This is a single-center, prospective interventional study evaluating noninvasive coronary function testing using transthoracic Doppler echocardiography of the left anterior descending coronary artery in patients with stable angina and nonobstructive coronary artery disease (ANOCA) who previously underwent invasive coronary function testing (adenosine and/or acetylcholine).

A group of age- and sex-matched healthy volunteers will be enrolled to support interpretation of potentially abnormal noninvasive responses observed in patients.

Patients referred to the catheterization laboratory of Fondazione Policlinico Universitario A. Gemelli IRCCS for stable angina who show non-obstructive coronary artery disease at invasive coronary angiography and underwent invasive coronary function testing will be enrolled.

During a transthoracic echocardiographic Doppler examination of the left anterior descending coronary artery, participants will undergo three standardized stimuli (hyperventilation, cold pressor test, and dipyridamole) separated by 30-minute intervals, with peak diastolic velocity measured at baseline and at the end of each test.

For each stimulus, the coronary blood flow velocity response will be expressed as the ratio between peak and basal peak diastolic velocity.

Participants will also complete the Seattle Angina Questionnaire to assess symptom burden.

The primary aim of the study is to investigate the usefulness of studying coronary flow reserve by transthoracic color Doppler echocardiogram in reaching the diagnosis of microcirculation dysfunction and/or coronary vasomotor disturbance.

The secondary aim of the study was to assess whether abnormalities on the stress echocardiogram with dipyridamole, hyperventilation, and cold-pressor test are related to the patient's symptoms.

Inclusion Criteria:

1. Age between 18 and 90 years;
2. ICA performed within the previous 12 months from enrollment and characterized by: (a) absence of obstructive CAD (<50% diameter reduction or FFR by >0.80); (b) invasive assessment of epicardial/microvascular spasm by acetylcholine test;
3. Signed informed consent.

Exclusion Criteria:

1. Presentation as an acute coronary syndrome (i.e. unstable chest pain) or a typical history of variant angina (frequent angina pain at rest with ST-segment elevation at the ECG, caused by recurrent coronary spasm);
2. Previous coronary revascularization with surgical intervention;
3. Asthma or known intolerance or contraindications to dipyridamole;
4. Serious medical conditions, including renal failure (eGFR <30 mL/min), liver diseases, malignancies, and acute or chronic inflammatory diseases;
5. Pregnancy;
6. Psychological conditions that might hamper patient co-operation;
7. Any condition that, in the judgment of the investigators, would make difficult for the patient to complete the study protocol;
8. Missed informed consent.