Prof. Xi-Ming Yuan
Linköping University, Sweden
Title: Inflammatory Biomarkers and Plaque Vulnerability in Human Carotid Atherosclerosis: Insights from the Linköping Carotid Study
Abstract:
Background
Inflammation is a central driver of atherosclerotic plaque progression and rupture. Identification of biomarkers reflecting inflammatory activity and plaque vulnerability remains a major clinical challenge. Analyses of human carotid endarterectomy specimens from the Linköping carotid cohort have demonstrated associations between macrophage accumulation, iron metabolism, oxidative stress, apoptosis, and clinical manifestations of atherosclerosis. In particular, biomarkers related to iron homeostasis, including ferritin, transferrin receptor-1 (TfR1), and hepcidin, have emerged as potential indicators of inflammatory plaque activity.
Objective
To investigate inflammatory biomarkers associated with plaque vulnerability in human carotid atherosclerosis and to evaluate the role of iron-regulating pathways in disease progression.
Methods
Carotid atherosclerotic plaques obtained during carotid endarterectomy were characterized using histology, immunohistochemistry, image analysis, and proteomic approaches. Biomarkers examined included CD68-positive macrophages, p53, ferritin, TfR1, cathepsin L, hepcidin and CD74. Plaque morphology, necrotic core formation, cap rupture, apoptosis, and clinical symptoms were assessed and correlated with biomarker expression. Sex-specific differences were also analyzed.
Results
Inflammatory macrophage infiltration was strongly associated with markers of iron accumulation and oxidative stress. Increased expression of ferritin, TfR1, cathepsin L, CD74 and p53 was observed in vulnerable plaques and correlated with necrotic core formation, plaque rupture, apoptosis. Patients presenting with cerebrovascular symptoms exhibited significantly higher levels of ferritin, TfR1, cathepsin L, CD74 and p53 than asymptomatic individuals.
Furthermore, plaques from male patients exhibited greater inflammatory burden, larger necrotic cores, increased macrophage infiltration, and elevated ferritin and TfR1 expression compared with plaques from female patients. These changes were associated with evidence of intraplaque hemorrhage and disturbed iron metabolism.
Most recently, hepcidin expression was found to increase progressively with plaque severity and was significantly associated with macrophage accumulation, TfR1 expression, and apoptosis. Plaques of male patients displayed higher hepcidin levels than female plaques. Experimental studies further showed that suppression of hepcidin reduced oxidative stress, lysosomal membrane permeabilization, and macrophage cell death, suggesting a mechanistic link between iron metabolism and vascular inflammation.
Conclusions
Data from the Linköping carotid cohort identify iron-related inflammatory biomarkers as important determinants of plaque vulnerability. Among these biomarkers, hepcidin emerges as a promising indicator of inflammatory plaque activity and disease progression. The combined assessment of hepcidin, ferritin, TfR1, and macrophage burden may improve risk stratification of patients with advanced carotid atherosclerosis and provide novel targets for therapeutic intervention.
Keywords: Atherosclerosis; Inflammation; Hepcidin; Iron metabolism; Macrophages; Carotid plaque; Biomarkers; Plaque vulnerability.
Biography: