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The not-so-simple HDL story

A new era for quantifying HDL and cardiovascular risk?

Nature Medicine volume 18, pages 1346–1347 (2012)Cite this article

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High levels of low-density lipoprotein (LDL) promote atherosclerosis by delivering cholesterol in an unregulated manner to artery-wall macrophages, a key step in atherosclerotic vascular disease. In contrast, clinical and epidemiological studies show a robust, inverse association of high-density lipoprotein (HDL) levels with cardiovascular disease risk. HDL's cardioprotective effects are mediated in part by its ability to remove cholesterol from macrophages. Mice with genetically engineered deficiencies in proteins involved in HDL metabolism provide compelling evidence that HDL is a key modulator of atherosclerosis in hypercholesterolemic models. These observations have triggered intense interest in targeting HDL for therapeutic intervention.

HDL can be quantified by blood concentrations of its major protein component, apoA-I, and by its content of cholesterol. Some studies suggest that low concentrations of apoA-I associate more strongly with cardiovascular disease risk than do HDL cholesterol (HDL-C) levels. Virtually all clinical studies have used HDL-C as a metric for quantifying HDL's cardioprotective effects. However, recent evidence has raised doubts about the hypotheses that elevating HDL-C is necessarily therapeutic. For example, genetic variations that associate with altered HDL-C do not strongly associate with altered cardiovascular disease risk1. Also, trials of two drugs that elevate HDL-C levels—niacin and the cholesteryl ester transfer protein (CETP) inhibitor dalceptrapib—were terminated prematurely because of an apparent lack of clinical benefit in subjects with established cardiovascular disease1.

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Figure 1: Overview of reverse cholesterol transport by HDL.

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Authors and Affiliations

  1. Jay W. Heinecke is in the Department of Medicine, University of Washington, Seattle, Washington, USA.,

    Jay W Heinecke

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  1. Jay W Heinecke
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Correspondence to Jay W Heinecke.

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Competing interests

J.W.H. receives research support from Merck, GlaxoSmithKline and Bristol-Myers Squibb.

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Heinecke, J. A new era for quantifying HDL and cardiovascular risk?. Nat Med 18, 1346–1347 (2012). https://doi.org/10.1038/nm.2930

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