To determine the effectiveness of the beta-blocker nebivolol in controlling symptoms and improving the quality of life in patients with angina and coronary microvascular dysfunction.

Objective To determine the effectiveness of the beta-blocker nebivolol in controlling symptoms and improving the quality of life in patients with angina and coronary microvascular dysfunction.

Hypothesis Treatment with titrated nebivolol will result superior to placebo in symptoms control in patients presenting with coronary microvascular disease (CMD).

Study design Prospective, multicenter, controlled, double-blinded, randomized clinical trial.

Inclusion criteria • Patients over 18 years old with symptoms or evidence of myocardial ischemia and coronary arteries without lesions or with epicardial lesions (<50% by visual estimation or FFR >0.80 / RFR >0.90), and

• CFR ≤ 2.0 and/or IMR≥25 Exclusion criteria Life expectancy <1 year, inability to provide informed consent, severe valve disease, left ventricular ejection fraction <30%, clinical contraindication for betablockers treatment.

Treatment arms Randomization will be performed after invasive diagnostic of CMD:

Study group: Nebivolol • Patients will start with a dose of 5 mg every 24 hours. Biweekly dose adjustments will be performed during the first two months, increasing the dose (if tolerated with respect to heart rate, blood pressure, and symptoms) up to a maximum of 20 mg/24 hours.

Control group: Placebo

• Patients will be treated with one tablet every 24 hours. Primary endpoint: The effectiveness of nebivolol treatment in improving angina symptoms was measured using the SAQ questionnaire after 6 months of treatment.

Secondary endpoints • Quality of life at 6 months.

• Functional capacity at 6 months.
• Major cardiac events at 1 year.

Inclusion Criteria:

• Age 18 years or older.

  • Presence of stable angina symptoms, defined as compatible symptoms occurring at least once weekly in the last three months.
  • Absence of functionally significant epicardial coronary artery disease (FFR > 0.80).
  • Microvascular functional study showing CFR< 2,0 and/or IMR ≥ 25.

Exclusion Criteria:

• Allergy or contraindication to the use of beta-blockers.
• Indication for beta-blocker treatment due to another pathology.
• Ventricular dysfunction (LVEF < 45%).
• Percutaneous coronary revascularization in the last 6 months.
• History of surgical revascularization.
• First-degree atrioventricular block or bifascicular block.
• Presence of hemodynamically significant valvulopathy.
• Presence of cardiomyopathy or congenital cardiac anomaly.
• Severe renal insufficiency (eGFR < 30 ml/min).
• Liver failure (history of cirrhosis or transaminase elevation > 3 times the upper limit of normal).
• Pregnant or lactating women.