Cardiovascular

• Novo Nordisk A/S
• Novo Nordisk Foundation
• Aarhus University
• Ghent University
• Team Danmark
• Sygeforsikringen Danmark

Individual differences in exercise-induced cardiovascular adaptations and improvements in endurance performance in men – with a special focus on the significance of testosterone and androgen receptors.

The overall aim of the project is to investigate individual variations in training-induced cardiovascular adaptations and whether these variations are linked to the amount of androgen receptors/testosterone or other signaling pathways in young untrained men.

Background

It is well known that there are large individual differences in the extent of cardiovascular and skeletal muscle adaptations achieved after a period of continuous exercise training.

However, which factors that explain the variation in training response have so far remained unanswered.

Androgens, such as testosterone, are steroid hormones that have significant effects on both skeletal muscle and the cardiovascular system and are believed to influence and initiate the signaling pathways that induce training adaptations.

However, there is limited evidence in humans regarding the role of testosterone levels and the amount of androgen receptors in individual adaptations to cardiovascular exercise.

About the Study 

Individual differences will be investigated in 40 untrained healthy males following six weeks of three weekly highly controlled exercise training.

Before and after the training period, cardiovascular, skeletal muscle, epigenetic, and exercise performance responses are assessed.

Status

All subjects have completed the study. Currently all data is being analyzed and are expected to be done around July 2025.

Funding

Danish Ministry of Culture

Project period: 2023 - 2025.

Contact

Postdoc Jan Sommer Jeppesen

Professor Ylva Hellsten

Long-term consequences for fertility and cardiovascular health of relative energy deficiency in sport (REDs) and/or eating disorders in female athletes – 15-year follow-up.

In this follow-up study, our overall aim is to investigate whether female athletes who experienced menstrual disturbances and/or eating disorders during their sports careers have an increased risk later in life (measured after 15 years) of: Fertility and pregnancy-related complications, osteoporosis, gastrointestinal issues, cardiovascular changes, eating disorders, and/or other psychosocial problems.

Background

Female athletes who experience pressure to achieve or maintain a low body weight are at increased risk of low energy availability (LEA) and developing relative energy deficiency in sport and eating disorders, which are associated with reduced physical performance and health issues such as menstrual disturbances, decreased bone health, gastrointestinal problems, cardiovascular risk factors, and negative effects on psychological and physiological systems.

Even though LEA-induced complications are often reversible, it remains unknown whether long periods of relative energy deficiency in sport lead to long-term, non-reversible physiological consequences, such as impaired fertility.

In 2012-2013, we conducted a clinical assessment of a group of female endurance athletes (n=45) and found that 60% had functional hypothalamic amenorrhea (FHA), 45% had low bone mineral density, with 17% having osteoporosis, and 23% had LEA/eating disorders, FHA, and low bone mineral density.

About the Study 

Female participants included in the original study is invited to participate in the follow-up study.

Status

The recruitment and experimental phase will begin in the spring of 2025.

Funding

Centrum för Idrottsforskning, Sverige

Project period:2025 - 2026.

Contact

Postdoc Jan Sommer Jeppesen

Professor Ylva Hellsten

Identification and exercise-induced reversal of mechanisms behind microvascular dysfunction in Ischemia with No Obstructive Coronary Artery (ExINOCA)

Background       

A significant number of patients with ischemic heart disease are not diagnosed with coronary obstruction, instead, the symptoms are attributed to coronary microvascular dysfunction. This condition is termed ischemia with no obstructive coronary artery disease (INOCA).

Despite the large proportion of patients with INOCA, the mechanisms underlying the microvascular dysfunction remain unresolved and, commonly, these patients receive no treatment. Exercise capacity is associated with coronary microvascular function and exercise training may be useful in reversing microvascular dysfunction and its underlying mechanistic causes. This has never been examined.

About the Study

Primary objective 
to identify mechanisms underlying microvascular dysfunction in INOCA.

Secondary objectives 
to determine the impact of an exercise training intervention on coronary microvascular function and on molecular pathways identified in our project to be coupled to microvascular dysfunction in INOCA.

Status 

If you're interested in participating, click this link (Danish).

With the project spanning from 2024 to 2028, we are conducting ongoing analyses of our results, expecting regular publications due to the project's long-term outlook.

Funding

Novo Nordisk Foundation

Contact

Mads Fischer
Postdoc

KISO will create important new knowledge about physiological and sociological changes through the menopause, which will have great relevance scientifically as well as for all women who, despite individual differences, sooner or later will encounter this phase in life.

Background

As women enter menopause, their risk of developing serious cardiovascular diseases such as blood clots in the heart or brain increases dramatically. This dramatic increase is probably connected to the fact that the production of the female sex hormone, estrogen, stops at menopause. However, there is very little knowledge about why and how the menopause as a whole and the time afterwards affects the heart, brain, blood vessels and blood.

