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Article ; Online: The role of interleukin-6 in glucose homeostasis and lipid metabolism.

Lehrskov, Louise Lang / Christensen, Regitse Højgaard

2019 Volume 41, Issue 4, Page(s) 491–499

Abstract: Low-grade inflammation is recognized as an important factor in the development and progression of a multitude of diseases including type 2 diabetes mellitus and cardiovascular disease. The potential of using antibody-based therapies that neutralize key ... ...

Abstract	Low-grade inflammation is recognized as an important factor in the development and progression of a multitude of diseases including type 2 diabetes mellitus and cardiovascular disease. The potential of using antibody-based therapies that neutralize key players of low-grade inflammation has gained scientific momentum as a novel therapeutic strategy in metabolic diseases. As interleukin-6 (IL-6) is traditionally considered a key pro-inflammatory factor, the potential of expanding the use of anti-IL-6 therapies to metabolic diseases is intriguing. However, IL-6 is a molecule of a very pleiotropic nature that regulates many aspects of not only inflammation but also metabolism. In this review, we give a brief overview of the pro- and anti-inflammatory aspects of IL-6 and provide an update on its role in metabolic regulation, with a specific focus on glucose homeostasis and adipose tissue metabolism. Finally, we shall discuss the metabolic implications and clinical potential of blocking IL-6 signaling, focusing on glucose homeostasis and lipid metabolism.
MeSH term(s)	Adipose Tissue/metabolism ; Adipose Tissue/pathology ; Animals ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Diabetic Cardiomyopathies/metabolism ; Diabetic Cardiomyopathies/pathology ; Glucose/metabolism ; Humans ; Interleukin-6/metabolism ; Lipid Metabolism ; Signal Transduction
Chemical Substances	IL6 protein, human ; Interleukin-6 ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2019-05-17
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2316828-6
ISSN	1863-2300 ; 1863-2297
ISSN (online)	1863-2300
ISSN	1863-2297
DOI	10.1007/s00281-019-00747-2
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Article: Vascular Inflammation as a Therapeutic Target in COVID-19 "Long Haulers": HIITing the Spot?

Christensen, Regitse Højgaard / Berg, Ronan M G

Frontiers in cardiovascular medicine

2021 Volume 8, Page(s) 643626

Language	English
Publishing date	2021-03-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2021.643626
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Article: Fidelity and tolerability of two high-intensity interval training protocols in patients with COPD: a randomised cross-over pilot study.

Nymand, Stine Buus / Hartmann, Jacob / Rasmussen, Iben Elmerdahl / Iepsen, Ulrik Winning / Ried-Larsen, Mathias / Christensen, Regitse Højgaard / Berg, Ronan Martin Griffin

BMJ open sport & exercise medicine

2023 Volume 9, Issue 1, Page(s) e001486

Abstract: Objectives: High-intensity interval training (HIIT) during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) may alleviate the symptom burden, but the fidelity and tolerability of HIIT using long or short intervals ... ...

Abstract	Objectives: High-intensity interval training (HIIT) during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) may alleviate the symptom burden, but the fidelity and tolerability of HIIT using long or short intervals in patients with COPD are unknown. Methods: Twelve patients with moderate-to-severe COPD were included in a randomised cross-over pilot study. They completed two supervised HIIT protocols (4×4 and 10×1). To compare the two HIIT protocols, completed training amount, exercise intensity and perceived tolerability (assessed by a 10-point Likert scale) were integrated in a red-amber-green rating system. If a training session received a red ranking, it was considered unacceptable, if it received an amber ranking it was applicable with precautions, and if it received a green ranking it was considered feasible. Results: All patients completed the total training amount in both protocols. The 4×4 protocol resulted in three amber training sessions due to low perceived tolerability. The 10×1 protocol resulted in two red training sessions due to intensity reductions, and two amber training sessions because of low perceived tolerability. There was no statistical difference in perceived tolerability or time spent with an HR ≥85% of HR Conclusions: HIIT using longer intervals (4×4) at a relatively lower intensity resulted in higher fidelity expressed by fewer adjustments to the protocol, whereas there was no difference between protocols in perceived tolerance. The 4×4 protocol seems to have a higher fidelity compared with the 10×1 protocol in patients with moderate-to-severe COPD. Trial registration number: NCT05273684.
Language	English
Publishing date	2023-03-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2817580-3
ISSN	2055-7647
ISSN	2055-7647
DOI	10.1136/bmjsem-2022-001486
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Article ; Online: Exercise adaptations in COPD: the pulmonary perspective.

