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Background: Extrapulmonary manifestations including cognitive impairment, reduced muscle and cardiovascular function is common in COPD. While high-intensity exercise offers extrapulmonary benefits, its implementation in COPD is challenging. This randomised cross-over trial examined the feasibility and physiological responses of a novel supramaximal high-intensity interval-training (SupraHIIT) protocol compared to moderate-intensity continuous training (MICT) in people with COPD and matched healthy controls (HCs).

Methods: Sixteen people with COPD and 16 HCs performed SupraHIIT and MICT. SupraHIIT consisted of 10x6 sec intervals at ≈150% and ≈200% of maximum aerobic power (MAP), while MICT was performed for 20 min at 60% of MAP. Outcomes were exercise intensity, change in exerkines, feasibility, and cardiorespiratory demand of the modalities.

Results: SupraHIIT was feasible and enabled up to a 3.5-fold increase in external exercise intensity compared to MICT (184±66 and 245±88 watt versus 71±22 watt in COPD, p<0.001). All participants could complete SupraHIIT which was the preferred modality in both groups (p<0.01) while 5/16 participants with COPD interrupted MICT due to intolerable dyspnea or exhaustion (p=0.005). Both modalities increased plasma brain-derived neurotrophic factor (pBDNF) by an average of 59% (range 30%-87%, p<0.05). When normalised for duration at target power, SupraHIIT produced a 5–10-fold greater increase than MICT. Both modalities lead to a variable response in other exerkines including clusterin, lactate, hepatocyte growth factor and interleukin-6.

Conclusion: In COPD, short duration SupraHIIT is more feasible and enables markedly higher external exercise intensities than MICT. By elevating pBDNF and other potentially beneficial exerkines, it shows potential for extrapulmonary benefits.

Background

Chronic obstructive pulmonary disease (COPD) is a leading global health burden and a major cause of morbidity and mortality. Beyond airflow limitation and respiratory symptoms, COPD is associated with multiple extrapulmonary manifestations including cognitive impairment, decreased cardiovascular fitness and muscle dysfunction. These systemic effects contribute to lower physical capacity and increased mortality, independent of lung function. To treat extrapulmonary manifestations among individuals with COPD, exercise training has an important role. However, traditional exercise methods are often difficult for individuals with COPD to tolerate, given their ventilatory limitations and muscle dysfunction, resulting in sub-optimal treatment effects. Short-duration watt-controlled supramaximal high-intensity interval training (HIIT) consisting of 10 × 6 second intervals is promising for individuals with COPD, as it enables high external intensities while allowing for ventilatory relief. Yet, evaluation of its feasibility, physiological response, prescription and long-term effectiveness is lacking. Furthermore, reporting quality in aerobic exercise trials in COPD may be incomplete, hindering reproducibility and the translation of research findings into clinical practice.  The overarching aim of this thesis therefore was to advance the development of effective exercise strategies for COPD by evaluating the feasibility, physiological responses, and methodological aspects of supramaximal HIIT, and by assessing the reporting quality of aerobic exercise interventions in the COPD literature.

Methods

This thesis comprises four papers based on two clinical trials and one systematic review. In a randomised cross-over trial, Paper I examined the feasibility and acute physiological responses to supramaximal HIIT, compared to moderate-intensity continuous training (MICT), in 16 individuals with COPD and 16 matched healthy controls (HCs). Paper II, using data from the same trial, evaluated the feasibility and applicability of the modified Borg Cycle Strength Test (mBCST) for prescribing supramaximal workloads. Paper III presents the study protocol of an ongoing, international multicentre randomised controlled trial (RCT), the COPD-HIIT RCT. The trial compares supramaximal HIIT and MICT over 3 months in individuals with COPD and HC, with continued training for 24 months in the COPD group. Paper IV was a systematic review assessing the reporting quality and application of exercise training principles in RCTs that included aerobic training in individuals with COPD.

