Evaluation of A Clinical Diagnostic Test for CRDS (DIAGNOSE CRDS)

Evaluation of a Clinical Diagnostic Test for Calcium Release Deficiency Syndrome: The DIAGNOSE CRDS Study

Calcium Release Deficiency Syndrome (CRDS) is a novel inherited arrhythmia syndrome secondary to RyR2 loss-of-function that confers a risk of sudden cardiac death. Diagnosis of CRDS presently requires cellular-based in vitro confirmation that an RyR2 variant causes loss-of-function. We hypothesize that CRDS can be diagnosed clinically through evaluation of the repolarization response to brief tachycardia, mediated by cardiac pacing, and a subsequent pause.

Study Overview

• Status: Recruiting
• Conditions: Calcium Release Deficiency Syndrome (CRDS)
• Intervention / Treatment: Diagnostic test: Pacing

Detailed Description

RyR2 loss-of-function variants have recently been established as causative for a new disease termed calcium release deficiency syndrome (CRDS) that confers a risk of malignant ventricular arrhythmias and sudden cardiac death. RyR2 encodes the cardiac ryanodine receptor, the calcium release channel on the sarcoplasmic reticulum that mediates excitation-contraction coupling through calcium-induced calcium-release. In contrast to CRDS, pathogenic RyR2 gain-of-function variants result in an autosomal dominant form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The adrenergic-mediated ventricular arrhythmias characteristic of CPVT can be readily reproduced on exercise stress testing (EST), making EST the standard clinical diagnostic tool for CPVT.

In contrast to CPVT, the CRDS clinical phenotype is concealed with standard cardiac testing tools and its diagnosis presently requires cellular-based in vitro confirmation that an RyR2 variant causes loss-of-function. Beyond the significant time delay associated with in vitro functional analysis, this testing requires specialized expertise that is not widely available and remains research-based, making it impractical for routine use in clinical care. In this overall context, it is likely that the vast majority of global CRDS cases have yet to be diagnosed.

A prior report of an "atypical CPVT" family carrying an RyR2-p.M4109R variant observed marked and transient repolarization changes following pacing mediated tachycardia and a subsequent pause. Since publication of this report, in vitro characterization of the RyR2-p.M4109R variant has confirmed its being loss-of-function and the familial diagnosis has been revised to CRDS. Driven by these observations and promising preliminary findings, the DIAGNOSE CRDS study seeks to further investigate this apparent electrocardiographic signature of CRDS following brief tachycardia and subsequent pause as a potential method to clinically diagnose the condition.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1090
    • Not yet recruiting
    • Universitair Ziekenhuis Brussel (UZB)
    • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • Principal Investigator: Carlo de Asmundis, MD, PhD
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • Not yet recruiting
      • Antwerp University Hospital (UZA)
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
      • Principal Investigator: Johan Saenen, MD
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3N1
      • Not yet recruiting
      • BC Children's Hospital
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
      • Principal Investigator: Shubhayan Sanatani, MD
    • Vancouver, British Columbia, Canada, V6T 1Z3
      • Not yet recruiting
      • The University of British Columbia
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
      • Principal Investigator: Thomas M Roston, MD
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Recruiting
      • Hamilton General Hospital
      • Principal Investigator: Jason D Roberts, MD MAS
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • London, Ontario, Canada, N6A 5A5
      • Not yet recruiting
      • London Health Sciences Centre - University Hospital
      • Principal Investigator: Habib R Khan, MD
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • Ottawa, Ontario, Canada
      • Not yet recruiting
      • Ottawa Heart Institute
      • Principal Investigator: Simon Hansom, MD
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • Toronto, Ontario, Canada
      • Not yet recruiting
      • Toronto General Hospital
      • Principal Investigator: Michael H Gollob, MD
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
  • Quebec
    • Montréal, Quebec, Canada, H1T 1C8
      • Not yet recruiting
      • Montreal Heart Institute
      • Principal Investigator: Rafik Tadros, MD PhD
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • Québec City, Quebec, Canada, G1V 4G5
      • Recruiting
      • Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval
      • Principal Investigator: Christian Steinberg, MD
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
• Denmark
  • Aarhus, Denmark, DK-8200 N
    • Recruiting
    • Aarhus University Hospital
    • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • Principal Investigator: Henrik Jensen, MD
• France
  • Pessac, France
    • Not yet recruiting
    • Hôpital Cardiologique Du Haut-Lévêque
    • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • Principal Investigator: Frederic Sacher, MD
• Israel
  • Jerusalem, Israel, 9103102
    • Not yet recruiting
    • Shaare Zedek Medical Center
    • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
    • Principal Investigator: Ziv Dadon, MD
• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, 0X3 9DU
      • Not yet recruiting
      • Oxford Heart Centre, John Radcliffe Hospital
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
      • Principal Investigator: Julian O. M. Ormerod, MD
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Not yet recruiting
      • Boston Children's Hospital
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
      • Principal Investigator: Dominic Abrams, MD
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Not yet recruiting
      • Mayo Clinic
      • Contact: Project Manager; Phone Number: 905-521-2100; Email: crds@phri.ca
      • Principal Investigator: John R Giudicessi, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Cohort 1: Calcium Release Deficiency Syndrome (CRDS) Cases