The many bodily changes during menopause, which can both be felt internally and seen externally, also give rise to concerns about how the body's internal health is doing, and reflections about who you are. Two out of three Danish women talk to their doctor about the menopause, even if they do not necessarily have bothersome symptoms or signs of illness. Nevertheless, Danish middle-aged women feel more experienced, competent and free in this life phase. All in all, we know very little about why and how self-identity and body understanding change in step with the physiological changes through menopause.

Physical activity is a well-known means of preventing cardiovascular disease and, in addition, can also influence self-identity and body understanding in a positive direction. However, it has never been elucidated whether a physically active lifestyle can actually reduce the negative changes that occur in the body's health during menopause or whether a physically active lifestyle can help to influence the concerns and challenges around self-identity and the body that many women experience at menopause.

About the Study

The included women take part in the below surveys of three rounds (however, the preliminary survey is only relevant for the first round). The first time is before menopause, the second time is approximately four months after the last period and the third time is after three years.

Physiological studies

Preliminary examination: During the preliminary examination, which is carried out by a doctor, the menstrual cycle is mapped and a blood sample is taken in order to determine the time to expected menopause. Blood pressure is recorded and cholesterol and blood sugar are measured as well as liver and kidney function. Final offer of inclusion is made when blood test results are submitted showing that the participant is healthy and that menopause is likely to occur within one to three years.

Physiological test day: The participant is invited to a test day of approx. duration of four hours, during which the following examinations are carried out:

Cardiac examination: The structure and function of the heart are examined with echocardiography and MRI scanning during stress testing of the heart.

Brain examination: The blood vessels of the brain are examined by inhaling CO2, while the blood flow is monitored with ultrasound doppler.

Arterial examination: Atherosclerosis and function of the body's large arteries are examined with ultrasound doppler.

Blood analysis: The blood's ability to coagulate is determined with a newly developed advanced method in a blood test which gives an answer to how likely the blood is to form a blood clot and how strong the blood clot will be.

Sociological studies

Focus groups: Through 10 focus group interviews with a total of 50 informants, Danish society's rules and social structures for menopause and training that both limit and enable middle-aged women's actions are examined.

Individual interviews: In order to understand how active and inactive women experience their changing bodies, menopause, exercise and their own options, 25 in-depth qualitative individual interviews are conducted.

Questionnaire survey: To elucidate quantitative aspects around the menopause (symptoms, seeking a doctor), training (level and type of activity) and socio-demographic variables, a questionnaire survey is carried out before, during and after the menopause.

Status

The project period runs from 2021 – 2027. Click this link if you are interested in participating (Danish).

The project's results are being analyzed continuously. It typically takes a few years. Due to the project's long-term perspective, regular publications are expected.

Funding

Sygeforsikringen Danmark (Health insurance)

Velux Foundation

Contact

PhD fellow Andrea Tamariz-Ellemann

Anthocyanin Reduces Cardiovascular risks in Hypertensive people

The purpose of the study is to assess the effect of eight weeks of anthocyanin ingestion on arterial blood pressure, vascular function, and microbiome composition in subjects with hypertension.

Background

Hypertension is a public health concern, a silent disease in which the number of people affected grows annually, increasing the risk of cardiovascular events that potentially lead to death. The reduction of blood pressure in hypertensive individuals are therefore of central importance for health.

The current project is a comprehensive study designed to investigate how daily ingestion of anthocyanin (an antioxidant) may improve the cardiovascular health of hypertensive people.

About the Study

The study is separated into 2 parts: (1) daily arterial blood pressure monitoring, and (2) the assessment of the vascular function at the periphery and the brain.

A randomized, double-blind, placebo-controlled study design was chosen to investigate the effect of 8 weeks of anthocyanin ingestion on arterial blood pressure and artery function in subjects with hypertension.

The participants will be randomly assigned into 4 different groups: (1) Anthocyanin; (2) Lactobacillus plantarum; (3) Lactobacillus plantarum + Anthocyanin; (4) Placebo group.

The primary outcome is the reduction of arterial blood pressure, i.e., systolic, and diastolic blood pressure of hypertensive subjects and improvement of the functionality of the subjects' arteries (vascular function).

The secondary outcome is to examine changes in microbiome composition in hypertensive individuals before and after treatment, aiming to gain insights into its role in regulating arterial blood pressure.

We aim to gain deeper insights into the chronic effects of anthocyanin consumption in hypertensive individuals, its potential role in lowering blood pressure, and the underlying mechanisms driving this reduction.

