An interventional study of Pacing in Calcium Release Deficiency Syndrome (CRDS), sponsored by Population Health Research Institute. Recruiting at 20 sites in 7 countries. Per ClinicalTrials.gov, last updated 2026-07-22.
Sponsored by Population Health Research Institute · Not applicable, Interventional, and Diagnostic
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.
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.
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Cohort 1: Calcium Release Deficiency Syndrome (CRDS) Cases
Inclusion criteria:
Exclusion criteria:
Cohort 2: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cases
Inclusion criteria:
Exclusion criteria:
Cohort 3: Survivors of Unexplained Cardiac Arrest (UCA)
Inclusion criteria:
Exclusion criteria:
Use of a QT prolonging medication at the time of the burst pacing maneuvers
Cohort 4: SVT controls
Inclusion criteria:
Exclusion criteria:
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
1. Ventricular 10 beat burst at 500ms (120bpm) 2. Ventricular 10 beat burst at 400ms (150bpm) 3. Atrial 10 beat burst at 500ms (120bpm) 4. Atrial 10 beat burst at 400ms (150bpm).
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
Time frame: 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
Time frame: At time of pacing maneuver
Absolute QT value
Absolute QT value on first post-pause sinus beat
Time frame: At time of pacing maneuver
Absolute T-wave amplitude
Absolute T-wave amplitude on first post-pause sinus beat
Time frame: At time of pacing maneuver
Plan to share: No
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Population Health Research Institute