Validation of a Non Invasive Blood Marker of SIDS and Vagal Disorders

Circulating Biomarker(s) of Muscarinic Receptor Overexpression and Vagal Disorders.

Context

The investigators recently demonstrated a highly significant increase in muscarinic receptor density in the myocardium of infants deceased from sudden infant death syndrome (SIDS) compared to those of infants deceased from identified causes 1. Muscarinic receptor overexpression was found in all SIDS samples studied to date. It was associated with an average increase in acetylcholinesterase activity, appearing as a compensatory mechanism to oppose the cardiac muscarinic receptor overexpression. Similar vago-cardiac abnormalities were detected in a rabbit model of vagal hyperreactivity that the investigators first described some years ago2. In these hyperreactive animals, expression of muscarinic receptors was also enhanced in blood white cells. Noticeably, the pattern of changes in these cells paralleled the pattern of changes in the heart. Thus, muscarinic abnormalities in cardiac tissues could be inferred with high confidence from those measured in lymphocytes.This was the first report of a vago-cardiac abnormality in sudden infant death syndrome. The investigators findings also provided original and important perspectives for the identification and therapeutic management of infants at risk of sudden death. As such, the publication of the investigators work raised a major interest from the population and from the scientific and medical communities, in particular cardio-pediatricians. ObjectivesThe objective of the present clinical project is to validate, in human lymphocytes, muscarinic receptor expression level (assessed by quantitative RT-PCR) as a circulating biomarker of autonomic nervous system dysfunction and more specifically, of vagal hyperactivity and of risk of sudden death. The project will include 2 major items, conducted in parallel:1. evaluation of the muscarinic receptor expression in lymphocytes from adults with vagal syncopes (n=60 patients from an existing file versus 60 controls) (Cardiology unit + Clinical Investigation Centre (CIC) + Laboratory of Neurobiology and Cardiovascular Pharmacology); 2. evaluation of the muscarinic receptor expression in lymphocytes from children with vagal syncopes (n=60 versus 60 controls) (Pediatry unit + Clinical Investigation Centre + Laboratory of Neurobiology and Cardiovascular Pharmacology).PerspectivesThis project represents the first step of validation of a circulating marker of vagal hyperactivity and of risk of SIDS in human. Once this step is completed, the investigators will start with the prospective study " muscarinic receptor expression in lymphocytes and SIDS " (cord blood collected at birth and follow up of the new-borns) (Maternity ward + CIC + Laboratory of Neurobiology and Cardiovascular Pharmacology). Then therapeutic preventive management becomes a realistic objective. A therapeutic clinical study will then be started with atropinic drugs, in order to test their potential protective action against sudden death. The final objective of the investigators research is the prevention of SIDS through i) identification - as soon as birth - of new-borns at high risk and ii) appropriate prophylactic therapy. The investigators work also opens exciting perspectives in the field of the still poorly understood vagal disorders in children and adults such as vagal pauses.1 Livolsi et coll, Plos One 5, e9464, 2010 ; 2 Livolsi et coll, Circulation 106, 2301-2304, 2002

Study Overview

• Status: Completed
• Conditions: Vagal Syncope
• Intervention / Treatment: Biological: Blood sampling; Other: ECG-Holter 24 h tape and sino-carotid stimulation test

• Study Type: Observational
• Enrollment (Actual): 240

Contacts and Locations

Study Locations

• France
  • Strasbourg, France, 67000
    • Hôpitaux Universitaires de Strasbourg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 51 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

University Hospital

Description

Inclusion Criteria:

• Man or woman aged 1 month to 50 years
• Patients with clinical signs of recurrent severe vagal syncopes
• Controls without clinical signs of recurrent severe vagal syncopes
• Mandatory clinical examination prior to enrolment

Exclusion Criteria:

• Autonomic nervous system disorders
• Cardiovascular, neurologic, psychiatric or metabolic diseases
• Drugs interfering with autonomic nervous system
• Doping or drug abuse
• Chronic smoking (more than 3 cigarettes a day
• Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with vagal syncopes; Patients with vagal syncopes (n=120 : 60 adults & 60 children)	Biological: Blood sampling; Blood sampling; Other: ECG-Holter 24 h tape and sino-carotid stimulation test; ECG-Holter 24 h tape and sino-carotid stimulation test
Subjects controls without vagal syncopes; Subjects controls without vagal syncopes (n=120:60 adults & 60 children	Biological: Blood sampling; Blood sampling; Other: ECG-Holter 24 h tape and sino-carotid stimulation test; ECG-Holter 24 h tape and sino-carotid stimulation test

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France
• Investigators: Principal Investigator: Angelo LIVOLSI, Hôpitaux Universitaires de Strasbourg

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2011
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: May 20, 2011
• First Submitted That Met QC Criteria: May 20, 2011
• First Posted (Estimate): May 23, 2011

Study Record Updates

• Last Update Posted (Actual): September 8, 2017
• Last Update Submitted That Met QC Criteria: September 7, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Unconsciousness; Consciousness Disorders; Syncope
• Other Study ID Numbers: 4900 (2010 - A01451-38)