The Protective Potential of Exercise Training on the Cardiopulmonary Morbidity After COVID-19

40 COVID-19 survivors that have been discharged from the hospital will be included in this investigator-blinded randomised study with a 12-week exercise intervention. Patients will be 1:1 block-randomised by sex to either a supervised high intensity interval-based exercise group or standard care (control group).

40 patients will be recruited and undergo baseline testing, including examination, biochemistry, ECG, DXA, OGTT, Pulmonary function, VO2max, RM, plasma volume, AX3, CGM, echocardiography, cardiac MRI. After baseline testing, participants will be randomly allocated into one group receiving standard of care (control group) or a group performing supervised high-intensity interval training three times a week over a period of 12 weeks. The randomization procedure involves a computer-generated block randomization schedule in a ratio of 1:1 stratified by sex by an independent person. Following the 12-week intervention period, both groups will complete a series of follow-up tests (as baseline testing). A 1-year follow-up experimental day is also planned in order to evaluate fitness, cardiac and pulmonary structure and function.

The experimental group will on top of standard care undergo a 12 weeks supervised exercise high intensity interval exercise training on an ergometer bike three times a week for 38 minutes. The specific intervals will be determined from our ongoing pilot study (NCT04549337)

Three days of continuous glucose monitoring (CGM) is performed using enzyme-coated electrodes (iPro MMT- 7745WW; Medtronic, Northridge, CA, USA) placed subcutaneously in the abdominal wall. For calibration of the CGM system, finger-prick blood glucose measurements are performed by the participant four times daily.

Free-living physical activity is measured using axial accelerometer-based physical activity monitors (AX3; Axivity, Newcastle upon Tyne, UK) for a 4-day period

Including high-sensitivity C-reactive protein, tumour necrosis factor-α, IL-1RA, interferon-γ and interleukins (IL-6, IL-10 and others) Following an overnight fast (10 hours), blood samples, are collected and processed by a trained laboratory technician and analysed according to standard procedures. Plasma is stored at - 80 °C prior to analysis.

Including total troponins, D-dimer, creatinine kinase, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, glycated haemoglobin, fasting insulin, fasting plasma glucose, pro-brain natriuretic peptide, haematology, electrolytes and liver and renal status. Following an overnight fast (10 hours), blood samples, are collected and processed by a trained laboratory technician and analysed according to standard procedures. Plasma is stored at - 80 °C prior to analysis.

Inclusion Criteria: Age ≥ 40 years A laboratory-confirmed initial positive test followed by one negative tests of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ≤ 6 months after hospital discharge ≤10 L oxygen requirement during hospitalization Exclusion Criteria: Present atrial fibrillation Diagnosed with acute myocarditis Health conditions that prevent participating in the exercise intervention Patients who cannot undergo MR scans (e.g. kidney disease or metallic implants) Treatment with IL-6 receptor antagonists (tocilizumab, kevzara) within the last month due to drug interference with the cardiopulmonary exercise adaptations.

Rasmussen IE, Foged F, Bjorn Budde J, Rasmussen RS, Rasmussen V, Lyngbaek M, Jonck S, Krogh-Madsen R, Lindegaard B, Ried-Larsen M, Jorgensen PG, Lund MAV, Kober L, Vejlstrup N, Pedersen BK, Berg RMG, Christensen RH. Protective potential of high-intensity interval training on cardiac structure and function after COVID-19: protocol and statistical analysis plan for an investigator-blinded randomised controlled trial. BMJ Open. 2021 Nov 18;11(11):e048281. doi: 10.1136/bmjopen-2020-048281. Erratum In: BMJ Open. 2023 Apr 21;13(4):e048281corr1.