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: 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 E Taffet, Robert T Dirksen, Mark E Anderson, Susan L Hamilton
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 32 Pg. 12179-84 (Aug 08 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16873551 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Catecholamines
• Central Nervous System Stimulants
• Ryanodine Receptor Calcium Release Channel
• Vasoconstrictor Agents
• Caffeine
• Epinephrine

Topics

• Animals
• Caffeine (pharmacology)
• Cardiomyopathies (genetics, pathology)
• Catecholamines (metabolism)
• Central Nervous System Stimulants (pharmacology)
• Epinephrine (pharmacology)
• Genetic Predisposition to Disease
• Male
• Mice
• Mice, Transgenic
• Mutation
• Myocardium (metabolism)
• Ryanodine Receptor Calcium Release Channel (genetics, physiology)
• Tachycardia, Ventricular (genetics, pathology)
• Vasoconstrictor Agents (pharmacology)