The present study has the following objectives:

1. To investigate the prevalence of INOCA in patients referring for a clinically indicated coronary angiography (CA) c/o Division of Cardiology - Federico II University Hospital;
2. To stratify in INOCA endotypes patients according to the presence or absence of alternative (i.e. non obstructive CAD) causes of myocardial ischemia detected during CA clinically indicated through physiology tests;
3. to implement a stratified therapy in these patients considering the different INOCA endotypes and evaluate the impact on angina class and quality of life as well as cardiac hospitalization and coronary revascularization during 5 year follow up

Eligible patients with angina and/or positive stress test undergoing clinical indicated CA detecting non-obstructive CAD will be studied as follows:

• Functional evaluation by fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), Resting Full-Cycle Ratio (RFR) of any stenosis that is angio- graphically considered > 50%;

• In case of stenosis <50% or >50% but with negative functional evaluation (FFR >0.80 and iFR/RFR

  >0.90), coronary flow reserve (CFR) and index of microvascular resistance (IMR) will be performed. IMR and CFR will be evaluated, using an intracoro- nary wire;

• In case of CFR>2.0 and IMR<25, acetylcholine test will be performed. Intracoronary acetylcholine (ACh) will be administrated to detect epicardial (fo- cal or diffuse) or microvascular spasm.

Inclusion Criteria:

• Clinical presentation of chronic ischemic heart dis- ease (IHD), requiring coronary angiography for the diagnosis;
• Absence of obstructive coronary artery disease (CAD) at coronary angiography;
• Age > 18 years.
• Ability to provide a valid informed consent to the study procedure at the time of baseline evaluation;

Exclusion Criteria:

Clinical presentation of acute coronary syndrome (ACS) or cardiogenic shock;

• Presence of obstructive CAD with at least 1 significant coronary artery stenosis, defined as diameterstenosis >50% and FFR ≤0.80 (or iFR/RFR ≤0.89);
• Previous coronary artery bypass grafting (CABG);
• Left ventricular systolic dysfunction, defined as ejection fraction (EF) <40%;
• Severe valvular heart disease;
• Pregnant or breastfeeding women
• Known hypersensitivity or contraindication to any of the drugs used for coronary physiology testing (adenosine, nitrates, acetylcholine)
• Inability or unwillingness to provide a valid in- formed consent to the study procedure at the time of baseline evaluation.

All patients presenting with signs or symptoms potentially related to myocardial ischemia and requiring a functional coronary angiography for specific diagnosis will be enrolled.

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