Tetrodotoxin-Sensitive Neuronal-Type Na+ Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation.
Tetrodotoxin-Sensitive Neuronal-Type Na+ Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation.
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河豚毒素敏感神经元型 Na 通道：预防心房颤动的新型药物靶点。
DOI：
10.1161/jaha.119.015119
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发表时间：
2020
影响因子：
5.4
通讯作者：
Veeraragh
中科院分区：
文献类型：
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作者：
Munger,MarkA;Olğar,Yusuf;Koleske,MeganL;Struckman,HeatherL;Mandrioli,Jessica;Lou,Qing;Bonila,Ingrid;Kim,Kibum;RamosMondragon,Roberto;Priori,SilviaG;Volpe,Pompeo;Valdivia,HéctorH;Biskupiak,Joseph;Carnes,CynthiaA;Veeraragh
心房颤动（AF）是心力衰竭和儿茶酚胺能多形性室性心动过速的合并症。尽管这两种病理都具有Ca 2+依赖性，但AF通常对Na+通道阻滞剂有反应。我们研究了如何针对相互依赖的Na+/Ca 2+失调可能会防止局灶性活动和控制AF。方法和结果我们研究了AF在2个模型的钙依赖性疾病，小鼠模型的儿茶酚胺能多形性室性心动过速和犬模型的慢性快速起搏诱导的心力衰竭。成像研究显示神经元型Na+通道（nNav）与兰尼碱受体和Na+/Ca 2+交换器密切相关。仅在nNavactivity的药理学增强期间，儿茶酚胺刺激诱导野生型小鼠的细胞和体内房性心律失常。相比之下，单独的儿茶酚胺刺激足以引起儿茶酚胺能多形性室性心动过速小鼠和犬心房衰竭的房性心律失常。重要的是，这些被废除急性nNavinhibition（河豚毒素或利鲁唑）牵连Na+/Ca 2+失调AF。这些研究结果进行了测试，然后在2个非随机回顾性队列：肌萎缩侧索硬化症诊所和学术医疗中心。阿曲唑治疗的患者调整基线特征证明心律失常的发生率显着降低，包括新发AF，支持preclinical results.ConclusionsThese data suggests，nNaVs介导Na+-Ca 2 +crosstalk内nanodomains含有Ca 2+释放机制，从而有助于AF触发。通过nNavinhibition破坏这一机制可以有效预防多种原因引起的AF。
BackgroundAtrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca2+‐dependent nature of both of these pathologies, AF often responds to Na+channel blockers. We investigated how targeting interdependent Na+/Ca2+dysregulation might prevent focal activity and control AF.Methods and ResultsWe studied AF in 2 models of Ca2+‐dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing‐induced heart failure. Imaging studies revealed close association of neuronal‐type Na+channels (nNav) with ryanodine receptors and Na+/Ca2+exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild‐type mice only during pharmacological augmentation of nNavactivity. In contrast, catecholamine stimulation alone was sufficient to elicit atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia mice and failing canine atria. Importantly, these were abolished by acute nNavinhibition (tetrodotoxin or riluzole) implicating Na+/Ca2+dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole‐treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new‐onset AF, supporting the preclinical results.ConclusionsThese data suggest that nNaVs mediate Na+‐Ca2+crosstalk within nanodomains containing Ca2+release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNavinhibition can effectively prevent AF arising from diverse causes.