Mice with the R176Q Cardiac Ryanodine Receptor Mutation Exhibit Catecholamine-Induced Ventricular Tachycardia and Cardiomyopathy
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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2006 |
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| Erschienen: |
2006 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:103 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kannankeril, Prince J. [VerfasserIn] |
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| Links: |
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| Themen: |
Arrhythmogenic right ventricular dysplasia |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
JST06950380X |
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| 100 | 1 | |a Kannankeril, Prince J. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mice with the R176Q Cardiac Ryanodine Receptor Mutation Exhibit Catecholamine-Induced Ventricular Tachycardia and Cardiomyopathy |
| 264 | 1 | |c 2006 | |
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| 520 | |a 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. | ||
| 540 | |a Copyright 2006 National Academy of Sciences of the United States of America | ||
| 650 | 4 | |a arrhythmogenic right ventricular dysplasia | |
| 650 | 4 | |a catecholaminergic polymorphic ventricular tachycardia | |
| 650 | 4 | |a calcium-release channel | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Symptoms |x Disease manifestations |x Cardiovascular manifestations |x Dysrhythmias |x Tachycardia |x Ventricular tachycardia | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Symptoms |x Disease manifestations |x Cardiovascular manifestations |x Dysrhythmias | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical elements |x Alkaline earth metals |x Calcium | |
| 650 | 4 | |a Biological sciences |x Biology |x Zoology |x Animals |x Mammals |x Rodents |x Mice | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Diseases |x Cardiovascular diseases |x Heart diseases |x Cardiomyopathies | |
| 650 | 4 | |a Biological sciences |x Biology |x Neuroscience |x Neurophysiology |x Electrophysiology | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Phenotypes | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Population genetics |x Genetic variation |x Genetic mutation | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Chemicals |x Polymers |x Biopolymers |x Proteins |x Receptors | |
| 650 | 4 | |a Physical sciences |x Metrology |x Telemetry | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Symptoms |x Disease manifestations |x Cardiovascular manifestations |x Dysrhythmias |x Tachycardia |x Ventricular tachycardia | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Symptoms |x Disease manifestations |x Cardiovascular manifestations |x Dysrhythmias | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical elements |x Alkaline earth metals |x Calcium | |
| 650 | 4 | |a Biological sciences |x Biology |x Zoology |x Animals |x Mammals |x Rodents |x Mice | |
| 650 | 4 | |a Health sciences |x Medical conditions |x Diseases |x Cardiovascular diseases |x Heart diseases |x Cardiomyopathies | |
| 650 | 4 | |a Biological sciences |x Biology |x Neuroscience |x Neurophysiology |x Electrophysiology | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Phenotypes | |
| 650 | 4 | |a Biological sciences |x Biology |x Genetics |x Population genetics |x Genetic variation |x Genetic mutation | |
| 650 | 4 | |a Physical sciences |x Chemistry |x Chemical compounds |x Chemicals |x Polymers |x Biopolymers |x Proteins |x Receptors | |
| 650 | 4 | |a Physical sciences |x Metrology |x Telemetry | |
| 655 | 4 | |a research-article | |
| 700 | 1 | |a Mitchell, Brett M. |e verfasserin |4 aut | |
| 700 | 1 | |a Goonasekera, Sanjeewa A. |e verfasserin |4 aut | |
| 700 | 1 | |a Chelu, Mihail G. |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Sood, Subeena |e verfasserin |4 aut | |
| 700 | 1 | |a Kearney, Debra L. |e verfasserin |4 aut | |
| 700 | 1 | |a Danila, Cristina I. |e verfasserin |4 aut | |
| 700 | 1 | |a De Biasi, Mariella |e verfasserin |4 aut | |
| 700 | 1 | |a Wehrens, Xander H. T. |e verfasserin |4 aut | |
| 700 | 1 | |a Pautler, Robia G. |e verfasserin |4 aut | |
| 700 | 1 | |a Roden, Dan M. |e verfasserin |4 aut | |
| 700 | 1 | |a Taffet, George E. |e verfasserin |4 aut | |
| 700 | 1 | |a Dirksen, Robert T. |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Mark E. |e verfasserin |4 aut | |
| 700 | 1 | |a Hamilton, Susan L. |e verfasserin |4 aut | |
| 773 | 1 | 8 | |g volume:103 |g year:2006 |g number:32 |g pages:12179-12184 |
| 856 | 4 | 0 | |u https://www.jstor.org/stable/30051685 |3 Volltext |
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