Gender Difference in NET Activation in Patients With Congenital Heart Disease and Heart Failure (FIBRONETx)

January 6, 2023 updated by: Assistance Publique - Hôpitaux de Paris

Différences de Genre Dans l'Activation Des NET et Son Implication Dans la Formation de Fibrose Cardiaques Chez Les Patients Adultes Avec Une Cardiopathie congénitale Complexe FIBRONETx Gender

Neutrophil hyperactivation has detrimental effects on cardiac tissue after injuries, leading to fibrosis lesions and cardiac dysfunction. It is now well-established that women present with different clinical symptoms in cardiovascular disease compared to men. A cardioprotective effect in women has been suggested in some studies including patients with congenital heart disease (CHD) and heart failure. Our hypothesis is that estrogen protects the hearts of female patients aged 18-45 with CHD. There is no information available as to the involvement of neutrophils in heart failure in females compared to male patients, and therefore this study will provide important information for both the CHD and neutrophil biology fields comparing NET activation in women and men with severe CHD.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

100 patients (50 men and 50 women including 25% with a history of pregnancy) aged 18-45 years with moderate and severe CHD (Fallot, systemic RV, and single ventricle), where fibrosis has been identified as a risk factor for heart failure, will be included. A control group of 50 patients (25 men and 25 women) were matched on age and sex.

The main objective of the study is to study the difference in NET activation between men and women with complex congenital heart disease.

Secondary objectives are:

  • To compare the NET activity between healthy subjects vs. patients at inclusion.
  • To compare male vs. female NET activity in healthy subjects at inclusion.
  • To study the existence of associations of NET with biomarkers of fibrosis (biological and imaging) at baseline in men and women with complex congenital heart disease.
  • To study the protective value of pregnancy on inflammatory mechanisms and the formation of fibrosis involved in impaired ventricular function and heart failure in these patients.

The enrolled patients will have blood samples collected for analysis of PAD4/NETs biomarkers, and fibrosis markers. NET/fibrosis markers will be correlated with clinical/laboratory parameters, notably NET/PAD4 levels with markers of fibrosis such as collagen biomarkers, ECG, echocardiographic, and cardiac magnetic resonance imaging biomarkers.

Study Type

Observational

Enrollment (Anticipated)

150

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Paris, France, 75015
        • Recruiting
        • C01 - Hôpital Européen Georges Pompidou - Unité des cardiopathies congénitales de l'adulte
        • Contact:
      • Paris, France, 75015
        • Not yet recruiting
        • C02- Hôpital Européen Georges Pompidou - CIC
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The study population will therefore be represented by:

  • heart diseases at risk of heart failure with an equal proportion of men and women to be able to study the protective character of the female sex on the inflammatory process and the development of myocardial fibrosis.
  • healthy adult subjects.

Description

Inclusion Criteria:

Patients:

Male or female aged 18 to 45; having one of the following 3 complex congenital heart disease:

Congenital heart disease with a systemic right ventricle Congenital heart disease with a single ventricle palliated by Fontan's circulation Tetralogy of Fallot repaired - Patient benefiting from a social security scheme or having rights, or CMU; obtaining informed consent from the patient

Healthy subjects:

Age over 18 years old, matched by sex and age +/- 5 years; Normal ECG; with a prior clinical examination; benefiting from social security; obtaining informed consent from the patient

Exclusion Criteria:

Patients:

patients with cyanosis defined as saturation ≤ 90% at rest; Usual MRI contraindications Possible confounding factors with increased NET formation unrelated to thrombosis, namely cancer, rheumatoid arthritis, lupus, antiphospholipid syndrome, history of pre-Eclampsia or hypertension; Contraindication to performing a stress test; Glomerular filtration rate <30ml / min / 1.73m² of body surface area A physical or mental disability that does not allow for a stress test; Pregnant or lactating patient;Patient under legal protection

- Healthy subjects: Known or detectable history of a heart attack on the ECG; known or detectable primary or secondary cardiomyopathy on ECG; history of chest radiation therapy or chemotherapy;Possible confounding factors with increased NET formation unrelated to thrombosis, namely cancer, rheumatoid arthritis, lupus, antiphospholipid syndrome, history of pre-Eclampsia or hypertension Contraindication to performing a stress test;Glomerular filtration rate <30ml / min;BMI>30; Pregnant or lactating patient;Patient under legal protection

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
controls
healthy subjects
Diagnostic test: Biological markers of myocardial fibrosis
Blood sample for measurements of NET activation and collagen biomarkers
Patients
Patients with a complex congenital heart disease
Diagnostic test: Biological markers of myocardial fibrosis
Blood sample for measurements of NET activation and collagen biomarkers

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
NET activation levels and PAD4 Levels
Time Frame: baseline
Measurements of MPO-DNA, citrullinated histone, Elastase, Calprotectine, MMP9, NGAL, and MPO, IL-8
baseline