Results

Paper I demonstrated that supramaximal HIIT was feasible and enabled participants with COPD to achieve higher external intensities  (245 ± 88 vs. 71 ± 22 W) compared to MICT, with reduced ventilatory demand. Both exercise modalities increased plasma brain-derived neurotrophic factor by an average of 59%. Paper II deemed the mBCST feasible and applicable for prescription of supramaximal intensities in COPD. The COPD-HIIT RCT, presented in Paper III, have enrolled 133 participants of which 82 are individuals with COPD. The participants with COPD constitute a representative cohort with a varied disease severity. Compared to matched healthy controls, they exhibit reduced cognitive function, cardiorespiratory fitness and quadriceps function at baseline. Paper IV included 298 trials, in which the quality of reporting was generally poor. This was demonstrated by a mean of 5.4 ± 3.0 reported items (out of a maximum of 19) on the Consensus on Exercise Reporting Template.

Conclusions

This thesis supports the feasibility of short-duration, watt-controlled supramaximal HIIT for individuals with COPD, allowing higher exercise intensities with lower ventilatory demand than MICT. The mBCST appears feasible and applicable for prescribing supramaximal workloads, while further research is warranted for its clinical implementation. Preliminary data from the ongoing COPD-HIIT RCT indicates good adherence to supramaximal HIIT and representative recruitment. Finally, the systematic review revealed suboptimal reporting of aerobic exercise interventions in COPD research, emphasizing the need for improved reporting to strengthen reproducibility and clinical translation.

Introduktion

Kroniskt obstruktiv lungsjukdom (KOL) är en av vår tids största folksjukdomar. Globalt lever hundratals miljoner människor med KOL, och sjukdomen är en av de vanligaste dödsorsakerna i världen. Sjukdomen kännetecknas av långvariga symptom från luftvägarna och en begränsning av luftflödet, vilket gör att fysisk aktivitet och träning ofta blir ansträngande. 

Utöver påverkan på lungorna leder KOL till en påverkan utanför lungorna – så kallade extrapulmonella manifestationer. Dessa inkluderar bland annat nedsatt kondition, försämrad muskelfunktion och försämrad kognitiv funktion. Dessa konsekvenser är nära kopplade till lägre livskvalitet och ökad dödlighet, oberoende av hur nedsatt lungfunktionen är. 

Fysisk träning är en viktig del av behandlingen vid KOL, särskilt avseende förändringar utanför lungorna. Trots god effekt av fysisk träning på gruppnivå är det på individnivå en stor variation och många får endast små effekter av den träning som erbjuds idag. Det beror bland annat på att många med KOL behöver stanna upp, eller till avbryta sin fysiska träning på grund av andfåddhet, detta innan belastningen på exempelvis hjärta och muskulatur är tillräckligt hög. Det finns därför ett behov av nya behandlingsmetoder. En möjlig lösning är supramaximal högintensiv intervallträning (HIIT) – mycket korta och intensiva cykelintervaller på sex sekunder, som kan möjliggöra hög belastning utan att andningen blir alltför påfrestande.

Vidare, trots att träning är en central del av behandlingen vid KOL är beskrivningen av träningsupplägg i tidigare studier ofta bristfällig. Detta gör det svårt att jämföra resultat och att omsätta forskningen i praktiken. 

Syftet med avhandlingen var att undersöka om supramaximal HIIT är genomförbart för personer med KOL, hur kroppen reagerar på sådan träning, hur träningen kan individanpassas och vilka metodologiska faktorer som behöver beaktas. Dessutom granskades hur väl tidigare studier om konditionsträning vid KOL har beskrivit sina träningsmetoder.

Metod

Avhandlingen bygger på fyra vetenskapliga artiklar baserade på två kliniska studier och en systematisk litteraturöversikt. I artikel I-III studeras både personer med KOL och en kontrollgrupp med lungfriska deltagare. 

