Calcium release deficiency syndrome

CRDS typically manifests with sudden cardiac arrest or ventricular fibrillation and may occur without prior warning symptoms.

CRDS is newly recognized, and its true prevalence remains unknown. Emerging evidence indicates that it may account for 3% of idiopathic ventricular fibrillation cases overall, up to 9% of exertion‑related cardiac arrests.

CRDS is caused by biophysical or biogenic loss‑of‑function mutations in RYR2, leading to impaired calcium release channel activity and insufficient systolic calcium release during excitation–contraction coupling. Unlike , which results from increased channel leak (gain‑of‑function), CRDS reflects an insufficient calcium release response, producing a distinct arrhythmogenic mechanism.

CRDS follows an autosomal dominant inheritance pattern, consistent with other RYR2‑mediated ryanodinopathies.

Correct diagnosis requires a high index of suspicion, especially in individuals with cardiac arrest and normal ECG findings. Patients usually show normal resting and stress ECGs, in contrast to classic in which adrenergic stimulation reveals arrhythmias. This absence of typical electrocardiographic markers renders CRDS particularly difficult to detect with standard clinical testing. In 2021 the LBLPS protocol has been introduced (long‑burst, long‑pause, short‑coupled extra‑stimulus) as a potential diagnostic tool for CRDS, although its diagnostic sensitivity appears to be only modest. The protocol was developed to reproduce the arrhythmogenic sequence recorded by ICDs immediately before successful termination of ventricular fibrillation in affected individuals. Subsequent work has shown that CRDS patients display a characteristic ventricular repolarization response after either spontaneous or paced brief tachycardia followed by a pause, essentially the LBLP protocol without the extra stimulus. This distinctive pattern, reflected in QT interval changes and a marked increase in T‑wave amplitude (“T‑wave ballooning”), is not observed in healthy individuals or in patients with .

• Identification of the underlying pathogenic variant can establish the molecular diagnosis in individuals with an appropriate clinical phenotype, supports differentiation from other RYR2-related arrhythmia syndromes, and enables informed genetic counselling for the affected individual and their family. A confirmed molecular diagnosis can further inform individualised clinical management, surveillance, and risk assessment; specific measures are determined by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive genetic testing of at-risk relatives becomes possible, allowing targeted clinical evaluation and surveillance.

• Roston TM, Wei J, Guo W, Li Y, Zhong X, Wang R, et al. Clinical and functional characterization of ryanodine receptor 2 variants implicated in calcium-release deficiency syndrome. JAMA Cardiol. 2022;7(1):84-92. PMID: .
• Sun B, Yao J, Ni M, Wei J, Zhong X, Guo W, et al. Cardiac ryanodine receptor calcium release deficiency syndrome. Sci Transl Med. 2021;13(579). PMID: .
• Steinberg C, Roston TM, van der Werf C, Sanatani S, Chen SRW, Wilde AAM, et al. RYR2-ryanodinopathies: from calcium overload to calcium deficiency. Europace. 2023;25(6). PMID: .