The Cardiovascular group

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

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 and vascular function 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 reducing the reactive oxygen species (ROS) generated during physiological processes, which can act as cell signalling molecules and promoters of oxidative stress. However, ROS is often high in hypertension.

We hope to gain more knowledge about hypertensive disease and the effects of anthocyanin use on blood pressure reduction and what mechanisms may explain the reduction in blood pressure.

Status

We have just started recruiting participants for the 1st part of the project, with 5 people already started. We aim for 356 people.

The second part of the project, with a more invasive approach to investigate the participants’ vascular function, is planned to start by May. We aim for 40 people to be recruited.

The analysis of the project’s result is expected to be done by August 2024.

Funding

Innovation Foundation Denmark.

Suku Nordic

Project period: 2023 - 2024.

Contact

PhD fellow Marcos Paulo Rocha Alves 

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

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

Background

Exercise training has been shown to benefit the health of patients with insulin resistance and/or type 2 diabetes (NIH, 2020). However, how the cells adapt to regular exercise training is unexplored in type 2 diabetic patients.

There is a vast amount of literature from our institute on the effects of acute exercise on skeletal muscle take up glucose (Richter et al., 1989; Wojtaszewski et al., 2002; Frosig & Richter, 2009; Sylow et al., 2017). However, there is a lack of information on the molecular and cellular mechanisms for how regular physical training increases insulin sensitivity and particularly how the cells change and adapt to 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

We are recruiting on a rolling basis, and currently on the third year. Our last subject is scheduled for summer 2023 and we are in the process of analyzing the samples. We expect to be finished by the end of the 2023.

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 duration

This project will run for three years from December 2020-2025. 

Contact

Postdoc Sophie Møller, sopm@nexs.ku.dk

Year-long Exercise Study

The present project aims to investigate the time course and interaction between short and long-term training-induced blood volume expansion (plasma and red blood cell volume responses) as well as central and peripheral cardiovascular adaptations over a year of exercise training.

Background       

One of the most important determinants for aerobic performance is the blood's oxygen-carrying capacity, which is dictated by the total hemoglobin mass (Hbmass) and the heart's pumping function, both of which are significantly higher/larger in endurance athletes compared to untrained individuals.

If untrained, you will see significant increases in circulatory function and blood volume during the first few weeks (2 to 8) after starting a regular exercise program. Thereafter, the changes will level off at the new elevated level.

About the Study

Primary objective 

To investigate the interaction between changes in circulation and blood volume as a result of one year of sustained training. 

Secondary objectives 

To examine the hypothesis that the changes in circulatory function and oxygen uptake short (8 weeks) and long (4 to 12 months) after initiation of regular exercise can be attributed to changes in plasma volume.

To evaluate whether the effect on central and peripheral circulatory function of an acute increase in blood-plasma volume by ingestion of a hypertonic drink is different in endurance-trained and untrained, and whether this possible differential function can predict physical fitness. 

To investigate whether acclimatization-induced changes in blood-plasma volume can be attributed to increased stroke volume that occurs during exercise in the heat and whether long-term acclimatization can have positive effects on cardiac function.

Status 

All participants are recruited for this study. Half of the participants are finished with the training intervention and the second group of participants are currently undergoing exercise training. The results are expected to be published in late 2024.

Funding

Novo Nordisk Foundation

Team Danmark

Project period: 2021 - 2024.

Contact

PhD fellow Mads Fischer

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

Studying the effect of healthy bioactive molecules released from mitochondria during exercise affecting metabolism and oxidative stress on the skeletal muscle and microvascular cellular function.

Background 

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.

This will be done using state-of-the-art cellular models including primary human and mice cellular isolations of skeletal muscle cells and microvascular cells.

About the Study 

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

To determine if MOTS-c is released from skeletal muscle in response to exercise we will, in healthy humans, measure MOTS-c in the muscle interstitium and determine the femoral arterial and femoral venous concentration difference of MOTS-c. This will allow for determination of whether MOTS-c is taken up or released by the muscle tissue.

Measurements will be conducted at rest and during exercise in a knee-extensor model at two intensities. Interstitial measurements are conducted by collection of dialysate from microdialysis probes, placed in the muscle. Muscle and adipose tissue biopsies before and after the acute exercise bout will be obtained from the subjects for determination of MOTS-c and for isolation and culture of cells for further experiments as described below. For the cell experiments, a fraction of the collected microdialysate will be added to cultured cells as well as metabolic and redox changes will be analyzed. 

