Profiling Cardiovascular Disease-Associated Changes in the Composition of High-Density Lipoprotein Particles

Cardiovascular disease remains the leading cause of death worldwide, imposing significant morbidity and healthcare costs. While low serum high-density lipoprotein (HDL)-cholesterol levels have traditionally been linked to cardiovascular risk, most pharmacological interventions aimed at raising HDL-cholesterol levels have not consistently improved cardiovascular outcomes. Epidemiologic and genetic studies further suggest that circulating HDL-cholesterol levels may not directly determine cardiovascular risk, underscoring the complexity of HDL particles in cardiovascular health. HDL particles are dynamic, multifunctional complexes composed of diverse proteins and lipids, whose composition determines their cardioprotective properties. In cardiovascular disease, the composition of HDL particles is frequently remodeled, resulting in dysfunctional particles with impaired antioxidant, anti-inflammatory, and lipid transport functions. Consequently, the composition and functionality of HDL particles, rather than their cholesterol content, appear to be the primary determinants of their protective capacity. A deeper understanding of HDL particles' compositional changes in cardiovascular disease may guide therapies that restore their protective capacity, thus offering a more effective strategy to reduce cardiovascular risk. This review summarizes current knowledge on changes in the proteomic and lipidomic composition of HDL particles associated with cardiovascular disease, highlighting molecular alterations that may drive HDL particle dysfunction.