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

Abstract

Aims: Exercise stress test (EST) represents the gold standard for diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed to determine the relevance of exercise induced VT for the occurrence of LAE at follow-up.

Methods and results: In RYR2-related CPVT patients who underwent a baseline EST, we assessed the incidence and severity of ventricular arrhythmias (VA). Data were analysed using logistic regression models and Cox proportional hazards models. The primary outcome was the occurrence of life-threatening arrhythmic event (LAE; composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated VT) at follow-up. In 102 RYR2-related CPVT patients (65 females; median age 16 years, IQR: 11-36 years), exercise-induced VT (bidirectional in 64% of cases) was elicited in 56% patients. VT could not be induced in pre-school children. Lower basal heart rate, early onset VA (within the first step of EST) and heart rate at the first minute of recovery were associated with exercise-induced VT. Cox analyses showed that early onset VA (HR 6.0, 95% CI: 1.3-27.9, P = 0.022) and exercise-induced VT (HR 6.6, 95% CI: 1.5-29.1, P = 0.012) at baseline EST were significantly associated with the occurrence of LAE at follow-up, and remained associated even after correction for symptoms.

Conclusion: Early onset VA and exercise-induced VT at baseline EST was associated with LAE at follow-up, allowing to identify a sub-set of patients at higher risk already at diagnosis.

Keywords: CPVT; Exercise stress test; Life-threatening arrhythmic event; Sudden cardiac death; Ventricular tachycardia.

Graphical Abstract

Exercise stress test (EST) in the absence of antiarrhythmic therapy has, in addition to diagnostic implications, relevant prognostic insights that should not be missed. In our cohort (upper panel), exercise-induced ventricular tachycardia (VT) was elicited in 56% of patients. Lower basal heart rate, early onset VA and lower heart rate at the first minute of recovery were associated with the occurrence of VT at baseline EST (middle panel). At follow-up, patients with exercise-induced VT at baseline EST were at significantly higher risk of life-threatening events (lower panel).

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).