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Roston TM, Wei J, Guo W, et al. Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome. JAMA Cardiol. 2021;doi: 10.1001/jamacardio.2021.4458.
Roston, T. M., Wei, J., Guo, W., Li, Y., Zhong, X., Wang, R., Estillore, J. P., Peltenburg, P. J., Noguer, F. R. I., Till, J., Eckhardt, L. L., Orland, K. M., Hamilton, R., LaPage, M. J., Krahn, A. D., Tadros, R., Vinocur, J. M., Kallas, D., Franciosi, S., Roberts, J. D., Wilde, A. A. M., Jensen, H. K., Sanatani, S., & Chen, S. R. W. (2021). Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome. JAMA cardiology, . https://doi.org/10.1001/jamacardio.2021.4458
Roston, Thomas M, et al. "Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome." JAMA cardiology vol. (2021). doi: https://doi.org/10.1001/jamacardio.2021.4458
Roston TM, Wei J, Guo W, Li Y, Zhong X, Wang R, Estillore JP, Peltenburg PJ, Noguer FRI, Till J, Eckhardt LL, Orland KM, Hamilton R, LaPage MJ, Krahn AD, Tadros R, Vinocur JM, Kallas D, Franciosi S, Roberts JD, Wilde AAM, Jensen HK, Sanatani S, Chen SRW. Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome. JAMA Cardiol. 2021 Nov 03; doi: 10.1001/jamacardio.2021.4458. Epub 2021 Nov 03. PMID: 34730774; PMCID: PMC8567190.
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JAMA Cardiol. 2021 Nov 03; doi: 10.1001/jamacardio.2021.4458. Epub 2021 Nov 03.

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

JAMA cardiology

Thomas M Roston, Jinhong Wei, Wenting Guo, Yanhui Li, Xiaowei Zhong, Ruiwu Wang, John Paul Estillore, Puck J Peltenburg, Ferran Rosés I Noguer, Jan Till, Lee L Eckhardt, Kate M Orland, Robert Hamilton, Martin J LaPage, Andrew D Krahn, Rafik Tadros, Jeffrey M Vinocur, Dania Kallas, Sonia Franciosi, Jason D Roberts, Arthur A M Wilde, Henrik K Jensen, Shubhayan Sanatani, S R Wayne Chen

Affiliations

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

PMID: 34730774 PMCID: PMC8567190 DOI: 10.1001/jamacardio.2021.4458

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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