Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome.
Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome.
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DOI：
10.1371/journal.pone.0077843
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Isom LL
中科院分区：
文献类型：
--
作者：
Auerbach DS;Jones J;Clawson BC;Offord J;Lenk GM;Ogiwara I;Yamakawa K;Meisler MH;Parent JM;Isom LL
Dravet综合征是一种严重形式的难治性小儿癫痫，具有高发生率的SUDEP：癫痫中的意外猝死。心律失常是某些SUDEP病例的可能原因，但Dravet综合征心律失常发生的易感性和潜在机制仍不清楚。大多数Dravet综合征患者在SCN 1A中具有新发突变，导致单倍不足。我们认为，除了神经元过度兴奋，SCN 1A单倍不足改变心脏电功能，并产生心律失常，提供了一个潜在的机制SUDEP。出生后第15-21天，表达人Dravet综合征突变的杂合SCN 1A-R1407 X基因敲入小鼠用于研究可能的心脏表型。进行单细胞电生理学和体内心电图（ECG）记录的组合。我们观察到2倍的增加，在孤立的Dravet综合征心室肌细胞的瞬时和持续的Na+电流密度，导致河豚毒素耐Na+电流的活性增加，可能Nav1.5。Dravet综合征心肌细胞表现出兴奋性增加，动作电位持续时间延长，触发活动。连续无线电遥测ECG记录显示QT间期延长、心室异位病灶、室性自主节律、搏动间变异性、心室颤动和局灶性心动过缓。在2只DS小鼠中记录到自发死亡，第三只小鼠濒死并需要人道处死。这些来自单细胞和整体动物实验的数据表明，Dravet综合征中心脏电功能的改变可能有助于对血栓形成和SUDEP的易感性。这些机械的见解可能会导致人类患者的关键风险评估和干预。
Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP. Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed. We observed a 2-fold increase in both transient and persistent Na+ current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na+ current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia. These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients.
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DOI：
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