Identification of Mechanisms Behind Microvascular Dysfunction in Ischemia With No Obstructive Coronary Artery Disease
Conditions: Coronary Microvascular Dysfunction, Ischaemia With Non Obstructed Coronary Arteries
Sponsor: Bispebjerg Hospital

Study Protocol, including Statistical Analysis plan: ExINOCA part 1 
Official title - Ischemia with No Obstruction of Coronary Arteries: Underlying mechanisms and 
the impact of exercise training (EXINOCA)  
Brief Title: Mechanisms Behind Microvascular Dysfunction in INOCA (ExINOCA-P1)   
 
Date of document: July 29th 2024 
Unique Protocol ID: not yet assigned 
 
Ethical application no. H-24005644 as approved by the Regional Ethical Committee of the Copenhagen 
Region (De Videnskabsetiske Komiteer Region Hovedstaden),  
Phone: +4538666395 
Email: vek@regionh.dk  
Adress: Borgervænget 3, st. 2100 København Ø 
The study is monitored by the Danish Data-protection Agency. 
 
Study is planned to be conducted from October 2024-October 2027  
FDA Regulated: No 
FDA Regulated Intervention: No Sponsor: Bispebjerg-Frederiksbjerg Hospital 
 
Principal investigator: Eva Prescott, M.D., D.M.Sc., Prof. 
Co-Principal investigator: Ylva Hellsten., Prof. 
Co-investigators: Mads Fischer, PhD 
Co-investigators: Signe Liner, MD, PhD candidate 
 
Contacts/Locations 
Eva Prescott, MD, DMSc 
Telephone:   22572614 
Email:   Eva.Irene.Bossano.Prescott@regionh.dk   
 
Central Contact Backup: 
Mads Fischer, Ph.D. 
Telephone:   24485450 
Email:   mf@nexs.ku.dk   
 
Study Officials:  
Ylva Hellsten, Professor 
Department of Nutrition, Exercise and sports, University of Copenhagen   
 
Locations: Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57, 
Frederiksberg, Denmark, 2400 
 

 
Short Description 
This study aims to identify mechanisms underlying Coronary microvascular dysfunction (CMD) in 
angina and to assess whether exercise training can improve the condition.  
 
In this study 30 patients with impaired coronary microvascular function and 30 asymptomatic controls 
will be studied to identify vascular and related molecular mechanisms underlying INOCA by 
investigating microvascular function in the heart and in cutaneous tissue, skeletal muscle, and adipose 
tissue.  
 
 
Background 
Recent evidence shows that INOCA can manifest from general microvascular disease affecting small 
arteries other than the coronary artery. For example, the vascular response in the finger of patients with 
coronary microvascular disease has been shown to be abnormal (8) and small arteries isolated from skin 
and adipose tissue of patients with coronary microvascular disease display increased response to the 
vasoconstrictor endothelin and reduced response to the endothelium dependent vasodilator 
acetylcholine when compared to controls (9,10). Other experiments have shown a shift in endothelial 
mediated vasodilation from nitric oxide to the vasodilator H2O2, and preliminary evidence indicates that 
this could be rectified through induction of the transcriptional coactivator PGC-1a (11). This is 
consistent with the evidence for inflammation associated with coronary microvascular disease (12). 
 
The mechanistic findings are exceedingly interesting as they provide the first targets, which may 
potentially be exploited to treat patients with microvascular disease. Accordingly, there is strong 
preliminary data to suggest a way forward with respect to treatment of the large population – mostly 
women – with coronary microvascular disease. In the first part of this project two groups will be 
compared at baseline; a matched control group and a group with angina symptoms and reduced 
myocardial blood flow reserve as an indication of microvascular dysfunction; INOCA. The two groups 
are compared to allow for an assessment of functional and molecular mechanisms in angina patients 
with- versus without coronary microvascular dysfunction and to relate these aspects in both groups to a 
matched control group.  
 
We have found that INOCA is associated with development of renal and cerebral microvascular disease 
(13) strongly suggesting that coronary microvascular disease is a manifestation of a generalized 
microvascular disease. As direct investigations of microcirculatory mechanisms in the human heart are 
difficult, the systemic aspect of microcirculatory dysfunction provides an excellent opportunity to study 
the microcirculation of more accessible organs in patients with INOCA. Accordingly, in the current 
project we will study the microcirculation in skeletal muscle, skin and adipose tissue of patients and 
matched control participants to obtain insight into the mechanisms underlying INOCA. 
 
Objective 
The overarching aim of the project is to identify mechanisms underlying impaired coronary 
microvascular dysfunction in INOCA and to assess whether exercise training can improve the condition. 
The underlying premise is that microvascular dysfunction is a systemic disease and to fulfil our aim we 
will study multiple aspects of microvascular function in cardiac, skeletal muscle, fat and skin by 
different techniques. Although not part of this ethics application, these studies in humans will, in parallel 

studies, be combined by studies in an animal model of INOCA. 
 
The project consists of two parts with the following aims and hypotheses. The following statistical 
analysis plan apply for study part 1 (Mechanisms Behind Microvascular Dysfunction in INOCA 
(ExINOCA-P1)) 
 
Study Part I: To identify vascular and related molecular mechanisms underlying INOCA by 
investigating microvascular function in cardiac, cutaneous, skeletal muscle and adipose tissue. 
Study Part II.” Impact of Exercise Training on Ischemia With Non-Obstructive Coronary Arteries 
(INOCA): The ExINOCA Study” aim to determine the impact of a structured exercise training program 
on patients with INOCA on coronary microvascular function, symptom burden, physical capacity and 
systemic microvascular function and related mechanisms. 
Study I and II are separate studies. However, we consider it correct to merge the two studies in one main 
study protocol as there will be overlap in angina patients included  
 
 
To provide the best overview, in the following we describe study Part I. 
 
Hypotheses 
The hypothesis of the overall project is that microvascular dysfunction is a systemic disease and that 
underlying mechanisms can be identified in several tissues in INOCA patients and moreover that the 
dysfunction can be reversed by a period of exercise training.  
• In Part I (figure 1) the hypothesis is that coronary microvascular dysfunction is part of a systemic 
vascular dysfunction, and that we, by thorough assessment of microcirculatory function in several 
tissues (cardiac, skeletal muscle, skin and fat tissue), will be able to identify aspects of microvascular 
dysfunction and related molecular mechanisms underlying INOCA. Such mechanisms will be valuable 
as potential future therapeutic targets.  

 
Methods 
 
The current study is a clinical cross-sectional study in which a group of INOCA patients and a matched 
control group without angina are compared. The control group is included to allow for assessment of 
how the microvascular function compares between the patient and the control group. 
 
Seventy (70) participants are recruited:  30 controls without angina, and 40 patients with angina and 
reduced myocardial blood flow reserve. The study is exploratory and conducted to obtain mechanistic 
insight into the pathophysiology of microvascular disease.  
 
Based on the premise that microvascular dysfunction is a systemic disease, all participants will undergo 
assessment of cardiac microvascular function, stress echocardiography, forearm skeletal muscle- and 
skin microcirculation, and will have an adipose tissue biopsy taken for in vitro assessment of adipose 
microvascular function.  
 
Measurements 

Trial endpoints 
As this study is exploratory there is no primary or secondary outcome. Exploratory outcomes include 
identification of microvascular mechanisms and related molecular pathways specific for INOCA 
(Please see table below for list of outcomes) 
Table 1. List of outcomes in Study Part I  
 
