Integrated biomarker landscape for the early detection and management of calcific aortic valve disease

Background Calcific aortic valve disease (CAVD) is the predominant valvular pathology in older adults, advancing from aortic sclerosis to life‐threatening stenosis. Without effective medical therapies, intervention mainly relies on timely valve replacement, although silent myocardial and valvular damage may progress before symptoms arise. Early, non‐invasive detection of disease activity is a crucial unmet need. Aims To review circulating and mechanistic biomarkers reflecting the core pathogenic pathways of CAVD and asses their potential for early detection and patient‐specific risk stratification. Methods Narrative review of literature focusing on traditional protein biomarkers, emerging non‐coding RNAs, and extracellular vesicles (EVs) associated with lipid oxidation and inflammation, bone and mineral metabolism, extracellular matrix (ECM) remodelling, endothelial dysfunction and non‐coding RNA regulation. Results Traditional protein biomarkers—such as lipoprotein(a), osteopontin, fetuin‐A, galectin‐3 and matrix metalloproteinases—offer insights into the disease and correlate with disease burden but lack sensitivity for detecting early‐stage CAVD. Emerging non‐coding RNA markers, including long non‐coding RNAs (lncRNAs) and microRNAs (like miR‐30b and miR‐125b), show promise as predictive and diagnostic tools by mediating key molecular pathways involved in calcification and inflammation. EVs, which carry proteins, lipids and nucleic acids across all pathogenic pathways, provide stable and comprehensive signatures that enhance risk stratification compared to conventional markers. Notably, no single biomarker has demonstrated sufficient sensitivity or specificity across all stages of the disease. Combining proteins, RNAs and EV cargo into integrative, multimodal panels—supported by proteomics and transcriptomics—provides the greatest potential for early detection and patient‐specific management. However, further validation in prospective cohorts and standardization of assays are necessary before clinical implementation. Conclusion Biomarker‐guided approaches could revolutionize CAVD management by enabling early detection and patient stratification before irreversible valvular damage occurs.