TY - JOUR
T1 - Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node
AU - Li, Ning
AU - Kalyanasundaram, Anuradha
AU - Hansen, Brian J
AU - Artiga, Esthela J
AU - Sharma, Roshan
AU - Abudulwahed, Suhaib H
AU - Helfrich, Katelynn M
AU - Rozenberg, Galina
AU - Wu, Pei-Jung
AU - Zakharkin, Stanislav
AU - Gyorke, Sandor
AU - Janssen, Paul
AU - Whitson, Bryan A
AU - Mokadam, Nahush A
AU - Biesiadecki, Brandon J
AU - Accornero, Federica
AU - Hummel, John D
AU - Jichao Zhao, Jichao
AU - Mohler, Peter J
AU - Dobrzynski, Halina
AU - Fedorov, Vadim V
N1 - Funding Information:
This work was supported by NIH HL115580 and HL135109, American Heart Association Grant in Aid #16GRNT31010036 (V.V.F.), NIH T32HL134616, NIH F30HL142179 (B.J.H.), HL114940 (B.J.B.), and by funding from the Dorothy M. Davis Heart and Lung Research Institute. We thank the Lifeline of Ohio Organ Procurement Organization and the Division of Cardiac Surgery at The OSU Wexner Medical Center for providing the explanted hearts. We thank Mr Farbod Fazlollahi, Ms Salome Kiduko, and Ms Kyra Peczkowski for their help with tissue processing.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1/24
Y1 - 2020/1/24
N2 - 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.
AB - 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.
KW - Action Potentials/physiology
KW - Adult
KW - Aged
KW - Alcoholism/genetics
KW - Arrhythmias, Cardiac/genetics
KW - Chronic Disease
KW - Computer Simulation
KW - Female
KW - Heart Atria/metabolism
KW - Heart Conduction System/metabolism
KW - Heart Failure/genetics
KW - Humans
KW - Male
KW - Middle Aged
KW - Models, Cardiovascular
KW - Neurons/metabolism
KW - Optical Imaging
KW - Protein Subunits/metabolism
KW - RNA, Messenger/genetics
KW - Sinoatrial Node/metabolism
KW - Sodium Channels/genetics
KW - Stress, Physiological
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=85078277462&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-14039-8
DO - 10.1038/s41467-019-14039-8
M3 - Article
C2 - 31980605
SN - 2041-1723
VL - 11
SP - 512
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 512
ER -