Intercalated disk nanoscale structure regulates cardiac conduction.
Intercalated disk nanoscale structure regulates cardiac conduction.
复制标题
DOI：
10.1085/jgp.202112897
复制
发表时间：
2021-08-02
期刊：
影响因子：
--
通讯作者：
Weinberg SH
中科院分区：
文献类型：
--
作者：
Moise N;Struckman HL;Dagher C;Veeraraghavan R;Weinberg SH
Moise等人开发了一种考虑纳米级结构的夹层盘（ID）的有限元模型。在心脏组织模型中描述这些细节预测ID结构的改变可以影响心脏中的电传导。闰盘（ID）是一个专门的亚细胞区域，提供心脏中肌细胞之间的电和机械连接。ID在心脏组织中具有明确定义的被动作用，在细胞之间传递机械力和电流。最近的研究表明，Na+通道（负责心脏兴奋的主要电流）优先定位于ID，特别是在纳米域内，如差距连接相邻的perinexus和机械连接相关的粘附兴奋性节点，并且ID结构的扰动会改变心脏传导。这表明ID可能在调节传导中发挥重要的积极作用。然而，结构的ID和细胞间的裂缝没有得到很好的表征，到目前为止，没有模型已纳入的ID结构对心脏组织中的传导的影响。在这项研究中，我们开发了一种方法来生成逼真的有限元模型（FEM）网格复制纳米尺度的ID结构，基于实验测量从透射电子显微镜图像。然后，我们集成的细胞间裂隙电导率的测量，来自有限元网格，到一个新的心脏组织模型制定。基于有限元的计算预测，裂缝电导的分布对ID结构的区域变化敏感，特别是膜间分离和间隙连接分布。组织规模的模拟预测，ID结构的异质性导致显着的空间变化，在细胞间的裂缝内的电极化。重要的是，我们发现，这种异质性的裂缝极化调节传导desperizing激活的连接后Na+电流。此外，这些异质性导致传导速度对间隙结耦合的依赖性较弱，与忽略或简化ID结构的先前建模公式相比。此外，我们发现局部ID纳米畴的破坏可以减缓或增强传导，这取决于间隙结耦合强度。因此，我们的研究表明，ID纳米结构可以在调节心脏传导中发挥重要作用。
Moise et al. develop a finite element model of the intercalated disk (ID) that takes into account the nanoscale structure. Incorporating these details in a cardiac tissue model predicts that alterations in ID structure can affect electrical conduction in the heart. The intercalated disk (ID) is a specialized subcellular region that provides electrical and mechanical connections between myocytes in the heart. The ID has a clearly defined passive role in cardiac tissue, transmitting mechanical forces and electrical currents between cells. Recent studies have shown that Na+ channels, the primary current responsible for cardiac excitation, are preferentially localized at the ID, particularly within nanodomains such as the gap junction–adjacent perinexus and mechanical junction–associated adhesion-excitability nodes, and that perturbations of ID structure alter cardiac conduction. This suggests that the ID may play an important, active role in regulating conduction. However, the structures of the ID and intercellular cleft are not well characterized and, to date, no models have incorporated the influence of ID structure on conduction in cardiac tissue. In this study, we developed an approach to generate realistic finite element model (FEM) meshes replicating nanoscale of the ID structure, based on experimental measurements from transmission electron microscopy images. We then integrated measurements of the intercellular cleft electrical conductivity, derived from the FEM meshes, into a novel cardiac tissue model formulation. FEM-based calculations predict that the distribution of cleft conductances is sensitive to regional changes in ID structure, specifically the intermembrane separation and gap junction distribution. Tissue-scale simulations predict that ID structural heterogeneity leads to significant spatial variation in electrical polarization within the intercellular cleft. Importantly, we found that this heterogeneous cleft polarization regulates conduction by desynchronizing the activation of postjunctional Na+ currents. Additionally, these heterogeneities lead to a weaker dependence of conduction velocity on gap junctional coupling, compared with prior modeling formulations that neglect or simplify ID structure. Further, we found that disruption of local ID nanodomains can either slow or enhance conduction, depending on gap junctional coupling strength. Our study therefore suggests that ID nanoscale structure can play a significant role in regulating cardiac conduction.
登录
查看更多内容
影响因子：
4.6
作者：
Mezache L;Struckman HL;Greer-Short A;Baine S;Györke S;Radwański PB;Hund TJ;Veeraraghavan R
通讯作者：
Veeraraghavan R
影响因子：
20.1
作者：
LUO, CH;RUDY, Y
通讯作者：
RUDY, Y
影响因子：
16.6
作者：
Leo-Macias A;Agullo-Pascual E;Sanchez-Alonso JL;Keegan S;Lin X;Arcos T;Feng-Xia-Liang;Korchev YE;Gorelik J;Fenyö D;Rothenberg E;Rothenberg E;Delmar M
通讯作者：
Delmar M
DOI：
10.1161/circep.116.004400
发表时间：
2017-02
期刊：
Circulation. Arrhythmia and electrophysiology
影响因子：
--
作者：
Greer-Short A;George SA;Poelzing S;Weinberg SH
通讯作者：
Weinberg SH
影响因子：
4.8
作者：
Hong, Miyoun;Bao, Li;Coetzee, William A.
通讯作者：
Coetzee, William A.