Ischemia With No Obstruction of Coronary Arteries: Underlying Mechanisms and the Impact of Exercise Training (EXINOCA)
Phase: NA
Conditions: Coronary Microvascular Disease, CMD
Sponsor: Bispebjerg Hospital

Study Protocol, including Statistical Analysis plan:  ExINOCA part 2 
Brief Title: The Impact of Exercise Training on Ischemia With Non-
Obstructive Coronary Arteries (INOCA): The ExINOCA Study   
Official Title: Ischemia With No Obstruction of Coronary Arteries: 
Underlying Mechanisms and the Impact of Exercise Training (EXINOCA)   
 
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.  
 
This study is a randomized controlled trial testing the effect of exercise training in patients with coronary 
microvascular dysfunction. 100 patients will be randomized 1:1 to exercise training or control. The 
primary outcome is coronary microvascular function, secondary outcomes include symptoms and 
microvascular function 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.  
a 
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 study registration, these studies in humans will, in parallel studies, 

be combined by studies in an animal model of INOCA. 
 
The project consists of the following aims and hypotheses. 
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 
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.  
Our main hypothesis is that exercise training can improve myocardial microvascular dysfunction and 
related mechanisms in INOCA patients and thereby reduce symptom burden and improve physical 
capacity. 
 
Methods 
Measurements  
METHODS OF ASSESSMENT 
ENDPOINT 
SITE 
PET 
Change in MBFR assessed by [15O]H2O-PET-scan from 
baseline to end of intervention (ie. MBFR6end -MBFRBaseline)* 
 
BFH 
Seattle angina questionnaire/selfreported 
Change in Symptom burden assessed by Seattle Angina 
Questionnaire at baseline and end of intervention 
BFH 
Oxygen uptake during exhaustive exercise 
Change in VO2peak from baseline to end of intervention 
NEXS/BFH 
 
Change in MBF assessed by [15O]H2O-PET-scan from 
baseline and after 6 months (ie. MBF6 months -
MBFBaseline). 
 
BFH 
 
Change in hMBF assessed by [15O]H2O-PET-scan from 
baseline and after 6 months (ie. hMBF6 months -
hMBFBaseline). 
 
BFH 
Laser Speckle contrast Imaging 
Skin microvascular function 
BFH/UCPH 
Skeletal muscle microvascular function  
Brachial artery ultrasound Doppler in response to stimuli 
BFH/UCPH 
Arterial compliance  
Calculation made from intraarterial pressure and arterial 
diameter measured by ultrasound doppler 
BFH/UCPH 
Plasma levels of markers related to vascular function Mesoscale/ELISA 
UCPH 
Arterial blood pressure 
Automated blood pressure at rest and during exercise 
BFH/UCPH 
In vitro adipose tissue microvascular function from 
fat biopsy** 
Myography, proteomics and histology of vessels derived 
from fat biopsy 
UCPH-BMI 

Clinical chemical analysis 
Plasma HbA1c, HDL and triglycerides 
BFH/UCPH 
Plasma levels of inflammatory markers 
Mesoscale/ELISA/OLink 
BFH/UCPH 
In vitro adipose tissue microvascular function from 
fat biopsy 
Myography, proteomics, and histology of vessels derived 
from fat biopsy 
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 
The following examinations will be performed at baseline in Study and at baseline and follow-
up in Study 2, unless otherwise indicated 
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). 
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:  
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  

 
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 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 
• 
Uncontrolled hypertension 
• 
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. Myocardial Blood Flow Reserve (MBFR) 
o Measure: Change in MBFR assessed by [15O]H2O-PET-scan from baseline 
to end of intervention (MBFR_end - MBFR_Baseline) 
Secondary Outcome Measures: 
1. Symptom Burden 
o Measure: Change in Symptom burden assessed by Seattle Angina 
Questionnaire at baseline and end of intervention 
2. Exercise Capacity 
o Measure: Change in VO2peak (oxygen uptake) during exhaustive exercise  
3. Global Rest Perfusion 
o Measure: Change in MBF assessed by [15O]H2O-PET-scan  
4. Global Stress Perfusion 
o Measure: Change in hMBF assessed by [15O]H2O-PET-scan  
Exploratory Outcome Measures: 
6. Vascular Function Adaptations 
Measure: Changes in Arterial compliance (C = ΔV/ ΔP) calculated from intraarterial 
pressure ΔP and arterial diameter (ΔD) measured by ultrasound Doppler  
7. Skin microvascular function  
Hand microcirculatory blood flow  assessed by Laser Speckle Contrast Imaging 
(LSCI) 
8. Plasma Markers Related to Vascular Function 
Plasma levels of markers related to vascular function assessed by Mesoscale/ELISA 
9. Blood Pressure 
Automated blood pressure at rest  
10. Plasma Lipids 
Conducted through clinical chemical analysis to measure levels of HDL, and 
triglycerides in the blood, providing insights into lipid profiles. 
 
