title: Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.
abstract: The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca(2+) cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca(2+) transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Signore
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sorrentino
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Borghetti
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cannata
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Meo
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Kannappan
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pasqualini
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: O'Malley
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sundman
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tsigkas
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Arranto
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mangiaracina
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Isobe
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Brena F
authors.initials: BF
authors.lastname: Sena
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Junghyun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Isom
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
mesh_terms: D000200:Action Potentials; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D009202:Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D003094:Collagen; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit / Q000235:genetics / Q000378:metabolism
chemical_list: C524974:Scn1b protein, mouse; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D003094:Collagen; D012964:Sodium; D002118:Calcium