Details

Autor(en) / Beteiligte

• 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 H. T.
• Pautler, Robia G.
• Roden, Dan M.
• Taffet, George E.
• Dirksen, Robert T.
• Anderson, Mark E.
• Hamilton, Susan L.

Titel

Mice with the R176Q Cardiac Ryanodine Receptor Mutation Exhibit Catecholamine-Induced Ventricular Tachycardia and Cardiomyopathy

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2006-08, Vol.103 (32), p.12179-12184

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 $RyR2^{Rl76Q/+}$ mice. Isoproterenol administration during programmed stimulation increased both the number and duration of VT episodes in $RyR2^{Rl76Q/+}$ mice, but not in controls. Isolated cardiomyocytes from $RyR2^{Rl76Q/+}$ 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.