Status

We have just started recruiting participants for the 1st part of the project, with 89 people completing the intervention. We aim for 356 people.

The second part of the project, which uses a more invasive approach to investigate the participants’ vascular function, is concluded.

The first project’s result is expected to be analyzed in May 2025.

Funding

Innovation Foundation Denmark.

Suko Nordic

Project period: 2023 - 2025.

Contact

PhD fellow Marcos Paulo Rocha Alves 

Studying the effect of training on the microvascular cellular function in men and women (40-60 years) with and without type 2 diabetes.

This study explores the molecular and cellular mechanisms underpinning improved insulin sensitivity following a period of regular physical training. Specifically, this study focuses on how the cells change and adapt to exercise training in patients with type 2 diabetes.

About the Study

The aim of this project is to study the skeletal muscle-derived microvascular cellular adaptations; and the transcriptional differences at single cell resolution in skeletal muscle and adipose tissue before and after a 12-week training intervention in patients with type 2 diabetes and in control subjects. This will be done using a unique combination of clinical experiments and state-of-the-art cellular models (single nuclei transcriptomics and microvascular cellular isolations).

From this, we expect to map in detail the skeletal muscle-derived microvascular cells and adipose tissue with insulin resistance, at baseline and in response to training. This detailed map would allow opportunities to identify novel therapeutic targets for treating insulin resistance.

Status

All subjects were completed in 2024 and we are in the process of finalizing the analysis of the samples. We expect to be finished by the end of the 2025.

Collaborations

This project is in collaboration with Novo Nordisk A/S and Faculty of Medical and Health Sciences UCPH (SUND)

Funding

Novo Nordisk A/S

Project period: 2020 - 2025. 

Contact

Professor Ylva Hellsten

Mitochondria derived peptides – novel regulators of endothelial and skeletal muscle metabolism and function?

The aim of this project is to determine the effect of MOTS-c and humanin (small bioactive peptides released from mitochondria) on primary skeletal muscle and vascular endothelial cell metabolism, oxidative stress and function in health and cardiovascular disease. Hereunder, we will evaluate molecular signaling underlying the effects.

About the Study

The project combines experiments in mice, healthy- and hypertensive humans and isolated primary human cells.

Status

The project and analysis is almost completed and two manuscripts are under way.

Collaboration

The study is conducted in collaboration with Prof. Henriette Pilegaard from The Department of Biology at The University of Copenhagen.

Funding

Novo Nordisk Foundation.

Project period: 2022 – 2025.

Contact

Professor Ylva Hellsten

Cardiovascular function And Metabolic profile in Adolescents born after Assisted Reproductive Technologies

We investigate possible cardiovascular and metabolic adverse alterations in young individuals (15-17 years of age) born after Assisted Reproductive Technologies. Our results will indicate if screenings of cardiovascular and metabolic health should be implemented in individuals born after Assisted reproductive technologies.

Background

Infertility is experienced by up to 20% of couples, and 10% of all couples will eventually undergo fertility treatment. Assisted reproductive technologies account for up to 6.5% of births in industrialized countries and account for over a total of 10 million births world-wide.

Cardiovascular and metabolic dysfunction, e.g. arterial hypertension, cardiac diastolic dysfunction, decreased insulin sensitivity, are major risk factors or even cause of future cardiovascular disease.

Very few studies have investigated the possible cardiovascular and metabolic compromises in individuals born after ART.

About the Study

The overall objective of this study is to investigate the cardiovascular and metabolic profile differences in a clinical cohort study of young adults (15-17 years of age) conceived after frozen embryo transfer (n=100), and fresh embryo transfer (n=100) compared to young adults conceived naturally (n=100).

Objective 1

To investigate the 24-hours systemic arterial blood pressure.

Primary outcome: The adjusted mean systolic and diastolic blood pressure over 24 hours.

Objective 2

To investigate blood pressure and cardiac function at rest and during dynamic exercise.

Secondary outcome: E/e´ ratio at rest and moderate intensity exercise.

Objective 3

To investigate the insulin sensitivity and biochemical and anthropometric metabolic parameters.

Secondary outcome: Mean HOMA-IR (insulin sensitivity).

Worldwide freezing strategies have been implemented, and cryopreservation now accounts for more than half of all ART cycles without taking the risk of the offspring into account. Our findings will help utilizing the fertility treatment option with lesser risk and complications in the offspring.

Furthermore, we will identify if young adults born after ART are in increased risk of cardiovascular and metabolic disease and signify if screenings of cardiovascular and metabolic health should be implemented for individuals born after ART.

Status

We started invitations in May 2022, and after 9 months we have included 50% of the study participants (n=150/300) and completed examinations in 25% of the participants (n=75/300). We plan to invite and examine participants till fall 2024.

