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Tetrodotoxin-Sensitive Neuronal-Type Na+ Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation.
Munger, Mark A; Olgar, 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; Radwanski, Przemyslaw B.
Afiliação
  • Munger MA; Departments of Pharmacotherapy and Internal Medicine University of Utah Health Sciences Center Salt Lake City UT.
  • Olgar Y; Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH.
  • Koleske ML; Division of Pharmacy Practice and Sciences College of Pharmacy The Ohio State University Columbus OH.
  • Struckman HL; Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH.
  • Mandrioli J; Division of Pharmacy Practice and Sciences College of Pharmacy The Ohio State University Columbus OH.
  • Lou Q; Department of Biomedical Engineering College of Engineering The Ohio State University Columbus OH.
  • Bonila I; Department of Neuroscience St. Agostino Estense Hospital Azienda Ospedaliero Universitaria di Modena Italy.
  • Kim K; Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH.
  • Ramos Mondragon R; Department of Physiology and Cell Biology College of Medicine The Ohio State University Columbus OH.
  • Priori SG; Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH.
  • Volpe P; Department of Physiology and Cell Biology College of Medicine The Ohio State University Columbus OH.
  • Valdivia HH; Department of Pharmacotherapy University of Utah Health Sciences Center Salt Lake City UT.
  • Biskupiak J; Department of Internal Medicine and of Molecular & Integrative Physiology University of Michigan Ann Arbor MI.
  • Carnes CA; Molecular Cardiology Istituti Clinici Scientifici Maugeri IRCCS University of Pavia Italy.
  • Veeraraghavan R; Department of Molecular Medicine University of Pavia Italy.
  • Györke S; Department of Biomedical Sciences University of Padova Italy.
  • Radwanski PB; Department of Internal Medicine and of Molecular & Integrative Physiology University of Michigan Ann Arbor MI.
J Am Heart Assoc ; 9(11): e015119, 2020 06 02.
Article em En | MEDLINE | ID: mdl-32468902
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.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 1_ASSA2030 Base de dados: MEDLINE Assunto principal: Fibrilação Atrial / Tetrodotoxina / Canais de Sódio / Taquicardia Ventricular / Riluzol / Bloqueadores dos Canais de Sódio / Insuficiência Cardíaca / Frequência Cardíaca / Antiarrítmicos Tipo de estudo: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Animals / Female / Humans / Male / Middle aged País/Região como assunto: America do norte / Europa Idioma: En Revista: J Am Heart Assoc Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 1_ASSA2030 Base de dados: MEDLINE Assunto principal: Fibrilação Atrial / Tetrodotoxina / Canais de Sódio / Taquicardia Ventricular / Riluzol / Bloqueadores dos Canais de Sódio / Insuficiência Cardíaca / Frequência Cardíaca / Antiarrítmicos Tipo de estudo: Diagnostic_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Animals / Female / Humans / Male / Middle aged País/Região como assunto: America do norte / Europa Idioma: En Revista: J Am Heart Assoc Ano de publicação: 2020 Tipo de documento: Article