背景:癫痫突然意外死亡(SUDEP)是健康的癫痫患者所经历的致命并发症。Dravet综合征(DS)是由于电压门控钠通道功能丧失而导致的遗传性癫痫,NaV1.1,并与特别高的SUDEP风险相关。越来越多的证据表明,大脑中丰富的Navs也发生在心脏中,提示癫痫潜在的分子机制也可能导致心律失常和猝死。尽管在DS中NaV1.1功能性表达显著减少,致病性晚期钠电流(INa,L)在DS心脏中矛盾地增加。然而,DS直接影响心脏促进猝死的机制尚不清楚.
目的:在这项研究中,作者试图提供有关Na和Ca2处理机械重塑的证据,在DS相关的心律失常中,包括横向(T)小管内的NaV1.6和Na/Ca2交换剂(NCX)。
方法:作者进行了扫描离子电导显微镜(SICM)引导的膜片钳,超分辨率显微镜,共聚焦Ca2+成像,和Scn1a单倍体不足的DS小鼠模型的体内心电图研究。
结果:DS促进了INa,L在T管纳米域中,但不是在其他亚细胞区域。与这些地区NaV活性增加一致,超分辨率显微镜显示Ca2+释放通道附近的NaV1.6密度增加,相对于WT心脏,DS中的ryanodine受体(RyR2)和NCX。由此产生的INA,这些区域中的L促进了异常的Ca2+释放,导致体内室性心律失常。NaV1.6的心脏特异性缺失可保护成年DS小鼠免受T肾小管晚期NaV活性增加和导致的心律失常的影响,以及突然死亡。
结论:这些数据表明,NaV1.6在成年DS心脏的T小管内进行重塑,作为Ca2介导的心律失常的底物,并且可能是预防成人DS受试者SUDEP的药物靶标。
BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaVs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of NaV 1.1 functional expression in DS, pathogenic late sodium current (INa,L) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear.
OBJECTIVE: In this study, the authors sought to provide evidence implicating remodeling of Na+ - and Ca2+ -handling machinery, including NaV 1.6 and Na+/Ca2+exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias.
METHODS: The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca2+ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS.
RESULTS: DS promotes INa,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased NaV activity in these regions, super-resolution microscopy revealed increased NaV 1.6 density near Ca2+release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting INa,L in these regions promoted aberrant Ca2+ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of NaV 1.6 protects adult DS mice from increased T-tubular late NaV activity and the resulting arrhythmias, as well as sudden death.
CONCLUSIONS: These data demonstrate that NaV 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca2+ -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.