2. Academic Validation
  3. Cardiac ryanodine receptor calcium release deficiency syndrome

Cardiac ryanodine receptor calcium release deficiency syndrome

  • Sci Transl Med. 2021 Feb 3;13(579):eaba7287. doi: 10.1126/scitranslmed.aba7287.
Bo Sun 1 2,  Jinjing Yao 1,  Mingke Ni 1,  Jinhong Wei 1,  Xiaowei Zhong 1,  Wenting Guo 1,  Lin Zhang 1,  Ruiwu Wang 1,  Darrell Belke 1,  Yong-Xiang Chen 1,  Krystien V V Lieve 3 4,  Anders K Broendberg 5,  Thomas M Roston 6,  Ivan Blankoff 7,  Janneke A Kammeraad 8,  Johannes C von Alvensleben 9,  Julieta Lazarte 10,  Alexander Vallmitjana 11,  Loryn J Bohne 12,  Robert A Rose 12,  Raul Benitez 11,  Leif Hove-Madsen 13,  Carlo Napolitano 4 14 15,  Robert A Hegele 10,  Michael Fill 16,  Shubhayan Sanatani 17,  Arthur A M Wilde 18 4,  Jason D Roberts 19,  Silvia G Priori 20 14 15 21,  Henrik K Jensen 22,  S R Wayne Chen 23 16
Affiliations

Affiliations

  • 1 Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 4Z6, Canada.
  • 2 Medical School, Kunming University of Science and Technology, Kunming 650504, China.
  • 3 Amsterdam University Medical Centre, location AMC, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam 1105AZ, Netherlands.
  • 4 European Reference Network 'ERN GUARD-Heart', Amsterdam, Netherlands.
  • 5 Department of Cardiology, Aarhus University Hospital, and Department of Clinical Medicine, Health, Aarhus University, Palle Juul-Jensens Blv 99, DK-8200 Aarhus N, Denmark.
  • 6 Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
  • 7 C.H.U. Charleroi, Hôpital Civil Marie Curie Chaussée de Bruxelles 140 6042 Charleroi, Belgium.
  • 8 Department of Pediatric Cardiology, Sophia Children's Hospital, Erasmus University Medical Centre, Doctor Molewaterplein 40, 3015 GD Rotterdam, Netherlands.
  • 9 Division of Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado, Aurora, CO 80045, USA.
  • 10 Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5B7, Canada.
  • 11 Department of Automatic Control, Universitat Politècnica de Catalunya, 08034 Barcelona, Spain.
  • 12 Departments of Cardiac Sciences and Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada.
  • 13 Biomedical Research Institute Barcelona (IIBB-CSIC) and IIB Sant Pau, Hospital de Sant Pau, Barcelona 08025, Spain.
  • 14 Division of Cardiology and Molecular Cardiology, IRCCS Maugeri Foundation-University of Pavia, 27100 Pavia, Italy.
  • 15 Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
  • 16 Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL 60612, USA.
  • 17 Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada. swchen@ucalgary.ca hkjensen@clin.au.dk silvia.priori@icsmaugeri.it jason.roberts@lhsc.on.ca a.a.wilde@amsterdamumc.nl ssanatani@cw.bc.ca.
  • 18 Amsterdam University Medical Centre, location AMC, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam 1105AZ, Netherlands. swchen@ucalgary.ca hkjensen@clin.au.dk silvia.priori@icsmaugeri.it jason.roberts@lhsc.on.ca a.a.wilde@amsterdamumc.nl ssanatani@cw.bc.ca.
  • 19 Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON N6A 5A5, Canada. swchen@ucalgary.ca hkjensen@clin.au.dk silvia.priori@icsmaugeri.it jason.roberts@lhsc.on.ca a.a.wilde@amsterdamumc.nl ssanatani@cw.bc.ca.
  • 20 European Reference Network 'ERN GUARD-Heart', Amsterdam, Netherlands. swchen@ucalgary.ca hkjensen@clin.au.dk silvia.priori@icsmaugeri.it jason.roberts@lhsc.on.ca a.a.wilde@amsterdamumc.nl ssanatani@cw.bc.ca.
  • 21 Molecular Cardiology Laboratory, Centro de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain.
  • 22 Department of Cardiology, Aarhus University Hospital, and Department of Clinical Medicine, Health, Aarhus University, Palle Juul-Jensens Blv 99, DK-8200 Aarhus N, Denmark. swchen@ucalgary.ca hkjensen@clin.au.dk silvia.priori@icsmaugeri.it jason.roberts@lhsc.on.ca a.a.wilde@amsterdamumc.nl ssanatani@cw.bc.ca.
  • 23 Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 4Z6, Canada. swchen@ucalgary.ca hkjensen@clin.au.dk silvia.priori@icsmaugeri.it jason.roberts@lhsc.on.ca a.a.wilde@amsterdamumc.nl ssanatani@cw.bc.ca.
PMID: 33536282 DOI: 10.1126/scitranslmed.aba7287
Abstract

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to Catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 CA2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.

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