COMA.NET (Coronary Microcirculation Analysis Network) is a prospective, randomized, open-label, parallel-group clinical trial designed to determine whether endotype-guided pharmacotherapy is superior to standard care in improving quality of life in patients with ischemia with non-obstructive coronary arteries. Approximately 180-190 participants with objective ischemia will be randomized to either the control or the intervention group.

Pharmacotherapy based on the endotype established during intracoronary assessment will be introduced in the intervention arm of the study. The primary endpoint is the change in the Seattle Angina Questionnaire (SAQ) score from baseline to 3 months. Secondary endpoints include the diagnostic accuracy of transthoracic echocardiographic coronary flow velocity reserve (CFVR), the incidence of adverse events, associations between biomarkers and coronary microvascular dysfunction (CMD), and the identification of risk factors for specific CMD endotypes.

Participants will undergo invasive functional evaluation of the coronary microcirculation, measurement of echocardiographic CFVR, and analysis of selected circulating biomarkers. The study cohort will be followed up at three and six months and will include reassessment of quality of life (Seattle Angina Questionnaire, EuroQol 5-Dimensions 5-Level questionnaire, 12-item Short Form Health Survey), anxiety (Generalized Anxiety Disorder-7 score), and functional status (6-minute walk test).

The study began in October 2025. Primary completion is anticipated in October 2027, and the overall study completion date is expected in March 2028.

According to the European Society of Cardiology (ESC) guidelines on chronic coronary syndromes, up to 70% of patients presenting with anginal symptoms and ischemia on non-invasive tests demonstrate no significant coronary artery disease on coronary angiography (INOCA - ischemia with non-obstructive coronary arteries). The underlying pathophysiology of this condition may include functional or structural abnormalities of the coronary microcirculation.

The aforementioned ESC guidelines recommend invasive coronary functional testing as a primary diagnostic strategy in persistently symptomatic patients with ischemia with non-obstructive coronary arteries (INOCA) or angina with non-obstructive coronary arteries (ANOCA) and impaired quality of life, despite medical treatment (Class I recommendation). Identification of the specific coronary microvascular dysfunction (CMD) endotype or epicardial vasospastic angina is crucial for the introduction of optimal, targeted pharmacological therapy. Therefore, this study addresses a critical evidence gap. As a superiority trial, it aims to determine whether endotype-guided pharmacotherapy is superior to standard care in improving quality of life and relieving symptoms over a 3-month period. The primary hypothesis is that endotype-guided therapy will result in a greater improvement in the Seattle Angina Questionnaire (SAQ) score compared with standard therapy at 3 months of follow-up.

COMA.NET (Coronary Microcirculation Analysis Network) is a prospective, randomized, open-label, interventional clinical trial with a parallel-group design. The eligible sample for this study consists of adults with chronic coronary syndrome, proven myocardial ischemia, and excluded obstructive coronary disease, either by invasive coronary angiography or coronary computed tomography angiography (CCTA) (defined as no significant epicardial coronary stenosis).

The sample size was calculated using a conservative approach comparing mean change scores between groups, with a two-sided alpha level of 0.05 and 80% statistical power. Under these assumptions, approximately 160 evaluable participants are required. We anticipate an attrition rate of 15% (including loss to follow-up and incomplete questionnaire data); thus, the total planned enrollment is approximately 180-190 participants.

Participants will be randomized in a 1:1 allocation ratio to one of two arms: the intervention group or the control group. Randomization will be performed using a simple randomization procedure based on a computer-generated randomization sequence with permuted blocks of variable size (4 and 6).

According to the study protocol, prior to hospital admission, all participants will be adequately prepared by discontinuing pharmacotherapy known to interfere with vasoreactivity (e.g., non-dihydropyridine calcium channel blockers such as verapamil and diltiazem), in accordance with appropriate washout periods.

On admission, blood and urine samples will be collected for analysis of redox and inflammatory biomarkers, including non-enzymatic antioxidants, enzymatic antioxidants, total antioxidant capacity and oxidative status, markers of oxidative damage, cytokines, chemokines, growth factors, damage-associated molecular patterns (DAMPs), and matrix metalloproteinases (MMPs 1-14) and their tissue inhibitors. All biomarker analyses will be performed using validated laboratory methods according to established protocols.

Overall quality of life (QoL) assessment will be performed using the Seattle Angina Questionnaire (SAQ), EuroQol 5-Dimensions 5-Level questionnaire (EQ-5D-5L), Generalized Anxiety Disorder-7 (GAD-7) score, 12-item Short Form Health Survey (SF-12), and Six-Minute Walk Test (6MWT) distance at baseline and follow-up.