11. Plasma Levels of Inflammatory Markers 

Measured using Mesoscale/ELISA/O-Link platforms to evaluate the presence and 
levels of inflammatory markers, indicating systemic inflammation. 
12. Proteomic and transcriptomic analyses 
Changes in gene and protein expressions patterns in small arteries 
Time frame for all measures are: Baseline and after the intervention (3 months) 
Trial design 
Study Type: Interventional Estimated Enrollment: 100 participants 
Allocation: Randomized Intervention Model: Parallel Assignment 
Randomized controlled trial in which 100 angina patients with reduced flow reserve (INOCA 
patients) are randomized 1:1 to either exercise training or control (no exer-cise training). 
 
 
Figure 2. Study overview 
 
  
Arms and Interventions 
 
Arm 
Intervention/treatment 

Active Comparator: Exercise 
The exercise intervention consists of
supervised training 40-50 minutes x 3
weekly for 12 weeks. 
Exercise training 
The training sessions are consist of cycling and as follows: a
10 min warm-up at a light intensity, 20-35 min of cycling
exercise in intervals at varying intensities from light (~60%
of max heart rate) to more intensive (80-90% of max heart
rate) and ending with 5 min of warm-down at a light
intensity. The training intensity will be progressive during
the course of the intervention period. The cycling training
sessions are supervised . 
Home training is allowed up to once a week if participants
are able to adhere to the prescribed intensity levels. 
Training sessions are closely monitored to ensure
effectiveness and safety. This includes heart rate monitoring
perceived exertion assessment. 
Other Names: 
Physical activity Endurance training 
No Intervention: Control 
The participants who are randomized
to the no- training group will be offered
exercise train-ing after the intervention
is completed. 
Participants will be encouraged to not
change their lifestyle or medication
throughout the study period. 
 
Contacts and Locations 
 
Contacts 
Eva Prescott, MD, DMSc 
 
 
+45 22 57 26 14      Eva.Irene.Bossano.Prescott@regionh.dk 
Mads Fischer, PhD 
+45 
23 46 36 66 
  
mf@nexs.ku.dk 

Locations 
Denmark 
Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57, 
Frederiksberg, Denmark, 2000 
Contact: Eva Prescott, MD, DMSc 
 
+45 4026 2134 Eva.Irene.Bossano.Prescott@regionh.dk 
 
Contact: Mads Fischer, PhD  
+4524485450 mf@nexs.ku.dk Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, 
Nordre Fasanvej 57 Frederiksberg, Denmark, 2000 
 
Investigators 
Principal Investigator: 
Eva Prescott MD, DMSc 
Co-Principal Investigator:  
Ylva Hellsten, Professor, PhD 
Department of Nutrition, Exercise, and Sports, University of Copenhagen 
Universitetsparken 13, 2100 København Ø 
E-mail: yhellsten@nexs.ku.dk Phone: +45 3532 1616 
 
Co-investigators: 
 