Artikel I undersökte genomförbarheten och fysiologisk respons till supramaximal HIIT jämfört med traditionell konditionsträning på måttlig intensitet med konstant belastning. Artikel II använde data från samma studie och undersökte genomförbarheten och användbarheten av ett cykeltest, Borgs cykelstyrketest, för att bestämma lämplig träningsintensitet vid supramaximal HIIT. 

Artikel III är ett studieprotokoll som beskriver en pågående internationell randomiserad kontrollerad träningsstudie, där effekterna av supramaximal HIIT och traditionell träning jämförs över tre samt 24 månader. Här studeras effekter på bland annat kognitiv funktion, kondition och lårmuskelkraft. 

Artikel IV var en systematisk granskning av tidigare träningsstudier vid KOL, med fokus på hur väl träningsupplägg rapporterats och hur principer för träning har tillämpats.

Resultat

Supramaximal HIIT var genomförbar för personer med KOL och gjorde det möjligt att nå högre belastningar med mindre upplevd andfåddhet än vid traditionell måttligt intensiv träning. Båda träningsformerna ökade nivåerna av brain-derived neurotrophic factor i blodet, vilket kan vara gynnsamt för hjärnans hälsa. Borgs cykelstyrketest visade sig praktiskt genomförbart och användbart för att individanpassa träningsintensitet vid supramaximal HIIT.

I den pågående randomiserade kontrollerade träningsstudien har hittills 133 personer inkluderats, varav 82 med KOL. Deltagarna representerar olika sjukdomsgrader och har överlag god träningsföljsamhet. Preliminära resultat visar att personer med KOL har lägre kognitiv funktion, kondition och lårmuskelfunktion jämfört med friska kontrollpersoner.

Den systematiska granskningen omfattade 298 studier. Resultaten visade på bristfällig beskrivning av träningsmetoder inom KOL-forskning. Viktig information som träningsintensitet samt deltagarnas följsamhet till träningen, saknades ofta. 

Slutsatser

Supramaximal HIIT framstår som en lovande och genomförbar träningsform för personer med KOL, eftersom den möjliggör hög träningsintensitet utan att öka den upplevda andfåddheten. Forskningen fortsätter nu med att undersöka hur väl denna typ av träning fungerar på längre sikt och dess effekter på bland annat kognitiv funktion, kondition och muskelfunktion

Eftersom personer med KOL uppnår högre intensitet vid genomförande av Borgs cykelstyrketest än vid ett traditionellt arbetsprov, indikerar resultaten att testet kan vara användbart vid förskrivning av träningsintensitet vid supramaximal HIIT. Borgs cykelstyrketest kan alltså användas för att individanpassa supramaximal HIIT, men mer forskning om testets implementering behövs.

Slutligen visar avhandlingen att forskare behöver vara mer tydliga i hur de beskriver sina träningsupplägg och resultat, för att framtida studier bättre ska kunna tolkas, jämföras och användas inom vården.

Accurate prescription of supramaximal exercise requires exercise tests covering the intensity domain between maximal aerobic and peak power output. All-out tests are commonly used for this objective but are considered challenging for people with chronic obstructive pulmonary disease (COPD) due to the extreme physiological demand. The modified Borg cycle strength test (mBCST), previously used in older adults to achieve supramaximal intensities, might be a suitable alternative in people with COPD. We aimed to determine the feasibility of the mBCST in people with COPD and to compare the physiological response with that of healthy older adults. Eighteen people with COPD and 16 age-, sex- and physical activity-matched healthy adults performed a cardiopulmonary exercise test and a mBCST. The mBCST is an incremental test [30 s:30 s cycling:rest; with individualized starting load and step size (15-50 W)] with end-of-test criteria of a rating of perceived exertion of >= 17 or cadence of <75 RPM for >5 s. Feasibility was assessed using a framework covering the aim, interpretability, familiarity, duration, scoring/completion complexity, costs and safety. Measurements of external exercise intensity, rating of perceived exertion, symptoms and cardiorespiratory demand were obtained. The mBCST was deemed feasible according to the feasibility framework. Expressed relative to the cardiopulmonary exercise test, all participants reached supramaximal external exercise intensities during the mBCST [COPD, 145 (125-168)%; healthy, 154 (148-163)%], without differences in intensity or physiological response between groups (p > 0.05). The mBCST is feasible in people with COPD and enables supramaximal external exercise intensities, with similar physiological response to healthy older adults. The mBCST could be considered when selecting an exercise test to prescribe supramaximal exercise.