Funding

The Danish Cardiovascular Academy

Novo Nordisk Foundation

Project period: 2022 - 2025.

Contact

Visiting researcher Jakob Solgaard Jensen

We to aim develop a reliable anxiety inducing stress test and investigate the effect of stress exposure training and military physical training on psychobiological resilience in army personnel.

Background

Due to prolonged stress and traumatic experiences during e.g. combat exposure, Military personnel suffer an increased risk for developing severe and debilitating stress reactions like anxiety and PTSD.

The main predictor of developing PTSD is the experience of intense emotions like fear and anxiety due to the perception of life-threatening stressors. With this project we want to investigate possible interventions to enhance the psychobiological resilience to stressors that invoke anxiety in soldiers.

Results from these studies will inform and possibly revise educational practice in the Danish Defense with the aim of preventing mental health decline in deployed soldiers.

About the Study

To project is divided into a methodological study and a main intervention study. In the methodological studies we investigate a new anxiety stress paradigm combining a biological challenge that utilizes breathing of CO₂-enriched air with a recreational fear experience such as horror movies or 360^o horror video in virtual reality.

In two studies using a balanced cross-over design and a test-retest design, we investigate the criterion validity and reliability, respectively. The main study will use a quasi-experimental design to investigate the two interventions in army conscripts or private soldiers.

Primary outcomes are differences in self-rated anxiety during the stress test. Secondary outcomes are differences in release of stress and anxiety-buffering neurochemicals, such as Neuropeptide Y, Galanin and DHEA, and stress hormones like cortisol, norepinephrine and epinephrine. We expect an increase in anxiolytic chemical and a decrease in anxiety and stress hormones.

Status

Development and Recruiting-phase.

Collaboration

The Danish Armed Forces Medical Command.

Contact

PhD student Frank Dyrehuage Thøgersen

Low Energy Availability

Project has ended. Period: 2022 - 2024.

The study explored the impact of short-term severe low energy availability on the immune system, inflammation, metabolism, and exercise performance in female endurance athletes.

Publications

Jeppesen JS, Caldwell HG, Lossius LO, Melin AK, Gliemann L, Bangsbo J, Hellsten Y. Low energy availability increases immune cell formation of reactive oxygen species and impairs exercise performance in female endurance athletes. Redox Biol. 2024 Sep;75:103250. doi: 10.1016/j.redox.2024.103250. Epub 2024 Jun 19. PMID: 38936255; PMCID: PMC11260862.

Caldwell HG, Jeppesen JS, Lossius LO, Atti JP, Durrer CG, Oxfeldt M, Melin AK, Hansen M, Bangsbo J, Gliemann L, Hellsten Y. The whole-body and skeletal muscle metabolic response to 14 days of highly controlled low energy availability in endurance-trained females. FASEB J. 2024 Nov 15;38(21):e70157. doi: 10.1096/fj.202401780R. PMID: 39530548.

Funded by

Team Danmark

Danish Ministry of Culture

Fridmodt-Heineke Foundation

Contact

Postdoc Jan Sommer Jeppesen

Professor Ylva Hellsten

Thrombosis In Menopause and Exercise training

Project has ended. Period: 2020 - 2023.

This study explored the vascular and thrombogenic adaptations to 8 weeks of high-intensity exercise training in recent (≤5 years) and late (≥10 years) postmenopausal women.

Publications

Exercise training alters skeletal muscle microvascular endothelial cell properties in recent postmenopausal females. Nørregaard LB, Hansen CC, Wickham KA, Møller S, Olsen K, Ehlers T, Bangsbo J, Hellsten Y.J Physiol. 2024 Jul;602(14):3449-3468. doi: 10.1113/JP286269. Epub 2024 Jun 1. PMID: 38822814.

Exercise transiently increases the density of incipient blood clots in antiplatelet-treated lacunar stroke patients. Nørregaard LB, Wickham KA, Jeppesen JS, Rytter N, Christoffersen LC, Gliemann L, Lawrence M, Evans PA, Kruuse C, Hellsten Y.Thromb J. 2024 Apr 5;22(1):35. doi: 10.1186/s12959-024-00604-9. PMID: 38581046 Free PMC article.

Wickham KA, Nørregaard LB, Lundberg Slingsby MH, Cheung SS, Hellsten Y. High-Intensity Exercise Training Improves Basal Platelet Prostacyclin Sensitivity and Potentiates the Response to Dual Anti-Platelet Therapy in Postmenopausal Women. Biomolecules. 2022; 12(10):1501. https://doi.org/10.3390/biom12101501

Funded By

Nordea Foundation

Danish Ministry of Culture 

Project period:  2020 - 2023.

Contact

Professor Ylva Hellsten