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The association of NET / PAD4 biomarker levels will be analyzed to NYHA functional class.
Time Frame: baseline

The association between NYHA functional class (I, II, III and IV) and the following measurements will be analyzed:

  • MPO-DNA (UA/mL)
  • Citrullinated histone (optic density unit)
  • Elastase (pg/mL)
  • Calprotectine (pg/mL)
  • MMP9 (pg/mL)
  • NGAL (pg/mL)
  • MPO (UA/mL)
  • IL-8 (pg/ml)
baseline
The association of NET / PAD4 biomarker levels will be analyzed in relation to QRS width and late potentials.
Time Frame: baseline

The association between each ECG parameters: QRS width (ms) and late potentials (present or absent) and the following measurements will be analyzed:

  • MPO-DNA (UA/mL)
  • Citrullinated histone (optic density unit)
  • Elastase (pg/mL)
  • Calprotectine (pg/mL)
  • MMP9 (pg/mL)
  • NGAL (pg/mL)
  • MPO (UA/mL)
  • IL-8 (pg/ml)
baseline
The association of NET / PAD4 biomarker levels will be analyzed in relation to ventricular function, ventricular longitudinal strain, diastolic parameters, presence of valvular disease, change in systemic ventricular filling profile after exercise
Time Frame: baseline

The association between each echographic measurement: ventricular function, ventricular longitudinal strain, diastolic parameters, presence of valvular disease, change in systemic ventricular filling profile after exercise and the following measurements will be analyzed:

  • MPO-DNA (UA/mL)
  • Citrullinated histone (optic density unit)
  • Elastase (pg/mL)
  • Calprotectine (pg/mL)
  • MMP9 (pg/mL)
  • NGAL (pg/mL)
  • MPO (UA/mL)
  • IL-8 (pg/ml)
baseline
The association of NET / PAD4 biomarker levels will be analyzed in relation to measurement of myocardial stiffness.
Time Frame: baseline

The association between myocardial stiffness (in KPa, measured with ultrafast cardiac echography) and the following measurements will be analyzed :

  • MPO-DNA (UA/mL)
  • Citrullinated histone (optic density unit)
  • Elastase (pg/mL)
  • Calprotectine (pg/mL)
  • MMP9 (pg/mL)
  • NGAL (pg/mL)
  • MPO (UA/mL)
  • IL-8 (pg/ml)
baseline
The association of NET / PAD4 biomarker levels will be analyzed in relation to volumes, masses and ventricular ejection fraction, late enhancement and T1 measurement
Time Frame: baseline

The association between each parameters of cardiac magnetic resonance imaging: volumes, masses and ventricular ejection fraction, late enhancement and T1 measurement and the following measurements will be analyzed :

  • MPO-DNA (UA/mL)
  • Citrullinated histone (optic density unit)
  • Elastase (pg/mL)
  • Calprotectine (pg/mL)
  • MMP9 (pg/mL)
  • NGAL (pg/mL)
  • MPO (UA/mL)
  • IL-8 (pg/ml)
baseline
The association of NET / PAD4 biomarker levels will be analyzed in relation to biological markers: BNP, CRPus, troponin, biomarkers of collagen metabolism.
Time Frame: baseline

The association between each biological markers: BNP (pg/ml), CRPus (mg/L), troponin (ng/L), biomarkers of collagen metabolism (PICP (ng/Ml), P3NP (ng/ml), ICTP (microgr/L), MMP1 (ng/ml), TIMP1 (ng/ml), galactine 3 (ng/ml)) and the following measurements will be analyzed :

  • MPO-DNA (UA/mL)
  • Citrullinated histone (optic density unit)
  • Elastase (pg/mL)
  • Calprotectine (pg/mL)
  • MMP9 (pg/mL)
  • NGAL (pg/mL)
  • MPO (UA/mL)
  • IL-8 (pg/ml)
baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

National Research Agency, France
European Commission

Investigators

  • Principal Investigator: Magalie Ladouceur, Pr, Hopital Europeen Georges-Pompidou

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 22, 2022

Primary Completion (Anticipated)

February 23, 2025

Study Completion (Anticipated)

February 23, 2025

Study Registration Dates

First Submitted

February 9, 2022

First Submitted That Met QC Criteria

February 21, 2022

First Posted (Actual)

March 3, 2022

Study Record Updates

Last Update Posted (Estimate)

January 9, 2023

Last Update Submitted That Met QC Criteria

January 6, 2023

Last Verified

January 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • APHP211359

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared

IPD Sharing Time Frame

Two years after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the PI based on a scientific project and scientific involvement of the PI team. Collaboration will be fostered.

Data sharing must respect the agreements made with funders.

Teams wishing obtain IPD must meet the sponsor and IP team to present scientific (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractual agreement.

Processing of shared data must comply with European General Data Protection Regulation (GDPR).

IPD Sharing Supporting Information Type

  • Study Protocol
  • Informed Consent Form (ICF)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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