Circulating Endothelin-2 and Endothelin-3 as Potential Non-Invasive Biomarkers of Carotid Plaque Instability in Patients Undergoing Carotid Endarterectomy

Background: Carotid plaque instability is an important determinant of stroke risk, but circulating biomarkers of plaque vulnerability remain limited. This study aimed to investigate circulating endothelin 2 (ET-2) and endothelin 3 (ET-3) as potential non-invasive biomarkers of plaque instability in patients with carotid atherosclerosis. Methods: Serum ET-2 and ET-3 concentrations were measured in 76 patients undergoing carotid endarterectomy (40 with stable and 36 with unstable plaque phenotypes) and in 12 control subjects without carotid atherosclerosis. Endothelin receptor A (ETA) and endothelin receptor B (ETB) expression within carotid plaques were also assessed. The discriminatory performance of endothelins for distinguishing stable from unstable plaque phenotypes was evaluated using receiver operating characteristic (ROC) analysis, and logistic regression analyses were performed to identify factors associated with plaque instability. Results: Serum ET-2 and ET-3 concentrations were lower in patients with stable plaque phenotype than in controls, and were further reduced in patients with unstable phenotype. Both endothelins showed good discrimination between unstable and stable plaque phenotypes (AUCs 0.847 and 0.817, respectively; both p < 0.0001). In univariable logistic regression, both ET-2 and ET-3 were significantly associated with unstable plaque phenotype. These associations remained significant after adjustment for clinical confounders in separate multivariable models (ET-2: OR 0.963, p < 0.0001; ET-3: OR 0.971, p = 0.001). ETA receptor expression was higher in unstable than stable plaques, whereas ETB expression did not differ significantly. Conclusions: Circulating ET-2 and ET-3 concentrations may represent promising candidates for non-invasive assessment of carotid plaque phenotype but their diagnostic performance requires further validation in larger and independent cohorts.