Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation.
Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation.
复制标题
计算心脏模型揭示 8 型长 QT 综合征的室性心律失常发生机制：CACNA1C R858H 突变与心室颤动相关
DOI：
10.3389/fphys.2017.00771
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发表时间：
2017
影响因子：
4
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Bai J;Wang K;Liu Y;Li Y;Liang C;Luo G;Dong S;Yuan Y;Zhang H
L型钙通道的功能分析表明，与严重QT间期延长相关的CACNA 1C R858 H突变可能导致心室颤动（VF）。这项研究调查了CACNA 1C R858 H突变促进和维持VF的多种潜在机制。将10个Tusscher-Panfilov（TP 06）人心室细胞模型整合到一维（1D）纤维、2D片层和3D心室模型中，通过定量细胞内钙处理、动作电位曲线、动作电位时程恢复（APDR）曲线、复极离散度（DOR）、QT间期和螺旋波动力学。R858 H“突变体”L型钙电流（ICaL）增加肌浆网钙含量，导致单细胞水平的后去极化和组织水平的局灶性活动。它还产生不均匀的APD延长，导致QT延长和复极离散放大，使R858 H“突变”组织与其他条件相比更容易诱导折返。总之，由于CACNA 1C R858 H突变导致的ICaL改变增加了后去极化导致的心律失常风险，并增加了组织对单向传导阻滞的脆弱性。然而，观察到的再入是由于后去极化（不存在于我们的模型），而是一种新的阻断机制。
Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF). This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF. The Ten Tusscher-Panfilov (TP06) human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D) fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR) curves, dispersion of repolarization (DOR), QT interval and spiral wave dynamics. R858H “mutant” L-type calcium current (ICaL) augmented sarcoplasmic reticulum calcium content, leading to the development of afterdepolarizations at the single cell level and focal activities at the tissue level. It also produced inhomogeneous APD prolongation, causing QT prolongation and repolarization dispersion amplification, rendering R858H “mutant” tissue more vulnerable to the induction of reentry compared with other conditions. In conclusion, altered ICaL due to the CACNA1C R858H mutation increases arrhythmia risk due to afterdepolarizations and increased tissue vulnerability to unidirectional conduction block. However, the observed reentry is not due to afterdepolarizations (not present in our model), but rather to a novel blocking mechanism.
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DOI：
10.1161/circgenetics.113.000138
发表时间：
2013-06
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Boczek NJ;Best JM;Tester DJ;Giudicessi JR;Middha S;Evans JM;Kamp TJ;Ackerman MJ
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4.8
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3.7
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DOI：
10.1152/ajpheart.00648.2005
发表时间：
2006-01-01
影响因子：
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