title: Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release.
abstract: OBJECTIVE
  Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study.
  
  
  RESULTS
  We performed optical Ca2+ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) colocalize with ryanodine receptor Ca2+ release channels (RyR2). Disruption of the crosstalk between nNav and RyR2 by nNav blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice.
  
  
  CONCLUSIONS
  Thus, our study offers the first evidence that nNav contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus, OH, USA sandor.gyorke@osumc.edu przemyslaw.radwanski@osumc.edu.
authors.forename: Przemysław B
authors.initials: PB
authors.lastname: Radwański
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Brunello
authors.affiliation: VTC Research Institute, School of Biomedical Engineering and Sciences, Virginia Tech, Roanoke, VA, USA.
authors.forename: Rengasayee
authors.initials: R
authors.lastname: Veeraraghavan
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lou
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Makara
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.affiliation: Department of Biological and Allied Health Sciences, Ohio Northern University, Ada, OH, USA.
authors.forename: Mircea
authors.initials: M
authors.lastname: Anghelescu
authors.affiliation: Division of Cardiology and Molecular Cardiology, Maugeri Foundation-University of Pavia, Pavia, Italy.
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Pompeo
authors.initials: P
authors.lastname: Volpe
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: John H B
authors.initials: JH
authors.lastname: Bridge
authors.affiliation: VTC Research Institute, School of Biomedical Engineering and Sciences, Virginia Tech, Roanoke, VA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA sandor.gyorke@osumc.edu przemyslaw.radwanski@osumc.edu.
authors.forename: Sándor
authors.initials: S
authors.lastname: Györke
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D002155:Calsequestrin / Q000235:genetics; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000493:pharmacokinetics*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; D026941:Sodium Channel Blockers; D002118:Calcium
keywords: Diastolic Ca2+ release; Neuronal Na+ channels; Ventricular arrhythmias