Evaluation of A Clinical Diagnostic Test for CRDS

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Диагностический тест 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).

Первичные конечные точки

• ΔT-wave amplitude value [Срок оценки: At time of pacing maneuver]
• ΔQT value [Срок оценки: At time of pacing maneuver]

Вторичные конечные точки (2)

• Absolute QT value [Срок оценки: At time of pacing maneuver]
• Absolute T-wave amplitude [Срок оценки: At time of pacing maneuver]

Критерии участия

Cohort 1: Calcium Release Deficiency Syndrome (CRDS) Cases

Критерии включения

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

Критерии исключения

• Unable to provide informed consent

Cohort 2: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cases

Критерии включения

• 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

Критерии исключения

• 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)

Критерии включения

• 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\*

Критерии исключения

• 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

Критерии включения

• Undergoing an invasive electrophysiology study

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Диагностика

Центры проведения

Канада · 10 центров

• University of Calgary — Calgary
• Alberta Health Services — Edmonton
• Children's & Women's Health Centre of British Columbia — Vancouver
• The University of British Columbia — Vancouver
• Hamilton General Hospital — Hamilton
• London Health Sciences Centre - University Hospital — London
• Ottawa Heart Institute — Ottawa
• Toronto General Hospital — Toronto
• … и ещё 2 центра

США · 4 центра

• University of California — San Francisco
• Boston Children's Hospital — Boston
• Mayo Clinic — Rochester
• University of Washington — Seattle

Бельгия · 2 центра

• Antwerp University Hospital — Edegem
• Universitair Ziekenhuis Brussel — Brussels

Дания · 1 центр

• Aarhus University Hospital — Aarhus

Франция · 1 центр

• CHU de Bordeaux — Bordeaux

Израиль · 1 центр

• Shaare Zedek Medical Center — Jerusalem

Великобритания · 1 центр

• Oxford University Hospitals — Oxford

Публикации

• 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 PMID 33536282
• 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. PMID 21699856
• 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. PMID 34949103
• 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 J PMID 34730774
• Ni M, Dadon Z, Ormerod JOM, Saenen J, Hoeksema WF, Antiperovitch P, Tadros R, Christiansen MK, Steinberg C, Arnaud M, Tian S, Sun B, Estillore JP, Wang R, Khan HR, Roston TM, Mazzanti A, Giudicessi JR, Siontis KC, Alak A, Acosta JG, Divakara Menon SM, Tan NS, van der Werf C, Nazer B, Vivekanantham H, Pandya T, Cunningham J, Gula LJ, Wong JA, Amit G, Scheinman MM, Krahn AD, Ackerman MJ, Priori SG, PMID 38900490

Идентификаторы

NCT: NCT06188689 · 14546

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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