Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death
Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death
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DOI：
10.1016/s0008-6363(00)00293-5
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发表时间：
2001-05-01
影响因子：
10.8
通讯作者：
Rudy, Y
中科院分区：
文献类型：
--
作者：
Clancy, CE;Rudy, Y
背景资料：HERG是心脏延迟整流I-Kr的快速激活成分的主要亚基，已发现HERG中的各种突变是先天性长QT综合征LQT 2的基础。LQT 2可能引起严重的致心律失常表型，导致心脏性猝死。目的：我们试图阐明异质性LQT 2基因型导致动作电位时程（APD）延长的机制，从而延长心电图上的QT间期。研究方法：我们开发了野生型（WT）和突变型I-Kr通道的马尔可夫模型，并将这些模型纳入到一个全面的模型的心脏心室细胞。结果如下：使用这个虚拟的转基因细胞模型，我们描述了HERG突变对心室动作电位（AP）的影响，并提供了深入了解的机制，每个缺陷导致复极电流的净损失和APD的延长。结论：这项研究证明了哪些突变可以延长APD足以产生早期后除极（埃兹），这可能会引发危及生命的心律失常。表型的严重程度取决于特定的动力学变化以及它们在动作电位的时间过程中如何影响I-Kr。阐明HERG缺陷如何导致细胞电生理学受损可以提高我们对通道结构和细胞功能之间联系的理解。(C)2001 Elsevier Science B. V.保留所有权利。
Background: A variety of mutations in HERG, the major subunit of the rapidly activating component of the cardiac delayed rectifier I-Kr, have been found to underlie the congenital Long-QT syndrome, LQT2. LQT2 may give rise to severe arrhythmogenic phenotypes leading to sudden cardiac death. Objective: We attempt to elucidate the mechanisms by which heterogeneous LQT2 genotypes can lead to prolongation of the action potential duration (APD) and consequently the QT interval on the EGG. Methods: We develop Markovian models of wild-type (WT) and mutant I-Kr channels and incorporate these models into a comprehensive model of the cardiac ventricular cell. Results: Using this virtual transgenic cell model, we describe the effects of HERG mutations on the cardiac ventricular action potential (AP) and provide insight into the mechanism by which each defect results in a net loss of repolarizing current and prolongation of APD. Conclusions: This study demonstrates which mutations can prolong APD sufficiently to generate early afterdepolarizations (EADs), which may trigger life-threatening arrhythmias. The severity of the phenotype is shown to depend on the specific kinetic changes and how they affect I-Kr during the time course of the action potential. Clarifying how defects in HERG can lead to impaired cellular electrophysiology can improve our understanding of the link between channel structure and cellular function. (C) 2001 Elsevier Science B.V. All rights reserved.