Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients

Abstract

Background: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. Methods and results: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On b blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2-37) years. Conclusion: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with b blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of b blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies.

Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death

“…Most cases of sudden cardiac death in CPVT are considered to be due to ventricular tachycardia/fibrillation driven by sympathetic stimulation (47). Paradoxically, many patients show sinus bradycardia at rest (22,(48)(49)(50), and not a small fraction of death is related to AV block and bradycardia (51). The RQ mouse showed this bradycardia phenotype (Fig.…”

“…Leaky RyR2 mutations generate intrinsic cardiac instability commonly assumed to explain cardiac arrest, but these patients also experience sinus bradycardia (22), suggestive of abnormal regulation of premotor vagal nerve excitability. It is unknown whether they might also contribute to premature death by lowering the threshold for hypoxic depolarization that silences brainstem cardiorespiratory pace-making circuitry.…”

Effective cascade screening through identification of a mutation in RYR2 in a large family with a history of sudden death

“…Although some individuals with RYR2 mutations may have a slightly lower resting heart rate than individuals without mutations, the resting ECG is usually unremarkable. Exercise tests are often used in the diagnosis and monitoring of therapy in CPVT, however mutation carriers may display no features during testing [4]. As in our family, there are reports of symptomatic RYR2 mutation carriers who have inherited the pathogenic mutation from completely asymptomatic parents [5].…”

“…The molecular basis of CPVT is due to mutations in RYR2 in 50-60% of affected individuals [1]. The phenotype is variable [7] and penetrance among RYR2 mutation carriers is incomplete, estimated to be 78% [4]. In our pedigree, two obligate carriers (III:5 and III:9) were asymptomatic at 66 and 67 years.…”

“…Unlike other inherited arrhythmogenic disorders, individuals with CPVT usually have a normal resting electrocardiogram and are often asymptomatic prior to a lethal event [4]. Multiple exercise-or emotion-induced ventricular dysrhythmias may occur and bidirectional ventricular tachycardia is pathognomonic.…”