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(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.
Kannankeril
Prince J
PJ
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Mitchell
Brett M
BM
Goonasekera
Sanjeewa A
SA
Chelu
Mihail G
MG
Zhang
Wei
W
Sood
Subeena
S
Kearney
Debra L
DL
Danila
Cristina I
CI
De Biasi
Mariella
M
Wehrens
Xander H T
XH
Pautler
Robia G
RG
Roden
Dan M
DM
Taffet
George E
GE
Dirksen
Robert T
RT
Anderson
Mark E
ME
Hamilton
Susan L
SL
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D002395:Catecholamines / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002395:Catecholamines; D000697:Central Nervous System Stimulants; D019837:Ryanodine Receptor Calcium Release Channel; D014662:Vasoconstrictor Agents; D002110:Caffeine; D004837:Epinephrine