title: Hyperglycemia induces defective Ca2+ homeostasis in cardiomyocytes.
abstract: Diabetes and other metabolic conditions characterized by elevated blood glucose constitute important risk factors for cardiovascular disease. Hyperglycemia targets myocardial cells rendering ineffective mechanical properties of the heart, but cellular alterations dictating the progressive deterioration of cardiac function with metabolic disorders remain to be clarified. In the current study, we examined the effects of hyperglycemia on cardiac function and myocyte physiology by employing mice with high blood glucose induced by administration of streptozotocin, a compound toxic to insulin-producing β-cells. We found that hyperglycemia initially delayed the electrical recovery of the heart, whereas cardiac function became defective only after ~2 mo with this condition and gradually worsened with time. Prolonged hyperglycemia was associated with increased chamber dilation, thinning of the left ventricle (LV), and myocyte loss. Cardiomyocytes from hyperglycemic mice exhibited defective Ca2+transients before the appearance of LV systolic defects. Alterations in Ca2+transients involved enhanced spontaneous Ca2+releases from the sarcoplasmic reticulum (SR), reduced cytoplasmic Ca2+clearance, and declined SR Ca2+load. These defects have important consequences on myocyte contraction, relaxation, and mechanisms of rate adaptation. Collectively, our data indicate that hyperglycemia alters intracellular Ca2+homeostasis in cardiomyocytes, hindering contractile activity and contributing to the manifestation of the diabetic cardiomyopathy.
  We have investigated the effects of hyperglycemia on cardiomyocyte physiology and ventricular function. Our results indicate that defective Ca2+handling is a critical component of the progressive deterioration of cardiac performance of the diabetic heart.
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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, Boston, Massachusetts.
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, Boston, Massachusetts.
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, Boston, Massachusetts.
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, Boston, Massachusetts.
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, Boston, Massachusetts.
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, Boston, Massachusetts.|Fondazione Cardiocentro Ticino, University of Zurich, Lugano, Switzerland.
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, Boston, Massachusetts.|Fondazione Cardiocentro Ticino, University of Zurich, Lugano, Switzerland.
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, Boston, Massachusetts.
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Khaled
authors.identifier: http://orcid.org/0000-0003-2943-1245
authors.initials: K
authors.lastname: Qanud
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.|Department of Cardiology, Westchester Medical Center, Valhalla, New York.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Jacobson
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.affiliation: Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; marcello_rota@nymc.edu.|Department of Physiology, New York Medical College, Valhalla, New York; and.
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
mesh_terms: D000200:Action Potentials; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism*; D000067268:Isolated Heart Preparation; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*
chemical_list: D000697:Central Nervous System Stimulants; D002110:Caffeine; D002118:Calcium
keywords: Ca2+ handling; diabetes; myocytes; ventricular function