Prospective, interventional, multicentre, non-randomized, single-arm open-label study that aims to enroll 200 consecutive patients with suspected chronic ischemic heart disease in the absence of obstructive coronary artery disease (INOCA) at clinically indicated coronary angiography in 3 Italian centers.

During coronary angiography, these patients will be simultaneously subjected to a functional and coronary physiology study (according to the methods reported below):

• Functional evaluation with fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), Resting Full-Cycle Ratio (RFR) of angiographic stenosis> 50%;
• In the presence of coronary angiographic stenosis <50% or> 50% but in the presence of a negative functional assessment (FFR> 0.80 and iFR / RFR> 0.90), coronary flow reserve (CFR) and index of microvascular resistance (IMR) will be measured. IMR and CFR will be assessed using intra-coronary guidance;
• In the presence of CFR> 2.0 and IMR <25, tests with acetylcholine will also be performed in order to evaluate the possible presence of epicardial (focal or diffuse) or microvascular spasm.

Inclusion Criteria:

• Clinical presentation of chronic ischemic heart disease (IHD), requiring coronary angiography for the diagnosis
• Absence of obstructive 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 diameter stenosis >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 informed consent to the study procedure at the time of baseline evaluation