July 2, 2002
View Full PaperClinical and Molecular Characterization of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia
Key Result
RyR2 mutations in CPVT are associated with earlier symptom onset compared to nongenotyped CPVT, and male sex is a significant risk factor for syncope in RyR2-CPVT patients (RR 4.2).
Study Design
Type
Observational (n=148)
Structured PICO
What are the clinical and genetic characteristics of patients with CPVT, and how do RyR2 mutation carriers differ from nongenotyped patients?
P
Population
148 individuals (30 probands and 118 family members) with documented polymorphic ventricular arrhythmias occurring during physical or emotional stress with a normal heart.
I
Intervention
Mutation screening on the cardiac ryanodine receptor (RyR2) gene and clinical phenotype evaluation.
C
Comparator
Patients with nongenotyped CPVT compared to patients with RyR2-CPVT.
O
Outcome
Clinical features, age of onset, and risk factors for cardiac events (syncope).hard clinical
Genetic analysis in CPVT identifies RyR2 mutation carriers who become symptomatic earlier and have a higher risk of cardiac events in males, guiding prompt evaluation and treatment.
Main Result
Effect estimate: RR 4.2
Abstract
BACKGROUND: Mutations in the cardiac ryanodine receptor gene (RyR2) underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disease occurring in the structurally intact heart. The proportion of patients with CPVT carrying RyR2 mutations is unknown, and the clinical features of RyR2-CPVT as compared with nongenotyped CPVT are undefined. METHODS AND RESULTS: Patients with documented polymorphic ventricular arrhythmias occurring during physical or emotional stress with a normal heart entered the study. The clinical phenotype of the 30 probands and of 118 family members was evaluated, and mutation screening on the RyR2 gene was performed. Arrhythmias documented in probands were: 14 of 30 bidirectional ventricular tachycardia, 12 of 30 polymorphic ventricular tachycardia, and 4 of 30 catecholaminergic idiopathic ventricular fibrillation; RyR2 mutations were identified in 14 of 30 probands (36% bidirectional ventricular tachycardia, 58% polymorphic ventricular tachycardia, 50% catecholaminergic idiopathic ventricular fibrillation) and in 9 family members (4 silent gene carriers). Genotype-phenotype analysis showed that patients with RyR2 CPVT have events at a younger age than do patients with nongenotyped CPVT and that male sex is a risk factor for syncope in RyR2-CPVT (relative risk=4.2). CONCLUSIONS: CPVT is a clinically and genetically heterogeneous disease manifesting beyond pediatric age with a spectrum of polymorphic arrhythmias. beta-Blockers reduce arrhythmias, but in 30% of patients an implantable defibrillator may be required. Genetic analysis identifies two groups of patients: Patients with nongenotyped CPVT are predominantly women and become symptomatic later in life; patients with RyR2 CPVT become symptomatic earlier, and men are at higher risk of cardiac events. These data provide a rationale for prompt evaluation and treatment of young men with RyR2 mutations.