Mechanisms of Disease: Proatherogenic HDL-An Evolving Field

Mohamad Navab; Gattadahalli M Anantharamaiah; Srinivasa T Reddy; Brian J Van Lenten; Benjamin J Ansell; Alan M Fogelman


Nat Clin Pract Endocrinol Metab. 2006;2(9):504-511. 

In This Article

Summary and Introduction


It is well known that, in large populations, HDL-cholesterol levels are inversely related to the risk of atherosclerotic clinical events; however, in an individual, the predictive value of an HDL-cholesterol level is far from perfect. As a result, other HDL-associated factors have been investigated, including the quality and function of HDL in contradistinction to the level of HDL-cholesterol. Regarding their quality, HDL particles are highly heterogeneous and contain varying levels of antioxidants or pro-oxidants, which results in variation in HDL function. It has been postulated that HDL functions to promote reverse cholesterol transport. Recent studies support this role for HDL but also indicate that HDL is a modulator of systemic inflammation. In the absence of inflammation, HDL has a complement of antioxidant enzymes that work to maintain an anti-inflammatory state. In the presence of systemic inflammation, these antioxidant enzymes can be inactivated and HDL can accumulate oxidized lipids and proteins that make it proinflammatory. Under these conditions the main protein of HDL, apolipoprotein A-I, can be modified by reactive oxygen species. This modification impairs the ability of HDL to promote cholesterol efflux by the ATP-binding cassette transporter A-1 pathway. Animal studies and small-scale human studies suggest that measures of the quality and novel functions of HDL might provide an improved means of identifying subjects at increased risk for atherosclerotic events, compared with the current practice of only measuring HDL-cholesterol levels. The quality and function of HDL are also attractive targets for emerging therapies.


It is well accepted that HDL-cholesterol levels are inversely related to the risk of clinical events due to atherosclerosis. Careful review of the literature, however, reveals that, even in the original Framingham study (which established the importance of HDL-cholesterol levels in predicting coronary events), more than 40% of events occurred in subjects with normal HDL-cholesterol levels.[1,2,3,4,5] The Air Force–Texas Coronary Atherosclerosis Prevention Study tested the efficacy of statin therapy in a population with 'average' total cholesterol levels over a period of 5.2 years. In this study, the event rate in the placebo group was 2.1%, 2.9%, and 3.4% for those with HDL-cholesterol levels of >40, 35–39, and ≤34 mg/dl, respectively (>1.03, 0.91–1.00, and ≤0.88 mmol/l, respectively), where values less than 40 mg/dl (<1.03 mmol/l) were considered abnormal.[4] The event rate in subjects with normal HDL-cholesterol levels who were given placebo was, therefore, approximately two-thirds of the event rate in the subjects with the lowest HDL-cholesterol levels.[1]

Evolving knowledge that a significant number of cardiovascular events occur in subjects with normal levels of both LDL-cholesterol and HDL-cholesterol[1,6]has fueled a search for additional biomarkers with better predictive value.[3,4,7] This review will present evidence that HDL can mitigate or potentiate risk for any given LDL-cholesterol level, and will also consider the mechanisms by which HDL might exert these effects.


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