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Failure of ACAT Inhibition to Retard Atherosclerosis
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     Medical management of atherosclerosis is based on the control of its risk factors (dyslipidemia, hypertension, family history, and smoking) and predisposing conditions (e.g., the metabolic syndrome and diabetes), but no drugs specifically target the arterial plaque. The search is on for therapeutic interventions that can act as antiatherosclerosis agents, selectively targeting one or more of the features of the atheroma, such as endothelial dysfunction, inflammation, or foam-cell formation.

    Approaches that target arterial plaque through the use of acyl–coenzyme A:cholesterol acyltransferase (ACAT) inhibitors have been investigated experimentally for two decades. ACAT inhibitors interfere with intracellular cholesterol transport within plaque macrophages and may delay the formation of foam cells while activating reverse cholesterol transport.1 There are at least two forms of this intracellular enzyme. ACAT2 esterifies the free cholesterol that will form the core of lipoproteins assembled in hepatocytes and intestinal epithelium, whereas ACAT1 esterifies free cholesterol so that it can be stored as cholesteryl ester droplets in macrophages.2 Inhibition of ACAT2 may reduce plasma cholesterol levels,3 whereas inhibition of ACAT1 may reduce the cholesterol burden in plaque macrophages.4

    As arterial macrophages internalize modified lipoproteins, they have to deal with the flow of free cholesterol from lysosomes to the cytoplasm. This excess free cholesterol either is eliminated from the cell and incorporated into reverse cholesterol transport — the high-density lipoprotein (HDL) pathway — or is esterified by ACAT to form cholesteryl ester, filling droplets that eventually take up most of the cytoplasm and turn the active macrophage into the moribund foam cell.5 Because free cholesterol can exit the cell and become part of HDL, whereas cholesteryl ester is deposited in lipid droplets and contributes to the expansion of atheroma, the expectation has been that altering the cholesterol balance in favor of free cholesterol production would promote efficient cholesterol efflux, activation of reverse cholesterol transport, and deflation of the atheroma. However, it is also possible that the ACAT enzyme is in such a pivotal position because excess cholesterol is less harmful when stored as inert cholesteryl ester than as free cholesterol, which is available for export but becomes toxic to the cell when present in excess.6

    Experimental evidence suggests that ACAT inhibition reduces atherosclerosis in animals.1 However, we reported that macrophages without ACAT1 paradoxically increase atherosclerosis in mice with dyslipidemia, probably owing to the toxic effects of free cholesterol and to the apoptosis of macrophages in the vessel wall.7 Since then, others have shown that ACAT inhibition may promote rather than decrease atherosclerosis in animals,8,9 and there is no doubt that excess free cholesterol is toxic to macrophages.10

    In the clinical setting, things have not gone well for ACAT inhibitors. The Avasimibe and Progression of Lesions on Ultrasound (A-PLUS) study enrolled more than 600 patients with coronary disease and randomly assigned them to receive placebo or increasing doses of the ACAT inhibitor avasimibe.11 After two years, not only was there no evidence on intravascular ultrasonography that avasimibe decreased plaque volume, but also there was a trend toward unfavorable effects of treatment. Unexpectedly, avasimibe raised low-density lipoprotein (LDL) cholesterol levels by about 9 percent, possibly through pharmacokinetic interactions with statins, thus making it difficult to determine the direct vascular effects of this ACAT inhibitor.

    In this issue of the Journal, Nissen and collaborators present the results of the ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) trial, an 18-month study of the effects of another nonselective ACAT inhibitor, pactimibe, on plaque burden, as measured by intravascular ultrasonography, in 408 patients with coronary atherosclerosis.12 Most patients (75 to 80 percent) were receiving statin therapy, and their mean LDL cholesterol level at the end of the study was approximately 90 mg per deciliter (2.3 mmol per liter). The main outcome of the study was the change in the percent atheroma volume, which showed a nonsignificant trend toward worsening in the group given pactimibe. However, secondary outcome measures (the total atheroma volume and the change in volume in the 10-mm segment with the greatest disease severity) were significantly worse in the pactimibe group than in the placebo group. Pactimibe had no significant effects on plasma lipid or C-reactive protein levels. Interestingly, the trend toward worsening atheroma volume was stronger in the subgroup of patients with diabetes than in the subgroup without diabetes. Because of the relatively short duration of this study, the negative effects of the experimental treatment on coronary plaques did not translate into an increased number of cardiovascular events. Pactimibe will not undergo any further clinical testing, and the authors recommend that any ACAT inhibitor evaluated in clinical trials should be strictly monitored for negative cardiovascular outcomes.

