Angina with non-obstructive coronary arteries (ANOCA) is highly prevalent, impairing quality of life and independently associated with cardiovascular events, yet effective treatments are lacking. The endothelin-1 (ET-1)-endothelin receptor (ETR) system is pivotal in ANOCA pathogenesis. Preclinical studies show that ETR blockade or pericyte-specific knockout of ETA receptor improves coronary microcirculatory function in models of myocardial ischemia-reperfusion and diabetes. Clinical evidence indicates ETR antagonists can enhance microvascular endothelial function and myocardial perfusion in ANOCA patients. However, prior studies diagnosed ANOCA based only on symptoms and angiography without precise microvascular functional assessment. Early ETR antagonists also showed frequent adverse effects (e.g., edema, headache), reducing treatment satisfaction. To address this, the investigators will conduct an open-label, single-center, single-arm trial using invasive coronary microcirculatory function testing to accurately phenotype ANOCA and assess microvascular changes. Patients on standard therapy will receive macitentan-a novel ETR antagonist with improved vasodilatory efficacy and safety-to evaluate its effects on coronary microcirculatory function, angina symptoms, and adverse events. Additionally, the investigators will perform multi-omics profiling (proteomics, transcriptomics, metabolomics) on patient blood samples to identify molecular signatures linked to ANOCA subtypes and treatment response, providing evidence for precision intervention strategies in ANOCA.
Age 18-75 years old.
With typical angina symptoms.
Excluding obstructive coronary lesions (coronary stenosis ≤50% or FFR ≥0.8) by CAG.
Coronary microcirculatory function was confirmed via pressure wire-based thermodilution technique.（Patients were classified into subtypes based on coronary microcirculatory function indices: 1) Type I: CFR ≥ 2.5 and IMR < 25; 2) Type II: CFR ≥ 2.5 and IMR ≥ 25; 3) Type III: CFR < 2.5 and IMR < 25; 4) Type IV: CFR < 2.5 and IMR ≥ 25.）
Pregnant or lactating women.
History of heart attack within the last 90 days.
Severe heart disease (e.g., moderate to severe heart failure, severe heart valve disease).
Severe renal impairment (GFR <30 ml/min/1.73m2).
Single group
Macitentan 10 mg tablet, once daily.
DrugAfter the patient signed an informed consent form, Macitentan was given as an oral medication (10 mg once daily) for a period of 4 weeks
Changes in coronary microcirculation function parameters assessed by CFR from baseline to week 4
Coronary Flow Reserve (CFR): A unitless ratio quantifying maximal coronary blood flow augmentation capacity, measured via thermodilution as the ratio of hyperemic to resting coronary flow. The commonly used cut-off value is 2.0 or 2.5. Increased ratio indicates improved microvascular dilation capacity.
Changes in coronary microcirculation function parameters assessed by IMR from baseline to week 4
Index of Microcirculatory Resistance (IMR): A pressure-derived metric (units: mmHg·s) assessing microvascular resistance using thermodilution, calculated as distal coronary pressure multiplied by mean transit time during maximal hyperemia. The commonly used cut-off value is 25. Decreased value indicates reduced microvascular resistance.
Change in Score of the Seattle Angina Questionnaire (SAQ)
The Seattle Angina Questionnaire (SAQ) is a 19-item instrument designed to assess the impact of angina on patients' daily lives across five domains: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. Each item is scored on a 0-100 scale, where higher scores indicate fewer symptoms and better quality of life.
Re-hospitalization due to angina pectoris or heart failure, myocardial infarction, and cardiac death.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
All adverse events such as edema, anemia, headache, dizziness, and hypotension.
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