To assess the influence of MOTS-c on mitochondrial uncoupling and formation of reactive oxygen species (ROS) in different cell types eg. skeletal muscle and vascular cells, we will treat mice with MOTS-c for 3 weeks.

Status 

The project is ongoing, with a project period from January 2022 – January 2025. 

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: January 2022 – January 2025.

Contact

Posdoc Camilla Collin Hansen

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 - 2024.

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

The study investigates how short-term low energy availability affect the immune system, inflammation, metabolism, and exercise performance in young healthy trained female triathletes.

Background

Low energy availability (LEA) is defined as inadequate amount of dietary energy available to sustain physiological function and is a well-known phenomenon among female endurance trained athletes.

Short- and long-term LEA is known to negatively affect metabolism, bone mineral density, hormone profile, muscle protein synthesis and may impair exercise performance. However, despite being highly relevant for endurance athletes, less is known about whether LEA affect the immune system, inflammation, and endurance exercise performance. 

About the Study 

The study utilizes a randomized controlled crossover design. 12 female endurance triathletes are randomly assigned to begin with either 14 days of energy balance diet (50 kcal/kg FFM) or low energy availability (22 kcal/kg FFM) separated by a 14-day washout period.

Before, after, and 3 days following each diet intervention period, endurance exercise performance was assessed by a 20-min time trial performance with blood samples being analyzed for immune system and inflammatory markers at rest and immediately post exercise.

Status

All subjects have completed the study. Currently all data is being analyzed and are expected to be done around July 2023.

Funding

Team Danmark

Danish Ministry of Culture

Fridmodt-Heineke Foundation

Project period: 2021 - 2024.

Contact

PhD fellow Jan Sommer Jeppesen

Copenhagen Cycling Study

The aim of the project is to investigate the cardiovascular responses to training-induced blood volume expansion and the interaction between central and peripheral adaptations in both men and women.

Additionally, the project seeks to evaluate the effectiveness of environmental heat-stress interventions in promoting further adaptations in blood volume and cardiac function.

Background

Research in sport science is much like research in formula one racing: a lot of the findings, innovations and inventions achieving improved performance top athlete (i.e. the formula one car) tend to trickle down to the common folks (i.e. Skoda Octavia)

The topic of investigating training-induced blood volume expansion and cardiovascular adaptations is important to the community for several reasons. Firstly, understanding how exercise training affects blood volume and cardiovascular function is crucial for optimizing athletic performance, especially in endurance sports. By investigating these interactions, we can identify ways to improve oxygen delivery to muscles during exercise, which is essential for a physical performance.

Secondly, there is a need to address the "ceiling effect" observed in some individuals where further adaptation to exercise training becomes limited. By studying the factors that contribute to this effect, such as pericardial constraint or vascular capacitance, we can develop strategies to overcome these limitations and continue enhancing cardiovascular adaptations in athletes.

About the Study

Thermoregulatory induced cardiovascular insufficiency impairs the ability to exercise in the heat, while heat adaptation through heat acclimatization (HA) improves cardiovascular stability and performance while under heat stress. HA also results in plasma volume (PV) expansion within the first few days of exposure as well as improve cardiac efficiency and pressure generation, leading to increased cardiac output without a significant increase in heart rate.

The increase in cardiac function have to some extent been attributed to an increase in PV, but the relation has not been assessed following longer (6 week) acclimatization periods. In addition, the time for these adaptations to lessen short term have not been investigated.

Aim

To investigate the impact of active HA, this study aimed to assess whether resting and stress trans-thoracic echocardiography (TTE) could identify differences in measurable echocardiographic cardiovascular parameters following HA compared to exercise in temperate conditions.

Status

Data collection on all 20 subjects is complete. The data are currently being analyzed and we expect to submit the manuscript October 2023.

Funding

Team Danmark

Project period: 2022 - 2024.

Contact

PhD fellow Mads Fischer

Thrombosis In Menopause and Exercise training

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

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 

Two more publications are expected from this work.

Funded By

Nordea Foundation

Danish Ministry of Culture 

Project period:  2020 - 2023.

Contact

Professor Ylva Hellsten