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.

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.

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

50 male and 50 female including half of them with a history of pregnancy

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.

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

Two years after the last publication

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).