Nymand, Stine B / Hartmann, Jacob P / Ryrsø, Camilla Koch / Rossen, Ninna Struck / Christensen, Regitse Højgaard / Iepsen, Ulrik Winning / Berg, Ronan M G

American journal of physiology. Lung cellular and molecular physiology

2022 Volume 323, Issue 6, Page(s) L659–L666

Abstract: In chronic obstructive pulmonary disease (COPD), the progressive loss of lung tissue is widely considered irreversible. Thus, various treatment and rehabilitation schemes, including exercise-based pulmonary rehabilitation (PR) are thought to slow down ... ...

Abstract	In chronic obstructive pulmonary disease (COPD), the progressive loss of lung tissue is widely considered irreversible. Thus, various treatment and rehabilitation schemes, including exercise-based pulmonary rehabilitation (PR) are thought to slow down but not reverse or halt the disease. Nonetheless, the adult lung conceals the intrinsic capacity for de novo lung tissue formation in the form of abundant progenitor/stem cell populations. In COPD, these maintain their differentiation potential but appear to be halted by a state of cellular senescence in the mesenchyme, which normally functions to support and coordinate their function. We propose that notably high-intensity interval training may improve pulmonary gas exchange during exercise in patients with COPD by interrupting mesenchymal senescence, thus reestablishing adaptive angiogenesis. By means of this, the downward spiral of dyspnea, poor quality of life, physical inactivity, and early death often observed in COPD may be interrupted. If this is the case, the perception of the regenerative capacity of the lungs will be fundamentally changed, which will warrant future clinical trials on various exercise schemes and other treatments targeting the formation of new lung tissue in COPD.
MeSH term(s)	Adult ; Humans ; Quality of Life ; Pulmonary Disease, Chronic Obstructive/therapy ; Lung ; Dyspnea/rehabilitation ; Exercise ; Exercise Tolerance ; Exercise Therapy
Language	English
Publishing date	2022-09-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00549.2020
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Article: Epicardial adipose tissue: an emerging biomarker of cardiovascular complications in type 2 diabetes?

Christensen, Regitse Højgaard / von Scholten, Bernt Johan / Lehrskov, Louise Lang / Rossing, Peter / Jørgensen, Peter Godsk

Therapeutic advances in endocrinology and metabolism

2020 Volume 11, Page(s) 2042018820928824

Abstract: Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular disease and heart failure, which highlights the need for improved understanding of factors contributing to the pathophysiology of these complications as they are the leading ... ...

Abstract	Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular disease and heart failure, which highlights the need for improved understanding of factors contributing to the pathophysiology of these complications as they are the leading cause of mortality in T2D. Patients with T2D have high levels of epicardial adipose tissue (EAT). EAT is known to secrete inflammatory factors, lipid metabolites, and has been proposed to apply mechanical stress on the cardiac muscle that may accelerate atherosclerosis, cardiac remodeling, and heart failure. High levels of EAT in patients with T2D have been associated with atherosclerosis, diastolic dysfunction, and incident cardiovascular events, and this fat depot has been suggested as an important link coupling diabetes, obesity, and cardiovascular disease. Despite this, the predictive potential of EAT in general, and in patients with diabetes, is yet to be established, and, up until now, the clinical relevance of EAT is therefore limited. Should this link be established, importantly, studies show that this fat depot can be modified both by pharmacological and lifestyle interventions. In this review, we first introduce the role of adipose tissue in T2D and present mechanisms involved in the pathophysiology of EAT and pericardial adipose tissue (PAT) in general, and in patients with T2D. Next, we summarize the evidence that these fat depots are elevated in patients with T2D, and discuss whether they might drive the high cardiometabolic risk in patients with T2D. Finally, we discuss the clinical potential of cardiac adipose tissues, address means to target this depot, and briefly touch upon underlying mechanisms and future research questions.
Language	English
Publishing date	2020-05-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2554822-0
ISSN	2042-0196 ; 2042-0188
ISSN (online)	2042-0196
ISSN	2042-0188
DOI	10.1177/2042018820928824
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Article ; Online: Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis - study protocol for a randomised controlled trial.