METHODS 
FOR 
ASSESSMENT 
METHOD 
SITE OF ASSESSMENT 
Cardiac structure and 
function  
Echocardiography during rest and 
stress 
BFH/UCPH 
Skin 
microvascular 
function 
LSCI 
BFH/UCPH 
Skeletal 
muscle 
microvascular function 
Brachial artery ultrasound Doppler 
in response to stimuli 
BFH/UCPH 
In vitro adipose tissue 
microvascular function 
Myography, 
proteomics, 
transcriptomics 
UCPH-BMI 
Arterial compliance 
Calculation made from intraarterial 
pressure 
and 
arterial 
diameter 
measured by ultrasound doppler  
BFH/UCPH 
Plasma HbA1c and 
lipids 
Clinical chemical analysis 
BFH 
Plasma 
levels 
of 
markers 
related 
to 
vascular function 
Mesoscale/ELISA 
UCPH 
Plasma 
levels 
of 
inflammatory markers 
Mesoscale/ELISA/O-Link 
BFH/UCPH 
Arterial 
blood 
pressure 
Automated blood pressure at rest 
and during exercise 
BFH/UCPH 
*Change in MBFR is defined as 
Myocardial Blood flow reserve =
Global stress perfusion 
Global rest perfusion , 𝑖𝑒 𝑢𝑛𝑖𝑡𝑙𝑒𝑠𝑠. The primary analysis will be of comparison (intention 
to treat) of mean/median change in MBFR between the two groups. 
**In the substudy the small arteries are derived from adipose tissue subsamples (first 20 participants in intervention group 
and first 20 participants from control group). 

 
 
Department of Nutrition, Exercise, and Sports, University of Copenhagen (UCPH) 
Department of Cardiology, Bispebjerg Frederiksberg Hospital (BFH) 
Department of Biomedical Science, (UCPH-BMI) 
 
 
 
Procedures 
PET-scan with [15O]H2O  
[15O]H2O-PET scan is an examination routinely used in clinical practice. At Bispebjerg Frederiksberg 
Hospital approximately 1000 [15O]H2O-PET scans are performed annually. 
[15O]H2O-PET uses water labeled with the radioactive isotope oxygen-15 (15O) as the radiotracer. This 
radiotracer is injected into the patient’s bloodstream, allowing for the reconstruction of three-
dimensional images of the distribution of the radiotracer in the body. 
By dynamic measurements of the concentration of the radiotracer in the myocardium, it is possible to 
obtain information about blood flow and tissue perfusion, thereby aiding in the diagnosis and 
management of coronary artery disease (17,18). 
For this procedure patients will have one peripheral venous catheter. They will be given continuous 
adenosine 0.14 mg/kg for 6 min to provoke vasodilation.  
Participants are not allowed to drink or eat coffee, tea, dark chocolate, or any other substance containing 
caffeine for 24 hours before their [15O]H2O-PET scan [15O]H2O-PET involves a small amount of 
radiation and the use of a radioactive tracer.  
The healthcare professionals adhere to radiation safety protocols and regulations to ensure the patient 
receives the lowest possible radiation dose while still obtaining diagnostic images.  
 
Maximum oxygen uptake 
To determine maximal oxygen uptake, the participants complete a maximal incremental cycling test 
during which expired air is continuously analyzed. The test begins at a workload of 50 W with a 
continuous increase in power of 25 W per minute until exhaustion. If expected max capacity is <100W, 
the protocol will be adapted. During the test heart rate and blood pressure are continuously monitored. 
If expected maximal exercise capacity is <75 Watt an adapted protocol will be used. The same protocol 
will be used before and after intervention. 
 
Echocardiography 
Echocardiographic assessment will be conducted by ultrasound doppler at baseline, guided by a 
standardized protocol in accordance with internationally recognized consensus guidelines. This 
comprehensive protocol covers various aspects of cardiac structure and function, evaluation of the heart 
valve system, and assessment of cardiac vasculature. 
Echocardiographic outcomes will encompass a range of parameters, including but not limited to left 
ventricular (LV) dimensions, LV mass, LV ejection fraction (LVEF), diastolic function, and left atrial 
volume (LAV). 
 
Stress Echocardiography 
Stress Echocardiography is performed with the study-participant in a supine bicycle. Echo-cardiography 
is performed under increasing resistance using a standardized protocol. This study will assess cardiac 
function during stress with particular emphasis on diastolic function. 
 
Seattle Angina Questionnaire:  
The Seattle Angina Questionnaire (SAQ) is a self-administered questionnaire used in cardiac patients 
to quantify angina based on five scales: physical limitation scale, anginal stability scale, anginal 
frequency scale, treatment satisfaction scale, and the disease perception scale. The questionnaire will 

be in Danish. It will be answered electronically using REDCap, or by paper if the participant does not 
wish to do it electronically.  
 
Skeletal muscle microcirculatory function 
The procedure involves catheterization of the brachial artery and vein for blood sampling, intraarterial 
pressure measurement by a pressure transducer and for infusions of vasoactive compounds as described 
below. Catheters are placed under sterile conditions and after local anaesthesia of the skin with Lidocain.   
Throughout the experiments brachial artery blood flow is measured by ultrasound doppler. The 
procedure also involves short term (3-10 min) infusions of vasoactive compounds. Subjects will be 
randomly allocated to one out of two similar infusion protocols: A and B. The design for the two 
protocols is as follows:  
 
Anthropometric measurements of the arm will be made to estimate arm volume for calculation of 
infusion dose. During the assessment of microvascular function heart rate and blood pressure are 
continuously monitored. After the experiment is completed, the catheters are removed and pressure is 
applied. 
 
Protocol A.   
- 
Infusion of adenosine, two doses (60-120 mikrog/min/l arm volume)  
- 
Infusion of acetylcholine in three doses (Miochol-E, Bausch & Lomb Inc.) (25-50-100 
mikrog/min/l arm volume) 
- 
Handgrip exercise at 15% of maximal capacity for 14 min, first 4 min without infusion and then 
with 10 min of infusion of ascorbic acid (80 mg min/l arm volume).  
 
Illustration of Protocol A  
 
 
 
Protocol B 
- 
Infusion of adenosine, two doses (60-120 mikrog/min/l arm volume)  
- 
Infusion of noradrenaline two doses (20-80 ng/min/l arm volume)  
- 
Infusion of acetylcholine in two doses (Miochol-E, Bausch & Lomb Inc.) (25-50 mikrog/min/l 
arm volume) 
- 
combined infusion of 50 mikrog/min/l arm volume acetylcholine and infusion of ketorolac 
(Toradol; Roche) (200 mikrog/min/l arm volume) for 5 min.  
 
Illustration of Protocol B  

 
 
Laser Speckle contrast Imaging (LSCI) 
LSCI is an imaging technique that will help to visualize and quantify the blood perfusion of the skin 
(15).  
The method will be used to quantify blood perfusion in the hand of the participant at resting baseline, 
after short term occlusion of the arm (reactive hyperaemia test) and during adenosine infusion 
(vasodilation) conducted concomitant with the measurements described above in Skeletal muscle 
microcirculatory function.  
Description of the LSCI method: Laser light will be sent to the tissue and the reflected laser light is 
detected as a ‘Speckle’ pattern. This ‘Speckle pattern’ is used to make a map of the blood perfusion of 
the skin. The LSCI imaging will be performed using an LSCI system that was constructed in 
collaboration with Center for Functionally Integrative Neuroscience at Aarhus University Hospital. The 
system consists of a 785 nm laser that is equipped with a diffuser thereby enabling large-area 
illumination of the skin surface. A compact CMOS camera is used to detect the reflected laser light. 
The camera is equipped with a polarizing filter to eliminate the surface reflected laser light and optimize 
the visualization of the skin perfusion. Image data are acquired using dedicated data acquisition software 
and post-processed in MATLAB to generate blood flow index (BFI) and relative BFI images. 
 
Reactive hyperemia test 
Occlusion by application of a tourniquet will be conducted on the upper arm for 90 seconds.  
 
Vasodilation test  
Involves a stressor-test in which low-dose adenosine is given intraarterially. The procedure is conducted 
concomitant with the skeletal muscle microcirculation procedure when adenosine is infused.  
 
