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HDL Cholesterol Efflux Capacity: Cardiovascular Risk Factor and Potential Therapeutic Target

  • Coronary Heart Disease (S. Virani and S. Naderi, Section Editors)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Low high-density lipoprotein cholesterol (HDL-C) levels are associated with incident cardiovascular events; however, many therapies targeting increases in HDL-C have failed to show consistent clinical benefit. Thus, focus has recently shifted toward measuring high-density lipoprotein (HDL) function. HDL is the key mediator of reverse cholesterol transport, the process of cholesterol extraction from foam cells, and eventual excretion into the biliary system. Cholesterol efflux from peripheral macrophages to HDL particles has been associated with atherosclerosis in both animals and humans. We review the mechanism of cholesterol efflux and the emerging evidence on the association between cholesterol efflux capacity and cardiovascular disease in human studies. We also focus on the completed and ongoing trials of novel therapies targeting different aspects of HDL cholesterol efflux.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Stone NJ et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1–S45.

    Article  PubMed  Google Scholar 

  2. Cholesterol Treatment Trialists, C et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581–90.

    Article  Google Scholar 

  3. Sabatine MS et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9.

    Article  CAS  PubMed  Google Scholar 

  4. Robinson JG et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99.

    Article  CAS  PubMed  Google Scholar 

  5. Assmann G et al. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. 1996;124 Suppl:S11–20.

    Article  CAS  PubMed  Google Scholar 

  6. Barter P et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357(13):1301–10.

    Article  CAS  PubMed  Google Scholar 

  7. Emerging Risk Factors, C et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993–2000.

    Article  Google Scholar 

  8. Gordon T et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707–14.

    Article  CAS  PubMed  Google Scholar 

  9. Prospective Studies Collaboration, Lewington S, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370(9602):1829–39.

    Article  Google Scholar 

  10. Sharrett AR et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001;104(10):1108–13.

    Article  CAS  PubMed  Google Scholar 

  11. Turner RC et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316(7134):823–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Keene D et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014;349:g4379.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Group, H.T.C. et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–12.

    Article  Google Scholar 

  14. The AIM-HIGH Investigators et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.

    Article  Google Scholar 

  15. Barter PJ et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109–22.

    Article  CAS  PubMed  Google Scholar 

  16. Schwartz GG et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–99. Dal-OUTCOMES was a randomized controlled trial studying the effects of CETP inhibition on recurrent cardiovascular events. Over 15,000 patients were randomized to dalcetrapib or placebo and followed for a median of 31 months. Despite a significant increase in HDL-C in the dalcetrapib group, there was no significant reduction in recurrent cardiovascular events. This study emphasized that targeting HDL-C reduction may not reduce cardiovascular events.

    Article  CAS  PubMed  Google Scholar 

  17. Terasaka N et al. High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1. Proc Natl Acad Sci U S A. 2007;104(38):15093–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Rosenson RS et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125(15):1905–19.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Tall AR et al. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 2008;7(5):365–75.

    Article  CAS  PubMed  Google Scholar 

  20. Rader DJ et al. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res. 2009;50(Suppl):S189–94.

    PubMed Central  PubMed  Google Scholar 

  21. Out R et al. Combined deletion of macrophage ABCA1 and ABCG1 leads to massive lipid accumulation in tissue macrophages and distinct atherosclerosis at relatively low plasma cholesterol levels. Arterioscler Thromb Vasc Biol. 2008;28(2):258–64.

    Article  CAS  PubMed  Google Scholar 

  22. Rohatgi A. High-density lipoprotein function measurement in human studies: focus on cholesterol efflux capacity. Prog Cardiovasc Dis. 2015;58(1):32–40.

    Article  PubMed  Google Scholar 

  23. Yvan-Charvet L et al. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J Clin Invest. 2007;117(12):3900–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Khera AV et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364(2):127–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Bauer M et al. Carotid intima-media thickness as a biomarker of subclinical atherosclerosis. Swiss Med Wkly. 2012;142:w13705.

