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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Congenital Heart Disease, Heart Failure, Gender

Intervention / Treatment
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* Diagnostic Test: Biological markers of myocardial fibrosis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients with a complex congenital heart disease | Diagnostic Test: Biological markers of myocardial fibrosis<br>* Blood sample for measurements of NET activation and collagen biomarkers<br>|
| controls<br>healthy subjects | Diagnostic Test: Biological markers of myocardial fibrosis<br>* Blood sample for measurements of NET activation and collagen biomarkers<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NET activation levels and PAD4 Levels | 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. | 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. | 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 | 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. | 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 | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gender, Fibrosis, Inflammation, Congenital heart disease, Heart failure