Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Figures

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  Figure 1. Myocardial strand and ring models. (A) Schematic diagram of phase-2 reentry concept. (B) Schematic representation of a myocardial strand model comprising cylindrical 300 cells (a), of intercellular junction between myocytes (b), of each ventricular myocyte model (c), and of the equivalent circuit of the myocardial strand model (d). The cell membrane in each myocyte is divided into post-junctional (post-JM), lateral (LM), and pre-junctional membrane (pre-JM) segments, and each membrane segment comprises a modified O’Hara-Rudy dynamic (mORd) ventricular myocyte model10–12 and membrane capacitance, Cm,l, for l = post-JM, LM, and pre-JM (c). In (d), \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${V}_{\text{j}}^{k}$$\end{document}Vjk represents extracellular cleft potential just after the kth myocyte. \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek}…

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  Figure 2. Effects of changes in the subcellular Na+ channel expression on action potential (AP) morphology and conduction velocity (CV). (A) AP propagation observed in the myocardial strand model with a spatially-homogeneous reduction in Na+ channel conductance in the lateral membrane (LM) of 100%gNa,LM (a), 35%gNa,LM (b), 7%gNa,LM (c), and 0%gNa,LM (d). (B) AP morphological changes (a), INa at the LM, INa,LM (b), Ito (c), ICaL (d), INaK (e), IKs (f), IKr (g), and IK1 (h) at the LM. (C) Schematic diagram of a intercellular junction part in the myocardial strand model (a), the post-junctional (Im,post-JM) and pre-junctional transmembrane currents (Im,pre-JM) (b), the transmembrane current (Im,LM) and INa in the LM segments (c), the INa,JM of the pre-junctional membrane (pre-JM) in the 150th myocyte and of the post-junctional membrane (post-JM) in the 151st myocyte (d), the extracellular cleft potential (Vj) between the 150th and 151st myocytes (e), the intracellular potential (Vi) of the LM and pre-JM in 150th myocyte and of the post-JM in 151st myocyte (f), and the gap junctional current (Ig) between the 150th and 151st myocytes (g). The APs and ion currents were recorded in a myocyte…

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  Figure 3. Simulated phase-2 reentry (P2R) development in the strand model. (A) Examples of typical patterns of AP propagation observed in the myocardial strand model with a spatially-heterogeneous Na+ channel distribution. The Na+ channel conductances on the LM in the proximal (cell #1–200) and the distal (cell #201–300) were set to 6%gNa,LM and 7%gNa,LM, respectively, to cause 2:1 AP alternans (a), 4%gNa,LM and 0%gNa,LM, respectively, to cause 4:1 AP alternans (b), 4%gNa,LM and 7%gNa,LM, respectively, to cause 2:1 retrograde P2R (c), and 2%gNa,LM and 3%gNa,LM, respectively, to cause 3:1 P2R consisting of a retrograde P2R and twice conductions with abbreviated AP (d). Arrows and black short bars indicate the direction of AP propagation and blockage, respectively. (B) A phase diagram of AP propagation patterns for the %gNa,LM in proximal myocytes vs. %gNa,LM in distal myocytes. Open circles labeled as a–d correspond to the parameter sets at which the AP propagation patterns shown in panels Aa–d. SC, stable conduction consisting of typical AP morphology of human ventricular myocytes; 2:1 AL, 2:1 AP alternans pattern; k:1 AL, AP alternans pattern including a typical AP conduction and k − 1…

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  Figure 4. Mechanism of phase-2 reentry (P2R). (A) The simulated AP propagation in the myocardial strand model during the development of 2:1 P2R shown in Fig. 3Ab. (B) Simulated behaviors of the membrane potential (Vm) in several myocytes (#100–220) during the 2:1 P2R development. (C) The gap junctional currents, Ig, flowing from the cell #100 to #220. (D) INa in the post-junctional membrane (INa,post-JM) (a), the lateral membrane (INa,LM) (b), and the pre-junctional membrane (INa,pre-JM) (c). (E) The extracellular cleft potential, Vj, in the cell #100 to #220. F, ICaL (a), Ito (b), IKr (c), and IK1 (d) during the P2R development.

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  Figure 5. Mechanisms for the prevention of phase-2 reentry (P2R) under β-AS condition. (A,B) The simulated AP propagation (A) and the membrane potential (Vm) change (B) of several myocytes in the myocardial strand model under the same condition as for Fig. 3Ab but during β-AS. (C–F) The gap junctional current, Ig (C), INa in the post-junctional membrane (JM), INa,post-JM (Da), INa in the lateral membrane, INa,LM (Db), and INa in the pre-JM, INa,pre-JM (Dc), The extracellular cleft potentials, Vj (E), ICaL (Fa), Ito (Fb), IKr (Fc), and IK1 (Fd) during β-AS.

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  Figure 6. Rotatory reentry induction in the myocardial ring model. (A) Overall views (top) of simulated AP propagations in the myocardial ring with spatially-homogeneous Na+ channel distribution with 10%gNa,LM (a), 7%gNa,LM (b), and 5%gNa,LM (c) in the lateral membrane (LM) segment of each myocyte and enlarged views (bottom) of the time-dependent behaviours of membrane potential (Vm) of the 150th myocyte. (B) Overall (left) and enlarged views (right) of simulated AP propagations in the same model but with a spatially-heterogeneous Na+ channel distribution with gNa,LM in the LM of the 1st to 200th myocytes (Region A) and of the 201st to 600th myocytes (Region B): 5%gNa,LM in Region A and 3%gNa,LM in Region B (a) and 9%gNa,LM in Region A and 1%gNa,LM in Region B (b). Arrows and black short bars indicate the direction of AP propagation and blockage, respectively. Asterisks and dagger symbols represent the collision of excitation wavefronts, and the blockade of AP propagation, respectively. The red trace represents the AP behavior at the stimulus site (cell #300). (C) A phase diagram of AP propagation patterns for the %gNa,LM of each myocyte within Region A vs. %gNa,LM of each myocyte within…