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.arrhythmogenic right ventricular dysplasia ͉ catecholaminergic polymorphic ventricular tachycardia ͉ calcium-release channel T he cardiac ryanodine receptor 2 (RyR2) regulates calcium release from the sarcoplasmic reticulum in cardiomyocytes (1). Two inherited arrhythmogenic syndromes have been linked to mutations in RyR2, arrhythmogenic right ventricular dysplasia (ARVD) and catecholaminergic polymorphic ventricular tachycardia (CPVT) (2, 3). ARVD and CPVT are both characterized by ventricular arrhythmias and a high rate of juvenile sudden death. Patients with CPVT exhibit catecholamine-induced bidirectional ventricular tachycardia (VT) in the setting of a structurally normal heart, whereas patients with ARVD exhibit progressive fibrofatty replacement of the right ventricular myocardium in addition to polymorphic VT. ARVD arising from RyR2 mutations (ARVD2) is typically associated with exercise-induced ventricular arrhythmias and relatively mild structural abnormalities compared with other forms of ARVD and, in some ways, mimics the CPVT phenotype. In fact, the diagnosis of ARVD2 in patients with RyR2 mutations is controversial because of the differences in degree of cardiac structural abnormalities between ARVD2 and other forms of ARVD (4).Disease-causing mutations in RyR2 and the skeletal muscle isoform RyR1 cluster in three highly conserved regions: a cytosolic N-terminal region, a cytosolic central region, and a C-terminal portion containing the transmembrane and pore regions of the channel (5, 6). Multiple mutations in RyR2 have been reported in patients with ...

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