Jønck, Simon / Adamsen, Malte Lund / Højgaard, Pil / Rasmussen, Iben Elmerdahl / Ellingsgaard, Helga / Lund, Morten Asp Vonsild / Jørgensen, Peter Godsk / Jacobsen, Søren / Køber, Lars / Vejlstrup, Niels / Dreyer, Lene / Pedersen, Bente Klarlund / Berg, Ronan M G / Christensen, Regitse Højgaard

BMJ open

2023 Volume 13, Issue 5, Page(s) e068600

Abstract: Introduction: The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, ... ...

Abstract	Introduction: The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, biological disease-modifying antirheumatic drugs (bDMARDs) may attenuate that risk. IL-6 is also a myokine, secreted from exercising skeletal muscles, where IL-6 exhibits anti-inflammatory effects that may ameliorate the risk of CVD. In healthy humans treated with IL-6 signalling inhibitors (IL-6i), exercise induced loss of visceral fat mass and cardiac adaptations were abolished. We hypothesise that IL-6 signalling inhibition will impair the cardiac and metabolic adaptions to exercise training compared with TNF inhibition in RA patients. Methods and analysis: 80 RA patients treated with IL-6i (n=40) or TNF inhibitors (n=40) are included in a 12-week randomised investigator-blinded 4×4 min high-intensity interval training (HIIT) study. Patients are stratified for medical treatment and sex and allocated 1:1 to an exercise or a no exercise control group (four groups). The supervised exercise intervention comprises 3 weekly HIIT sessions on an ergometer bicycle. The primary outcome is the change in left ventricular mass (LVM), and key secondary outcome is change in visceral fat mass. Both outcomes are measured by MRI. Primary statistical analysis will evaluate LVM at follow-up in a regression model. Intention-to-treat and per protocol analyses will be conducted. The latter necessitates a minimum attendance rate of 80%, adherence to bDMARDs treatment of ≥80% and minimum 8 min (50%) of maximal heart rate above 85% per session. Ethics and dissemination: The study has been approved by the Capital Region Ethics Committee (H-21010559 amendments 86424, 87463 and 88044) and the Danish Medicines Agency (2021-b005287-21). The trial will follow ICH-GCP guidelines. Regardless of outcome, results will be published in relevant peer-reviewed journals. Trial registration numbers: Eudra-CT: 2021-b005287-21 and NCT05215509.
MeSH term(s)	Humans ; Antirheumatic Agents/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor Inhibitors/therapeutic use ; Arthritis, Rheumatoid/drug therapy ; Exercise ; Exercise Therapy/methods ; Tumor Necrosis Factor-alpha ; Cardiovascular Diseases/drug therapy ; Randomized Controlled Trials as Topic
Chemical Substances	Antirheumatic Agents ; Interleukin-6 ; Tumor Necrosis Factor Inhibitors ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2023-05-11
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2022-068600
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Article: Fidelity, tolerability and safety of acute high-intensity interval training after hospitalisation for COVID-19: a randomised cross-over trial.

Foged, Frederik / Rasmussen, Iben Elmerdahl / Bjørn Budde, Josephine / Rasmussen, Rasmus Syberg / Rasmussen, Villads / Lyngbæk, Mark / Jønck, Simon / Krogh-Madsen, Rikke / Lindegaard, Birgitte / Ried-Larsen, Mathias / Berg, Ronan Martin Griffin / Christensen, Regitse Højgaard

BMJ open sport & exercise medicine

2021 Volume 7, Issue 3, Page(s) e001156

Abstract: Objectives: Many patients with COVID-19 suffer from persistent symptoms, many of which may potentially be reversed by high-intensity interval training (HIIT). Yet, the safety and tolerability of HIIT after COVID-19 is controversial. This study aimed to ... ...

