Dysfunctional HDL

HDL Functions and Dysfunctional HDL

  • 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.
  • Identification of the dysfunctional HDL with diagnostic tools that are feasible will be the basis for launching a new approach into the future of HDL therapeutics. Unfortunately, we are still far from a workable consensus.4
  • Dysfunctional HDL may be returned to normal functioning HDL-C by diet, exercise, degree of fat intake, and pharmacologic approaches. Orally active mimetic proteins are in development and have shown clinical promise.1

Dysfunctional HDL-C in Asian Indians 

  • 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
  • More than 90% of Asian Indians have low levels of HDL2b.11 A very high correlation was found between the more cardioprotective large HDL (HDL2 or α 1 HDL)  levels and premature CAD.9, 10
  • 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


1. Ragbir S, Farmer JA. Dysfunctional high-density lipoprotein and atherosclerosis. Curr Atheroscler Rep. Sep 2010;12(5):343-348.

2. Genest J. The Yin and Yang of high-density lipoprotein cholesterol. J Am Coll Cardiol. Feb 12 2008;51(6):643-644.

3. Kaul S, Shah PK. ApoA-I Milano/phospholipid complexes emerging pharmacological strategies and medications for the prevention of atherosclerotic plaque progression. Curr Drug Targets Cardiovasc Haematol Disord. Dec 2005;5(6):471-479.

4. Feldman DS, Novack DH, Gracely E. Effects of managed care on physician-patient relationships, quality of care, and the ethical practice of medicine: a physician survey. Arch Intern Med. 1998;158(15):1626-1632.

5. Khera Amit V, Cuchel M, de la Llera-Moya M, et al. Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis. New England Journal of Medicine. 2011;364(2):127-135.

6. Dodani S, Kaur R, Reddy S, Reed GL, Mohammad N. Can dysfunctional HDL explain high coronary artery disease risk in South Asians? Int J Cardiol. Feb 4 2008.

7. Bhalodker N, Blum S, Rana T, Enas E. Impaired reverse cholesterol transport in Asian Indian males compared to Framingham Ofspring Study population. J Am Coll Cardiol. 2002:(in press).

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.

9. Asztalos BF. HDL particles, coronary artery disease and niacin. J Clin. lipidology. 2010;4:405-410.

10. Superko HR, King S, 3rd. Lipid management to reduce cardiovascular risk: a new strategy is required. Circulation. Jan 29 2008;117(4):560-568; discussion 568.

11. Superko HR, Enas EA, Kotha P, Bhat N. Impaired cholesterol transport in Asian Indians. Preventive Cardiology. 2001:(in press).

12. Williams PT, Feldman DE. Prospective study of coronary heart disease vs. HDL2, HDL3, and other lipoproteins in Gofman’s Livermore Cohort. Atherosclerosis. Jan 2011;214(1):196-202.

13. Heinecke JW. The HDL proteome: a marker–and perhaps mediator–of coronary artery disease. Journal of lipid research. Apr 2009;50 Suppl:S167-171.

14. Enas EA, Chacko V, Pazhoor SG, Chennikkara H, Devarapalli HP. Dyslipidemia in South Asian patients. Curr Atheroscler Rep. Nov 2007;9(5):367-374.

15. Enas EA. How to Beat the Heart Disease Epidemic among South Asians: A Prevention and Management Guide for Asian Indians and their Doctors. Downers Grove: Advanced Heart Lipid Clinic  USA; 2010.


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