All participants will undergo transthoracic echocardiography. Coronary flow velocity in the left anterior descending (LAD) artery will be assessed using pulsed-wave Doppler at rest and during regadenoson-induced hyperemia. Coronary flow velocity reserve (CFVR) will be calculated as the ratio of hyperemic to resting coronary flow velocity.

Subsequently, invasive diagnostics will be performed in both groups in two consecutive stages:

1. Coronary vasomotor testing: Intracoronary bolus administration of acetylcholine in increasing concentrations during coronary angiography will be used to evaluate epicardial and microvascular vasomotor function.
2. Microcirculatory function evaluation: Coronary flow reserve (CFR) and the index of microvascular resistance (IMR) will be assessed using the Coroventis CoroFlow™ Cardiovascular System, with hyperemia induced by intravenous regadenoson. CMD endotypes will be defined according to prespecified ESC criteria based on invasive coronary measurements.

Thereafter, following the examinations, patients will complete a numerical rating scale evaluating discomfort associated with the procedures.

In the intervention arm, antianginal treatment will be initiated in accordance with current ESC guidelines and tailored to specific CMD endotypes. The control group will receive standard pharmacotherapy according to current clinical practice, without endotype-specific treatment selection.

Participants initially assigned to the control group will cross over to the intervention arm at the 3-month follow-up. Following treatment revision according to the diagnosed endotype, both groups will be reassessed by telephone at 6 months from baseline using the previously described scales. Participants in the intervention arm will receive a follow-up telephone call one month after initiation of the intervention to assess clinical status, medication tolerance, adherence, and, if appropriate, to up-titrate prescribed medications.

At 3 months after the index hospitalization, participants in the intervention arm will undergo outpatient follow-up evaluation, including the SAQ, EQ-5D-5L, SF-12, 6-minute walk test, and GAD-7 score. Statistical analyses will be performed according to the intention-to-treat (ITT) and per-protocol principles.

The primary endpoint is the between-group difference in change in SAQ Summary Score at 3 months.

Secondary endpoints include:

• Comparison of treatment strategies
• Assessment of the diagnostic accuracy of echocardiographic CFVR
• Incidence of adverse events
• Associations between biomarkers and CMD
• Identification of risk factors for specific CMD endotypes The study commenced in October 2025. Participants will be recruited for approximately 21 months. The primary completion date will occur when the last enrolled patient completes follow-up (estimated October 2027). The overall study completion date, defined as completion of all study-related procedures and follow-up, is expected in March 2028.

This trial is designed to provide comprehensive data regarding the epidemiology, pathophysiological endotypes, and biomarkers of coronary vasomotor disorders in patients with INOCA. Furthermore, it will evaluate the clinical utility of invasive and non-invasive diagnostic tests and assess the impact of endotype-based pharmacotherapy on patient-related outcomes. The findings may contribute to the refinement of diagnostic algorithms and patient-centered management strategies.

Inclusion Criteria:

a. Chronic coronary syndrome c. Anginal symptoms > CCS class I or angina equivalent d. Myocardial ischemia confirmed by non-invasive testing e. Provision of informed consent to participate in the study

Exclusion Criteria:

1. Angiographically significant coronary artery stenosis or FFR < 0.8
2. Renal insufficiency with eGFR < 30 ml/min/1.73 m²
3. Left ventricular ejection fraction < 40%
4. Hypertrophic cardiomyopathy
5. Acute coronary syndrome within < 90 days
6. Percutaneous coronary intervention (PCI) within < 90 days
7. Previous coronary artery bypass grafting (CABG)
8. Anemia < 10 g/dL or thrombocytopenia < 100,000/µL
9. Intraventricular conduction disturbances preventing ST-T segment assessment
10. Severe concomitant valvular heart disease
11. Active malignancy
12. Type 1 diabetes mellitus
13. Coronary artery anatomical abnormalities precluding assessment using PressureWire X (myocardial bridge causing > 50% luminal narrowing of the investigated vessel, severe coronary tortuosity, inability to properly cannulate coronary ostia)
14. Pregnancy
15. Heart failure ≥ NYHA class III
16. Asthma or COPD with severe irreversible airflow obstruction
17. Atrial fibrillation
18. Second- or third-degree atrioventricular block without pacemaker implantation (IPG)
19. Manifest pre-excitation on ECG or history of AVRT episodes without prior ablation of the accessory pathway