COBRA3 (COngenital heart defects: BRidging the gap between growth, maturation,
Regeneration, Adaptation, late Attrition and Ageing)

We want to research the effects of growth, maturation and regeneration on the aging of the heart in patients with a congenital heart defect.

Congenital Heart Defect (ConHD) is the most common birth defect, affecting 0.8% of live births. After invasive treatment, many ConHD patients survive with relatively few problems for many years, despite abnormal loading conditions of the heart. However, about 50% of patients with ConHD reaching adulthood die from heart failure, arrhythmias or pulmonary hypertension, especially in diseases affecting the right ventricle (RV). This morbidity and mortality in young adulthood has created a new health care problem, affecting over 4 million patients with ConHD in North-America and Europe. Current progress in management, prognosis and therapy is hampered by our lack of: 1) mechanistic insight into the impact of ConHD on postnatal growth, function and homeostasis of the heart, 2) ability to identify patients at risk in an early stage and 3) specific therapies aimed to prevent or reverse heart failure in the setting of ConHD. The heart of children grows rapidly, proliferates, remodels and has the potential to renew its cells. Our hypothesis is that these properties are important factors in preserving homeostasis in the context of ConHD and abnormal cardiac loading conditions during childhood, keeping attrition at bay. Therefore, the aims of our study are to gain mechanistic insight into the impact of ConHD on growth, renewal and homeostasis of the heart, especially the RV, to improve identification of patients at risk for attrition of heart function in ConHD and to establish the context to develop therapies to prevent or reverse heart failure or arrhythmias in ConHD patients. This study will enroll patients of several academic hospitals in the Netherlands.

We think that the postnatal growth period is critical for establishing normal heart function, and that the interaction of growth and effects of ConHD in this period are clinically highly relevant. Because the postnatal growth period precedes the period of development of pathology seen in adult ConHD patients, the pediatric age range is the most suitable target age for establishing predictive parameters and targets for early, preventive, treatment.


To address the issues described above, we hypothesize that:

- in the pediatric age range favorable factors are active that help maintain myocardial homeostasis through identified (e.g. Hippo) and unidentified pathways.

- these pathways may be affected by the genetic and structural differences that were causative for - and result from - congenital heart defects.

- excess demand on these pathways, or their dysfunction, due to repeated and continued abnormal loading, leads to premature exhaustion of (regenerative) capacity to maintain homeostasis in adults with ConHD.

- favorable factors to stimulate maintenance of myocardial homeostasis as well as harmful factors related to pending failure and arrhythmias may be detected in blood of children and adults.



The overall aims of the consortium project are:

1. Assess the impact of ConHD on growth, renewal and premature ageing.

2. Identify mechanisms and factors of growth, renewal and cell death, epigenetic status, and the origin of cardiac cells during postnatal development and homeostasis.

3. Assess characteristics of the clinical state of the patients (including exercise capacity), (pro-) arrhythmic changes and quantification of ventricular function.

Timeline study procedures group 1

Before operation:

- Echo

- Bloodsampling

- 24-h Holter monitoring

- MRI (>7 years of age)

- Exercise test (>5 years of age)

During operation/catheter intervention:

- Biopsy

2 weeks after operation/catheter intervention:

- Echo

- Blood sampling

- 24-h Holter monitoring



1 years after operation/catheter intervention:

- Echo

- Blood sampling

- 24-h Holter monitoring

- MRI (>7 years of age)

- Exercise test (>5 years of age)

Timeline study procedures group 2

During long-term follow-up after operation/catheter intervention

- Echo

- Blood sampling

- 24-h Holter monitoring

- MRI (>7 years of age)

- Exercise test (>5 years of age)

Methods/instruments:

ECG: Standard 12-lead and 24-hour ECG’s will be performed in all study participants.

24 hour Holter monitoring: In all participants 24 hour monitoring of heart rhythm with locally available Holter monitors will be performed.

Echocardiography: Two-dimensional and 3-dimensional echocardiography will be used to assess the following variables of cardiac size and function:

Magnetic resonance imaging, using 1.5 Tesla scanners and dedicated coils will allow assessment of variables of cardiac size and function:



Exercise testing will be used in children > 5 years of age and adults to assess
- peak oxygen uptake (in VSD, ASD, Fallot and Fontan patient)
- peak workload (in VSD, ASD, Fallot and Fontan patient)

Assessment of neurohumoral markers and new candidate biomarkers In both patients group as well as healthy controls, NT-pro BNP will be assessed using commercially availalable kits. New candidate biomarkers as obtained from the animal experiments in the consortium research will be assessed using relevant and available methods, depending on findings in the course of the project.
A maximum 5 ml (age 0-4 years) to 20 ml (age 10 and up) of blood will be drawn from an Intravenous cannula, directly prior to heart catheterization, surgery or imaging procedures, after > 10 min. rest in supine position

All study procedures in patients in group 1 and 2 will be part of normal clinical follow-up and are explained in the subheading ‘timepoints’