Inclusion criteria:

• Presence of an RyR2 variant confirmed to be loss-of-function on in vitro testing

Exclusion criteria:

• Unable to provide informed consent

Cohort 2: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cases

Inclusion criteria:

• Satisfy a clinical phenotype consistent with the Expert Consensus Statement
• Presence of a confirmed or presumed pathogenic gain-of-function RyR2 variant OR homozygous or compound heterozygous for likely pathogenic/pathogenic CASQ2 variants

Exclusion criteria:

• Unable to provide informed consent
• Use of a QT prolonging medication, aside from flecainide, at the time of the burst pacing maneuvers

Cohort 3: Survivors of Unexplained Cardiac Arrest (UCA)

Inclusion criteria:

• Cardiac arrest requiring cardioversion or defibrillation that remains unexplained following an ECG, echocardiogram, coronary assessment, cardiac MRI, and exercise treadmill test
• Undergone genetic testing that includes screening of RyR2*

Exclusion criteria:

• Unable to provide informed consent

• Use of a QT prolonging medication at the time of the burst pacing maneuvers

  • Among survivors of UCA that possess a rare RyR2 variant in the absence of a CPVT phenotype, in vitro functional testing will be performed in order to confirm it is not loss- or gain-of-function (and will be arranged through the laboratory of Dr. Wayne Chen at the University of Calgary).

Cohort 4: SVT controls

Inclusion criteria:

• Undergoing an invasive electrophysiology study

Exclusion criteria:

• Ventricular cardiomyopathy
• Ventricular pre-excitation
• Long QT syndrome
• Use of a QT prolonging medication at the time of the EP study
• Use of a Class I or Class III anti-arrhythmic drug at the time of the EP study
• Known obstructive coronary artery disease (existing coronary stenosis >50%)
• Unable to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pacing; Separate ventricular and atrial pacing trains will be administered at different cycle lengths and the ventricular repolarization response on the first sinus beat following the subsequent pause will be evaluated.	Diagnostic test: Pacing; Ventricular 10 beat burst at 500ms (120bpm); Ventricular 10 beat burst at 400ms (150bpm); Atrial 10 beat burst at 500ms (120bpm); Atrial 10 beat burst at 400ms (150bpm).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ΔT-wave amplitude value	T-wave amplitude on first post-pause sinus beat subtracted by the T-wave amplitude on the last sinus beat prior to pacing	At time of pacing maneuver
ΔQT value	Absolute QT value on first post-pause sinus beat subtracted by the absolute QT value on the last sinus beat prior to pacing	At time of pacing maneuver

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute QT value	Absolute QT value on first post-pause sinus beat	At time of pacing maneuver
Absolute T-wave amplitude	Absolute T-wave amplitude on first post-pause sinus beat	At time of pacing maneuver

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Study Director: Ziv Dadon, MD, Shaare Zedek Medical Center; Principal Investigator: Jason D Roberts, MD MAS, McMaster University; Principal Investigator: Wayne Chen, PhD, University of Calgary

Publications and helpful links

General Publications

• Sun B, Yao J, Ni M, Wei J, Zhong X, Guo W, Zhang L, Wang R, Belke D, Chen YX, Lieve KVV, Broendberg AK, Roston TM, Blankoff I, Kammeraad JA, von Alvensleben JC, Lazarte J, Vallmitjana A, Bohne LJ, Rose RA, Benitez R, Hove-Madsen L, Napolitano C, Hegele RA, Fill M, Sanatani S, Wilde AAM, Roberts JD, Priori SG, Jensen HK, Chen SRW. Cardiac ryanodine receptor calcium release deficiency syndrome. Sci Transl Med. 2021 Feb 3;13(579):eaba7287. doi: 10.1126/scitranslmed.aba7287.
• Nof E, Belhassen B, Arad M, Bhuiyan ZA, Antzelevitch C, Rosso R, Fogelman R, Luria D, El-Ani D, Mannens MM, Viskin S, Eldar M, Wilde AA, Glikson M. Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene. Heart Rhythm. 2011 Oct;8(10):1546-52. doi: 10.1016/j.hrthm.2011.05.016. Epub 2011 May 26.
• Ormerod JOM, Ormondroyd E, Li Y, Taylor J, Wei J, Guo W, Wang R, Sarton CNS, McGuire K, Dreau HMP, Taylor JC, Ginks MR, Rajappan K, Chen SRW, Watkins H. Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome. Circ Genom Precis Med. 2022 Feb;15(1):e003589. doi: 10.1161/CIRCGEN.121.003589. Epub 2021 Dec 24.
• 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. 2022 Jan 1;7(1):84-92. doi: 10.1001/jamacardio.2021.4458.

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2023
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: December 18, 2023
• First Submitted That Met QC Criteria: December 18, 2023
• First Posted (Estimated): January 3, 2024

Study Record Updates

• Last Update Posted (Estimated): January 3, 2024
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: cardiac arrhythmia, sudden cardiac death, cardiac ryanodine receptor, unexplained cardiac arrest
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Syndrome
• Other Study ID Numbers: 14546

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No