Catecholaminergic Polymorphic Ventricular Tachycardia: Phenotype Characterization, Response to BB Therapy and Long-Term Outcome of The Typical Form

BACKGROUND: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is one of the most severe inherited arrhythmogenic disorders, causing exercise and emotion-induced cardiac arrest since childhood. The “typical” phenotype of CPVT is caused by mutations in RYR2 and CASQ2 genes, leading to defective intracellular calcium handling. Five other genes have been associated with a rarer “atypical” form, different in arrhythmogenesis and clinical presentation. While resting ECG is unremarkable in CPVT patients, arrhythmias progress in complexity with accumulation of catecholamines. Hence, beta-blockers (BBs) have been considered as first-line therapy since the description of the disease and still represent the mainstay of treatment. Due to the rarity of the disease which has restricted the assembly of exhaustive cohorts of patients, genotype-specific knowledge on natural history and long-term effectiveness of therapy is limited. How BBs modulate the occurrence of ventricular arrhythmias during exercise in CPVT patients is unclear. AIMS: Characterize the natural history of typical CPVT, providing genotype specific information; Investigate how different BB therapies modulate the arrhythmic phenotype during exercise; Determine long-term outcome of typical CPVT patients and identify predictors of BB therapy failure. METHODS: The study was conducted prospectively on the largest single-center cohort of patient affected by typical CPVT. The study population included 227 patients with genetically confirmed disease. Of these, 217 (96%) patients were carriers of RYR2 mutations and 10 (4%) of CASQ2 mutations. The selected endpoint was the occurrence of an LAE: sudden cardiac death [SCD], aborted cardiac arrest or documented hemodynamically non-tolerated ventricular tachycardia (VT). Survival analysis was performed using Kaplan-Meier method. 622 exercise stress tests (ESTs) from 72 patients were analysed (n=72 EST off therapy, n=550 EST on therapy, median 5 ESTs [3-12] per patient). Initially, to investigate the effects of BB therapy introduction on arrhythmias, the analysis was conducted on the first EST performed off and on therapy. Subsequently, it was extended to all the ESTs using a mixed models generalized logistic regression to assess the effect of therapy considering intrapersonal and interpersonal variability. To quantify the risk of experiencing an LAE during BB treatment, we used a Kaplan-Meier estimator of the LAE-free survival function with follow-up during BB treatment as a timescale. Multivariable Cox proportional hazards models were used to evaluate predictors of experiencing LAE while on therapy with BB. RESULTS: Overall, the probability of experiencing an LAE in absence of therapy between birth and 40 years of age was estimated between 38% and 71%. At any given age, the probability of a first LAE in absence of therapy was higher in patients with CASQ2 as compared to RYR2 mutations (p=0.007). Our data confirms Nadolol superiority in respect to B1-selective BBs. For the majority of patients 1 mg/kg/day of Nadolol is effective in suppressing VT. In patients with breakthrough arrhythmias 1.6 mg/kg/day significantly suppresses VT. Lastly, the study focused on identification of predictors of BB failure. In our cohort, 31/227 (14%) patients experienced an LAE during BB treatment, corresponding to an annual rate of of 2.0%. Multivariable analysis demonstrated that history of LAE before diagnosis, of unexplained syncope before diagnosis, documented VTs before diagnosis and treatment with different BB were all independent predictors of LAE. CONCLUSIONS: In absence of therapy typical CPVT patients with CASQ2 mutations have a poorer outcome compared to patients with RYR2 mutations. Once diagnosed, Nadolol must be preferred as it has been shown to suppress arrhythmias, and reduces by 78% the risk of LAE as compared to patients treated with selective BBs.