High-Density Lipoproteins

Low plasma levels of cholesterol carried by high-density lipoprotein (HDL) particles are firmly established as a major cardiovascular risk factor. Paradoxically, cardiovascular mortality is also elevated at extremely high levels of HDL cholesterol. Furthermore, genetic epidemiology often does not support a causal relationship between HDL cholesterol and cardiovascular risk.HDL particles contain multiple protein and lipid components and are highly heterogeneous in their metabolism, structure and biological function. Small, dense, protein-rich HDLs display elevated anti-atherogenic activities as compared to large, light, lipid-rich particles.HDL metabolism and function are altered in both low and extremely high HDL cholesterol (HDL-C) states. Low HDL-C levels are typically accompanied by reduced circulating levels of large HDL and deficient biological activities of small HDL particles. Reduced capacity of HDL to efflux cholesterol from lipid-loaded macrophages is associated with both the presence of cardiovascular disease and the risk of future cardiovascular events. However, therapeutic HDL-C raising, which predominantly increases levels of large HDL, have repeatedly failed to reduce cardiovascular events in patients treated with statins. Such flagrant controversy between classic epidemiology, genetic epidemiology and clinical trials needs to be urgently resolved in order to allow further development of HDL-targeting therapies.