    PubMed  Google Scholar 

  26. Taylor AJ et al. Progression of calcified coronary atherosclerosis: relationship to coronary risk factors and carotid intima-media thickness. Atherosclerosis. 2008;197(1):339–45.

    Article  CAS  PubMed  Google Scholar 

  27. Salahuddin T, Natarajan B, Playford MP, Joshi AA, Teague H, Masmoudi Y, et al. Cholesterol efflux capacity in humans with psoriasis is inversely related to non-calcified burden of coronary atherosclerosis. Eur Heart J. 2015;36(39):2662–5.

  28. Lim TK et al. Normal value of carotid intima-media thickness—a surrogate marker of atherosclerosis: quantitative assessment by B-mode carotid ultrasound. J Am Soc Echocardiogr. 2008;21(2):112–6.

    Article  PubMed  Google Scholar 

  29. Ishikawa T et al. High-density lipoprotein cholesterol efflux capacity as a relevant predictor of atherosclerotic coronary disease. Atherosclerosis. 2015;242(1):318–22.

    Article  CAS  PubMed  Google Scholar 

  30. Li XM et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol. 2013;33(7):1696–705. This study prospectively followed 1150 patients with high cardiovascular risk after measuring baseline CEC. The highest tertile of CEC exhibited an increased risk of both incident nonfatal myocardial infarction and cardiovascular death. These results are in contrast with other observational studies.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Rohatgi A et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383–93. This study analyzed almost 3000 patients in the Dallas Heart Study, a low-risk population free of cardiovascular disease. Baseline CEC was shown to be inversely proportional to ASCVD, even after adjustment for HDL-C levels. This study established that baseline HDL function associates with incident cardiovascular disease.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Saleheen D et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol. 2015;3(7):507–13. In this analysis of the EPIC-Norfolk cohort, a low-risk population, increasing tertiles of baseline CEC were associated with a reduced incidence of coronary heart disease. This association did not attenuate after adjustment for HDL-C levels. This study also showed that baseline CEC associates with incident events.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Ritsch A, Scharnagl H, Marz W. HDL cholesterol efflux capacity and cardiovascular events. N Engl J Med. 2015;372(19):1870–1.

    PubMed  Google Scholar 

  34. Calabresi L, Franceschini G. Lecithin:cholesterol acyltransferase, high-density lipoproteins, and atheroprotection in humans. Trends Cardiovasc Med. 2010;20(2):50–3.

    Article  CAS  PubMed  Google Scholar 

  35. Tanigawa H et al. Lecithin: cholesterol acyltransferase expression has minimal effects on macrophage reverse cholesterol transport in vivo. Circulation. 2009;120(2):160–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Holleboom AG et al. Plasma levels of lecithin:cholesterol acyltransferase and risk of future coronary artery disease in apparently healthy men and women: a prospective case-control analysis nested in the EPIC-Norfolk population study. J Lipid Res. 2010;51(2):416–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Dullaart RP et al. High plasma lecithin:cholesterol acyltransferase activity does not predict low incidence of cardiovascular events: possible attenuation of cardioprotection associated with high HDL cholesterol. Atherosclerosis. 2010;208(2):537–42.

    Article  CAS  PubMed  Google Scholar 

  38. Rousset X et al. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor? Curr Atheroscler Rep. 2011;13(3):249–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Yvan-Charvet L et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30(7):1430–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Khera AV et al. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol. 2013;62(20):1909–10.

    Article  CAS  PubMed  Google Scholar 

  41. Mani P, Rohatgi A. Niacin therapy, HDL cholesterol, and cardiovascular disease: is the HDL hypothesis defunct? Curr Atheroscler Rep. 2015;17(8):521.

    Article  PubMed  Google Scholar 

  42. Ray KK et al. The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the Dal-ACUTE randomized trial. Eur Heart J. 2014;35(27):1792–800. Dal-ACUTE studied 300 patients who were randomized to dalcetrapib or placebo within 1 week of an acute coronary syndrome. Only a modest increase in CEC was noted in the dalcetrapib group and mostly via a non-ABCA-1-mediated pathway. These results demonstrated the effects of dalcetrapib on specific efflux pathways.

