Modified LDL variants in atherosclerosis: molecular pathways, diagnostic potential, and therapeutic perspectives

Modified low-density lipoproteins (LDL) play a pivotal role in the pathogenesis of atherosclerosis, contributing to plaque formation and vascular inflammation. This review explores how a diverse array of forms of modified LDL, including carbamylated LDL, nitrated LDL, and desialylated LDL, along with various enzymatic modifications, contribute to disease progression. We discuss how these alterations promote the formation of a heterogeneous, highly atherogenic pool of particles known as electronegative LDL (LDL(-)). Mechanistic insights highlight pathways involving upregulated scavenger receptors, foam cell formation, and chronic inflammatory responses. The diagnostic and prognostic implications of LDL(-), including its association with autoimmune conditions like rheumatoid arthritis and chronic conditions such as type 2 diabetes, underscore its potential as a biomarker for cardiovascular risk. Emerging therapies targeting LDL(-), such as nanoformulations of single-chain fragment variable antibodies, demonstrate promising efficacy in reducing lesion size and inflammation without adverse systemic effects. Despite these advances, a critical barrier to clinical translation is the lack of standardised, high-throughput assays suitable for routine laboratory use. Future research must therefore prioritise the development and validation of robust clinical assays to quantify these atherogenic particles, a crucial step for establishing their role in advanced risk stratification and for guiding novel therapeutic strategies..