The evidence above demonstrates that microvascular dysfunction is an important determinant of patient prognosis, which however remains poorly classified. Given the high burden of disease and the severity of the functional impairment in these patients, the lack of a clear definition for this disease has a potentially large clinical importance. It is important to better describe the phenotype of these patients, identify the predictors of prognosis, and determine the impact of diagnosis.

The study is designed as prospective registry. Patients with angina CCS II-IV undergoing assessment of microvascular function will be enrolled.

The study does not interfere with the medical standards at the sites with regards to patient treatment or follow-up care.

Study duration and schedule The duration of this study is expected to be 7 years. The subject recruitment is planned to start in January 2020 and end in January 2022. The actual overall study duration or subject recruitment period may differ from these time periods. Per-patient, the duration of participation will be up to 5 years. Patients will be evaluated at hospital discharge, at 12 months and 5 years (the latter two as telephone contacts).

Number of subjects and study centers It is planned to enroll 1000 subjects in the registry based on power calculations as described. Recruitment and treatment of subjects is expected to be performed in 10 study centers.

Primary endpoint The primary endpoint is the composite of cardiovascular death, myocardial infarction, rehospitalization for angina or heart failure, and unplanned coronary angiography at 12 months.

Secondary endpoints Each of the components of the primary endpoint Seattle Angina Questionnaire SAQ-7 Physical limitation scale SAQ-7 angina stability scale SAQ-7 angina frequency scale SAQ-7 angina quality of life EQ-5D-5L Beck depression inventory

The SAQ-7 "angina frequency" domain has been shown to correlate to improvements in microvascular function in the WISE study. SAQ-7-7 has been also used in a number of studies, including the ISCHEMIA study.

Other patient questionnaires are also standardized tests for the assessment of quality of life, depression and symptom severity in coronary artery disease studies.

Inclusion Criteria:

• Age ≥ 18 and <85 years.

• Chronic coronary syndrome (including patients with anginal equivalents)

• Angina CCS class II-IV

• Evidence of reversible ischemia on non-invasive testing

• Availability of the following measurements:

  1. Index of microvascular resistances (IMR),
  2. Resting full-cycle ratio (RFR),
  3. Fractional flow reserve (FFR),
  4. Coronary flow reserve (CFR)

• Willingness to participate and ability to understand read and signed the informed consent document before the procedure

Exclusion Criteria:

At least one of the following:

• Pregnancy and or lactation.
• Medical or psychological conditions that would jeopardize an adequate and orderly participation.
• Left ventricular ejection fraction lower than 30%
• Previous coronary artery bypass surgery (CABG) to all major branches in the LAD and left circumflex (LCX) territory, such that IMR cannot be measured
• Decompensated congestive heart failure (CHF)
• Chronic or acute renal failure with creatinine >2mg/dl
• Severe valvular heart disease
• Patients with comorbidities limiting life expectancy to less than one year

Patients with angina without apparent obstructive coronary artery disease (no coronary stenosis >75% at angiography) undergoing clinically-indicated assessment of coronary microvascular function.