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Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation

BACKGROUND: Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca(2+)‐dependent nature of both of these pathologies, AF often responds to Na(+) channel blockers. We investigated how targeting interdependent N...

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Autores principales: Munger, Mark A., Olğar, Yusuf, Koleske, Megan L., Struckman, Heather L., Mandrioli, Jessica, Lou, Qing, Bonila, Ingrid, Kim, Kibum, Ramos Mondragon, Roberto, Priori, Silvia G., Volpe, Pompeo, Valdivia, Héctor H., Biskupiak, Joseph, Carnes, Cynthia A., Veeraraghavan, Rengasayee, Györke, Sándor, Radwański, Przemysław B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429002/
https://www.ncbi.nlm.nih.gov/pubmed/32468902
http://dx.doi.org/10.1161/JAHA.119.015119
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author Munger, Mark A.
Olğar, Yusuf
Koleske, Megan L.
Struckman, Heather L.
Mandrioli, Jessica
Lou, Qing
Bonila, Ingrid
Kim, Kibum
Ramos Mondragon, Roberto
Priori, Silvia G.
Volpe, Pompeo
Valdivia, Héctor H.
Biskupiak, Joseph
Carnes, Cynthia A.
Veeraraghavan, Rengasayee
Györke, Sándor
Radwański, Przemysław B.
author_facet Munger, Mark A.
Olğar, Yusuf
Koleske, Megan L.
Struckman, Heather L.
Mandrioli, Jessica
Lou, Qing
Bonila, Ingrid
Kim, Kibum
Ramos Mondragon, Roberto
Priori, Silvia G.
Volpe, Pompeo
Valdivia, Héctor H.
Biskupiak, Joseph
Carnes, Cynthia A.
Veeraraghavan, Rengasayee
Györke, Sándor
Radwański, Przemysław B.
author_sort Munger, Mark A.
collection PubMed
description BACKGROUND: Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca(2+)‐dependent nature of both of these pathologies, AF often responds to Na(+) channel blockers. We investigated how targeting interdependent Na(+)/Ca(2+) dysregulation might prevent focal activity and control AF. METHODS AND RESULTS: We studied AF in 2 models of Ca(2+)‐dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing‐induced heart failure. Imaging studies revealed close association of neuronal‐type Na(+) channels (nNa(v)) with ryanodine receptors and Na(+)/Ca(2+) exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild‐type mice only during pharmacological augmentation of nNa(v) activity. In contrast, catecholamine stimulation alone was sufficient to elicit atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia mice and failing canine atria. Importantly, these were abolished by acute nNa(v) inhibition (tetrodotoxin or riluzole) implicating Na(+)/Ca(2+) dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole‐treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new‐onset AF, supporting the preclinical results. CONCLUSIONS: These data suggest that nNa(V)s mediate Na(+)‐Ca(2+) crosstalk within nanodomains containing Ca(2+) release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa(v) inhibition can effectively prevent AF arising from diverse causes.
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spelling pubmed-74290022020-08-18 Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation Munger, Mark A. Olğar, Yusuf Koleske, Megan L. Struckman, Heather L. Mandrioli, Jessica Lou, Qing Bonila, Ingrid Kim, Kibum Ramos Mondragon, Roberto Priori, Silvia G. Volpe, Pompeo Valdivia, Héctor H. Biskupiak, Joseph Carnes, Cynthia A. Veeraraghavan, Rengasayee Györke, Sándor Radwański, Przemysław B. J Am Heart Assoc Original Research BACKGROUND: Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca(2+)‐dependent nature of both of these pathologies, AF often responds to Na(+) channel blockers. We investigated how targeting interdependent Na(+)/Ca(2+) dysregulation might prevent focal activity and control AF. METHODS AND RESULTS: We studied AF in 2 models of Ca(2+)‐dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing‐induced heart failure. Imaging studies revealed close association of neuronal‐type Na(+) channels (nNa(v)) with ryanodine receptors and Na(+)/Ca(2+) exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild‐type mice only during pharmacological augmentation of nNa(v) activity. In contrast, catecholamine stimulation alone was sufficient to elicit atrial arrhythmias in catecholaminergic polymorphic ventricular tachycardia mice and failing canine atria. Importantly, these were abolished by acute nNa(v) inhibition (tetrodotoxin or riluzole) implicating Na(+)/Ca(2+) dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole‐treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new‐onset AF, supporting the preclinical results. CONCLUSIONS: These data suggest that nNa(V)s mediate Na(+)‐Ca(2+) crosstalk within nanodomains containing Ca(2+) release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa(v) inhibition can effectively prevent AF arising from diverse causes. John Wiley and Sons Inc. 2020-06-15 /pmc/articles/PMC7429002/ /pubmed/32468902 http://dx.doi.org/10.1161/JAHA.119.015119 Text en © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Munger, Mark A.
Olğar, Yusuf
Koleske, Megan L.
Struckman, Heather L.
Mandrioli, Jessica
Lou, Qing
Bonila, Ingrid
Kim, Kibum
Ramos Mondragon, Roberto
Priori, Silvia G.
Volpe, Pompeo
Valdivia, Héctor H.
Biskupiak, Joseph
Carnes, Cynthia A.
Veeraraghavan, Rengasayee
Györke, Sándor
Radwański, Przemysław B.
Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation
title Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation
title_full Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation
title_fullStr Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation
title_full_unstemmed Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation
title_short Tetrodotoxin‐Sensitive Neuronal‐Type Na(+) Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation
title_sort tetrodotoxin‐sensitive neuronal‐type na(+) channels: a novel and druggable target for prevention of atrial fibrillation
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429002/
https://www.ncbi.nlm.nih.gov/pubmed/32468902
http://dx.doi.org/10.1161/JAHA.119.015119
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