Adipose tissue biopsy  
Biopsies will be obtained either at The Department of Nutrition, Exercise and Sports or at 
Bispebjerg/Frederiksberg Hospital in collaboration with University of Copenhagen. 
Under local anesthesia (lidocaine 10 mg/ml with adrenalin 5 µg/ml) an adipose tissue biopsy (3x0.5x0.5 
cm) will be performed in sterile environment by a medical doctor or by a trained health care professional 
supervised by a medical doctor. 
The biopsy will be obtained from the gluteal region, where a small boat-shaped incision is made 
following the natural creases of the skin. The adipose tissue, along with a small skin flap, is removed 
(1-2 cm3). Subsequently, the subcutaneous tissue is closed with a self-absorbable suture, and the skin is 
sutured (approximately 3 stitches) that should be removed after 10 days. The wound is covered with a 
bandage that can be removed after 24 hours, but we recommend applying a new bandage until stich 
removal.  
The adipose biopsies are immediately transferred to ice-cold physiological buffer and transported to the 
laboratory at the Biomedical Institute, University of Copenhagen for analysis and storing.  
From these biopsies, segments of small arteries (diameter about 200 μm) will be promptly dissected 
free. One segment will be mounted in a myograph for recording of isometric tension (i.e., 
vasoconstriction and vasodilation) and for histochemical analysis, while the other segment will be snap-
frozen for proteomic and histological analysis and the adipose tissue/perivascular adipose tissue will be 

used for genomic and transcriptomic analysis (see below).  
 
 
The following methods will be used on the free-dissected arteries:  
Myography 
In the excised artery, we will evaluate the relaxation to adenosine and to acetylcholine and the 
dependence of the response to prostaglandins. To evaluate the role of NO and H2O2 we will also evaluate 
the relaxation to acetylcholine after inhibition of the NO-synthase with L-NAME and after metabolism 
of H2O2 with catalase. We will further evaluate the vasoconstrictor response to the neurotransmitter 
noradrenaline and the vasodilator response to the beta-receptor agonist isoprenaline to obtain a 
comprehensive evaluation of the pharmacological characteristics of the small arteries. Finally, 
assessment of the endothelin-1 vasoconstriction will be performed. 
Analysis of microvascular segments from adipose tissue and the adipose tissue:  
We will map the proteome of the small arteries. This will be done by using an arterial segment (~2 mm) 
obtained from the adipose tissue sample. 
In brief, digested peptides from arteries will be analyzed by liquid chromatography tandem mass 
spectrometry (LC-MS/MS), and data analysis will be used to identify proteins and their relative 
abundances, which enables statistical comparison. 
Significantly regulated proteins will be subjected to gene-overrepresentation analysis that can identify 
biological pathway associations in the data. This unbiased technology is advantageous for gaining novel 
understanding of the underlying biological mechanisms responsible for the dysfunction of the small 
arteries and arterioles in patients with microvascular disease and effect of exercise training on these. 
This discovery-based approach is essential hypothesis-generating research that will enable us to define 
the mechanisms underlying INOCA, which we will be able to test in our functional experiments. To 
stimulate new research and therapeutic development, we plan to make all data acquired publicly 
available, thereby enabling other research groups to use the data via the ProteomeXchange database. A 
small fraction of the arteries and perivascular fat-tissue will be sectioned for histological analysis. The 
adipose tissue/perivascular adipose tissue will be analyzed for mRNA and proteins by use of RNA-
sequencing and proteomic analysis. This analysis will be done as part of the aim to understand 
microvascular changes in INOCA and how training may influence the microvasculature.  The analysis 
will enable an assessment of how changes in mRNA and proteins are altered in relation to structure and 
function of the tissue.  The assessment includes isolation of cell nuclei from the fat biopsies. 
 
Oxidative stress 
A part of the biopsy (mainly fat cells, connective tissue, and small arteries) will be stained for lipid 
peroxidation as a measure of oxidative stress of the tissue. For this we will quantify malondialdehyde 
which is a general product of nonenzymatic peroxidation of polyunsaturated fatty and arachidonic acids 
as done by us before (14). 
 
Medical History and Concomitant Medicine 
Medical history will be registered at the baseline visit (V1) and evaluated in relation to the protocol’s 
exclusion criteria. All medication that is necessary for the participants health and which is not in the 
protocol exclusion criteria may be continued during the study. At the following visits participant will 
be asked if they have taken any new medicine or changes in dosage since last visit. Medical History 
will be registered in the Medicine form in the CRF and changes will be registered in the Concomitant 
Medicine Form in the CRF. 
 
