Atrial Septal Defect - Exercise Capacity and Pulmonary Hypertension

Study Overview
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Brief Summary
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The purpose of the study is to compare exercise capacity, cardiac contractility, pulmonary vascular pressures and heart rate variability between patients with an atrial septal defect and healthy controls.

Detailed Description
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Background Patients born with atrial septal defect (ASD) in the heart, have long been assumed healthy after closure of their defect. However, recent studies show, that despite closure of the ASD the risks of arrhythmia, stroke and pneumonia are increased. It is also shown that ASD patients die earlier than the background population and the cause of death is most often cardiac. The reason for this higher mortality and morbidity is unknown and the scope of this thesis. Aim To determine if closed (both surgical and transcatheter) ASD patients have reduced exercise capacity, impaired right and left ventricular function, increased pressure in the pulmonary system, and reduced heart rate variability when compared with healthy controls. The investigators will also examine if method of closure is of importance. Hypothesis Primary endpoint: The shunting effect alters the hemodynamic in the ASD heart resulting in lower cardiopulmonary exercise capacity when compared with healthy controls. Secondary endpoints: The shunting effect alters the hemodynamic in the ASD heart when compared with healthy controls resulting in Impaired force frequency relationship with a reduction in contractility at optimal heart rate. Increased pulmonary arterial pressure. Twice as many ASD patients with decreased heart rate variability. Surgical closure is thought to have a higher impact on the ventricular function than catheter closure resulting in Lower contractility in the surgically closed patients as compared to the catheter closure as evaluated by force frequency. Twice as many surgically closed patients with decreased heart rate variability compared to catheter closed patients. Materials and methods 4.1) Power calculation The number of participants needed in the project is calculated based on the exercise capacity test, which is the primary endpoint. The normal exercise test result is 48 ml O2/kg/min with a standard deviation of 7 ml O2/kg/min. With an expected difference between groups and healthy controls of 15% and a power of 85%, the number of patients needed in each group is 18. Possible drop-outs are taken into account and therefore 20 participants will be included in each ASD group, they will each be matched one to one with controls, resulting in a total of 80 project participants. The secondary endpoints are of a more explorative character, why 20 ASD patients in each group is assumed to be sufficient. 4.2) Exercise capacity, force frequency relationship and pulmonary hypertension 4.2.1) The exercise capacity test is conducted on a semi-supine bicycle, while the patients wears a mask measuring the ventilation, oxygen uptake, carbon dioxide release and respiratory exchange rate. Patients pedal until maximal exhaustion, which should be obtained after 8-12 minutes. 4.2.2) During exercise testing, the force frequency relationship is examined using echocardiography. 4.2.3) A Swan-Ganz catheter is used to measure right-sided hemodynamic pressures and blood saturation. 4.3) Heart rate variability Electrocardiographic (ECG) activity and heart rate variability will be monitored using a 2-channel Holter monitor. The data will be analyzed with the Pathfinder analysis software. Statistical analysis Results for each group will be expressed as means standard deviation or median range or 95% confidence intervals. One way analysis of variance (ANOVA), paired t-tests and regression analyses will be performed. Analyses will be adjusted for age and sex. The issue of multiple testing/multiple comparisons may arise and only relevant comparisons and analyses will be performed.

Official Title
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Atrial Septal Defect - Exercise Capacity and Pulmonary Hypertension

Conditions
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Atrial Septal Defect, Pulmonary Hypertension

Intervention / Treatment
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* Diagnostic Test: Echocardiography
* Diagnostic Test: Right side catheterization
* Diagnostic Test: Exercise test
* Diagnostic Test: Holter monitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years and above. Informed consent to participate. Patients: Diagnosed with an atrial septal defect. More than 3 years have passed since closure of the atrial septal defect. Controls: No history of heart or lung disease. Exclusion Criteria: Lung disease. Ischemic heart disease. Diabetes. Hypertension. Valve pathology. Patients: Concomitant heart disease Controls: Usage of prescription drugs interfering with the cardiopulmonary function.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| ASD patients with surgical closure<br>Patients diagnosed with an ASD who have had a surgical closure of the defect more than 3 years ago. Echocardiography, right side catheterization, exercise testing and Holter monitoring are performed on all participants. | Diagnostic Test: Echocardiography<br>* Standard echocardiography.<br>Diagnostic Test: Right side catheterization<br>* Right side catheterization with the purpose of measuring pulmonary vascular pressures and blood saturation.<br>Diagnostic Test: Exercise test<br>* Exercise test on a supine bicycle with gradual increase in work load while wearing a mask that measures ventilation, oxygen uptake, carbon dioxide release and respiratory exchange rate.<br>Diagnostic Test: Holter monitor<br>* Holter monitor worn for 2 whole days registering heart rate.<br>|
| ASD patients with transcatheter closure<br>Patients diagnosed with an ASD who have had a transcatheter closure of the defect more than 3 years ago. Echocardiography, right side catheterization, exercise testing and Holter monitoring are performed on all participants. | Diagnostic Test: Echocardiography<br>* Standard echocardiography.<br>Diagnostic Test: Right side catheterization<br>* Right side catheterization with the purpose of measuring pulmonary vascular pressures and blood saturation.<br>Diagnostic Test: Exercise test<br>* Exercise test on a supine bicycle with gradual increase in work load while wearing a mask that measures ventilation, oxygen uptake, carbon dioxide release and respiratory exchange rate.<br>Diagnostic Test: Holter monitor<br>* Holter monitor worn for 2 whole days registering heart rate.<br>|
| Controls<br>Controls who do not have any cardiac or pulmonary diagnoses nor use prescription drugs that may affect the cardiopulmonary function. Echocardiography, right side catheterization, exercise testing and Holter monitoring are performed on all participants. | Diagnostic Test: Echocardiography<br>* Standard echocardiography.<br>Diagnostic Test: Right side catheterization<br>* Right side catheterization with the purpose of measuring pulmonary vascular pressures and blood saturation.<br>Diagnostic Test: Exercise test<br>* Exercise test on a supine bicycle with gradual increase in work load while wearing a mask that measures ventilation, oxygen uptake, carbon dioxide release and respiratory exchange rate.<br>Diagnostic Test: Holter monitor<br>* Holter monitor worn for 2 whole days registering heart rate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak oxygen uptake (ml O2/kg/min) | using exercise testing | 8-12 minutes | 
| Peak exercise minute ventilation (ml/min) | using exercise testing | 8-12 minutes | 
| Peak heart rate (beats/min) | using exercise testing | 8-12 minutes | 
| Maximal workload (W/kg) | using exercise testing | 8-12 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tricuspid annular peak systolic velocity (mm) | using echocardiography | 8-12 minutes | 
| Return gradient at the tricuspid valve (mmHg) | using echocardiography | 8-12 minutes | 
| Cardiac output (L/min) | using right sided catheterization | 8-12 minutes | 
| Cardiac index (L/min) | using right sided catheterization, derived measure adjusted for body surface area | 8-12 minutes | 
| Central venous pressure (mmHg) | using right sided catheterization | 8-12 minutes | 
| Pulmonary artery wedge pressure (mmHg) | using right sided catheterization | 8-12 minutes | 
| Pulmonary artery pressure (mmHg) | using right sided catheterization | 8-12 minutes | 
| Mixed venous oxygen saturation (%) | using right sided catheterization | 8-12 minutes | 
| Heart rate variability | using Holter monitoring | 48 hours | 
| Heart rate, minimum, maximum and mean (beats/min) | using Holter monitoring | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial Septal Defect, Exercise Capacity, Pulmonary Hypertension, Heart Rate Variability, Congenital Heart Disease