{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:48:42Z","timestamp":1790189322020,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2020,6,2]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca\n              <jats:sup>2+<\/jats:sup>\n              \u2010dependent nature of both of these pathologies, AF often responds to Na\n              <jats:sup>+<\/jats:sup>\n              channel blockers. We investigated how targeting interdependent Na\n              <jats:sup>+<\/jats:sup>\n              \/Ca\n              <jats:sup>2+<\/jats:sup>\n              dysregulation might prevent focal activity and control AF.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We studied AF in 2 models of Ca\n              <jats:sup>2+<\/jats:sup>\n              \u2010dependent disorders, a murine model of catecholaminergic polymorphic ventricular tachycardia and a canine model of chronic tachypacing\u2010induced heart failure. Imaging studies revealed close association of neuronal\u2010type Na\n              <jats:sup>+<\/jats:sup>\n              channels (nNa\n              <jats:sub>v<\/jats:sub>\n              ) with ryanodine receptors and Na\n              <jats:sup>+<\/jats:sup>\n              \/Ca\n              <jats:sup>2+<\/jats:sup>\n              exchanger. Catecholamine stimulation induced cellular and in vivo atrial arrhythmias in wild\u2010type mice only during pharmacological augmentation of nNa\n              <jats:sub>v<\/jats:sub>\n              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\n              <jats:sub>v<\/jats:sub>\n              inhibition (tetrodotoxin or riluzole) implicating Na\n              <jats:sup>+<\/jats:sup>\n              \/Ca\n              <jats:sup>2+<\/jats:sup>\n              dysregulation in AF. These findings were then tested in 2 nonrandomized retrospective cohorts: an amyotrophic lateral sclerosis clinic and an academic medical center. Riluzole\u2010treated patients adjusted for baseline characteristics evidenced significantly lower incidence of arrhythmias including new\u2010onset AF, supporting the preclinical results.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              These data suggest that nNa\n              <jats:sub>V<\/jats:sub>\n              s mediate Na\n              <jats:sup>+<\/jats:sup>\n              \u2010Ca\n              <jats:sup>2+<\/jats:sup>\n              crosstalk within nanodomains containing Ca\n              <jats:sup>2+<\/jats:sup>\n              release machinery and, thereby, contribute to AF triggers. Disruption of this mechanism by nNa\n              <jats:sub>v<\/jats:sub>\n              inhibition can effectively prevent AF arising from diverse causes.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.119.015119","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T09:24:13Z","timestamp":1590744253000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Tetrodotoxin\u2010Sensitive Neuronal\u2010Type Na\n            <sup>+<\/sup>\n            Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation"],"prefix":"10.1161","volume":"9","author":[{"given":"Mark A.","family":"Munger","sequence":"first","affiliation":[{"name":"Departments of Pharmacotherapy and Internal Medicine University of Utah Health Sciences Center Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuf","family":"Ol\u011far","sequence":"additional","affiliation":[{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH"},{"name":"Division of Pharmacy Practice and Sciences College of Pharmacy The Ohio State University Columbus OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L.","family":"Koleske","sequence":"additional","affiliation":[{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH"},{"name":"Division of Pharmacy Practice and Sciences College of Pharmacy The Ohio State University Columbus OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Struckman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering College of Engineering The Ohio State University Columbus OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Mandrioli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience St. Agostino Estense Hospital Azienda Ospedaliero Universitaria di Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lou","sequence":"additional","affiliation":[{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH"},{"name":"Department of Physiology and Cell Biology College of Medicine The Ohio State University Columbus OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Bonila","sequence":"additional","affiliation":[{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH"},{"name":"Department of Physiology and Cell Biology College of Medicine The Ohio State University Columbus OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kibum","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy University of Utah Health Sciences Center Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Ramos Mondragon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and of Molecular &amp; Integrative Physiology University of Michigan Ann Arbor MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia G.","family":"Priori","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Istituti Clinici Scientifici Maugeri IRCCS University of Pavia Italy"},{"name":"Department of Molecular Medicine University of Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pompeo","family":"Volpe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor H.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and of Molecular &amp; Integrative Physiology University of Michigan Ann Arbor MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Biskupiak","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy University of Utah Health Sciences Center Salt Lake City UT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Carnes","sequence":"additional","affiliation":[{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH"},{"name":"Division of Pharmacy Practice and Sciences College of Pharmacy The Ohio State University Columbus OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rengasayee","family":"Veeraraghavan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering College of Engineering The Ohio State University Columbus OH"},{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University Wexner Medical Center Columbus OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e1ndor","family":"Gy\u00f6rke","sequence":"additional","affiliation":[{"name":"Dorothy M. 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