Familial Evaluation in Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Background-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome associated with mutations in the cardiac ryanodine receptor gene (RYR2) in the majority of patients. Previous studies of CPVT patients mainly involved probands, so current insight into disease penetrance, expression, genotype-phenotype correlations, and arrhythmic event rates in relatives carrying a RYR2 mutation is limited. Methods and Results-One-hundred sixteen relatives carrying a RYR2 mutation from 15 families who were identified by cascade screening of the RYR2 mutation causing CPVT in the proband were clinically characterized, including 61 relatives from 1 family. Fifty-four of 108 antiarrhythmic drug-free relatives (50%) had a CPVT phenotype at the first cardiological examination, including 27 (25%) with nonsustained ventricular tachycardia. Relatives carrying a RYR2 mutation in the C-terminal channel-forming domain showed an increased odds of nonsustained ventricular tachycardia (odds ratio, 4.1; 95% CI, 1.5-11.5; P=0.007, compared with N-terminal domain). Sinus bradycardia was observed in 19% of relatives, whereas other supraventricular dysrhythmias were present in 16%. Ninety-eight (most actively treated) relatives (84%) were followed up for a median of 4.7 years (range, 0.3-19.0 years). During follow-up, 2 asymptomatic relatives experienced exercise-induced syncope. One relative was not being treated, whereas the other was noncompliant. None of the 116 relatives died of CPVT during a 6.7-year follow-up (range, 1.4-20.9 years). Conclusions-Relatives carrying an RYR2 mutation show a marked phenotypic diversity. The vast majority do not have signs of supraventricular disease manifestations. Mutation location may be associated with severity of the phenotype. The arrhythmic event rate during follow-up was low. (Circ Arrhythm Electrophysiol. 2012;5:748-756.)

Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

“…Because permutation analysis shows that equal contribution of WT and mutant alleles to the formation of a tetrameric RyR2 channel yields variable populations of WT and mutation-containing channels (Fig. S3), it is possible that penetrance is related to the proportion of dysfunctional channels harbored by a given specimen, among other factors (20,21 2A). The current-voltage (I-V) relation for I CaL was similar for WT and RyR2-A4860G +/− myocytes (n = 10 from n = 8 mice in each group; Fig.…”

Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor

“…More recently, flecainide has emerged as an effective therapeutic agent for the treatment of CPVT both in combination with conventional β‐adrenoceptor blockade (van der Werf et al ., 2011; van der Werf et al ., 2012; Watanabe et al ., 2013) and as a monotherapy (Napolitano, 2016; Padfield et al ., 2016). …”

Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

“…3 Initially described by Coumel et al, 4 CPVT is an inherited disease characterized by the presence of adrenergic-induced bidirectional or polymorphic ventricular tachycardia in individuals with a normal basal electrocardiogram and structurally normal heart. CPVT patients can present syncope and SCD triggered by physical or emotional stress at young ages, and SCD can be the first manifestation in up to 30% of cases.…”

“…9,10 Genetic links to CPVT were established in 1999 for the type 2 ryanodine receptor (RyR2) 11 and in 2001 for calsequestrin (CASQ2). 12 However, heterogeneity in phenotypic expression of these genetic mutations was soon demonstrated, with an average disease penetrance of 54% 3,13 . The variable phenotype resulting from a single mutation among members of an affected family, suggests that additional factors might play a role in the phenotypic expression of RyR2 mutations, which highlights the need for a mechanistic understanding of the disease.…”