biostudies-literatureLi NAmerican Heart AssociationBritish Heart FoundationNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute512https://www.ebi.ac.uk/biostudies/studies/S-EPMC6981137biostudies-literatureUnknown11(1)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 I_Na 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.Nature communicationsImpaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node.PMC6981137F30 HL142179R01 HL135109R01 HL115580T32 HL134616RG/18/2/33392R01 HL114940115580 and 135109GRNT31010036Wu PJSharma RGyorke SZakharkin SJanssen PMDobrzynski HMohler PJFedorov VVLi NBiesiadecki BJAccornero FMokadam NAAbudulwahed SHWhitson BAHelfrich KMHummel JDKalyanasundaram AArtiga EJHansen BJRozenberg GZhao JfalseImpaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node.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 I_Na 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.2020-01-01T00:00:00Z2020 Jan2024-02-15T14:54:17.674Z2020-05-22T09:02:59ZS-EPMC69811373198060510.1038/s41467-019-14039-8