Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node

Ning Li, Anuradha Kalyanasundaram, Brian J Hansen, Esthela J Artiga, Roshan Sharma, Suhaib H Abudulwahed, Katelynn M Helfrich, Galina Rozenberg, Pei-Jung Wu, Stanislav Zakharkin, Sandor Gyorke, Paul Janssen, Bryan A Whitson, Nahush A Mokadam, Brandon J Biesiadecki, Federica Accornero, John D Hummel, Jichao Jichao Zhao, Peter J Mohler, Halina DobrzynskiVadim V Fedorov

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Article number512
Pages (from-to)512
JournalNature Communications
Issue number1
Publication statusPublished - 24 Jan 2020


  • Action Potentials/physiology
  • Adult
  • Aged
  • Alcoholism/genetics
  • Arrhythmias, Cardiac/genetics
  • Chronic Disease
  • Computer Simulation
  • Female
  • Heart Atria/metabolism
  • Heart Conduction System/metabolism
  • Heart Failure/genetics
  • Humans
  • Male
  • Middle Aged
  • Models, Cardiovascular
  • Neurons/metabolism
  • Optical Imaging
  • Protein Subunits/metabolism
  • RNA, Messenger/genetics
  • Sinoatrial Node/metabolism
  • Sodium Channels/genetics
  • Stress, Physiological
  • Young Adult


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