High prevalence of exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia mutation-positive family members diagnosed by cascade genetic screening

Abstract

AimCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease predisposing to lifethreatening arrhythmias. We aimed to determine the prevalence of arrhythmias and efficacy of b-blocker treatment in mutation-positive family members diagnosed by cascade genetic screening. Methods and resultsRelatives of six unrelated CPVT patients were tested for the relevant mutation in the ryanodine receptor-2 gene. Mutation carriers underwent an exercise test at inclusion time and 3 months after the initiation of b-blocker therapy in the highest tolerable dose. The occurrence of ventricular premature beats, couplets, and non-sustained ventricular arrhythmias (nsVT) were recorded in addition to the heart rate at which they occurred. Thirty family members were mutation carriers and were followed for 22 (13 -288) months. Previous undiagnosed CPVTrelated symptoms were reported by eight subjects. Exercise test induced ventricular arrhythmias in 23 of the 30 mutation carriers. On b-blocker treatment, exercise-induced arrhythmias occurred at a lower heart rate (117 + 17 vs. 135 + 34 beats/min, P ¼ 0.02) but at similar workload (P ¼ 0.78). b-Blocker treatment suppressed the occurrence of exercise-induced nsVT in three of the four patients, while less severe arrhythmias were unchanged. One patient died during follow-up. ConclusionExercise test revealed a high prevalence of arrhythmias in CPVT mutation carriers diagnosed by cascade genetic screening. b-Blocker therapy appeared to suppress the most severe exercise-induced arrhythmias, while less severe arrhythmias occurred at a lower heart rate.--

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

“…5 The main tools used in the diagnosis of CPVT are exercise treadmill test (ETT) and ECG Holter monitoring. 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 .…”

Catecholaminergic Polymorphic Ventricular Tachycardia in 2012

“…In one study on 30 RyR2 mutation-carrying relatives, eight (27%) reported CPVT-related symptoms. 30 During exercise testing 23 relatives (77%) showed signs of disease penetrance.…”

“…33,34 Ventricular arrhythmias tend to initiate at an individually fixed and reproducible threshold, usually between 110 and 135 beats per minute. 30 Typically ventricular arrhythmias evolve from single isolated ventricular premature beats (VPB) to bigeminy, couplets and non-sustained polymorphic or bidirectional VT (Figure 3B-D). However, complexity of ventricular arrhythmias may be limited in some patients (see Genetic testing).…”

“…Importantly, some events occurring on β-blockers may be explained by non-compliance rather than true β-blocker therapy failure. In one study, patients on β-blockers showed an earlier onset of ventricular arrhythmias during exercise testing (on the same workload) as compared to baseline, 30 which would not be a preferable effect. In 2002 Priori et al observed similar β-blocker efficacy in RyR2-mutation related and non-RyR2-mutation related CPVT, but event rates in this study were extremely high 23 and not in line with subsequent observations.…”

“…In particular, predictors for a very low risk for arrhythmias (which would make active treatment unnecessary) have not been identified, as silent mutation carriers are also at risk of arrhythmic events. 30,40 Thus, based on current knowledge all phenotypically and/or genotypically affected CPVT patients should receive treatment. The only exception may apply for older RyR2-mutation carrying individuals (over approximately 60 years of age) who are identified by cascade screening and have been asymptomatic lifelong.…”