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(Circulation. 2009;120:549-552.)
© 2009 American Heart Association, Inc.

Editorial

Lecithin: Cholesterol Acyltransferase and Atherosclerosis

Another High-Density Lipoprotein Story That Doesn’t Quite Follow the Script

Daniel J. Rader, MD

From the Institute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Daniel J. Rader, MD, University of Pennsylvania Medical Center, 654 Biomedical Research Building II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail rader@mail.med.upenn.edu

Key Words: Editorials • atherosclerosis • cholesterol • cholesterol, HDL • lipoproteins

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are strongly, consistently, and independently inversely associated with risk of atherosclerotic cardiovascular disease (CVD).¹ A series of animal studies in the 1990s, primarily involving overexpression of the major HDL protein apolipoprotein A-I (apoA-I) with subsequent increases in HDL-C, showed reduced progression or even regression of atherosclerosis, fitting nicely with the "HDL hypothesis" that raising HDL-C is causally associated with benefit. However, the last decade has seen several observations that do not follow this simple script. Some examples include the following: (1) the demonstration that scavenger receptor class BI knockout mice have increased HDL-C but increased atherosclerosis²; (2) the suggestion that some persons with high HDL-C levels have "dysfunctional" HDL that may not be protective³; and (3) the observation that the cholesteryl ester transfer protein inhibitor torcetrapib raised HDL-C levels considerably but did not decrease, and indeed increased, cardiovascular risk.^4,5 These developments have brought into major question the simple hypothesis that higher HDL-C directly and causally results in reduced atherosclerosis and challenge the approach of developing therapies that raise HDL-C levels.

Article see p 628

One of the paradoxes in the field of HDL for nearly 3 decades has been the fact that monogenic disorders of extreme low HDL-C are not generally associated with obviously accelerated atherosclerosis. The first report of this phenomenon was the apoA-I Milano mutation, heterozygous carriers of which have HDL-C levels <5th percentile but no increased CVD.⁶ A number of additional apoA-I point mutations causing very low HDL-C . . . [Full Text of this Article]

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Functional Lecithin: Cholesterol Acyltransferase Is Not Required for Efficient Atheroprotection in Humans

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Circulation 2009 120: 628-635. [Abstract] [Full Text]