title: Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts.
abstract: Beat-to-beat alternations in the amplitude of the cytosolic Ca2+transient (Ca2+alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca2+alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca2+release channel responsible for cytosolic Ca2+transients, in cardiac alternans. Using a unique mouse model harboring a suppression-of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca2+and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca2+release refractoriness and enhanced propensity for Ca2+alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca2+alternans in RyR2-SOF hearts, whereas carvedilol, a β-blocker that suppresses RyR2 activity and CPVT, promoted Ca2+alternans in these hearts. Thus, RyR2 function is an important determinant of Ca2+, APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
authors: Xiaowei
authors: X
authors: Zhong
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
authors: Bo
authors: B
authors: Sun
authors: Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona 08034, Spain.
authors: Alexander
authors: A
authors: Vallmitjana
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
authors: Tao
authors: T
authors: Mi
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
authors: Wenting
authors: W
authors: Guo
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
authors: Mingke
authors: M
authors: Ni
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
authors: Ruiwu
authors: R
authors: Wang
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors: Ang
authors: A
authors: Guo
authors: Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors: Henry J
authors: HJ
authors: Duff
authors: Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors: Anne M
authors: AM
authors: Gillis
authors: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors: Long-Sheng
authors: LS
authors: Song
authors: Cardiovascular Research Centre, CSIC-ICCC and IIB Sant Pau, Hospital de Sant Pau, Barcelona 08025, Spain.
authors: Leif
authors: L
authors: Hove-Madsen
authors: Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona 08034, Spain.
authors: Raul
authors: R
authors: Benitez
authors: Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
authors: S R Wayne
authors: SR
authors: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013610:Tachycardia / Q000235:genetics / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D007545:Isoproterenol
keywords: Ca2+ alternans; Ca2+ release refractoriness; ryanodine receptor; ryanodine receptors; sarcoplasmic reticulum; ventricular tachyarrhythmia