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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.

SUBMITTER: Kannankeril PJ

PROVIDER: S-EPMC1567715 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy.

Kannankeril Prince J PJ Mitchell Brett M BM Goonasekera Sanjeewa A SA Chelu Mihail G MG Zhang Wei W Sood Subeena S Kearney Debra L DL Danila Cristina I CI De Biasi Mariella M Wehrens Xander H T XH Pautler Robia G RG Roden Dan M DM Taffet George E GE Dirksen Robert T RT Anderson Mark E ME Hamilton Susan L SL

Proceedings of the National Academy of Sciences of the United States of America 20060727 32

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 arrhythmog ...[more]

PMID: 16873551

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Project description:RationaleMost cardiac ryanodine receptor (RyR2) mutations associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) are postulated to cause a distinctive form of Ca(2+) release dysfunction. Considering the spread distribution of CPVT mutations, we hypothesized that dysfunctional heterogeneity also was feasible.ObjectiveTo determine the molecular and cellular mechanisms by which a novel RyR2-V2475F mutation associated with CPVT in humans triggers Ca(2+)-dependent arrhythmias in whole hearts and intact mice.Methods and resultsRecombinant channels harboring CPVT-linked RyR2 mutations were functionally characterized using tritiated ryanodine binding and single-channel recordings. Homologous recombination was used to generate a knock-in mouse bearing the RyR2-V2475F mutation. Ventricular myocytes from mice heterozygous for the mutation (RyR2-V2475F(+/-)) and their wild-type littermates were Ca(2+)-imaged by confocal microscopy under conditions that mimic stress. The propensity of wild-type and RyR2-V2475F(+/-) mice to have development of arrhythmias was tested at the whole heart level and in intact animals. Recombinant RyR2-V2475F channels displayed increased cytosolic Ca(2+) activation, abnormal protein kinase A phosphorylation, and increased activation by luminal Ca(2+). The RyR2-V2475F mutation appears embryonic-lethal in homozygous mice, but heterozygous mice have no alterations at baseline. Spontaneous Ca(2+) release events were more frequent and had shorter latency in isoproterenol-stimulated cardiomyocytes from RyR2-V2475F(+/-) hearts, but their threshold was unchanged with respect to wild-type. Adrenergically triggered tachyarrhythmias were more frequent in RyR2-V2475F(+/-) mice.ConclusionsThe mutation RyR2-V2475F is phenotypically strong among other CPVT mutations and produces heterogeneous mechanisms of RyR2 dysfunction. In living mice, this mutation appears too severe to be harbored in all RyR2 channels but remains undetected under basal conditions if expressed at relatively low levels. β-adrenergic stimulation breaks the delicate Ca(2+) equilibrium of RyR2-V2475F(+/-) hearts and triggers life-threatening arrhythmias.

Dataset Information

Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy.

Publications

Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy.

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