Endothelin Role In COronary Microcirculation

Coronary microvascular dysfunction (CMD) is increasingly recognised as a major cause of myocardial ischaemia and angina in patients without obstructive epicardial coronary artery disease. CMD is a key mechanism underlying ischaemia with non-obstructive coronary arteries (INOCA) and is associated with impaired quality of life, recurrent healthcare utilisation, and adverse cardiovascular outcomes.

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor peptide that has been implicated in endothelial dysfunction, vascular inflammation, and microvascular dysregulation. Elevated circulating ET-1 concentrations have been reported in patients with microvascular angina and may contribute to increased coronary microvascular resistance and impaired myocardial perfusion.

The ERICOM study is a prospective, single-arm mechanistic study designed to investigate the relationship between ET-1 and coronary microvascular dysfunction and to assess the effects of endothelin receptor antagonism on coronary microvascular function.

Participants with angina symptoms and evidence of coronary microvascular dysfunction undergo baseline clinical assessment, blood sampling for ET-1 measurement, and stress cardiovascular magnetic resonance (CMR) imaging. Participants receive bosentan therapy for four weeks followed by repeat stress CMR imaging. A subset of participants undergoes invasive coronary angiography with physiological assessment, including measurements of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), fractional flow reserve (FFR), and resting full-cycle ratio (RFR).

The primary objective is to determine whether bosentan therapy improves coronary microvascular function as assessed by serial CMR-derived myocardial perfusion measurements. Secondary objectives include evaluating associations between ET-1 concentrations and CMD, assessing relationships between invasive and non-invasive measures of coronary microvascular function, and exploring mechanistic pathways linking endothelin signalling and coronary microvascular disease.

The study is sponsored by Liverpool University Hospitals NHS Foundation Trust and conducted in accordance with Good Clinical Practice, Research Ethics Committee approval, and Health Research Authority approval.

Inclusion criteria

• Clinical diagnosis of symptomatic angina, defined as the presence of substernal chest pain or discomfort provoked by exertion or emotional stress and relieved by rest and/or glyceryl trinitrate (nitroglycerin).
• Age 18 years or older.
• Able and willing to provide written informed consent.
• Able and willing to adhere to study procedures and follow-up requirements.

Exclusion criteria

• Symptoms consistent with unstable angina, including:
• Angina at rest lasting more than 20 minutes.
• New-onset severe angina.
• Angina increasing in frequency, duration, or occurring at a lower threshold.
• Angina occurring following a recent myocardial infarction.
• Known significant coronary artery disease, defined as previous investigations demonstrating greater than 50% epicardial coronary artery stenosis.
• Uncontrolled hypertension, defined as clinic blood pressure greater than 140/90 mmHg despite treatment with three or more antihypertensive medications.
• Pregnancy or breastfeeding.
• Poorly controlled asthma as defined in the study protocol.
• Severe heart failure or symptoms of active heart failure.
• Significant chronic kidney disease, defined as estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m².
• Clinical evidence of active infection at the time of recruitment.
• Significant liver disease, defined as Child-Pugh Class B or C liver disease (or worse than Child-Pugh Class A).
• Systolic blood pressure less than 90 mmHg at the time of recruitment.
• Previously documented allergy or hypersensitivity to endothelin receptor antagonists.
• Concurrent use of medications contraindicated with endothelin receptor antagonist therapy.
• Requirement for invasive coronary angiography for another clinical indication, including but not limited to valvular heart disease assessment or intervention.