Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges.

High-density lipoproteins (HDLs) represent a spectrum of particles that vary in their physicochemical and functional properties.' 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.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-ß-migrating particles [very small HDL] with the ATP-binding cassette transporter Al (ABCAl) 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 ofthe free cholesterol is subsequently esterified by lecithinxholesterol acyltransferase (LCAT); this enzyme generates a core of cholesteryl esters in a process that converts HDL particles from discoidal, very small, pre-ßj-migrating particles into spherical, a-migrating particles (small HDL]).' The interaction of spherical HDL particles with other active cellular transporters such as ABCGl 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.^ 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 cholesterol efflux. Small, protein-enriched, cholesterol-depleted HDL particles possess antioxidant, anti-inflammatory, cytoprotective, antithrombotic, anti-infective, and endotoxin-neutralizing activities.'-' Structure-function analyses suggest that the simple measurement of HDL-C may not always be reflective of HDL functionality. The challenge is to develop laboratory assays that quantify the various HDL functions that may improve CVD risk assessment and augment the evaluation of HDL-modifying therapies. Efforts to develop reproducible, cost-effective, validated assays that measure the potentially protective functions of HDL are now recognized as a major challenge for the cardiovascular fleld. Currently, there is no consensus concerning the HDL functions that should be targeted, nor are there standardized assays to measure HDL function as a tool to improve either CVD risk assessment or the assessment of therapeutic interventions (Figure 1). Another challenge is to validate measurements of HDL particles to be able to standardize assays of function with HDL quantification. In this article, we review currently available measures of HDL function, explore the potential contribution of functional assays to understanding the mechanisms of atherosclerotic CVD, and describe the involvement of the proteome and lipidome in HDL structure-function relationships. To improve the understanding of HDL functionality, we propose a framework for future investigations addressing the validation and clinical application of HDL functional assays that may have a role as surrogates of CVD (Figure 1).