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

Prince J. Kannankeril, Brett M. Mitchell, Sanjeewa A. Goonasekera, Mihail G. Chelu, Wei Zhang, Subeena Sood, Debra L. Kearney, Cristina I. Danila, Mariella De Biasi, Xander H.T. Wehrens, Robia G. Pautler, Dan M. Roden, George Taffet, Robert T. Dirksen, Mark E. Anderson, Susan L. Hamilton

Research output: Contribution to journalArticle

137 Scopus citations

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 RyR2R176Q/+ 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 RyR2R176Q/+, but not in WT, mice. Intracardiac electrophysiology studies with programmed stimulation also elicited VT in RyR2R176Q/+ mice. Isoproterenol administration during programmed stimulation increased both the number and duration of VT episodes in RyR2R176Q/+ mice, but not in controls. Isolated cardiomyocytes from RyR2R176Q/+ mice exhibited a higher incidence of spontaneous Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)12179-12184
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number32
DOIs
StatePublished - Aug 8 2006

Keywords

  • Arrhythmogenic right ventricular dysplasia
  • Calcium-release channel
  • Catecholaminergic polymorphic ventricular tachycardia

ASJC Scopus subject areas

  • Genetics
  • General

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