Background: A novel concept of controlled, short-duration supramaximal HIIT enables 3-4 times higher exercise intensities with reduced dyspnea, compared to moderate-intensity continuous training (MICT) in people with COPD. However, its effects on neurotrophic factors and brain health are yet to be investigated. We aimed to examine the acute response of neurotrophic factors to supramaximal HIIT and MICT in people with COPD.

Methods: Sixteen people with mild to severe COPD (75±6 years; 73±13 FEV1%pred) underwent supramaximal HIIT (comprising 10x6 sec intervals interspersed with 54 sec rest) and MICT (20 min at 60% CPET Wpeak). Supramaximal HIIT was performed at two intensities (HIIT60% and HIIT80%). We measured plasma levels of brain-derived neurotrophic factor (BDNF), irisin, cathepsin B and clusterin pre- and post- exercise.

Results: BDNF increased after both HIIT and MICT (Fig 1). Clusterin increased during HIIT80% (19940 [−35900 to 49600] ng/mL, +11%, p=0.01) and MICT (23390 [−5060 to 51010] ng/mL, +12%, p=0.03), but not HIIT60% (−1100 [−10060 to 113600] ng/mL, -1%, p=0.85). No changes were seen in irisin or cathepsin B.

Conclusion: For the first time, we showed that in COPD, supramaximal HIIT induces a similar increase in BDNF as MICT, with half the exercise duration. Supramaximal HIIT might be a viable exercise modality in COPD, while its long-term effects on brain health remain to be investigated.

Background: Beyond being a pulmonary disease, chronic obstructive pulmonary disease (COPD) presents with extrapulmonary manifestations including reduced cognitive, cardiovascular, and muscle function. While exercise training is the cornerstone in the non-pharmacological treatment of COPD, there is a need for new exercise training methods due to suboptimal adaptations when following traditional exercise guidelines, often applying moderate-intensity continuous training (MICT). In people with COPD, short-duration high-intensity interval training (HIIT) holds the potential to induce a more optimal stimulus for training adaptations while circumventing the ventilatory burden often associated with MICT in people with COPD. We aim to determine the effects of supramaximal HIIT and MICT on extrapulmonary manifestations in people with COPD compared to matched healthy controls.

Methods: COPD-HIIT is a prospective, multi-centre, randomized, controlled trial with blinded assessors and data analysts, employing a parallel-group designed trial. In phase 1, we will investigate the effects and mechanisms of a 12-week intervention of supramaximal HIIT compared to MICT in people with COPD (n = 92) and matched healthy controls (n = 70). Participants will perform watt-based cycling two to three times weekly. In phase 2, we will determine how exercise training and inflammation impact the trajectories of neurodegeneration, in people with COPD, over 24 months. In addition to the 92 participants with COPD performing HIIT or MICT, a usual care group (n = 46) is included in phase 2. In both phases, the primary outcomes are a change from baseline in cognitive function, cardiorespiratory fitness, and muscle power. Key secondary outcomes include change from baseline exercise tolerance, brain structure, and function measured by MRI, neuroinflammation measured by PET/CT, systemic inflammation, and intramuscular adaptations. Feasibility of the interventions will be comprehensively investigated.

Discussion: The COPD-HIIT trial will determine the effects of supramaximal HIIT compared to MICT in people with COPD and healthy controls. We will provide evidence for a novel exercise modality that might overcome the barriers associated with MICT in people with COPD. We will also shed light on the impact of exercise at different intensities to reduce neurodegeneration. The goal of the COPD-HIIT trial is to improve the treatment of extrapulmonary manifestations of the disease.

