Determinants of the Vascular Response to Training in Chronic Obstructive Pulmonary Disease (COPD) Patients

Study Overview
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Brief Summary
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Vascular comorbidities constitute a major burden in COPD patients. The atherosclerosis process is preceded by the onset of an endothelial dysfunction (assessed by the flow-mediated dilatation (FMD)), which is a risk factor for later ischemic vascular complications and death. In COPD, this endothelial dysfunction could be explained by intrinsic endothelial cell properties, or the effect of a pathogenic endothelial cell microenvironment (inflammation and/or oxidative stress). Exercise training constitue a powerful stimulus for the endothelial function, and could be mediated by the mobiliaztion and function of endothelial progenitors. While exercise training is an efficient intervention in COPD patients, its vascular effect appear blunted. The endothelial function response to training has appeared heterogeneous in COPD patients, and possibly linked to the endothelial cel lesion. Thus, endothelial function (assessed by the FMD) response to exercise training would be lower in COPD patients with a baseline impairment of the their FMD. In addition, of biological and functional factors could explained the magnitude of the FMD response in COPD patients.The aim of the study are thus : To compare the FMD change in COPD patients with FMD above (FMD+) and under the median FMD (FMD-) after 4 weeks of exercise training in the whole study population. To compare between COPD patients FMD+, COPD patients FMD- and healthy control subjects, the endothelial inflammation and senescence at baseline and the endothelial progenitor mobilization and function change induced by exercise (maximal exercise test and training). To compare between COPD patients FMD+, COPD patients FMD- and healthy control subjects the effect of the endothelial microenvironment on the cellular pathways regulating the endothelial function in vitro at baseline and changes after exercise training. To test in COPD patients the association between the magnitude of the FMD changes after training and biological, functional and clinical factors (inflammation oxidative stress markers, endothelial biomarkers, pulmonary impairment and phenotype, cardiovascular risks factors, vascular function, metabolic markers, physical activity level, …)

Official Title
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Biological and Functional Determinants of the Endothelial and Vascular Response to Exercise Training in COPD Patients

Conditions
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COPD Patients, Healthy

Intervention / Treatment
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* Other: FMD analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A/ COPD patients age between 35 and 85 years old spirometry showing an FEV1/VC < lower limit of normal with an indication for a pulmonary rehabilitation program written and informed consent for this study signed by the patient B/ Healthy subjects age between 35 and 85 years old no cardiovascular or respiratory disease normal spirometry Exclusion Criteria: Unstabilized comorbidity Subject in a period of exclusion relative to another protocol Major protected by law Subject participating in another research protocol Subject not affiliated to a social security scheme Pregnant or lactating woman Patient deprived of freedom by court or administrative order

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 85 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: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: COPD patients<br>FMD analysis Endothelial progenitors Exercise test Exercise training | Other: FMD analysis<br>* Blood sample and vascular exploration.<br>|
| Experimental: Healthy subject<br>FMD analysis Endothelial progenitors Exercise test | Other: FMD analysis<br>* Blood sample and vascular exploration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of Flow-Mediated Dilatation (FMD) | Measure of FMD by EndoPAT2000© | post exercise and after 4 +/- 2 weeks of training | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of biological vascular markers | E-selectin soluble (sE-sel), endotheline 1 (ET1), facteur von Willebrand (vWF), vascular endothelial growth factor A (VEGF-A), Fms-like tyrosine kinase receptor 1 soluble (sFlt-1), Angiopoietine 1 et 2 (Ang-1 Ang-2) | after 4 +/- 2 weeks of training | 
| Number of colonies and function of Endothelial-Colony Formaing cells (ECFC) in vitro |  | post exercise and after 4 +/- 2 weeks of training | 
| Number endothelial progenitors | CD34+, CD45+ and KDR + subpopulations by flow cytometry | post exercise and after 4 +/- 2 weeks of training | 
| Vascular function parameters | Systolic pressure index (in AU) | after 4 +/- 2 weeks of training | 
| Vascular function parameters | Intima-media thickness (in mm) | after 4 +/- 2 weeks of training | 
| Vascular function parameters | Pulse-wave velocity (in ms-1) | after 4 +/- 2 weeks of training | 
| Pulse-wave velocity (in ms-1) |  | after 4 +/- 2 weeks of training | 
| Markers of systemic inflammation | C-Reactive protein (in ng/ml) | after 4 +/- 2 weeks of training | 
| Markers of oxidative stress | Lipid peroxidation (in micromol/L) | after 4 +/- 2 weeks of training | 
| Muscle function parameters | Maximum isometric voluntary contraction (in N.m) | after 4 +/- 2 weeks of training | 
| Exercise capacity and vascular adaptation parameters | Maximal oxygen uptake (VO2max, in mL/kg/min) | after 4 +/- 2 weeks of training | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Flow-mediated dilatation, COPD, Pulmonary Rehabilitation, Comorbidities, endothelial cell, oxidative stress