    A bold conclusion can be drawn from the study by Nissen et al.: nonselective ACAT inhibition is an ineffective antiatherosclerosis therapy and is probably harmful. However, the study has much wider repercussions with respect to our understanding of the biology of the arterial plaque, since it dispels the long-held notion that interrupting the cholesteryl ester cycle will drive free cholesterol from macrophages into the arms of HDL. Obviously, the steps of cholesterol transport leading to the efflux of free cholesterol into the HDL pathway are more complex than we originally thought; the excess free cholesterol produced by blocking ACAT is not readily available for export and may accumulate in the macrophage above the toxic threshold (Figure 1). This could be the consequence of the compartmentalization of free cholesterol to sites disconnected from the efflux machinery, dysfunction of the efflux machinery caused by stiffening of the plasma membrane, or the presence of relatively low levels of extracellular cholesterol acceptors in the atheroma. For cholesterol to exit the cell, an acceptor must be present on the other side of the membrane. Apolipoprotein A-I, the HDL protein, is a physiologic cholesterol acceptor. Limited access of plasma-derived apolipoprotein A-I to the growing atheroma may result in inefficient elimination of cellular cholesterol, even when conditions are ripe for export.

    Figure 1. The Unintended Effects of Acyl–Coenzyme A:Cholesterol Acyltransferase (ACAT) Inhibition.

    In Panel A, the arterial macrophage transports incoming lipoprotein cholesterol as part of a cycle of interconversion of free cholesterol and cholesteryl ester controlled by ACAT and cholesteryl ester hydrolase (CEH). Liberated free cholesterol can be exported to high-density lipoprotein (HDL). Excess cholesteryl ester is stored in lipid droplets. In Panel B, the inhibition of ACAT (red X) increases free cholesterol levels and reduces the levels of cholesteryl ester, thus activating efflux and limiting storage. In Panel C, the continued inhibition of ACAT increases free cholesterol levels and limits the efflux of free cholesterol, thus inducing cytotoxic effects.

    The finding by Nissen et al. that treatment had no effects on plasma lipid levels reduces interest in the development of ACAT2-selective inhibitors. Moreover, the finding that pactimibe expands the plaque when LDL levels are well controlled suggests that ACAT inhibition may have catastrophic effects in patients with hypercholesterolemia. Finally, ACAT inhibitors may have the dubious privilege of being the only drugs capable of attenuating the vascular protection afforded by statins.

    As the authors point out, the ability of intravascular ultrasonography to detect detrimental vascular changes is reassuring, since antiatherosclerosis drugs may not only have beneficial effects or no effects on the plaque, but also have the unintended effect of promoting atherogenesis. The value of intravascular ultrasonography has been amply substantiated in terms of therapeutic interventions that reduce plaque. In another recent study, Nissen et al. found that five weekly injections of a mutant form of human apolipoprotein A I (apo-A-IMilano) mixed with phospholipids significantly reduced atheroma volume.13 The mechanism of this effect may be secondary to increasing the level of cholesterol acceptors in the plaque, an aim common to other HDL-based therapies.14 If there is a clinical future for ACAT inhibitors, it may be to combine them with therapies that increase the number of acceptor particles in the plaque, leading to the export of free cholesterol from macrophages into the HDL pathway.

    In conclusion, this definitive article by Nissen et al. conveys an important message for the pharmaceutical industry, academic medicine, regulatory agencies, and practicing physicians: the wait for an antiatherosclerosis therapy may be long.

    Supported by a grant (HL65709) from the National Institutes of Health.

    No potential conflict of interest relevant to this article was reported.

    We are indebted to Dr. Yan-Ru Su for assistance in preparing the figure.

    Source Information

    From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville.

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