Pulmonary Adaptive Responses to HIIT in COPD (COPDEX0)

Patients with chronic obstructive lung disease (COPD) suffer from a progressive loss of lung function that leads to poor quality of life, and often invalidity and early death. Regular exercise can improve quality of life in these patients, but the health care system lack the underlying mechanism of exercise-induced improvement in COPD and it is widely thought not to have any effect on lung function. The aim of the present study is to investigate to which extent lung tissue mass and rest-to-exercise diffusion capacity changes differ in COPD patients compared to the healthy state. In order to design prospective clinical trials on the putative impact of high-intensity interval training (HIIT) investigating these parameters, and a secondary aim is to assess the feasibility of such a study in terms of patient inclusion, adherence and methodology.

Patients with Chronic obstructive pulmonary disease (COPD) suffer from a progressive loss of lung function that leads to poor quality of life, and often invalidity and early death. Regular exercise is considered the most effective non-pharmacological intervention for improving quality of life in these patients. However, its use is halted by the lack of understanding of the mechanism of exercise-induced improvement in COPD, and is widely thought not to have any effect on lung function in the clinical setting. Exercise is thus mainly considered a way to alleviate symptoms, primarily by improving skeletal muscle function, but without the potential to reverse the disease. Therefore, relatively short and low-intensity exercise interventions are typically prescribed and are often not pursued in patients with the greatest symptom burden. The reasoning for not prescribing exercise more widely in COPD is based on two assumptions: 1) new tissue cannot be formed in the adult lung, and 2) no consistent exercise training-induced changes in lung function have previously been documented. However, de novo tissue formation has repeatedly been demonstrated in the adult lung, both in animals and humans, primarily in response to prolonged hypoxia and pneumonectomy. It has recently been reported that interval-based training counteracts the progressive loss of lung tissue in animal models of experimental COPD. The most likely stimulus is the mechanical strain, and if any measurable changes are to be induced by training, a high-intensity interval training (HIIT) scheme is preferable to be initiated in pulmonary rehabilitation. On this basis, this study aim to conduct a prospective randomised trial, in which the impact of HIIT on lung weight (assessed by CT), rest-to-exercise diffusion capacity, 3-dimensional distribution of pulmonary perfusion measured by single photon emission computed tomography (SPECT)-low dose CT are addressed. Indeed, the latter is an especially useful clinical tool for the pathophysiological classification of COPD patients, and rest-to-exercise SPECT has the potential as a diagnostic tool that 'pinpoints' the exact cause of dyspnoea in the individual COPD patient, but has not yet been validated for this purpose. While all the methods are established, there is a need for more information regarding COPD-associated changes in lung tissue mass ('lung weight') and rest-to-exercise pulmonary diffusion changes compared to the healthy state. An assessment of the feasibility of an extended HIIT-trial using these methods in COPD patients as well as estimates of the in-study changes in the resultant physiological estimates (for the purpose of sample size estimations) is warranted.

High intensity interval training (HIIT), Lung growth, Diffusion capacity, Blood flow, Lung tissue mass, Oxygen extraction

12 COPD will undergo the intervention in one arm and 12 healthy, age and BMI matched individuals will undergo the same intervention.

Participants will undergo 12 weeks of supervised HIIT training (3 times per week). The HIIT protocol will consist of 4x4 min.

Change in rest-to-exercise pulmonary diffusion capacity between COPD patients and matched healthy controls measured by DLNO/CO.

Rest-to-exercise pulmonary perfusion ratio change in COPD patients compared to matched controls measured by single photon emission computed tomography (SPECT).

Rest-to-exercise leg blood flow change in COPD patients compared to matched controls measured by ultrasound doppler in a single leg knee extensor model.

Confirmation of maximum oxygen consumption measured 20 minutes after intitial VO2 peak test at a 110 % of maximum workload.

Health-related quality of life - COPD Assessment Test, (CAT) score. Higher values meaning a smaller burden of symptoms.

Calculated from paired arterial and venous blood gases obtained from intraarterial and venous catheters.

Exercise attendance rate (%) defined as number of attended exercise sessions / by number of prescribed sessions x 100.

Incidence of early termination of attended exercise sessions, defined as termination of an exercise session before the prescribed exercises have been performed

Incidence of permanent discontinuations of the exercise intervention, defined as participants that withdraw entirely from the exercise intervention.

Exercise feasibility: Patient-reported symptomatic adverse events (paint, dizziness, nausea, fatigue, other)

Inclusion criteria -patients Men and women 45-80 years COPD (GOLD stage I to III) Forced expiratory volume in 1 sec (FEV1)/forced vital capacity ratio (FVC) < 0.8, FEV1 < 90% of predicted value Modified Medical Research Council score (mMRC 0 - 3) Resting arterial oxygenation > 90% Do not fulfil the physical activity recommendations by the Danish Health Authority Inclusion criteria - controls Men and women 45-80 years Normal FEV1, FVC, FEV1/FVC, and single-breath diffusion capacity Same sex, age (± 3 years) and BMI (± 10%) Do not fulfil the physical activity recommendations by the Danish Health Authority (19) BMI 18-35 Exclusion criteria - patients Symptoms of ischaemic heart disease Known heart failure Previous severe or current COVID-19 Unable to complete or understand HIIT training Claudication Symptoms of disease within 2 weeks prior to the study Participation in pulmonary rehabilitation within 6 months Known malignant disease Pregnancy Unstable cardiac arrhythmic disease Renal or liver dysfunction Exclusion criteria - controls COPD Asthma Known ischaemic heart disease Known heart failure Previous severe or current COVID-19 Unable to complete or understand HIIT training Symptoms of disease within 2 weeks prior to the study Known malignant disease Claudication Pregnancy Unstable cardiac arrhythmic disease Renal or liver dysfunction