Introduction 

Chronic obstructive pulmonary disease (COPD) is a major global health concern, characterised by ventilatory constraints, decreased cardiovascular fitness and reduced limb muscle function, profoundly affecting patients’ quality of life. Aerobic training plays a crucial role in the treatment of COPD, but the variability in methodologies and incomplete reporting of key components in aerobic training trials limits the assessment of their effectiveness. This systematic review aims to critically evaluate the application of training principles and reporting of key components in aerobic training trials in randomised controlled trials (RCTs) in the COPD literature.

Methods and analysis

The protocol adheres to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol guidelines. The review will include RCTs utilising aerobic training in individuals with COPD. A comprehensive search, following a predefined search strategy will identify studies published from 2007 to 2024 in English from MEDLINE, Embase, CINAHL, CENTRAL and PEDro. Studies including people with COPD and any aerobic training intervention will be included. Two reviewers will independently screen abstracts and titles for inclusion. Two reviewers will independently conduct the screening of full-text documents and data extraction. Study quality will be assessed using the Tool for the assESsment of sTudy quality and bias in Exercise, specifically developed for exercise training studies. The certainty of the evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. A systematic synthesis will be provided, with meta-analyses and meta-regression when appropriate.

Ethics and dissemination

As this review will involve the analysis of published data, ethical approval is not required. The findings of this review will be disseminated through peer-reviewed publications and conference presentations.

PROSPERO registration number CRD42021247343.

High-intensity exercise is essential for optimal development of cardiorespiratory fitness and health. This is, however, challenging for most people with chronic obstructive pulmonary disease (COPD) due to ventilatory limitations, leading to exercise at lower intensities accompanied by suboptimal stress on the cardiovascular and muscular system.

PURPOSE: To compare the acute effects of a novel concept of short-duration supramaximal high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) in people with COPD and matched healthy controls (HC).

METHODS: Sixteen people with mild to severe COPD (75 ± 6 yr; 8 males; 73 ± 13 FEV1%pred; 119 ± 37 W max aerobic power [MAP]) and 14 HC (74 ± 5 yr; 8 males; 106 ± 14 FEV1%pred; 169 ± 38 W MAP) performed HIIT and MICT on a cycle ergometer in a randomized order. HIIT consisted of 10x6s sprints interspersed with 1-min recovery and was performed at two intensities: 60% of max mean power output for 6-sec (MPO6) and 80%MPO6, estimated from the Borg cycle strength test. MICT consisted of 20-min at 60% of MAP, derived from a cardiopulmonary exercise test. Cardiorespiratory parameters, blood lactate concentration, ratings of exertion/symptoms, and exercise modality preference were obtained.

RESULTS: Exercise characteristics and physiological data collected at the end of exercise are shown in Table 1. All HIIT sessions were completed, while 1 in 3 people with COPD did not complete MICT. The HIIT modality was preferred by 13/16 (COPD) and 12/14 (HC).

CONCLUSION: Short-duration supramaximal HIIT was feasible and enabled a 3.5-fold increase in exercise intensity vs. MICT in people with COPD and HC. Notably, despite the higher exercise intensities, the cardiorespiratory demand during HIIT was similar to MICT and clinically relevant reductions in symptoms were seen in favor of HIIT, in people with COPD. Also, >80% of participants preferred HIIT over MICT.

Background: High-intensity exercise is essential for optimal physiological exercise adaptations but challenging to perform for most people with COPD due to ventilatory limitations, leading to use of lower exercise intensities accompanied by suboptimal stress on the cardiovascular and muscular system. This study compared the acute effects of a novel concept of short-duration supramaximal high-intensity interval training (HIIT) vs. traditional moderate-intensity continuous training (MICT) in people with COPD.

