Evaluation of A Clinical Diagnostic Test for CRDS

Not Applicable

Recruiting

• Conditions: Calcium Release Deficiency Syndrome (CRDS)

• Registration Number: NCT06188689
• Lead Sponsor: Population Health Research Institute

Brief Summary

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.

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 Timeline

• Study Start: 2023-02-02
• Study First Submitted: 2023-12-18
• Study First Submitted QC: 2023-12-18
• Study First Posted: 2024-01-03
• Status Verified: 2025-10
• Last Update Submitted: 2025-10-15
• Last Update Posted: 2025-10-20
• Primary Completion: 2025-12
• Study Completion: 2026-03-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Absolute QT value	At time of pacing maneuver	Absolute QT value on first post-pause sinus beat
Absolute T-wave amplitude	At time of pacing maneuver	Absolute T-wave amplitude on first post-pause sinus beat

Trial Locations

Locations (16)

Oxford University Hospitals; 🇬🇧 Oxford, Oxfordshire, United Kingdom

University of California; 🇺🇸 San Francisco, California, United States

University of Washington; 🇺🇸 Seattle, Washington, United States

Antwerp University Hospital; 🇧🇪 Edegem, Antwerp, Belgium

Universitair Ziekenhuis Brussel; 🇧🇪 Brussels, Belgium

Children's & Women's Health Centre of British Columbia; 🇨🇦 Vancouver, British Columbia, Canada

The University of British Columbia; 🇨🇦 Vancouver, British Columbia, Canada

Hamilton General Hospital; 🇨🇦 Hamilton, Ontario, Canada

London Health Sciences Centre - University Hospital; 🇨🇦 London, Ontario, Canada

Ottawa Heart Institute; 🇨🇦 Ottawa, Ontario, Canada

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