Abstract	Objectives: Many patients with COVID-19 suffer from persistent symptoms, many of which may potentially be reversed by high-intensity interval training (HIIT). Yet, the safety and tolerability of HIIT after COVID-19 is controversial. This study aimed to investigate the fidelity, tolerability and safety of three different HIIT protocols in individuals that had recently been hospitalised due to COVID-19. Methods: The study was a randomised cross-over trial. We compared three supervised HIIT protocols (4×4, 6×1, 10-20-30) in 10 individuals recently discharged after hospitalisation for severe COVID-19. Each HIIT protocol had a duration of 38 min and was performed with a 1-week washout between them. Outcomes included adverse events, exercise training intensity and tolerability assessed by the Likert scale (1-10). Results: All 10 participants aged 61 (mean, SD 8) years (5 males) completed all three HIIT protocols with no adverse events. High intensities were achieved in all three protocols, although they differed in terms of time spent with a heart rate ≥85% of maximum (mean (SD); 4×4: 13.7 (6.4) min; 10-20-30: 12.1 (3.8) min; 6×1: 6.1 (5.6) min; p=0.03). The three protocols were all well tolerated with similar Likert scale scores (mean (SD); 4×4: 8 (2), 10-20-30: 8 (2), 6×1: 9 (2), p=0.72). Conclusion: Our findings indicate that recently hospitalised individuals for severe COVID-19 may safely tolerate acute bouts of supervised HIIT as per protocol. This warrants future studies testing the potential of regular HIIT as a rehabilitation strategy in this context.
Language	English
Publishing date	2021-09-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2817580-3
ISSN	2055-7647
ISSN	2055-7647
DOI	10.1136/bmjsem-2021-001156
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Article ; Online: Therapeutic benefits of proning to improve pulmonary gas exchange in severe respiratory failure: focus on fundamentals of physiology.

Berg, Ronan M G / Hartmann, Jacob Peter / Iepsen, Ulrik Winning / Christensen, Regitse Højgaard / Ronit, Andreas / Andreasen, Anne Sofie / Bailey, Damian M / Mortensen, Jann / Moseley, Pope L / Plovsing, Ronni R

Experimental physiology

2021 Volume 107, Issue 7, Page(s) 759–770

Abstract: New findings: What is the topic of this review? The use of proning for improving pulmonary gas exchange in critically ill patients. What advances does it highlight? Proning places the lung in its 'natural' posture, and thus optimises the ventilation- ... ...

Abstract	New findings: What is the topic of this review? The use of proning for improving pulmonary gas exchange in critically ill patients. What advances does it highlight? Proning places the lung in its 'natural' posture, and thus optimises the ventilation-perfusion distribution, which enables lung protective ventilation and the alleviation of potentially life-threatening hypoxaemia in COVID-19 and other types of critical illness with respiratory failure. Abstract: The survival benefit of proning patients with acute respiratory distress syndrome (ARDS) is well established and has recently been found to improve pulmonary gas exchange in patients with COVID-19-associated ARDS (CARDS). This review outlines the physiological implications of transitioning from supine to prone on alveolar ventilation-perfusion (
MeSH term(s)	COVID-19 ; Humans ; Hypoxia/therapy ; Prone Position/physiology ; Pulmonary Gas Exchange/physiology ; Respiration, Artificial ; Respiratory Distress Syndrome/therapy ; Respiratory Insufficiency/therapy
Language	English
Publishing date	2021-08-13
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1016295-1
ISSN	1469-445X ; 0958-0670
ISSN (online)	1469-445X
ISSN	0958-0670
DOI	10.1113/EP089405
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Article ; Online: Impact of high-intensity interval training on cardiac structure and function after COVID-19: an investigator-blinded randomized controlled trial.

Rasmussen, Iben Elmerdahl / Løk, Mathilde / Durrer, Cody Garett / Foged, Frederik / Schelde, Vera Graungaard / Budde, Josephine Bjørn / Rasmussen, Rasmus Syberg / Høvighoff, Emma Fredskild / Rasmussen, Villads / Lyngbæk, Mark / Jønck, Simon / Krogh-Madsen, Rikke / Lindegaard, Birgitte / Jørgensen, Peter Godsk / Køber, Lars / Vejlstrup, Niels / Klarlund Pedersen, Bente / Ried-Larsen, Mathias / Lund, Morten Asp Vonsild /

Christensen, Regitse Højgaard / Berg, Ronan M G

Journal of applied physiology (Bethesda, Md. : 1985)

2023 Volume 135, Issue 2, Page(s) 421–435

Abstract: A large proportion of patients suffer from a persistent reduction in cardiorespiratory fitness after recovery from COVID-19, of which the effects on the heart may potentially be reversed through the effect of high-intensity interval training (HIIT). In ... ...

