Translation of High-Density Lipoprotein Function Into Clinical Practice

High-density lipoproteins (HDLs) represent a spectrum of particles that vary in their physicochemical and functional properties.1 It has been shown in many population studies that the concentration of HDL cholesterol (HDL-C) is inversely related to the risk of having a cardiovascular disease (CVD) event. In this paradigm, HDL-C has been considered to be a marker of the potentially cardioprotective functions of HDL. However, recent studies have suggested that the simple concentration of HDL-C may not always reflect HDL function, with growing evidence that under some circumstances HDL function may be compromised despite high concentrations of HDL-C.The best known of the potentially antiatherogenic functions of HDLs is their ability to promote cholesterol efflux from cells, including that from macrophages in the arterial wall.2 Cellular cholesterol efflux is achieved by several mechanisms. One involves the interaction of phospholipid-depleted and cholesterol-deficient apolipoprotein (apo) A-I complexes (discoidal, pre–β-migrating particles [very small HDL] with the ATP-binding cassette transporter A1 (ABCA1) in a process that results in the formation of a heterogeneous population of nascent HDL particles that are discoidal in shape and contain apoA-I, phospholipids, and free cholesterol. A proportion of the free cholesterol is subsequently esterified by lecithin:cholesterol acyltransferase (LCAT); this enzyme generates a core of cholesteryl esters in a process that converts HDL particles from discoidal, very small, pre-β1-migrating particles into spherical, α-migrating particles (small HDL]).1 The interaction of spherical HDL particles with other active cellular transporters such as ABCG1 and passive diffusion of cellular cholesterol further increase the cholesterol load of HDL. However, it is often unappreciated that peripheral cholesterol efflux contributes <5% of the cholesterol content of HDL.2 Thus, HDL-C is an inadequate surrogate measure for the most heralded of HDL functions.Various HDL subpopulations differ in other antiatherogenic functions that extend beyond macrophage …