Clinical trial NCT06188689: Evaluation of A Clinical Diagnostic Test for CRDS
Official title: Evaluation of a Clinical Diagnostic Test for Calcium Release Deficiency Syndrome: The DIAGNOSE CRDS Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Calcium Release Deficiency Syndrome (CRDS)
Keywords: cardiac arrhythmia, sudden cardiac death, cardiac ryanodine receptor, unexplained cardiac arrest
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2024-01-03
Enrollment: 400
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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.

Eligibility criteria: 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

Primary outcomes:
measure: ΔT-wave amplitude value
timeFrame: At time of pacing maneuver
measure: ΔQT value
timeFrame: At time of pacing maneuver
Secondary outcomes:
measure: Absolute QT value
timeFrame: At time of pacing maneuver
measure: Absolute T-wave amplitude
timeFrame: At time of pacing maneuver
Other outcomes:
Locations:
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Vancouver
country: Canada
facility: Children's & Women's Health Centre of British Columbia
state: British Columbia
city: Vancouver
country: Canada
facility: The University of British Columbia
state: British Columbia
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre - University Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Heart Institute
state: Ontario
city: Montréal
country: Canada
facility: Montréal Heart Institute
state: Quebec
city: Québec City
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval
state: Quebec
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
Study officials:
affiliation: Shaare Zedek Medical Center
name: Ziv Dadon, MD
role: STUDY_DIRECTOR
affiliation: McMaster University
name: Jason D Roberts, MD MAS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Calgary
name: Wayne Chen, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.