Physicians' Academy for Cardiovascular Education

Erik Stroes: “Increasing HDLc as a therapy remains promising”

Expert opinion

News - Jan. 28, 2014


Expert opinion of Prof.dr. E.S.G. Stroes (Internal Medicine, AMC Amsterdam, The Netherlands)

American scientists have shown that the protective HDL cholesterol can be impaired in locations with increased inflammatory activity. This could be in a diseased vessel wall, but also during peritonitis. Traditionally, it has been assumed that HDL has a cardioprotective function, while LDL causes atherosclerosis, thereby increasing the risk of cardiovascular disease. The protective function of HDL mostly depends on the major component of this type of cholesterol: the protein apolipoprotein A1 (apoA1). This protein can transport bad cholesterol away from the blood vessels towards the liver; the so-called reverse cholesterol transport.
The Americans detected that the apoA1 protein is present in a dysfunctional form in plaques in blood vessels, as a result of which this apoA1 can no longer exert its protective function in reverse cholesterol transport. Only very little dysfunctional apoA1, is circulating in the blood, because it is rapidly excreted by the kidney as ‘non-functioning’ apoA1.
So what does this study add? It is actually not very surprising that protective particles can also become dysfunctional and loose their protective action. In comparison; even the bad cholesterol, LDLc, can become damaged through which it can be modified or even oxidised. This modified LDLc is even more aggressive in causing atherosclerosis and vessel damage. New now is that HDLc can undergo exactly the same process. But, the vast majority of HDL (over 99% in blood and over 80% in the plaque) is still functioning properly and can thus protect against cardiovascular disease.

For years now, attempts are made to prove that ‘badly functioning’ HDL cholesterol may explain the disappointing results of HDL-increasing strategies. However, this paper cannot explain this. Indeed, even in patient groups with cardiovascular disease an inverse relationship exists between HDLc levels and cardiovascular risk, which corresponds to a protective role for HDLc.
It is impressive that Hazen and colleagues managed to identify a dysfunctional subset of HDLc in plaques and plasma. It is, however, hardly likely that this discovery of dysfunctional HDLc will be relevant in the clinic. Chances are high that patients with severe cardiovascular disease have a big inflammation somewhere at any point in time, where HDL can become dysfunctional. Nevertheless, the body is very capable of creating new functional HDL and of excreting the impaired HDL in time.
Increasing HDLc as a therapy therefore remains promising. For research purposes it may be interesting to study whether not too much dysfunctional HDL is produced; but the most important task is now to reveal HOW HDLc should be increased to yield the most protection.   

Literature • 27-1-2014 • Huang et al., Nature Medicine 2014

Dysfunctional and proinflammatory apoA1 detected in atherosclerotic plaque

Oxidised apoA1 in human atheroma does not associate with HDL and has proinflammatory effects. Circulating levels are predictive of CAD and CV risk, but not specific to atherosclerosis.