BETWEEN BEDSIDE AND BENCH depleted of the atherogenic lipoproteins LDL and VLDL, which deliver cholesterol to macrophage foam cells5. They showed that human serum HDL’s ability to promote sterol efflux from cultured macrophages can vary markedly, despite similar levels of HDL-C and apoA-I5, indicating the level of HDL-C is not the major determinant of macrophage sterol efflux in this system. It will be of great interest to determine the biochemical and genetic factors that regulate sterol efflux by serum HDL, as these factors may represent new therapeutic targets for the prevention of cardiovascular disease. The capacity of serum HDL to promote macrophage sterol efflux associated strongly and negatively with coronary artery disease status in two independent populations of humans6. That association was also independent of HDL-C and apoA-I levels. Differences in efflux capacity of serum HDL correlated with altered efflux by the ABCA1 pathway in macrophages. Taken together, these observations suggest that serum HDL’s capacity to promote sterol efflux from macrophages reflects its functionality, raising the possibility that the assay provides insights into HDL biology and cardiovascular disease risk. A key metric for assessing HDL function may be the concentration of HDL particles in blood (Fig. 1), which in turn could affect the concentration of HDL in the artery wall.

However, the protein and lipid compositions of large and small HDL particles differ7, 8, making interpretation of HDL-C and apoA-I levels problematic for the assessment of HDL particle number. Thus, a crucial issue confounding the interpretation of HDL-C as a measure of HDL concentration may be the relative balance between large and small HDL particles. At a given level of HDL-C, it is possible to have many small cholesterol-poor particles or far fewer large, cholesterol-rich particles7. Sterol efflux by the ABCA1 pathway is strongly dependent on the concentration of lipid-poor HDL, raising the possibility that particle number is an important determinant of macrophage cholesterol efflux. Notably, both niacin and CETP inhibitors promote the formation of large HDL particles1, which might not change HDL particle concentration despite the increase in HDL-C.