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


  • 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.

published proceedings

  • Proc Natl Acad Sci U S A

altmetric score

  • 6

author list (cited authors)

  • Kannankeril, P. J., Mitchell, B. M., Goonasekera, S. A., Chelu, M. G., Zhang, W., Sood, S., ... Hamilton, S. L.

citation count

  • 150

complete list of authors

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

publication date

  • August 2006