CIQTP Prolongation : Role and Mechanism in Sudden Cardiac Death

NCT03387072 | Completed

• 1 other identifier: RC17_0357
• Study Type: observational
• Target: 394
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Sudden Cardiac Death

Keywords

Mental stress; Sudden cardiac death; arrhythmias; long QT syndrome

Outcome Measures

Primary Outcomes (1)

• Number of families diagnosed with a CIQTP syndrome compared to the number of families who underwent a familial screening after a sudden cardiac death

  12 months

Secondary Outcomes (2)

• 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

Study Arms (2)

Patients affected with CIQTP

Patients affected with catecholamine-induced QT prolongation (CIQTP)

Other: Non interventional study

Healthy relatives of patients affected with CIQTP

Healthy relatives of patients affected with CIQTP identified during the familial screening

Other: Non interventional study

Interventions

Non interventional study OTHER

mental stress test and Blood (or salivary) sample

Healthy relatives of patients affected with CIQTP; Patients affected with CIQTP

Eligibility Criteria

• Sex: all
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients will be recruited by the Hereditary or rare heart rhythm disorders reference centre of the Nantes University Hospital, which specialises in the management of patients with sudden death risk pathologies and family screening. The reference centre works in network with the regional competence centres, including the Brest, Rennes and Tours University Hospital Centres. Patients will be included in a cardiological consultation or day hospitalization as part of the family screening for sudden death. Family screening is carried out within the usual framework of patient care and in accordance with international recommendations.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Nantes University Hospital: lead

Study Sites (4)

Brest University Hospital

Brest, 29609, France

Location

Nantes University Hospital

Nantes, 44093, France

Location

Rennes University Hospital

Rennes, 35000, France

Location

Tours University Hospital

Tours, 37000, France

Location

Biospecimen

Retention: SAMPLES WITH DNA

Blood sample (10mL ) for adult patient and teenagers and salivary sample for minor patients (under 12 years of age)

MeSH Terms

Conditions

Death, Sudden, Cardiac; Stress, Psychological; Arrhythmias, Cardiac; Long QT Syndrome

Condition Hierarchy (Ancestors)

Heart Arrest; Heart Diseases; Cardiovascular Diseases; Death, Sudden; Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavioral Symptoms; Behavior; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Jean-Baptiste GOURRAUD, Dr

  Nantes University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2017
• First Posted: December 29, 2017
• Study Start: March 14, 2018
• Primary Completion: March 16, 2021
• Study Completion: March 16, 2021
• Last Updated: March 17, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (4)