Could HDL be pro-atherogenic?

The negative association of HDL to cardiovascular risk has long been known. HDL is believed to reduce cardiovascular risk by a variety of mechanisms including: facilitating reverse cholesterol transport, reducing LDL oxidation, inhibiting cell adhesion molecules and lowering vascular inflammation. For every 1 mg/dL increase in HDL cholesterol, it has been estimated there is approximately a 3% decrease in future cardiovascular risk.

Nevertheless, it has been suggested that in certain situations, HDL may lose its protective anti-atherogenic function and possibly even become pro-inflammatory. I must admit that the first time I heard of this theory several years ago, I was skeptical.

Everyone knows that HDL is the “good” anti-atherogenic lipoprotein, right?

Studies have suggested that this assumption may not be correct. When systemic inflammation is present, the ability of HDL to participate in reverse cholesterol transport is reduced. More surprisingly, it has been discovered that at times HDL may even promote the oxidation of LDL and expression of cellular adhesion molecules. Circumstances under which this may occur include poorly controlled diabetes mellitus, infection, tobacco use and connective tissue disorders. Dietary modification, lifestyle change as well as statins seem to lower pro-inflammatory HDL, although not quite back to the level of healthy controls.

Moreover, elevated HDL is not always protective. In my practice, I have seen more than a few patients with history of cardiovascular or cerebrovascular disease even despite having an HDL of 100 mg/dL or more and no risk factors. In speaking with other lipidologists, I know that I am not alone in my experience.

Despite raising HDL markedly, the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, failed to decrease cardiovascular events. This was a great surprise to many as the animal and other preliminary studies were very encouraging. However, even before the effects of torcetrapib were known, many were cautious about the benefits of raising HDL through CETP inhibition. In northern Japan there is a higher incidence of genetic CETP deficiency than anywhere else in the world. Individuals with genetic CETP deficiency may have a very high HDL, often greater than 100 mg/dL. Although some families are protected, there are others in which premature events occur. The reason for this difference is unknown.

There is much we still do not understand about HDL. The conventional wisdom of “more HDL is better” probably holds true for the majority of patients we see in our practices. However, it is possible that in some individuals, HDL may not be protective or could even be pro-atherogenic.

Perhaps someday modulating the function of HDL will be a target of therapy?

In the meantime, I will continue to recommend therapies proven to lower cardiovascular risk including dietary and lifestyle modification, tobacco cessation, and treating diabetes, blood pressure and lipids to currently accepted goals.

Am J Cardiol. 2007;100:3N–9N, 47N–52N.