Small dense LDL: An underestimated driver of atherosclerosis (Review).

Abstract

Cardiovascular disease remains the leading cause of death globally, despite advances in lipid‑lowering strategies. A distinct subfraction of low‑density lipoprotein (LDL) particles, known as small LDL (sdLDL; particle size, 15‑20 nm), has been found to play a disproportionately large role in atherogenesis and residual cardiovascular risk when present at elevated concentrations, particularly in individuals with normocholesterolemia but underlying metabolic disorders. The present review critically examines the pathophysiological characteristics that render sdLDL highly atherogenic. These include increased permeability, prolonged circulation and heightened susceptibility to oxidative modification. The review also explores how sdLDL promotes endothelial dysfunction, foam cell formation, inflammation and plaque instability. Furthermore, it emphasizes the diagnostic challenges of sdLDL measurement, its clinical relevance in high‑risk populations and the limitations of current lipid panels in capturing its contribution to disease progression. Elevated sdLDL levels are commonly observed among individuals with metabolic syndrome, insulin resistance, type 2 diabetes and obesity. Multiple epidemiological studies indicate that elevated sdLDL levels are an independent predictor of cardiovascular events. Targeted lifestyle and pharmacological strategies to reduce sdLDL levels are also reviewed, including statins, fibrates, niacin, w‑3 fatty acids, proprotein convertase subtilisin/kexin type 9 inhibitors and RNA‑targeting agents. The greater incorporation of sdLDL testing into risk assessment tools and clinical guidelines is recommended, and strategies for advancing diagnostics, including artificial intelligence‑driven prediction models and advanced lipid profiling are proposed.