Tetrodotoxin-Sensitive Neuronal-Type Na+ Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation.

Abstract

Background Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca2+-dependent nature of both of these pathologies, AF often responds to Na+ channel blockers. We investigated how targeting interdependent Na+/Ca2+ dysregulation might prevent focal activity and control AF. Methods and Results We studied AF in 2 models of Ca2+-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 (nNav) with ryanodine receptors and Na+/Ca2+ exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild-type mice only during pharmacological augmentation of nNav 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 nNav inhibition (tetrodotoxin or riluzole) implicating Na+/Ca2+ 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 nNaVs mediate Na+-Ca2+ crosstalk within nanodomains containing Ca2+ release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNav inhibition can effectively prevent AF arising from diverse causes.

• Authors: Mark A Munger, Yusuf Olğar, Megan L Koleske, Heather L Struckman, Jessica Mandrioli, Qing Lou, Ingrid Bonila, Kibum Kim, Roberto Ramos Mondragon, Silvia G Priori, Pompeo Volpe, Héctor H Valdivia, Joseph Biskupiak, Cynthia A Carnes, Rengasayee Veeraraghavan, Sándor Györke, Przemysław B Radwański
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 9 Issue 11 Pg. e015119 (06 02 2020) ISSN: 2047-9980 [Electronic] England
• PMID: 32468902 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Catecholamines
• Ryanodine Receptor Calcium Release Channel
• Sodium Channel Blockers
• Sodium Channels
• Sodium-Calcium Exchanger
• Tetrodotoxin
• Riluzole

Topics

• Adult
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Atrial Fibrillation (metabolism, physiopathology, prevention & control)
• Calcium Signaling (drug effects)
• Cardiac Pacing, Artificial
• Catecholamines
• Disease Models, Animal
• Dogs
• Female
• Heart Failure (drug therapy, metabolism, physiopathology)
• Heart Rate (drug effects)
• Humans
• Italy
• Male
• Membrane Potentials (drug effects)
• Mice, Inbred C57BL
• Middle Aged
• Retrospective Studies
• Riluzole (pharmacology)
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sodium Channel Blockers (pharmacology)
• Sodium Channels (drug effects, metabolism)
• Sodium-Calcium Exchanger (metabolism)
• Tachycardia, Ventricular (drug therapy, metabolism, physiopathology)
• Tetrodotoxin (pharmacology)
• Utah