Clinical provocation with burst pacing or spontaneous arrhythmia demonstrated diagnostic T-wave augmentation in 5 RYR2 variant carriers with calcium release deficiency syndrome.
Case Report (n=5)
No
Does clinical provocation with burst pacing establish the diagnosis of CRDS in patients with unexplained sudden cardiac arrest?
The novel CRDS provocation test using burst pacing can clinically establish the diagnosis of CRDS, with pause dependence being essential for diagnostic sensitivity.
Importance: Calcium release deficiency syndrome (CRDS) is a recently described inherited arrhythmia caused by loss-of-function variants in the cardiac ryanodine receptor (RYR2). Diagnosis currently requires in vitro functional testing and availability limits diagnosis; a recently proposed burst pacing provocation test offers a potential clinical diagnostic tool, but its performance remains to be validated. Objective: To demonstrate how the novel CRDS provocation test can clinically establish the diagnosis in a family with unexplained sudden cardiac arrest and death. Design, Setting, and Participants: This case series examines a 5-generation pedigree with clinical, genetic, and functional data conducted among a large French Canadian family with an extensive history of unexplained sudden cardiac arrest and death. The study was conducted at a multidisciplinary cardiac genetics clinic at a tertiary referral center in Canada. Data were gathered and analyzed from June 2024 through March 2025. Exposures: Clinical provocation with burst pacing and/or spontaneous atrial or ventricular arrhythmia detected on ambulatory monitoring. Main Outcomes and Measures: The primary outcome was diagnostic T-wave augmentation following burst pacing or spontaneous atrial or ventricular arrhythmia. Results: In this case series, 5 RYR2 variant carriers (2 female 40%; age range at first evaluation, 17-59 years) demonstrated diagnostic T-wave augmentation after pacing or spontaneous arrhythmia consistent with CRDS. Pause dependence was essential for diagnostic sensitivity. Functional studies of the novel RYR2-p.Glu336Gly variant confirmed that it results in loss of function. This appears to be the first such variant reported within a hot spot previously restricted to gain-of-function variants. Conclusions and Relevance: This case series provides the first clinical application of the CRDS provocation test in a family with a history of unexplained sudden cardiac death. Findings underscore the diagnostic importance of pause dependence and highlight the need for improved risk stratification in CRDS.
Isbister et al. (Wed,) conducted a case report in Calcium release deficiency syndrome (CRDS) (n=5). Clinical provocation with burst pacing and/or ambulatory monitoring was evaluated on Diagnostic T-wave augmentation following burst pacing or spontaneous atrial or ventricular arrhythmia. Clinical provocation with burst pacing or spontaneous arrhythmia demonstrated diagnostic T-wave augmentation in 5 RYR2 variant carriers with calcium release deficiency syndrome.