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

Research output: Contribution to journalArticle

Authors

  • Ning Li
  • Brian J. Hansen
  • Esthela J. Artiga
  • Roshan Sharma
  • Suhaib H. Abudulwahed
  • Katelynn M. Helfrich
  • Galina Rozenberg
  • Pei Jung Wu
  • Stanislav Zakharkin
  • Sandor Gyorke
  • Bryan A. Whitson
  • Nahush A. Mokadam
  • Brandon J. Biesiadecki
  • John D. Hummel
  • Halina Dobrzynski
  • Jichao Zhao

External Institution(s)

  • Ohio State University
  • Auckland Bioengineering Institute, University of Auckland
  • University of Manchester
  • Jagiellonian University Medical College

Details

Original languageEnglish (US)
Article number512
JournalNature communications
Volume11
Issue number1
StatusPublished - Dec 1 2020
Peer-reviewedYes

Abstract

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.

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Li, N, Kalyanasundaram, A, Hansen, BJ, Artiga, EJ, Sharma, R, Abudulwahed, SH, Helfrich, KM, Rozenberg, G, Wu, PJ, Zakharkin, S, Gyorke, S, Janssen, PM, Whitson, BA, Mokadam, NA, Biesiadecki, BJ, Accornero, F, Hummel, JD, Mohler, PJ, Dobrzynski, H, Zhao, J & Fedorov, VV 2020, 'Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node', Nature communications, vol. 11, no. 1, 512. https://doi.org/10.1038/s41467-019-14039-8