Dysfunctional hdl cadi

• High-density lipoprotein cholesterol (HDL-C) may reduce the atherosclerotic burden by multiple mechanisms leading to reduced CVD (cardiovascular disease) risk independent of the LDL-C levels. 1 The best known function of HDL-C is the reverse cholesterol transport wherein , HDL-C interacts with foam cells to remove cholesterol from the periphery, allowing it to be cleared by the liver and then excreted into the bile. 1

• Other important functions of HDL-C include potentiation of endothelial function and repair, nitric oxide synthesis, prostacyclin production, and improvement in fibrinolytic balance. Normal HDL has significant anti-inflammatory, antithrombotic, and antioxidant activity. HDL is also a key player in innate immunity and the metabolism of other circulating lipoproteins. 1

• The quality of the HDL-C appears to be more important than the quantity of HDL. 2 Clinical conditions associated with inflammation and oxidative stress can adversely alter the normal functions of HDL. 1 High levels of HDL-C among people who consume liberal amounts of alcohol have been associated with increased rather than decreased cardiovascular risk.

• Dysfunctional HDL-C is generally thought of as not cardioprotective even if HDL-C is present in high levels. Multiple clinical studies have identified individuals with a significant atherosclerotic burden despite normal or elevated levels of HDL-C. Conversely some populations with very low levels of HDL-C have paradoxically lower rates of heart disease. 3

• Although there is evidence for the existence of “dysfunctional HDL,” the term has not been consistently defined. HDL dysfunction can be envisioned as a range of altered function, from lack of function (HDL does not exert one or more of the expected effects) to a function opposite of the natural mandate (i.e., HDL causes cholesterol deposition in the artery wall, induces oxidation, or activates the inflammatory response). 4 It is assumed that dysfunctional HDL has altered composition and /or altered functions.

• Studies in mice have demonstrated that decreased scavenger receptor B1 (SR-B1) reduces clearance of HDL-C and results in greater plasma concentrations. HDL-C particles become larger with more cholesterol content, but the cholesterol transport into the liver and into the bile is decreased. Besides, cholesterol transport from peripheral tissues is impeded and thus fails to protect against developing atherosclerosis. 4

• A better understanding of HDL-C functionality may lead to less emphasis on increasing HDL-C levels per se and more on improving HDL function. Indeed, only a functional HDL-C should be targeted with concentration-increasing strategies, while lowering levels of dysfunctional HDL can become a bona fide goal as well. 4

• Cholesterol efflux capacity from macrophages ─ a metric of HDL function ─ has a strong inverse association with CAD status independently of the HDL-C level. 5 Clinical assays have been developed to assess the functionality of HDL in research but are not available for use in clinical practice.

• Several lines of evidence suggests a high probability of dysfunctional HDL-C in Asian Indians. 6 At identical levels of HDL-C, Asian Indians have a higher proportion of less cardioprotective small HDL particles and a lower proportion of more cardioprotective large HDL particles compared to whites. 7 More importantly, the overall HDL particle size is smaller in Asian Indians. 7, 8

• Given the very high prevalence of low HDL2, 12 aggressive statin-niacin combination therapy that remodel HDL particle to resemble that of apparently healthy subjects seems warranted. 13 Such therapy has also favorable impact on all lipoproteins. 14

• Prescription Niacin is one of the few agents that not only raise the HDL-C, but also selectively increases the large HDL2 that has been shown to be associated with improved function as evidenced by reduction in coronary events as well as regression of atherosclerosis. 15

8. Bhalodkar NC, Blum S, Rana T, et al. Comparison of Levels of Large and Small High-Density Lipoprotein Cholesterol in Asian Indian Men Compared to Caucasian Men in the Framingham Offspring Study. American Journal of Cardiology. 2004;In press.