Natural History of Patients with Typical and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Abstract Background Recently, a novel genetic-based classification for Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) has been proposed to distinguish “typical” (RYR2 and CASQ2 genes) and “atypical” (TRDN, TECRL, CALM1–3, RYR2 loss-of-function [RYR2-LoF]) CPVT variants. Although some genetic forms were reported as malignant forms of CPVT, natural history data comparing typical and atypical CPVT variants are lacking. Purpose We compared the natural history of “typical” and “atypical” forms of CPVT in a large cohort of patients with genetically confirmed CPVT. Methods CPVT was diagnosed according to the criteria defined in the 2015 European Society of Cardiology Guidelines. Based on the genetic background, we classified the patients in two groups: 1) “Typical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in RYR2 and CASQ2 genes); 2) “Atypical” CPVT (i.e., carriers of pathogenic or likely pathogenic mutations in TRDN, TECRL, CALM1–3 and RYR2-LoF). Patients with mutations in the CALM1, CALM2 or CALM3 were not identified in our cohort. The outcome was the occurrence of a life-threatening arrhythmic event (LAE), defined as: sudden cardiac death, aborted cardiac arrest or hemodynamically non-tolerated ventricular tachycardia. The Kaplan-Meier life-table method was used to determine the cumulative probability of experiencing a first LAE before the age of 40 years and in the absence of treatment. Outcomes in two groups were compared using the log-rank test. Results The study cohort included 238 patients (56% females, median age at diagnosis 14 years [IQR: 9–28 years]), of whom 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). In the entire population, the cumulative probability of experiencing a first LAE between birth and the diagnosis of CPVT was 2.3%, 21.2 and 40.8% at 5, 20, and 40 years, respectively. At any given age, the probability of a first LAE in the absence of therapy was significantly higher in patients with atypical CPVT (25%, 36%, and 100% at 5, 20, and 40 years, respectively), as compared to patients with typical CPVT (1%, 20%, and 39% at 5, 20, and 40 years, respectively; p=0.003, Figure 1). Patients with atypical CPVT suffered LAEs in early childhood (i.e., by the age of 5 years) significantly more often than patients with typical CPVT (3/5 patients [60%] in atypical CPVT vs. 2/43 patients [5%] in typical CPVT, p<0.001; Figure 2). Conclusions The natural history of CPVT is modulated by the genetic cause. Atypical CPVT variants are rare but are characterized by a worse outcome and a greater likelihood of experiencing an LAE since the early childhood, as compared to typical CPVT. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ricerca Corrente funding scheme of the Italian Ministry of Health