CIQTP Prolongation : Role and Mechanism in Sudden Cardiac Death
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 394
- 试验地点
- 4
- 主要终点
- Number of families diagnosed with a CIQTP syndrome compared to the number of families who underwent a familial screening after a sudden cardiac death
研究概览
简要总结
Despite major progress in molecular and phenotypic characterization of primary electrical disorders, many (aborted) sudden cardiac deaths (SCD) occur in young victims without identifiable abnormalities. Investigator recently identified, in 4 families presenting unexplained SCD, a new arrhythmia entity (catecholamine-induced QT prolongation; CIQTP) characterized by normal QT duration at rest but major QT lengthening during mental stress test (MST).
Investigators aim to determine the prevalence of this new phenotype in unexplained SCD and identify its underlying pathophysiological mechanism.
More specifically, investigators aim to:
- determine the prevalence of CIQTP in unexplained SCD and identify new affected families;
- identify the role of mental stress in QT prolongation;
- identify the genetics basis underlying this life threatening disease;
- perform transcriptomic and electrophysiological profiling of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from CIQTP patients to identify putative biomarkers and pathophysiological mechanisms.
MST will be performed, additionally to the conventional screening, in families affected by unexplained SCD or long QT syndrome (LQTS) referred to university hospitals of Nantes, Rennes, Tours and Brest. Relevance of the MST on the different type of LQTS will be evaluated and compared to conventional provocative tests (epinephrine, exercise).
Whole-genome sequencing will first be performed in 3 distantly affected relatives within each of the 4 largest families identified. As previously performed in Nantes, analysis of the shared rare variants will allow identifying gene(s) associated with the disease.
Transcriptomic (high-throughput 3' Digital Gene Expression mRNA sequencing) and electrophysiological (96-well automated optical recordings of action potentials and patch-clamp recordings of ionic currents, using specific ion channel activators and inhibitors) profiling will be performed on iPSC-CMs from 2 affected and one unaffected first-degree relatives of these 4 large families.
详细描述
Sudden cardiac death (SCD) is a major cause of death in developed countries. An estimated 40,000 to 50,000 individuals die suddenly each year in France. Most of these deaths involve elderly people and are related to coronary artery disease. However, an estimated 4000 to 5000 individuals between 1 and 45 years of age die suddenly each year in France. SCD often occurs in young victims without identifiable ECG abnormalities and without structural defects. In consequence, most SCD events in the young adult remain unexplained and are classified in an elusive group known as idiopathic ventricular fibrillation (IVF).
Investigator recently identified a new arrhythmic entity (catecholamine-induced QT prolongation; CIQTP) responsible for SCD and characterized by normal QT duration at rest but major QT lengthening during mental stress test. The aim of this translational project is to determine the prevalence of this new phenotype of rare disease in unexplained SCD and identify its underlying pathophysiological mechanism.
The use of mental stress test could be extended to other inherited arrhythmic disease such as long QT syndrome. Given the potential of identification of new affected relatives it may lead to a significant reduction of the risk of sudden cardiac death recurrence in a family.
The main issue of this project is to describe the clinical implication and the pathophysiological mechanism of this new syndrome leading to SCD.
Based on our recent description of this cathecholamine induced QT prolongation, the investigators hypothesize that:
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Relatives seen for a familial screening after an unexplained sudden cardiac death in a young member of their family (<45 years old).
- •Patients affected with CIQTP characterized by normal QT duration at rest but major QT lengthening during mental stress test
- •Signed consent
排除标准
- •Patients who underwent a sudden cardiac death with an identified cause of the decease after an autopsy
- •Patients under trusteeship or under guardianship
- •Patients who didn't give their consent or who is not able to
结局指标
主要结局
Number of families diagnosed with a CIQTP syndrome compared to the number of families who underwent a familial screening after a sudden cardiac death
时间窗: 12 months
次要结局
- Identification of genetics variants involved in the occurrence of CIQTP syndrome(24 months)
- gene and ionic current expression modifications between healthy and affected relatives(24 months)