Methods: Thirteen people with COPD (75±6 yr; 8 males; 72±13 FEV1%pred; 124±37 Wpeak) performed short-duration supramaximal HIIT and MICT on a cycle ergometer in a randomized order. HIIT consisted of 10x6s sprints interspersed with 1-min recovery and was performed at two intensities (HIIT60% & HIIT80%). MICT consisted of 20-min at 60% of CPET Wpeak. Cardiorespiratory parameters, blood lactate concentration, ratings of exertion/symptoms, and exercise modality preference were obtained.

Results: Exercise characteristics and physiological data are seen in Table 1. All patients completed HIIT, while 4 out of 13 stopped MICT prematurely. Notably, 85% preferred HIIT over MICT.

Conclusion: The novel concept of short-duration supramaximal HIIT enabled a 3 to 4-fold increase in exercise intensity vs. MICT. Notably, the cardiorespiratory demand during HIIT was similar to MICT, and clinically relevant reductions in symptoms were even seen in favor of HIIT.

Introduction: Exercise training is a cornerstone in managing chronic obstructive pulmonary disease (COPD), leading to several physiological adaptations including, but not limited to, structural and muscular alterations, increased exercise capacity and improved cognitive function. Still, it is not uncommon that the acute physiological response to an exercise session and the extent of chronic adaptations to exercise training are altered compared with people without COPD. To date, potential differences in acute physiological responses and chronic adaptations in people with or without COPD are not fully understood, and results from individual studies are contradictory. Therefore, the current study aims to synthesise and compare the acute physiological responses and chronic adaptations to exercise training in people with COPD compared with people without COPD.

Methods and analyses: A systematic review of randomised controlled trials (RCTs), non-randomised studies of interventions (NRSIs) and cross-sectional studies (CSSs) will be conducted. A comprehensive search strategy will identify relevant studies from MEDLINE, Scopus, CINAHL, SPORTDiscus, CENTRAL and Cochrane Airways Trials Register databases. Studies including adults with and without COPD will be considered. Outcomes will include cardiorespiratory, muscular and cognitive function, intramuscular adaptations, lung volumes and cardiometabolic responses. The protocol is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and the Cochrane Methodological Expectations of Cochrane Intervention Reviews. Risk of bias assessment will be conducted using Cochrane Risk-of-Bias 2 Tool (for RCTs), Risk-of-Bias in Non-Randomised Studies Tool (for NRSIs) and Downs and Black checklist (for CSS). Meta-analyses will be conducted when appropriate, supplemented with a systematic synthesis without meta-analysis.

Ethics and dissemination: As this study is a systematic review, ethical approval is not required. The final review results will be submitted for publication in a peer-reviewed journal and presented at international conferences.

PROSPERO registration number: CRD42022307577

Background: The relative age effect (RAE) is a worldwide phenomenon, allowing sport participation and elite selection to be based on birthdate distribution. Negative consequences include both a narrow, non-optimal elite selection and negative health effects on entire populations. This study investigated the RAE and athletic performance in multiple individual sports in Sweden. Methods: Birthdates of athletes born between the years 1922 and 2015 were collected across 4-month periods (tertiles: T1, T2, T3) from cross-country skiing (N = 136,387), orienteering (N = 41,164), athletics (N = 14,503), alpine skiing (N = 508), E-sports (N = 47,030), and chess (N = 4889). In total, data from 244,560 athletes (women: N = 79,807, men: N = 164,753) was compared to the complete parent population of 5,390,954 births in Sweden during the same years. Chi-squared statistics compared parent and cohort distributions stratified by sport, sex, and age. Results: A significantly skewed distribution of birthdates was present in all sports, both sexes, and most age groups. The largest RAEs are seen in children where T1 often constitutes 40–50% and T3, 20–25% of the population. In E-sports, an inversed RAE was seen in adults. In most investigated sports, birthdate distribution was correlated to performance in children but not in adults. Conclusions: Skewed birthdate distributions were consistently prevalent in all investigated individual sports in Sweden, both physically demanding and cognitive/skill-based. As sport participation is related to total level of physical activity, both present and future, failing to address the RAE issue at an early age will result not only in a narrow and arbitrary selection for adult elite athletes but also in a negative impact on public health.