title: Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy.
abstract: Mutations in the cardiac ryanodine receptor 2 (RyR2) have been associated with catecholaminergic polymorphic ventricular tachycardia and a form of arrhythmogenic right ventricular dysplasia. To study the relationship between RyR2 function and these phenotypes, we developed knockin mice with the human disease-associated RyR2 mutation R176Q. Histologic analysis of hearts from RyR2(R176Q/+) mice revealed no evidence of fibrofatty infiltration or structural abnormalities characteristic of arrhythmogenic right ventricular dysplasia, but right ventricular end-diastolic volume was decreased in RyR2(R176Q/+) mice compared with controls, indicating subtle functional impairment due to the presence of a single mutant allele. Ventricular tachycardia (VT) was observed after caffeine and epinephrine injection in RyR2(R176Q/+), but not in WT, mice. Intracardiac electrophysiology studies with programmed stimulation also elicited VT in RyR2(R176Q/+) mice. Isoproterenol administration during programmed stimulation increased both the number and duration of VT episodes in RyR2(R176Q/+) mice, but not in controls. Isolated cardiomyocytes from RyR2(R176Q/+) mice exhibited a higher incidence of spontaneous Ca(2+) oscillations in the absence and presence of isoproterenol compared with controls. Our results suggest that the R176Q mutation in RyR2 predisposes the heart to catecholamine-induced oscillatory calcium-release events that trigger a calcium-dependent ventricular arrhythmia.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Prince J
authors.initials: PJ
authors.lastname: Kannankeril
authors.forename: Brett M
authors.initials: BM
authors.lastname: Mitchell
authors.forename: Sanjeewa A
authors.initials: SA
authors.lastname: Goonasekera
authors.forename: Mihail G
authors.initials: MG
authors.lastname: Chelu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Subeena
authors.initials: S
authors.lastname: Sood
authors.forename: Debra L
authors.initials: DL
authors.lastname: Kearney
authors.forename: Cristina I
authors.initials: CI
authors.lastname: Danila
authors.forename: Mariella
authors.initials: M
authors.lastname: De Biasi
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Robia G
authors.initials: RG
authors.lastname: Pautler
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D002395:Catecholamines / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D000697:Central Nervous System Stimulants; D019837:Ryanodine Receptor Calcium Release Channel; D014662:Vasoconstrictor Agents; D002110:Caffeine; D004837:Epinephrine