Inhibition of Late Sodium Current by Mexiletine: A Novel Pharmotherapeutical Approach in Timothy Syndrome
Inhibition of Late Sodium Current by Mexiletine: A Novel Pharmotherapeutical Approach in Timothy Syndrome
复制标题
美西律抑制晚钠电流：蒂莫西综合征的一种新的药物治疗方法
DOI：
10.1161/circep.113.000092
复制
发表时间：
2013-06-01
影响因子：
8.4
通讯作者：
Yan, Gan-Xin
中科院分区：
文献类型：
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作者：
Gao, Yuanfeng;Xue, Xiaolin;Yan, Gan-Xin
蒂莫西综合征（Timothy syndrome，TS）是一种罕见的长QT综合征，由CACNA 1C基因外显子8A（TS 1）G406 R和外显子8（TS 2）G402 S/G406 R突变引起。TS的管理是一个挑战，预后很差。本研究旨在探讨遗传模式和机制的I-Na阻滞剂，美西律，以改善TS的临床表现。方法和结果一个2岁的中国女孩与一个典型的TS 1表型进行了候选基因筛选。对家系成员进行定性和定量克隆测序及嵌合体分析。采用心电图和动态霍尔特监测评价美西律的疗效。采用兔心室楔形组织建立TS模型，评价美西律的电生理效应。先证者有严重的并指畸形和语言能力延迟，被确定为CACNA 1C中的G406 R突变。她的基线ECG显示QTc明显延长、2：1房室传导阻滞和大T波交替。G406 R在其母亲中不存在，但在其父亲的口腔粘膜、精子和白色血细胞中表达，表明为嵌合体携带者。尽管无症状，但患者表现出轻度QTc间期延长（470-490 ms）和并指。美西律使女孩的QTc由584缩短至515 ms，QT-RR关系变钝，2：1房室传导阻滞和T波电交替消失。在BayK 8644诱导的TS模型中，美西律可抑制迟发性I Na，IC 50为17.6 ± 1.9 μ mol/L，并可缩短QT间期，降低QT-RR斜率。结论美西律可通过抑制迟发性I Na，缩短TS 1患者和TS模型的QTc，降低QT-RR斜率，消除2：1房室传导阻滞和T波电交替。
BackgroundTimothy syndrome (TS) is a rare long-QT syndrome caused by CACNA1C mutations G406R in exon 8A (TS1) and G402S/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an I-Na blocker, mexiletine, to improve clinical manifestations in TS.Methods and ResultsA 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening. Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in CACNA1C. Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father's oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470-490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT-RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late I-Na with IC50 of 17.6 +/- 1.9 mu mol/L and attenuated brady-dependent QT prolongation and reduced QT-RR slope in the TS model using BayK 8644.ConclusionsMexiletine shortened QTc, attenuated QT-RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late I-Na.