Prognostic relevance of baseline exercise stress test in RYR2-related CPVT

Figure 1. Typical progression of VA at baseline EST in a RYR2 related CPVT patient. A 42-year-old female, with a pathogenic RYR2 mutation localized in the HD1 domain, had an unremarkable baseline ECG (A). In the first seconds of exercise, we documented first isolated PVCs (B) and successively, brief runs of atrial tachycardia (C) that suppressed the VA briefly. Continuation of exercise brought about the appearance of ventricular couplets (D) and finally sustained bidirectional VT, hemodynamically well-tolerated, all within the first minute of exercise. The EST was immediately interrupted, and the VT ceased spontaneously after three minutes of recovery.

Figure 2. Episodes of VT in patients with RYR2-related CPVT at baseline EST. Some examples of VT elicited at the baseline EST in different patients: typical bidirectional VT with relatively slow cycle length (upper panel); polymorphic VT followed by a bidirectional VT (central panel); and bursts of polymorphic VT interrupted by a sinus beat (lower panel).

Figure 3. VT at baseline EST based on age, sex, and localization of RYR2 mutation. In our cohort, pre-school children (i.e. under the age of 6, N = 8) did not have VT (0/8; shown in green), while among other age categories [pre-adolescents (14/20, 70%), adolescents (12/23, 52%), and adults (31/51, 61%)] VT incidence (shown in red) was comparable (A). In terms of sex (B), we did not identify significant differences between males (19/37, 51%) and females (38/65, 58%). Our data showed differences based on the location of the RYR2 mutation: carriers of mutations localizing in the transmembrane region had a particularly high burden of VT (16/20, 80%), as compared with carriers of N-terminal domain mutations (8/22, 36%).

Figure 4. Clinical outcomes of patients with RYR2-related CPVT stratified by baseline EST parameters. Kaplan–Meier estimate of cumulative survival free from an LAE at follow-up stratified by VT at baseline EST showed that the cumulative probability of experiencing a first LAE on BB therapy was 13.4% (95% CI: 3.6–22.2%) and 2.2% (95% CI: 0.0–6.4%) at 5 years of follow-up for patients with VT at baseline EST (in red) and patients without VT (in green) at baseline EST, respectively (A; P = 0.003). Same analysis stratified by the early onset of VA (i.e. in the first step of EST) showed that the cumulative probability of experiencing a first LAE on BB therapy was 10.0% (95% CI: 0.2–18.4%) and 0.0% (95% CI: 0.0–0.0%) at 5 years of follow-up for patients with VA in the first step at baseline EST (in red) and patients without VA (in green), respectively (B; P = 0.003).