Improving Care for Children With Congenital Heart Disease.

Study Overview
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Brief Summary
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Establish a cardiovascular biomarker profile to help screening for congenital heart disease in infants and children as well as use non-invasive cardiac imaging in combination with such profiling to better predict the need for future cardiac interventions such as open heart surgery or cardiac catheter intervention selected types of with congenital heart disease.

Detailed Description
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Analyzing circulating cardiovascular biomarkers using blood samples should improve identification of congenital heart disease in newborns, in particular for those needing future cardiac interventions. Comparing such biomarker profiles and non-invasive cardiac imaging results over time in infants and children should lead to better understanding of the complex cardiovascular remodeling processes in common congenital heart lesions such as atrial or ventricular septal defects. This in turn should lead to an improved risk factor assessment model to guide treatment decisions in children with congenital heart disease in the foreseeable future. To test our hypothesis, that cardiovascular biomarker profiling and non-invasive cardiac imaging findings in infants and children with congenital heart disease, differs from healthy controls, we will assess controls at enrolment and follow cases with predefined congenital heart disease lesions over a maximum of three years or up till one year after open heart surgery / cardiac catheter intervention to correct such lesions. Infants and children resident in designated healthcare regions of Sweden will be invited to participate after study advertisement. Written informed consent will be obtained from legal guardians and assent will be sought from children who can communicate verbally with the dedicated paediatric research team. Healthy subjects 0-17 years at enrolment will undergo standard electrocardiogram (ECG), echocardiography and blood sampling to evaluate the heart's anatomy and function and to obtain samples for subsequent biomarker analyses. Additionally, saliva will be sampled and/or neonatal blood samples from national biobank storage will be retrieved for comparison with cardiovascular biomarker profiles in these controls if available. To evaluate these cardiovascular assessments in predefined age groups, a subgroup of these participating subjects will be asked to complete additional cardiac magnetic resonance imaging based on study protocols. Incidental findings will be followed up according to standard care protocols in designated paediatric cardiology clinics throughout the participating healthcare regions in Sweden. Cases of congenital heart disease that lead to pulmonary over-circulation, such as atrial and ventricular septal defects, partial anomalous pulmonary venous drainage, aort-pulmonary windows and patent ductus arterious, will be asked to participate if the lesion has not been treated by open heart surgery or cardiac catheter interventions at enrolment. Subjects with these predefined types of congenital heart disease aged 0-17 years at enrolment will undergo standard electrocardiograms (ECG), echocardiography and blood sampling to assess biomarkers at baseline and at 6-12 month follow-up intervals in dedicated paediatric cardiology clinics over a maximum period of three years. Saliva samples and/or cardiovascular tissue obtained during open heart surgery may also be analysed for studied cardiovascular biomarkers. Additionally, neonatal blood samples from national biobank storage will be retrieved for comparison with current biomarker profiles if available. For those congenital heart disease cases referred for open heart surgery or cardiac catheter intervention to correct the congenital heart lesion based on standard care assessment decisions during the study period, follow-up will end one year after such intervention. To evaluate cardiovascular assessments in predefined age groups, a subgroup of participating cases will be asked to complete additional cardiac magnetic resonance imaging based on study protocols.

Official Title
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Improving Care for Children With Congenital Heart Disease by Cardiovascular Biomarker Profiling and Advanced Non-invasive Cardiac Imaging Techniques.

Conditions
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Heart Disease Congenital, Ventricular Septal Defect, Atrial Septal Defect, Patent Ductus Arteriosus, Partial Anomalous Pulmonary Venous Connection, Aortopulmonary Window, Cardiovascular Diseases

Intervention / Treatment
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* Diagnostic Test: Biomarker analysis at enrolment
* Diagnostic Test: Biomarker analyses throughout the study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: obtained written informed consent prior to enrolment resident within participating healthcare regions in Sweden during study age 0-17 years at enrolment Controls: No evidence of congenital heart disease and no history of cardiovascular disease Cases: one of the following congenital heart lesions prior to open heart surgery or cardiac catheter intervention: ventricular septal defect, atrial septal defect, patent ductus arteriosus, partial anomalous pulmonary venous drainage, aortopulmonary window. Exclusion Criteria: inability to obtain written informed consent prior to study enrolment non-resident in participating healthcare regions of Sweden during study age more than 17 years at enrolment presence of congenital heart disease where one of the above lesions is part of a more complex lesion or where the lesion has been treated by open heart surgery or cardiac catheter intervention participation in other research study with conflicting aims / interests

Ages Eligible for Study
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Maximum Age: 17 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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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: case-control cohort
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control subjects<br>Infants and Children with no evidence of congenital heart disease based on echocardiography and standard ECG assessment | |
| Active Comparator: Congenital heart disease subjects<br>Infants and Children with evidence of predefined congenital heart disease lesions based on echocardiography and standard ECG assessment | Diagnostic Test: Biomarker analysis at enrolment<br>* Controls will be compared to cases using biomarker analyses and non-invasive cardiac imaging techniques to improve risk stratification of cases<br>* Other names: non-invasive cardiac imaging modalities at enrolment;Diagnostic Test: Biomarker analyses throughout the study<br>* Controls will be compared to cases using biomarker analyses and non-invasive cardiac imaging techniques to improve risk stratification of cases<br>* Other names: non-invasive cardiac imaging modalities throughout the study;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days from diagnosis to open-heart surgery or cardiac catheter intervention in predefined congenital heart disease lesions | Number of days from date of diagnosis of predefined congenital heart disease lesion until date of open-heart surgery or cardiac catheter intervention to treat lesion | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Screening for congenital heart disease in newborns using circulating biomarkers in blood samples | Results will be based on circulating biomarker analysis in infants using dried blood spot samples to improve detection of congenital heart disease. Results in normal controls will be compared to predefined congenital heart disease lesions and results expressed in ng/l using cardiovascular biomarkers such as NT-pro-BNP, ST2 and troponin T. | 3 years | 
| Circulating cardiovascular protein biomarker profiling in infants and children with predefined congenital heart disease lesions vs normal controls using blood samples. | Circulating biomarker profiling results will be expressed in 'NPX' units (Normalized Protein eXpression concentrations from proximity extension assay analyses of protein concentrations in blood samples using O-link's 'Target 96 cardiovascular III' panel, link: https://www.olink.com/products/cvd-iii-panel/) | 3 years | 
| Measurement of cardiac magnetic resonance 4-dimensional flows to estimate 'kinetic energy' supported by advanced echocardiography in normal controls vs predefined lesions of congenital heart disease | Results will be based on cardiac magnetic resonance 4D flow and supported by advanced echocardiographic assessments and expressed as kinetic energy (milli Joule) to assess for normal and abnormal patterns of cardiac function. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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congenital heart disease