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.

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.

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

We are recruiting participants within the Nottinghamshire region. Specifically for patients with COPD, we are targeting outpatient respiratory clinics at the Nottingham University Hospitals Trust, inpatient admissions due to COPD exacerbation at the Nottingham City Hospital, pulmonary rehabilitation groups and respiratory focus groups within Nottingham and patients on the Nottingham Respiratory Research Unit database.