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Neonatal Scn1b-null mice have sinoatrial node dysfunction, altered atrial structure, and atrial fibrillation
Roberto Ramos-Mondragon, … , Luis F. Lopez-Santiago, Lori L. Isom
Roberto Ramos-Mondragon, … , Luis F. Lopez-Santiago, Lori L. Isom
Published May 23, 2022
Citation Information: JCI Insight. 2022;7(10):e152050. https://doi.org/10.1172/jci.insight.152050.
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Research Article Cardiology

Neonatal Scn1b-null mice have sinoatrial node dysfunction, altered atrial structure, and atrial fibrillation

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Abstract

Loss-of-function (LOF) variants in SCN1B, encoding the voltage-gated sodium channel β1/β1B subunits, are linked to neurological and cardiovascular diseases. Scn1b-null mice have spontaneous seizures and ventricular arrhythmias and die by approximately 21 days after birth. β1/β1B Subunits play critical roles in regulating the excitability of ventricular cardiomyocytes and maintaining ventricular rhythmicity. However, whether they also regulate atrial excitability is unknown. We used neonatal Scn1b-null mice to model the effects of SCN1B LOF on atrial physiology in pediatric patients. Scn1b deletion resulted in altered expression of genes associated with atrial dysfunction. Scn1b-null hearts had a significant accumulation of atrial collagen, increased susceptibility to pacing induced atrial fibrillation (AF), sinoatrial node (SAN) dysfunction, and increased numbers of cholinergic neurons in ganglia that innervate the SAN. Atropine reduced the incidence of AF in null animals. Action potential duration was prolonged in null atrial myocytes, with increased late sodium current density and reduced L-type calcium current density. Scn1b LOF results in altered atrial structure and AF, demonstrating the critical role played by Scn1b in atrial physiology during early postnatal mouse development. Our results suggest that SCN1B LOF variants may significantly impact the developing pediatric heart.

Authors

Roberto Ramos-Mondragon, Nnamdi Edokobi, Samantha L. Hodges, Shuyun Wang, Alexandra A. Bouza, Chandrika Canugovi, Caroline Scheuing, Lena Juratli, William R. Abel, Sami F. Noujaim, Nageswara R. Madamanchi, Marschall S. Runge, Luis F. Lopez-Santiago, Lori L. Isom

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Figure 3

Neonatal Scn1b-null mice have increased susceptibility to AF in vivo.

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Neonatal Scn1b-null mice have increased susceptibility to AF in vivo.
(A...
(A) Representative recordings of surface ECGs (top) and atrial electrograms (bottom) from P16 WT or Scn1b-null mice. Atrial burst pacing was delivered at 50 Hz for 2 seconds. A period of AF in the null mouse is indicated in red. (B) AF incidence under basal and vagotonic stimulation. AF testing was performed before and after i.p. administration of carbachol (Cch) (0.025 mg/kg). (C) Durations of basal and induced AF episodes in the mice shown in B. Each dot represents a single episode. Mean values are indicated by the bar. (D) Incidence of AF in the null mice before (red) and after i.p. administration of atropine (blue, 1 mg/kg). (E) Incidence of AF in the null mice before and after i.p. administration of atropine (1 mg/kg). Numbers of animals tested are shown in the bar graphs. *P < 0.05 using Fisher’s exact test.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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