Circulating biomarkers of carotid plaque vulnerability: current evidence, emerging markers, and barriers to clinical implementation

Carotid plaque instability is a major cause of ischemic stroke, whereas conventional imaging based mainly on luminal stenosis cannot fully capture the dynamic molecular processes that precede plaque rupture. Circulating biomarkers provide a noninvasive approach to identify vulnerable carotid plaques by reflecting inflammation, lipid dysregulation, endothelial activation, thrombogenicity, oxidative stress, extracellular matrix remodeling, and other biological changes within the plaque microenvironment. This review summarizes current evidence on both traditional and emerging biomarkers of carotid plaque vulnerability, with emphasis on their ability to discriminate unstable from stable plaques and to predict future cerebrovascular events. Among traditional biomarkers, inflammatory markers, modified lipid-related markers, endothelial and neovascularization-related markers, coagulation-fibrinolysis indicators, and oxidative stress/extracellular matrix remodeling markers show the most consistent associations with plaque vulnerability. Emerging evidence further supports the potential relevance of epigenetic markers, macrophage-related immunophenotypic markers, iron metabolism-related markers, TGF-β2, non-traditional lipid parameters, endoplasmic reticulum stress-related proteins, and several exploratory biomarkers. In addition, multi-biomarker and multimodal models integrating circulating markers with imaging features appear to outperform individual biomarkers alone in identifying high-risk plaques. However, despite these advances, most candidate biomarkers remain exploratory and have not yet entered routine clinical practice because of limited specificity and sensitivity, insufficient reproducibility, lack of assay standardization and universally accepted cutoff values, and the predominance of small, single-center, or early-stage studies without adequate external validation. Future progress will depend on large prospective multicenter studies, standardized detection methods, and integrated multimodal risk models that combine biomarkers with imaging and clinical variables. These efforts may ultimately improve early risk stratification and individualized management of patients with vulnerable carotid atherosclerotic plaques.