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.
Conditions
Calcium Release Deficiency Syndrome (CRDS)
Recruitment Status
Recruiting
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
Intervention
Intervention Type
Intervention Name
Diagnostic Test
Pacing
Phase
Not Applicable
Gender
All
Min Age
N/A
Max Age
N/A
Download Date
January 3, 2024
Principal Investigator
This field has been modified from ClinicalTrials.gov to show a contact specific to Boston Children's.
Primary Contact Information
dominic.abrams@cardio.chboston.org
This field has been modified from ClinicalTrials.gov to show a contact specific to Boston Children's.
For more information on this trial, visit clinicaltrials.gov.
Contact
For more information and to contact the study team: