Cerebral and Cardiac Blood Flow During Exercise in Patients With COPD

Study Overview
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Brief Summary
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Heart disease and conditions related to the blood vessels are responsible for a large proportion (over a quarter) of the deaths in people with chronic obstructive pulmonary disease (COPD). The changes can also affect the smaller smaller blood vessels within the body, in particular the brain and the kidneys. This might be related to how the heart pumps and if it is under any pressure. Investigations performed at the University in healthy older volunteers demonstrated how the blood flows in the brain and heart during exercise. Exercise gently puts the whole body under some pressure and therefore exposes any weaker areas. In this study the investigators are hoping to find out what happens to the blood flow in the brain and in the heart in patients who have COPD when they exercise and in the resting state. This will be compared to people of a similar age with a similar smoking history but without COPD. This will be examined using state of the art magnetic resonance imaging (MRI) and will allow us to assess whether changes in structure and function are related to this altered blood flow. Our hypothesis is that COPD will cause a larger change in blood flow during exercise compared to the healthy volunteers and that reduced cardiorespiratory fitness will be associated with increased age related structural within the brain.

Detailed Description
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The aim is to recruit 20 participants with COPD, who will be compared to 10 age and gender matched controls who also have a smoking history. The investigators aim for this number to complete the components of the study and therefore may have to over-recruit if some people drop out or are not eligible. The study elements are feasible, as the work extends a previous research study in healthy volunteers. This research trial will consist of a medical screening visit and three investigation study visits spaced ideally one week apart. The investigation visits will begin within 6 (ideally within 4) weeks of the medical screening visit. The total duration of the study and screening visits should be 12 weeks maximum for each participant. Screening visit: If the participant expresses an interest in the clinical trial and wants to take part they will be invited (at a convenient time for them) to attend a medical screening visit located at the Nottingham City hospital. Here the investigator will discuss the research trial and answer any questions or concerns they might have regarding the research trial. The participant, if willing, will then be required to sign a consent form so that the screening procedures can begin, which include: Blood sample: Approximately a 20ml sample (4 teaspoons) taken from their arm, for further investigation including full blood count (FBC), brain natriuretic peptide (BNP) and kidney function. Questionnaires: 5 different questionnaires that ask about symptoms and how they affect daily life, a physical activity questionnaire, quality of life questionnaire and a MRI safety questionnaire. Spirometry: A simple blowing test to assess the participants' breathing which is performed three times. 12 lead ECG. a hand grip dynamometer to assess muscle strength timed up and go test: a test used to measure gait speed, where participants are asked to get up from a chair and walking to 3 meters and back, whilst being timed. to wear a step counter (Sensewear armband) for a week during waking hours to record steps. Provided the ECG, step count (<10,000 steps) and other screening elements are ok, the participant will proceed to Study visit 1. Strength and exercise test protocol: The participant will be required to abstain from strenuous exercise for the 48 hours prior to the visit and also from alcohol and caffeine for 24 hours prior. Upon arrival they will perform a knee extension exercise so we can establish the muscle strength in the legs, specifically 3 maximal knee extensions with a 30 second rest in between. We will also measure fatigue by dong 20 extensions after a short break. After a break they will then undergo an exercise test using an MRI compatible stepper device (Ergospect Cardiostepper) whilst in a supine position. This has been adapted to be similar to how they will exercise in the MRI scanner. Volunteers will start off stepping at a frequency of 65-70 steps a minute at the minimum workload and every 3 minutes get gradually a little harder until exhaustion is reached. Heart rate at rest and in response to exercise will be measured using a heart monitor. Participants will be given the option to have their expired gases also measured during exercise using a face mask, though this is not necessary if not tolerated. In the final minute of each workload we will take a finger prick test to measure the gases in the patients blood. A 3 lead ECG and oxygen saturation probe will be attached during exercise as safety measures and the protocol will be halted if oxygen saturation falls below 80% or if any relevant rhythm abnormalities are seen on the ECG trace. The second study visit will be used to confirm the exercise and strength parameters measured in the first study visit. MRI protocol: A series of scans of the brain and heart will be taken at rest and then whilst stepping on the stepper machine within the MRI. The exercise will be at a steady state low level intensity determined by calculating the workload at which a fraction of maximum heart rate was achieved during first 2 study visits. The MRI scan itself will take about ¾ hour but upto 2 hours is allowed for preparation and introducing the scan to the participant. The scanner is quite noisy and so the participant will wear ear defenders during the scan. Because the scanner is built around a large magnet, the participant will be instructed to remove all metal from their body, including jewellery. There is no radiation involved.

Official Title
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Cardiac Output and Brain Perfusion and Architecture During Exercise in Patients With Chronic Obstructive Pulmonary Disease (COPD) and Healthy, Age Matched Volunteers

Conditions
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COPD, Cognitive Impairment

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 65-75 years old, >10 pack years smoking, FEV1/FVC <0.7 and FEV1<60% predicted (for COPD participants only) Sedentary lifestyle (<10,000 steps per day) Able to give informed consent Able to read, understand and communicate coherently in English Exclusion Criteria: Doctor diagnosis of ischaemic heart disease or heart failure Doctor diagnosis of dementia or Alzheimers disease History of previous cerebrovascular disease (stroke or TIA) or malignancy Pregnancy or childbearing in the last 6 months Maintenance oral corticosteroids in the past 6 months Requirement for oral corticosteroids or antibiotics in the past 6 weeks Active arthritis or other muscular condition limiting exercise Surgical intervention in the last 12 weeks Long term oxygen therapy requirement Other formal current respiratory diagnosis Thyroid disease Diabetes Mellitus Neurological or cognitive impairment Significant physical disability Any other conditions in addition to the above that the investigators consider may affect study measurements or safety Inability to understand verbal and/or written explanation of the study requirements

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 75 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 |
| --- | --- |
| Case<br>Participants with a pack year history of more than 10 pack years, diagnosed with COPD who have FEV1/FVC ratio of less than 0.7 AND FEV1 predicted value less than or equal to 60%. | |
| Control<br>Participants without a diagnosis of COPD who have a smoking history of more than 10 pack years | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting white and grey matter structural integrity | Grey and white matter volume (mm3) using the MRI MPRAGE sequences will be measured at rest | up to 12 weeks | 
| Cardiac structural integrity | Cardiac output (L/min) will be measured using the MRI sequence (Short axis Cine) at rest. | up to 12 weeks | 
| Cardiac structural integrity | Cardiac fibrosis (%) will be measured using the MRI MOLLI T1 sequence at rest. | up to 12 weeks | 
| Cardiac structural integrity | Myocardial strain (%) will be measured using the MRI cardiac tagging sequence at rest. | up to 12 weeks | 
| Whole body fat and muscle quantification | Whole body fat and muscle quantification (%) will be measured using the MRI whole body mdixon sequence at rest. | up to 12 weeks | 
| Aortic flow | Aortic flow (ml/min) will be measured during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls | up to 12 weeks | 
| Cerebral blood flow | Cerebral blood flow (ml/min) will be measured during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls | up to 12 weeks | 
| Cerebral perfusion | Cerebral artery perfusion (ml/100g/min) will be measured during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls | up to 12 weeks | 
| Oxygen extraction fraction | Oxygen extraction fraction (%) will be derived from the difference between arterial and venous cerebral oxygenation measured via TRUST MRI scan sequence during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls | up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle isometric strength (MVC) | Isometric muscle torque of the quadriceps (Nm) assessed using the cybex dynamometer | up to 6 weeks | 
| Muscle isokinetic fatigue | Fatiguability test of the quadriceps (Nm) assessed using the cybex dynamometer | up to 6 weeks | 
| Quality of life (SGRQ) | Assessed using the St Georges Respiratory Questionnaire. min value: 0, max value: 84, higher score means worse outcome | 1 week | 
| Physical activity level (IPAQ Physical activity questionnaire) | Assessed using the International Physical activity questionnaire. min value: 0, max value: 66000, higher score means better outcome | 1 week | 
| Montreal Cognitive Assessment (MoCA) cognition level | Assessed using the Montreal cognitive assessment questionnaire. min value: 0, max value: 30, higher score means better outcome | 1 week | 
| Hospital anxiety and depression scale (HADS) | min value: 0, max value: 21, higher score means worse outcome | 1 week | 
| Hand grip strength | Composite of hand grip strength (Kg), measured by a hand held dynamometer, | 1 week | 
| Timed up and go test | Timed up and go test (seconds) will be measured to assess degree of frailty. | 1 week | 
| Serum markers of inflammation for research purposes (likely to include IL-1, IL-6, and TNFα) | Blood test | 1 week | 
| Heart rate response to exercise | Heart rate response (Beats per minute) will be measured at rest and during incremental exercise to assess cardio-respiratory fitness. | up to 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Magnetic Resonance Imaging, Cerebrovascular physiology, Cardiovascular physiology, Supine ergometric stepper