TY - JOUR
T1 - Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome
AU - Roston, Thomas M.
AU - Wei, Jinhong
AU - Guo, Wenting
AU - Li, Yanhui
AU - Zhong, Xiaowei
AU - Wang, Ruiwu
AU - Estillore, John Paul
AU - Peltenburg, Puck J.
AU - Noguer, Ferran Rosés I.
AU - Till, Jan
AU - Eckhardt, Lee L.
AU - Orland, Kate M.
AU - Hamilton, Robert
AU - Lapage, Martin J.
AU - Krahn, Andrew D.
AU - Tadros, Rafik
AU - Vinocur, Jeffrey M.
AU - Kallas, Dania
AU - Franciosi, Sonia
AU - Roberts, Jason D.
AU - Wilde, Arthur A. M.
AU - Jensen, Henrik K.
AU - Sanatani, Shubhayan
AU - Chen, S. R. Wayne
N1 - Funding Information: reported receiving personal fees from My Gene Counsel outside the submitted work. Dr Wilde reported serving as a member of the scientific advisory board from LQT Therapeutics outside the submitted work. Dr Jensen reported receiving grants from the Novo Nordisk Foundation, Denmark, and personal fees from Biosense Webster, Inc, and Abbott Denmark outside the submitted work. Dr Sanatani reported receiving grants from Heart and Stroke Foundation during the conduct of the study and serving as medical advisor for emtelligent outside the submitted work. No other disclosures were reported. Funding Information: Funding/Support: This study was supported by the George Mines Traveling Fellowship in Cardiac Electrophysiology (Dr Roston); the University of British Columbia Clinician Investigator Program and a Friedman Scholar in Health (Dr Roston); the Libin Cardiovascular Institute and Cumming School of Medicine Postdoctoral Fellowship Award (Dr Wei); the Alberta Innovates–Health Solutions Studentship Award (Dr Guo); research grant PJT-155940 from the Canadian Institutes of Health Research (Dr Chen); grant CVON 2012-10 PREDICT2 from the Royal Netherlands Academy of Sciences (Dr Wilde); the E-Rare Joint Transnational Call for Proposals 2015 “Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science” (Drs Wilde, Sanatani, and Chen); grant NNF18OC0031258 from the Novo Nordisk Foundation (Dr Jensen); the Gary and Marie Weiner Professorship in Cardiovascular Medicine Research (Dr Eckhardt); the Sauder Family and Heart and Stroke Foundation Chair in Cardiology (Dr Krahn); the Paul Brunes Chair in Heart Rhythm Disorders (Dr Krahn); the Paul Albrechsten Foundation (Dr Krahn); and the Heart and Stroke Foundation Chair in Cardiovascular Research END611955 (Dr Chen). Publisher Copyright: © 2021 American Medical Association. All rights reserved.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118967134&partnerID=8YFLogxK
U2 - https://doi.org/10.1001/jamacardio.2021.4458
DO - https://doi.org/10.1001/jamacardio.2021.4458
M3 - Article
C2 - 34730774
SN - 2380-6583
VL - 7
SP - 84
EP - 92
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 1
ER -