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Original Investigation
November 3, 2021

Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome

Author Affiliations
  • 1Division of Cardiology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
  • 2Centre for Cardiovascular Innovation, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 3Libin Cardiovascular Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
  • 4Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam University Medical Centre, Amsterdam, the Netherlands
  • 5Department of Cardiology, Royal Brompton Hospital, London, United Kingdom
  • 6Division of Cardiovascular Medicine, University of Wisconsin, Madison
  • 7Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
  • 8Division of Cardiology, Department of Pediatrics, University of Michigan, Ann Arbor
  • 9Centre for Cardiovascular Innovation, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 10Division of Cardiology, Montreal Heart Institute, University of Montreal, Montreal, Québec, Canada
  • 11Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
  • 12currently affiliated with Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
  • 13Children’s Heart Centre, Division of Cardiology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
  • 14Section of Cardiac Electrophysiology, Division of Cardiology, Western University, London, Ontario, Canada
  • 15now affiliated with Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
  • 16Member of the European Reference Network ERN GUARD-Heart
  • 17Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  • 18Department of Medicine, Aarhus University, Aarhus, Denmark
JAMA Cardiol. 2022;7(1):84-92. doi:10.1001/jamacardio.2021.4458
Key Points

Question  What is the clinical spectrum of calcium-release deficiency syndrome (CRDS), a recently described arrhythmogenic syndrome caused by a ryanodine receptor 2 (RyR2) loss-of-function variant?

Findings  In this cohort study of patients undergoing testing for CRDS and family-based screening, 6 RyR2 loss-of-function variants were found in 6 probands and 13 family members with life-threatening arrhythmias without evident catecholaminergic polymorphic ventricular tachycardia during exercise testing; variants were associated with normal or near-normal exercise testing results, features consistent with CRDS. Ventricular fibrillation was preceded by a spontaneous ectopy pattern similar to the long-burst, long-pause, short-coupled ventricular extra-stimulus CRDS protocol.

Meaning  These findings suggest that CRDS is an emerging syndrome that differs from RyR2 gain-of-function catecholaminergic polymorphic ventricular tachycardia.

Abstract

Importance  Calcium-release deficiency syndrome (CRDS), which is caused by loss-of-function variants in cardiac ryanodine receptor 2 (RyR2), is an emerging cause of ventricular fibrillation. However, the lack of complex polymorphic/bidirectional ventricular tachyarrhythmias during exercise stress testing (EST) may distinguish it from catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, in the first clinical series describing the condition, mouse and human studies showed that the long-burst, long-pause, short-coupled ventricular extra stimulus (LBLPS) electrophysiology protocol reliably induced CRDS ventricular arrhythmias. Data from larger populations with CRDS and its associated spectrum of disease are lacking.

Objective  To further insight into CRDS through international collaboration.

Design, Setting, and Participants  In this multicenter observational cohort study, probands with unexplained life-threatening arrhythmic events and an ultrarare RyR2 variant were identified. Variants were expressed in HEK293 cells and subjected to caffeine stimulation to determine their functional impact. Data were collected from September 1, 2012, to March 6, 2021, and analyzed from August 9, 2015, to March 6, 2021.

Main Outcomes and Measures  The functional association of RyR2 variants found in putative cases of CRDS and the associated clinical phenotype(s).

Results  Of 10 RyR2 variants found in 10 probands, 6 were loss-of-function, consistent with CRDS (p.E4451del, p.F4499C, p.V4606E, p.R4608Q, p.R4608W, and p.Q2275H) (in 4 [67%] male and 2 [33%] female probands; median age at presentation, 22 [IQR, 8-34] years). In 5 probands with a documented trigger, 3 were catecholamine driven. During EST, 3 probands with CRDS had no arrhythmias, 1 had a monomorphic couplet, and 2 could not undergo EST (deceased). Relatives of the decedents carrying the RyR2 variant did not have EST results consistent with CPVT. After screening 3 families, 13 relatives were diagnosed with CRDS, including 3 with previous arrhythmic events (23%). None had complex ventricular tachyarrhythmias during EST. Among the 19 confirmed cases with CRDS, 10 had at least 1 life-threatening event at presentation and/or during a median follow-up of 7 (IQR, 6-18) years. Two of the 3 device-detected ventricular fibrillation episodes were induced by a spontaneous LBLPS-like sequence. β-Blockers were used in 16 of 17 surviving patients (94%). Three of 16 individuals who were reportedly adherent to β-blocker therapy (19%) had breakthrough events.

Conclusions and Relevance  The results of this study suggest that calcium-release deficiency syndrome due to RyR2 loss-of-function variants mechanistically and phenotypically differs from CPVT. Ventricular fibrillation may be precipitated by a spontaneous LBLPS-like sequence of ectopy; however, CRDS remains difficult to recognize clinically. These data highlight the need for better diagnostic tools and treatments for this emerging condition.

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