    Article  CAS  PubMed  Google Scholar 

  43. Yvan-Charvet L et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27(5):1132–8.

    Article  CAS  PubMed  Google Scholar 

  44. Nicholls SJ et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099–109.

    Article  CAS  PubMed  Google Scholar 

  45. Rader DJ et al. Abstract 12252: effects of the cholesteryl ester transfer protein inhibitor, evacetrapib, administered as monotherapy or in combination with statins on cholesterol efflux and HDL particles in patients with dyslipidemia. Circulation. 2014;130 Suppl 2:A12252.

    Google Scholar 

  46. van der Steeg WA et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol. 2008;51(6):634–42.

    Article  PubMed  Google Scholar 

  47. Diditchenko S et al. Novel formulation of a reconstituted high-density lipoprotein (CSL112) dramatically enhances ABCA1-dependent cholesterol efflux. Arterioscler Thromb Vasc Biol. 2013;33(9):2202–11.

    Article  CAS  PubMed  Google Scholar 

  48. Gille A et al. CSL112 enhances biomarkers of reverse cholesterol transport after single and multiple infusions in healthy subjects. Arterioscler Thromb Vasc Biol. 2014;34(9):2106–14.

    Article  CAS  PubMed  Google Scholar 

  49. Amar MJ et al. 5A apolipoprotein mimetic peptide promotes cholesterol efflux and reduces atherosclerosis in mice. J Pharmacol Exp Ther. 2010;334(2):634–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Krause BR, Remaley AT. Reconstituted HDL for the acute treatment of acute coronary syndrome. Curr Opin Lipidol. 2013;24(6):480–6.

    Article  CAS  PubMed  Google Scholar 

  51. Nissen SE et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292–300.

    Article  CAS  PubMed  Google Scholar 

  52. Uehara Y et al. FAMP, a novel apoA-I mimetic peptide, suppresses aortic plaque formation through promotion of biological HDL function in ApoE-deficient mice. J Am Heart Assoc. 2013;2(3):e000048.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Tardif JC et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297(15):1675–82.

    Article  PubMed  Google Scholar 

  54. Bailey D et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55(23):2580–9.

    Article  CAS  PubMed  Google Scholar 

  55. Nicholls SJ et al. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J Am Coll Cardiol. 2011;57(9):1111–9.

    Article  CAS  PubMed  Google Scholar 

  56. Nicholls SJ et al. ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies. Cardiovasc Drugs Ther. 2012;26(2):181–7.

    Article  CAS  PubMed  Google Scholar 

  57. Barylski M et al. Emerging therapies for raising high-density lipoprotein cholesterol (HDL-C) and augmenting HDL particle functionality. Best Pract Res Clin Endocrinol Metab. 2014;28(3):453–61.

    Article  CAS  PubMed  Google Scholar 

  58. Wong NC et al. Abstract 338: effects of RVX-208 a selective bromodomain extra-terminal protein inhibitor beyond raising ApoA-I/HDL. Arterioscler Thromb Vasc Biol. 2015;35 Suppl 1:A338.

    Google Scholar 

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8830, USA

    Anish Bhatt & Anand Rohatgi

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  1. Anish Bhatt
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  2. Anand Rohatgi
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Correspondence to Anand Rohatgi.

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Conflict of Interest

Anish Bhatt declares no conflict of interest.

Anand Rohatgi declares grants from the National Heart, Lung, and Blood Institute (NIH under award number K08HL118131) and Merck, personal fees from Vascular Strategies and CSL Limited for consultant work, personal fees from Cleveland HeartLab for serving on the advisory board, personal fees from Astra Zeneca for the Speaker’s Bureau, and non-financial support from Eli Lilly for being a site PI for the ACCELERATE trial (evacetrapib).

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This article is part of the Topical Collection on Coronary Heart Disease

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Bhatt, A., Rohatgi, A. HDL Cholesterol Efflux Capacity: Cardiovascular Risk Factor and Potential Therapeutic Target. Curr Atheroscler Rep 18, 2 (2016). https://doi.org/10.1007/s11883-015-0554-1

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