To the Editor: Dr Meuwese and colleagues1 presented results of the Carotid Atherosclerosis Progression Trial Investigating Vascular ACAT Inhibition Treatment Effects (CAPTIVATE). In this study, patients who were heterozygous for familial hypercholesterolemia were randomized to receive either pactimibe (a nonspecific acyl coenzyme A:cholesterol acyltransferase [ACAT] inhibitor) or placebo, in addition to standard lipid-lowering therapy. Consistent with data from macrophage ACAT1 knockout mice, treatment with a nonspecific ACAT inhibitor may not result in apparent positive effects on atherosclerosis.2
Although the authors did not provide evidence that either ACAT-1 or ACAT-2 was inhibited by the treatment regimen in this study, they discussed the possibility that the pactimibe treatment was accessing both ACAT enzymes. It is likely that any effect on thickness of the artery wall (where ACAT-1 resides2 ) would be related to ACAT-1 inhibition. However, the discussion focused on ACAT-2. It was suggested that ACAT-2 might be up-regulated in human atherosclerotic lesions, where it could contribute to the “toxic effect of free cholesterol accumulation.”1 We are aware of no evidence that ACAT-2 is functional in human lesions.
The idea that inhibition of ACAT-2 might lead to an increase of low-density lipoprotein cholesterol (LDL-C) is contrary to human and animal data. Based on its location in hepatocytes, ACAT-2 activity may be rate-limiting for apolipoprotein B–containing lipoprotein production.3 ACAT-2 appears to represent up to 50% of total ACAT activity in human liver, in which ACAT-1 expression is confined solely to Kupffer cells.3 In studies of Chinese patients,4 ACAT-2 activity in the intestinal mucosa was more than 40-fold higher than in the liver. Hence, intestinal ACAT-2 may also have a prominent function in intestinal cholesterol absorption and, thus, availability of cholesterol in the liver for apolipoprotein B–lipoprotein particle secretion.
The Uppsala Longitudinal Study of Adult Men5 suggested that plasma cholesteryl oleate and cholesteryl palmitate, which are ACAT-2–derived cholesteryl esters, are associated with increased coronary heart disease mortality.
Only when data demonstrate a selective effect of any drug on either ACAT-1 or ACAT-2 activity, which have distinct functions, should claims for effects of such inhibition on human cardiovascular disease be addressed.
Financial Disclosures: Dr Parini reported receiving grants from AstraZeneca AB, Sweden, and Pfizer AB, Sweden. Dr Eriksson reported receiving a grant from Pfizer AB, Sweden. Dr Rudel reported receiving grants from Amgen and Glaxo and being on the speakers' bureau for Merck.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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