Statistics 
Sample size determination relates to the primary outcome myocardial blood flow reserve. Sample size 
calculations are based on a power of 0.80 and alpha level of 0.05. We regard 0.3 as a clinically relevant 
improvement in myocardial blood flow reserve. SD of repeated measurement has been 0.2-0.4 in 
previous studies. With a conservatively estimated SD of 0.50, alfa 0.05, power 0.8 and allowing for 

15% drop-out, we will include 100 patients.  
 
Inclusion Criteria 
• 
Age>50 
• 
Only for angina patients: 
• 
Have CMD, defined as myocardial bloodflow reserve (MBFR) < 2.5 or hyperemic myocardial blood flow (hMBF) 
< 2.3ml/g/min 
• 
No obstructive CAD as determined by the clinical assessment of [15O]H2O-PET  
• 
Able and willing to provide informed consent 
 
Exclusion Criteria 
• 
Females of childbearing potential (defined as a premenopausal female capable of becoming pregnant). The female 
patient must either be postmenopausal, defined as amenorrhea for at least 1 year, or surgically sterile 
• 
Heart failure, defined as left ventricular ejection fraction of less than 40% 
• 
Uncontrolled hypertension defined as blood pressure above target 140/90 for all 
• 
Co-morbidity resulting in <1 year expected survival 
• 
Considered by the investigator, for any reason, to be an unsuitable candidate for the study. 
• 
Unable or unwilling to exercise, e.g. due to arthritis or injury 
• 
Already are regularly physically active and/or have a maximal oxygen uptake >45 ml/kg/min 
• 
The subject has a known allergy to either: norepinephrine, adenosine, ketorolac, and or ascorbic acid (vitamin C). 
 
 
Primary Outcome Measure: 
1. Vascular function 
Vascular conductance measured by ultrasound doppler during infusion of acetylcholine 
 
Secondary Outcome Measures: 
2.  Vascular function 
Vascular conductance measured by ultrasound doppler during infusion of Adenosine 
 
3. Myocardial Blood flow reserve  
Determined by the clinical assessment of [15O]H2O-PET 
 
4. Skeletal Muscle Microvascular Function 
Evaluated by brachial artery ultrasound Doppler in response to exercise stress to measure blood flow 
and vascular responsiveness in skeletal muscles. 
 
5. Changes in isolated small artery reactivity assessed with myography 
Analyzed using myograph to study the tone of smooth muscle cells 
 
6. Arterial Compliance 
Determined by calculations made from intra-arterial pressure and arterial diameter 
measurements obtained via ultrasound Doppler to assess arterial compliance. 
 
7. Plasma Lipids 
Conducted through clinical chemical analysis to measure levels of HDL, and triglycerides in the 

blood, providing insights into lipid profiles. 
8. Plasma HbA1c  
Conducted through clinical chemical analysis to measure levels of HbA1c in the blood, 
providing insights into glucose metabolism. 
 
9. Plasma Levels of Markers Related to Vascular Function 
Assessed using Mesoscale/ELISA to quantify biomarkers associated with vascular function, 
providing insights into endothelial health and vascular integrity. 
 
10. Plasma Levels of Inflammatory Markers 
Measured using Mesoscale/ELISA/O-Link platforms to evaluate the presence and levels of 
inflammatory markers, indicating systemic inflammation. 
 
11. Arterial Blood Pressure 
Monitored with automated blood pressure measurements at rest and during exercise to assess 
overall cardiovascular health and response to physical activity. 
 
12. Cardiac Function 
Changes in stroke volume using echocardiography during rest and exercise stress 
 
 
Other Pre-specified Outcomes: 
 
 
1. Tone of smooth muscle cells 
Changes in isolated small artery reactivity assessed with myography 
 
2. Proteomic and transcriptomic analyses 
Changes in gene and protein expressions patterns in small arteries 
Time frame for all measures are: Baseline only 
 
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