BACKGROUND High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden. METHODS We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima–media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B–depleted serum from the study participants. RESULTS The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima–media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P = 0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P = 0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins. CONCLUSIONS Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.)

arteries. Overall, however, the data do not support a policy of routine stenting of the celiac and SMA for treatment of CMI.

Abstract-The removal of excess free cholesterol from cells by HDL or its apolipoproteins is important for maintaining cellular cholesterol homeostasis. This process is most likely compromised in the atherosclerotic lesion because the development of atherosclerosis is associated with low HDL cholesterol. Multiple mechanisms for efflux of cell cholesterol exist. Efflux of free cholesterol via aqueous diffusion occurs with all cell types but is inefficient. Efflux of cholesterol is accelerated when scavenger receptor class-B type I (SR-BI) is present in the cell plasma membrane. Both diffusion-mediated and SR-BI-mediated efflux occur to phospholipid-containing acceptors (ie, HDL and lipidated apolipoproteins); in both cases, the flux of cholesterol is bidirectional, with the direction of net flux depending on the cholesterol gradient. The ATP-binding cassette transporter AI (ABCA1) mediates efflux of both cellular cholesterol and phospholipid. In contrast to SR-BI-mediated flux, efflux via ABCA1 is unidirectional, occurring to lipid-poor apolipoproteins. The relative importance of the SR-BI and ABCA1 efflux pathways in preventing the development of atherosclerotic plaque is not known but will depend on the expression levels of the two proteins and on the type of cholesterol acceptors available. Key Words: cholesterol efflux Ⅲ scavenger receptor class-BI Ⅲ ATP-binding cassette transporter AI Ⅲ reverse cholesterol transport H DL levels are inversely correlated with the incidence of coronary artery disease. 1-4 A long-standing hypothesis to explain this protective effect of HDL against atherosclerosis is the process of reverse cholesterol transport (RCT). 5 In RCT, HDL or its apolipoproteins mediate the removal of excess free cholesterol (FC) from peripheral cells and, after a series of reactions in plasma, the cholesterol is delivered via either LDL or HDL to the liver for excretion into the bile. The flux of FC between cells and extracellular acceptors is important at two points in the RCT pathway: (1) the removal of FC from peripheral cells and (2) the delivery of HDL FC to the liver. There are 3 known mechanisms of FC flux: (1) aqueous diffusion, (2) SR-BI-mediated FC flux, and (3) ABCA1-mediated efflux (Figure 1). The purpose of this review is to discuss each mechanism and the relative importance of each mechanism to RCT. Aqueous DiffusionCholesterol molecules are sufficiently water-soluble to be able to transfer from either model 6 or cell membranes 7 to an acceptor by the so-called aqueous diffusion mechanism. 8 This process involves desorption of cholesterol molecules from the donor lipid-water interface and diffusion of these molecules through the intervening aqueous phase until they collide with and are absorbed by an acceptor. At a constant donor particle concentration, there is a hyperbolic dependence of cholesterol transfer rate on the concentration of acceptor particles; the kinetics can be described in terms of the rate constants for At lower acceptor concentrations, the transfer rate is dependent on th...