title: Decreased RyR2 refractoriness determines myocardial synchronization of aberrant Ca2+ release in a genetic model of arrhythmia.
abstract: Dysregulated intracellular Ca(2+) signaling is implicated in a variety of cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia. Spontaneous diastolic Ca(2+) release (DCR) can induce arrhythmogenic plasma membrane depolarizations, although the mechanism responsible for DCR synchronization among adjacent myocytes required for ectopic activity remains unclear. We investigated the synchronization mechanism(s) of DCR underlying untimely action potentials and diastolic contractions (DCs) in a catecholaminergic polymorphic ventricular tachycardia mouse model with a mutation in cardiac calsequestrin. We used a combination of different approaches including single ryanodine receptor channel recording, optical imaging (Ca(2+) and membrane potential), and contractile force measurements in ventricular myocytes and intact cardiac muscles. We demonstrate that DCR occurs in a temporally and spatially uniform manner in both myocytes and intact myocardial tissue isolated from cardiac calsequestrin mutation mice. Such synchronized DCR events give rise to triggered electrical activity that results in synchronous DCs in the myocardium. Importantly, we establish that synchronization of DCR is a result of a combination of abbreviated ryanodine receptor channel refractoriness and the preceding synchronous stimulated Ca(2+) release/reuptake dynamics. Our study reveals how aberrant DCR events can become synchronized in the intact myocardium, leading to triggered activity and the resultant DCs in the settings of a cardiac rhythm disorder.
authors.affiliation: D. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Brunello
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Slabaugh
authors.forename: Przemyslaw B
authors.initials: PB
authors.lastname: Radwanski
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.forename: Qing
authors.initials: Q
authors.lastname: Lou
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Francesco
authors.initials: F
authors.lastname: Lodola
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.forename: Pompeo
authors.initials: P
authors.lastname: Volpe
authors.forename: Michael
authors.initials: M
authors.lastname: Fill
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Sándor
authors.initials: S
authors.lastname: Györke
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002155:Calsequestrin / Q000235:genetics* / Q000502:physiology; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D032383:Myocytes, Cardiac / Q000502:physiology; D010210:Papillary Muscles / Q000166:cytology / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; D002118:Calcium
keywords: RyR2 deactivation; calcium-induced calcium release; luminal calcium; sarcoplasmic reticulum