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 (nNa_v) 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 nNa_v activity. 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 nNa_v inhibition (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 nNa_Vs mediate Na⁺‐Ca²⁺ crosstalk within nanodomains containing Ca²⁺ release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa_v inhibition can effectively prevent AF arising from diverse causes.

中文翻译：

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河豚毒素敏感的神经元型 Na+ 通道：预防心房颤动的新型药物靶点。

背景房颤 (AF) 是一种与心力衰竭和儿茶酚胺能多形性室性心动过速相关的合并症。尽管这两种病理都具有Ca ²⁺依赖性，但 AF 经常对 Na ⁺通道阻滞剂有反应。我们研究了如何针对相互依赖的Na ⁺ /钙²⁺失调可能会阻止焦点活动和控制AF.Methods和ResultsWe研究AF 2种机型的Ca ²⁺依赖性疾病，儿茶酚胺多形性室性心动过速的小鼠模型和慢性犬模型快速起搏引起的心力衰竭。影像学研究揭示了神经元型 Na ⁺通道 (nNa _v) 与兰尼碱受体和 Na ⁺ /Ca ²⁺交换器。儿茶酚胺刺激仅在 nNa _v活性的药理学增强期间在野生型小鼠中诱导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，这些被涉及 Na ⁺ /Ca ^{2+ 的}急性 nNa _v抑制（河豚毒素或利鲁唑）消除了AF 失调。然后在 2 个非随机回顾性队列中测试了这些发现：肌萎缩侧索硬化诊所和学术医疗中心。校正基线特征利鲁唑治疗的患者证明心律失常包括新发AF的显著发生率较低，支持临床前results.ConclusionsThese数据表明NNA _V小号居间的Na ⁺ -Ca ²⁺含有Ca纳米畴内的串扰²⁺释放机械，因此，有助于 AF 触发。通过 nNa _v抑制破坏这种机制可以有效防止多种原因引起的 AF。