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 ML. Janssen, Bryan A. Whitson, Nahush A. Mokadam, Brandon J. Biesiadecki, Federica Accornero, John D. Hummel, Peter J. Mohler, Halina Dobrzynski, Jichao Zhao and Vadim V. Fedorov ()
Additional contact information
Ning Li: The Ohio State University Wexner Medical Center
Anuradha Kalyanasundaram: The Ohio State University Wexner Medical Center
Brian J. Hansen: The Ohio State University Wexner Medical Center
Esthela J. Artiga: The Ohio State University Wexner Medical Center
Roshan Sharma: The University of Auckland
Suhaib H. Abudulwahed: The Ohio State University Wexner Medical Center
Katelynn M. Helfrich: The Ohio State University Wexner Medical Center
Galina Rozenberg: The Ohio State University Wexner Medical Center
Pei-Jung Wu: The Ohio State University Wexner Medical Center
Stanislav Zakharkin: The Ohio State University Wexner Medical Center
Sandor Gyorke: The Ohio State University Wexner Medical Center
Paul ML. Janssen: The Ohio State University Wexner Medical Center
Bryan A. Whitson: The Ohio State University Wexner Medical Center
Nahush A. Mokadam: The Ohio State University Wexner Medical Center
Brandon J. Biesiadecki: The Ohio State University Wexner Medical Center
Federica Accornero: The Ohio State University Wexner Medical Center
John D. Hummel: The Ohio State University Wexner Medical Center
Peter J. Mohler: The Ohio State University Wexner Medical Center
Halina Dobrzynski: The University of Manchester
Jichao Zhao: The University of Auckland
Vadim V. Fedorov: The Ohio State University Wexner Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14039-8

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