Abstract 15656: Genotype-Specific Natural History of Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Based on the genetic background, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) has been recently classified in “typical” (RYR2 and CASQ2) and “atypical” (TRDN, TECRL, CALM1-3, RYR2 loss-of-function [RYR2-LoF]), but genotype-specific outcome is unknown.Hypothesis. We aimed to describe genotype-specific outcomes of patients with “typical” and “atypical” CPVT before treatment. Methods: Patients were classified in: 1) “Typical” CPVT (RYR2, CASQ2); 2) “Atypical” CPVT (TRDN, TECRL, CALM1-3 and RYR2-LoF). We assessed the occurrence of a first life-threatening arrhythmic event (LAE; sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia) before the initiation of therapy. We used the Kaplan-Meier life-table method and the log-rank test to compare the cumulative probability of experiencing a first LAE by the age of 40 years in the absence of treatment. Results: We included 238 patients (56% females, median age 14 years [IQR: 9-28 years]): 226/238 (95%) patients with “typical” CPVT (216 RYR2, 10 CASQ2), and 12/238 (5%) patients with “atypical” CPVT (5 RYR2-LoF, 4 TRDN, 3 TECRL). Interestingly, in 47% of probands the RYR2 variant was likely de novo. No patients experienced an LAE in the first year of age, but patients with atypical CPVT had an increased probability to experience a LAE by the age of 5 years (3/5, 60%), as compared with patients with typical CPVT (2/43, 5%; OR 30.8; p=0.003). In half of patients with LAE (23/48; 48%), the occurrence of LAE was the first clinical manifestation of CPVT. Overall, the probability to experience an LAE by the age of 40 years in the absence of treatment was higher in patients with atypical CPVT (100%), as compared to patients with typical CPVT (39%; p=0.003, Figure). Conclusions: Patients with atypical variants of CPVT are at increased risk to experience an LAE before treatment, especially during early childhood.