Mechanism-based biomarkers for early detection and plaque vulnerability assessment in atherosclerosis

Atherosclerosis is a chronic inflammatory disorder of the arterial wall and remains the leading pathological basis for myocardial infarction and ischemic stroke worldwide. Despite advances in imaging and risk-prediction models, early detection of subclinical atherosclerosis and identification of plaque vulnerability remain challenging. Conventional biomarkers such as low-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol provide valuable risk estimates but lack sufficient sensitivity and specificity for early disease detection and plaque vulnerability assessment, prompting growing interest in non-traditional and emerging biomarkers, as well as instrumental surrogate markers such as pulse wave velocity, which better reflect the complex molecular and mechanical processes underlying atherogenesis. This review provides a comprehensive, mechanism-based overview of traditional and emerging biomarkers associated with atherosclerosis, including inflammatory mediators, coagulation factors, cardiac-specific proteins, adhesion molecules, microRNAs, extracellular vesicles, and novel cytokines, alongside a comparative appraisal of the major non-invasive, functional, invasive, and nuclear imaging modalities used for plaque detection and characterization. Particular emphasis is placed on recently identified biomarkers such as midkine, pentraxin-3, soluble ST2, growth differentiation factor-15, and myeloperoxidase, including their tissue-specific origins and interpretive limitations, which show promise in improving early diagnosis, risk stratification, and prognostic evaluation. Biomarkers are further mapped to the key pathological stages of atherogenesis, endothelial dysfunction, lipid retention and oxidation, vascular inflammation, immune cell activation, plaque destabilization, and thrombotic activation, offering a physiologically intuitive framework for interpreting multi-marker panels. Understanding the biological relevance and clinical utility of these biomarkers may facilitate more precise cardiovascular risk assessment and support the development of targeted preventive and therapeutic strategies.