There is increasing evidence showing an association between COPD and cardiovascular disease which is independent from smoking. Recently, it has been shown that FMD of the brachial artery, a surrogate marker of endothelial function, is improving after lung volume reduction surgery (LVRS) in patients with severe emphysema. Thus, hyperinflation might be an independent risk factor of atherosclerosis. Bronchoscopic lung volume reduction (BLVR) using endobronchial valves is a minimal-invasive procedure to decrease hyperinflation in patients with severe emphysema. Eventually, successful BLVR with target atelectasis may have the same effect on FMD compared to LVRS, which would underpin the association between hyperinflation and endothelial function.

Patients receiving routinely performed BLVR using endobronchial valves due to severe emphysema with hyperinflation are eligible for this study. After obtaining written informed consent, the participating patients will be randomized into an immediate (within 1-2 weeks) BLVR group and a delayed BLVR group (6-8 weeks). Patients in both groups will undergo baseline measurement of primary and secondary endpoints.

Immediate BLVR group will be re-assessed 4-6 weeks after successful EBV treatment, whereas the delayed BLVR group will be re-assessed prior EBV treatment. Results of group 1 and 2 will be compared for final analysis.

Several studies were able to show an association between COPD and cardiovascular disease which is independent from smoking and other traditional cardiovascular risk factors. Although the mechanisms underlying the association between COPD and cardiovascular disease are not yet completely understood, it seems reasonable to hypothesize that COPD as a cause of hypoxemia, chronic systemic inflammation, and increased oxidative stress may be an important factor in the development and progression of atherosclerosis due to impaired endothelial function.

Endothelial function can be assessed by flow-mediated dilatation (FMD) of the brachial artery, which has been shown to provide predictive information concerning the future occurrence of cardiovascular events. Thus, assessment of FMD allows to identify patients at risk of cardiovascular events in the absence of clinically apparent vascular disease. One recent study was able to show that lung volume reduction surgery (LVRS) has a beneficial effect on endothelial function and blood pressure. They concluded that hyperinflation is a risk factor of atherosclerosis independent of cigarette smoking or others.

However, hyperinflation cannot solely be treated by LVRS but also by bronchoscopic lung volume reduction (BLVR) using endobronchial valves (EBV), coils, thermal vapour ablation, or lung sealant. The positive effects of EBV on pulmonary function, quality of life and symptoms have been shown in six randomized controlled trials. However, there is no evidence on the effect of BLVR on endothelial function. With this investigator's study, the aim is to contribute to the still limited evidence on the effects of LVR on endothelial function and to confirm the association of atherosclerosis and COPD. In addition, the investigators aim is to validate the data of the study which showed that LVRS had a beneficial effect on endothelial function, by showing similar effects after BLVR.

The investigators hypothesizes, that BLVR using endobronchial valves in patients with severe emphysema will improve endothelial function as previously shown in patients after receiving LVRS.

Patients who are study-independently planned for BLVR using endobronchial valves will be screened for study inclusion. At this time, all necessary baseline data except FMD, daily physical activity measurement and the ST George Respiratory Questionnaire (SGRQ) are already existing from routine clinical practice. Data collection will need the written informed consent of the patient on the "Patient information FMD after BLVR" after receiving further information by investigators.The investigators will explain to each participant the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits and any discomfort it may entail. Each participant will be informed that the participation in the study is voluntary and that he or she may withdraw from the study at any time and that withdrawal of consent will not affect his or her subsequent medical assistance and treatment. The participant will be informed that his or her medical records may be examined by authorised individuals other than their treating physician. The formal consent of a participant, using the approved consent form, will be obtained before the participant is submitted to any study intervention. The consent form will be signed and dated by the investigator or his designee at the same time as the participant sign. A copy of the signed informed consent will be given to the study participant. The consent form will be retained as part of the study records. The informed consent process will be documented in the patient file and any discrepancy to the process described in the protocol must be explained.

The investigators start the project on the 01.04.2020 and estimate a duration of approximately two years for the recruitment of 40 eligible patients. Referring to data analysis, the investigators plan to finish the project by 31.12.2022. Patients receiving routinely performed BLVR using endobronchial valves due to severe emphysema with hyperinflation are eligible for this study. After obtaining written informed consent, the participating patients will be randomized into an immediate (within 1-2 weeks) BLVR group and a delayed BLVR group (6-8 weeks) using counted and sealed envelopes. Patients in both groups will undergo baseline study specific measurements of primary and secondary endpoints (T0) (see more detailed description under the section 'Arms and Interventions'). The immediate BLVR group will be re-assessed 4-6 weeks after successful EBV treatment, whereas the delayed BLVR group will be re-assessed prior EBV treatment (T1). Results of group 1 and 2 will be compared for final analysis.

Routine data measured before and after BLVR will be included into the study as well: Pulmonary function test, 6-Minute-Walking-Test, Laboratory.

To investigate the hypothesis, whether BLVR can improve endothelial function assessed by FMD, differences in the outcomes between the group experiencing atelectasis after BLVR and the groups not experiencing atelectasis or not receiving ELVR will be evaluated by unpaired t-tests or by non-parametrical tests as appropriate. The confidence interval (CI) for statistical significance will be defined as 95%. A p value of less than .05 will be considered statistically significant. All statistical analyses will be performed by SPSS Statistics for Windows 25 (IBM, Armonk, NY). Data will be reported as median interquartile range (IQR) or as percentages, as appropriate.

The sample size was estimated on the assumption that a clinically relevant mean (SD) difference in FMD between the intervention group and the control group is 2.9% (2.1-3.6% [95% CI]) [8]. To achieve a power of 80%, 38 patients would be required to complete the study. Because of an anticipated dropout rate of two patients, 40 patients will be included.

Individual participants will not be identifiable from the results as submitted for publication. Data analysis will only use coded data records. As set out in the Informed Consent, authorized staff of the responsible Ethics Committee may obtain access to all study data under strict adherence to confidentiality rules. Patient baseline data (age, sex, BMI, smoker status, medication list), 6-minute walk test, bronchoscopy reports, lung function data, and radiological findings as well as blood pressure and heart rate measurements, lab results (CRP, BNP) and the result of the transthoracic echocardiography will be drawn from patient record files, coded and stored in hardcopy form. Where copies of the original source document as well as printouts of original electronic source documents are retained, these shall be signed and dated by a member of the investigation site team for validation of the original information. After the measurement of PAL, data will be downloaded from the Fitbit® device and stored as coded data. Data will not be accessible to the device producer and will be deleted from the device once it is transferred. Where copies of the original source document as well as printouts of original electronic source documents are retained, these shall be signed and dated by a member of the investigation site team for validation of the original information. At a later stage, pseudonym data will be analysed using statistic software (e.g. SPSS).The investigators will be responsible for data collection, confidentiality, and data management.

Data generation, transmission, archiving, and analysis of health related personal data within this project strictly follow the current Swiss legal requirements for data protection and according to ClinO, Art. 18. Prerequisite is the voluntary approval of the participant given by signing the informed consent prior start of participation of the research project.

Inclusion Criteria:

• Male or female subject between 40 and 75 years of age
• Written informed consent after participant's information signed by patient
• Scheduled for BLVR using endobronchial valves at the University Hospital Zurich
• Dyspnoea at rest or at minimal physical activity (MRC score ≥2), severe limitation of exercise capacity (6-min walk distance < 500 m).
• COPD (GOLD guidelines) with severe obstructive ventilator defect (FEV1 <40% predicted)
• Functional aspects of lung emphysema with irreversible hyperinflation, defined as a residual volume to total lung capacity ratio (RV/TLC) of >0.6
• Pulmonary emphysema confirmed by high resolution computer tomography

Exclusion Criteria:

• Age < 40 years, age > 75 years
• COPD exacerbation within the last 6 weeks or > 2 exacerbations per year
• Pregnancy
• Lacking ability to form an informed consent (including impaired judgement, communication barriers)
• Current smokers
• Overt active coronary artery disease, left ventricular function impairment
• Pulmonary hypertension with a mean pulmonary artery pressure >35 mmHg at rest
• Acute bronchopulmonary infection, bronchiectasis on high resolution tomography
• Pulmonary cachexia (body mass index <18kg/m2)
• Malignant disease with a life expectancy of less than 2 years
• Addiction to alcohol/drugs (= inability to withhold intake during 1 week)