 
Mads Fischer, PhD 
 
References 
 
1. P. Brainin, D. Frestad, and E. Prescott, “The prognostic value of coronary endothelial and microvascular 
dysfunction in subjects with normal or non-obstructive coronary artery disease: A systematic review and 
meta-analysis.,” Int J Cardiol, vol. 254, pp. 1–9, 2018, doi: 10.1016/j.ijcard.2017.10.052. 
2. J. Schroder et al., “Coronary flow velocity reserve predicts adverse prognosis in women with angina and no 
obstructive coronary artery disease: results from the iPOWER study.,” Eur Heart J, vol. 42, no. 3, pp. 
228–239, 2021, doi: 10.1093/eurheartj/ehaa944. 
3. P. S. Douglas et al., “Outcomes of anatomical versus functional testing for coronary artery disease.,” N Engl 
J Med, vol. 372, no. 14, pp. 1291–1300, 2015, doi: 10.1056/NEJMoa1415516. 
4. J. Reeh et al., “Prediction of obstructive coronary artery disease and prognosis in patients with suspected 
stable angina.,” Eur Heart J, vol. 40, no. 18, pp. 1426–1435, 2019, doi: 10.1093/eurheartj/ehy806. 
5. R. O. Cannon, “Microvascular angina and the continuing dilemma of chest pain with normal coronary 
angiograms.,” J Am Coll Cardiol, vol. 54, no. 10, pp. 877–885, 2009, doi: 10.1016/j.jacc.2009.03.080. 
6. C. J. Pepine et al., “Coronary microvascular reactivity to adenosine predicts adverse outcome in women 
evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE 
(Women’s Ischemia Syndrome Evaluation) study.,” J Am Coll Cardiol, vol. 55, no. 25, pp. 2825–2832, 
2010, doi: 10.1016/j.jacc.2010.01.054. 
7. M. B. Britten, A. M. Zeiher, and V. Schächinger, “Microvascular dysfunction in angiographically normal or 
mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome.,” Coron Artery 

Dis, vol. 15, no. 5, pp. 259–264, 2004, doi: 10.1097/01.mca.0000134590.99841.81. 
8. P. K. Mehta et al., “Mental stress peripheral vascular reactivity is elevated in women with coronary vascular 
dysfunction: Results from the NHLBI-sponsored Cardiac Autonomic Nervous System (CANS) study,” 
Int J Cardiol, vol. 251, pp. 8–13, Jan. 2018, doi: 10.1016/j.ijcard.2017.10.061. 
9. T. J. Ford et al., “Systemic microvascular dysfunction in microvascular and vasospastic angina.,” Eur Heart 
J, vol. 39, no. 46, pp. 4086–4097, 2018, doi: 10.1093/eurheartj/ehy529. 
10. H. Allaqaband, D. D. Gutterman, and A. O. Kadlec, “Physiological Consequences of Coronary Arteriolar 
Dysfunction and Its Influence on Cardiovascular Disease.,” Physiology., vol. 33, no. 5, pp. 338–347, 
2018, doi: 10.1152/physiol.00019.2018. 
11. A. O. Kadlec et al., “PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator 1-α) 
Overexpression in Coronary Artery Disease Recruits NO and Hydrogen Peroxide during Flow-Mediated 
Dilation and Protects Against Increased Intraluminal Pressure,” Hypertension, vol. 70, no. 1, pp. 166–
173, Jul. 2017, doi: 10.1161/HYPERTENSIONAHA.117.09289. 
12. H. E. Suhrs et al., “Inflammation, non-endothelial dependent coronary microvascular function and diastolic 
function-Are 
they 
linked?,” 
PLoS 
One, 
vol. 
15, 
no. 
7, 
p. 
e0236035, 
2020, 
doi: 
10.1371/journal.pone.0236035. 
13. S. Højstrup et al., “Coronary Microvascular Disease Assessed by 82-Rubidium Positron Emission 
Tomography Myocardial Perfusion Imaging Is Associated With Small Vessel Disease of the Kidney and 
Brain.,” J Am Heart Assoc, vol. 12, no. 12, p. e028767, 2023, doi: 10.1161/JAHA.122.028767. 
14. C. Staehr et al., “Migraine-Associated Mutation in the Na,K-ATPase Leads to Disturbances in Cardiac 
Metabolism and Reduced Cardiac Function.,” J Am Heart Assoc, vol. 11, no. 7, p. e021814, 2022, doi: 
10.1161/JAHA.121.021814. 
15. A. Lazaridis et al., “Skin microvascular function, as assessed with laser speckle contrast imaging, is impaired 
in untreated essential and masked hypertension.,” Hypertens Res, vol. 45, no. 3, pp. 445–454, 2022, doi: 
10.1038/s41440-021-00816-w.