Abstract	A large proportion of patients suffer from a persistent reduction in cardiorespiratory fitness after recovery from COVID-19, of which the effects on the heart may potentially be reversed through the effect of high-intensity interval training (HIIT). In the present study, we hypothesized that HIIT would increase left ventricular mass (LVM) and improve functional status and health-related quality of life (HRQoL) in individuals previously hospitalized for COVID-19. In this investigator-blinded, randomized controlled trial, 12 wk of supervised HIIT (4 × 4 min, three times a week) was compared with standard care (control) in individuals recently discharged from hospital due to COVID-19. LVM was assessed by cardiac magnetic resonance imaging (cMRI, primary outcome), whereas the pulmonary diffusing capacity (D
MeSH term(s)	Female ; Humans ; Quality of Life ; High-Intensity Interval Training ; COVID-19 ; Heart ; Cardiorespiratory Fitness
Language	English
Publishing date	2023-06-30
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219139-8
ISSN	1522-1601 ; 0021-8987 ; 0161-7567 ; 8750-7587
ISSN (online)	1522-1601
ISSN	0021-8987 ; 0161-7567 ; 8750-7587
DOI	10.1152/japplphysiol.00078.2023
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Article ; Online: Relation of cardiac adipose tissue to coronary calcification and myocardial microvascular function in type 1 and type 2 diabetes.

Zobel, Emilie H / Christensen, Regitse Højgaard / Winther, Signe A / Hasbak, Philip / Hansen, Christian Stevns / von Scholten, Bernt J / Holmvang, Lene / Kjaer, Andreas / Rossing, Peter / Hansen, Tine W

Cardiovascular diabetology

2020 Volume 19, Issue 1, Page(s) 16

Abstract: Background: Cardiac adipose tissue may have local paracrine effects on epicardial arteries and the underlying myocardium, promoting calcification and affecting myocardial microcirculation. We explored whether the total amount of cardiac adipose tissue ... ...

Abstract	Background: Cardiac adipose tissue may have local paracrine effects on epicardial arteries and the underlying myocardium, promoting calcification and affecting myocardial microcirculation. We explored whether the total amount of cardiac adipose tissue was associated with coronary artery calcium score (CAC) and myocardial flow reserve in persons with type 1 or type 2 diabetes and healthy controls. Methods: We studied three groups: (1) 30 controls, (2) 60 persons with type 1 diabetes and (3) 60 persons with type 2 diabetes. The three groups were matched for sex and age. The three groups derived from retrospective analysis of two clinical studies. All underwent cardiac Results: Mean (SD) cardiac adipose tissue volume was 99 (61) mL in the control group, 106 (78) mL in the type 1 diabetes group and 228 (97) mL in the type 2 diabetes group. Cardiac adipose tissue was positively associated with body mass index in all three groups (p ≤ 0.02). In the controls, cardiac adipose tissue was positively associated with CAC score (p = 0.008) and negatively associated with myocardial flow reserve (p = 0.005). However, cardiac adipose tissue was not associated with CAC or myocardial flow reserve in the groups including persons with type 1 or type 2 diabetes (p ≥ 0.50). Conclusions: In contrast to what was found in healthy controls, we could not establish a relation between cardiac adipose tissue and coronary calcification or myocardial microvascular function in person with type 1 or type 2 diabetes. The role of cardiac adipose tissue in cardiovascular disease in diabetes remains unclear.
MeSH term(s)	Adipose Tissue/diagnostic imaging ; Adipose Tissue/physiopathology ; Adiposity ; Coronary Artery Disease/diagnostic imaging ; Coronary Artery Disease/etiology ; Coronary Artery Disease/physiopathology ; Coronary Circulation ; Diabetes Mellitus, Type 1/complications ; Diabetes Mellitus, Type 1/diagnosis ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/diagnosis ; Humans ; Microcirculation ; Positron Emission Tomography Computed Tomography ; Predictive Value of Tests ; Retrospective Studies ; Vascular Calcification/diagnostic imaging ; Vascular Calcification/etiology ; Vascular Calcification/physiopathology
Language	English
Publishing date	2020-02-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1475-2840
ISSN (online)	1475-2840
DOI	10.1186/s12933-020-0995-x
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