Mechanisms for human sinoatrial node (SAN) dysfunction are poorly understood and whether human SAN excitability requires voltage-gated sodium channels (Nav) remains controversial. Here, we report that neuronal (n)Nav blockade and selective nNav1.6 blockade during high-resolution optical mapping in explanted human hearts depress intranodal SAN conduction, which worsens during autonomic stimulation and overdrive suppression to conduction failure. Partial cardiac (c)Nav blockade further impairs automaticity and intranodal conduction, leading to beat-to-beat variability and reentry. Multiple nNav transcripts are higher in SAN vs atria; heterogeneous alterations of several isoforms, specifically nNav1.6, are associated with heart failure and chronic alcohol consumption. In silico simulations of Nav distributions suggest that INa is essential for SAN conduction, especially in fibrotic failing hearts. Our results reveal that not only cNav but nNav are also integral for preventing disease-induced failure in human SAN intranodal conduction. Disease-impaired nNav may underlie patient-specific SAN dysfunctions and should be considered to treat arrhythmias.

中文翻译：

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神经元钠通道受损会导致人鼻窦结节内传导衰竭和折返性心律不齐。

人们对人类窦房结（SAN）功能障碍的机制了解甚少，并且人类SAN兴奋性是否需要电压门控钠通道（Nav）仍存在争议。在这里，我们报告在人类心脏的高分辨率光学映射过程中，神经元（n）Nav阻滞和选择性nNav1.6阻滞抑制结节内SAN传导，这在自主神经刺激和对传导衰竭的超速抑制期间会恶化。部分心脏（c）Nav阻滞进一步损害了自律性和结内传导，导致心跳间的变异性和折返。SAN与atria相比，多个nNav转录本更高。几种同工型，特别是nNav1.6的异质性改变与心力衰竭和慢性饮酒有关。Nav分布的计算机模拟表明，INA对于SAN传导至关重要，特别是在纤维化的心脏衰竭中。我们的研究结果表明，不仅cNav而且nNav还是预防人SAN结内传导疾病引起的衰竭所不可或缺的。疾病受损的nNav可能是患者特定的SAN功能障碍的基础，应考虑治疗心律不齐。