.4; P2R generates a delayed dome AP…

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  Figure 4. 2D simulation with altered electrophysiology in the BrS region without structural abnormalities. (a) Sequence of snapshots taken from the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$10 \times 10$$\end{document}10×10 cm tissue model. The value of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0 was 0.4, whereas the radius of the BrS region was 3.5 cm. Diffuse fibrosis was not present. Sustained reentry was not induced. (b) Membrane potential in the BrS region recorded in the point indicated by a black dot in the snapshots. After the first lost dome AP, orthodromic reentry generates a delayed dome AP caused by electrotonic currents from the healthy tissue. Red dashed lines indicate the time instants at which snapshots were taken.

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  Figure 5. 2D simulation with altered electrophysiology in the BrS region with diffuse fibrosis. (a) Sequence of snapshots taken from the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$10 \times 10$$\end{document}10×10 cm tissue model. The value of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0 was 0.4, whereas the radius of the BrS region was 3.5 cm. Percentage of fibrotic tissue was set to \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$35\%$$\end{document}35%. Sustained reentry was triggered. (b) Membrane potential in the BrS region recorded in the point indicated by a black dot in the snapshots. Both orthodromic and…

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  Figure 6. Generation of a lost dome spiral wave in the BrS region reproduced with the 2D model. (a) Sequence of snapshots taken from the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$10 \times 10$$\end{document}10×10 cm tissue model. The value of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0 was 0.3, whereas the radius of the BrS region was 3.5 cm. Percentage of fibrotic tissue was set to \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$20\%$$\end{document}20%. A quasi stable spiral wave is observed in the BrS region, and repeatedly stimulates the healthy tissue. (b) Membrane potential in the BrS region recorded in the point…

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  Figure 7. Failure to trigger sustained reentry when AP dome is always maintained. (a) Sequence of snapshots taken from the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$10 \times 10$$\end{document}10×10 cm tissue model. The value of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0 was 0.6, whereas the radius of the BrS region was 3.5 cm. Percentage of fibrotic tissue was set to \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$35\%$$\end{document}35%. Sustained reentry was not induced. (b) Membrane potential in the BrS region recorded in the point indicated by a black dot in the snapshots. The presence of the dome in the AP…

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  Figure 8. Normalized values of observed sustained re-entries over 20 tissue simulations. The original samples were 13 values of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$F_p$$\end{document}Fp and 7 of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R_B$$\end{document}RB, the images were linearly interpolated in order to better appreciate the behaviour of the model.

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  Figure 9. Average frequency of AP in the healthy tissue for different values of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$F_p$$\end{document}Fp and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$d_w^0$$\end{document}dw0. Frequency stimulation values were averaged across both the simulation runs and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R_B$$\end{document}RB. Only the simulations showing sustained reentry were considered.