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

Current Atherosclerosis Reports

Volumn 18, Issue 1, 2016, Pages 1-8

  Bhatt, Anish ^a   Rohatgi, Anand ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

Atherosclerosis; Cardiovascular; Cholesterol efflux; HDL; Reverse cholesterol transport

Indexed keywords

ABC TRANSPORTER A1; ANACETRAPIB; APABETALONE; APOLIPOPROTEIN A; CHOLESTEROL ESTER TRANSFER PROTEIN; DALCETRAPIB; EVACETRAPIB; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; NICOTINIC ACID; PHOSPHATIDYLCHOLINE STEROL ACYLTRANSFERASE; TORCETRAPIB;

ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CHOLESTEROL METABOLISM; CHOLESTEROL TRANSPORT; DISEASE ASSOCIATION; DRUG TARGETING; HUMAN; LIPID COMPOSITION; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; PROTEIN SYNTHESIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY MECHANISM; REVIEW; RISK ASSESSMENT; ANIMAL; CARDIOVASCULAR DISEASES; MACROPHAGE; METABOLISM; RISK FACTOR; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; ATHEROSCLEROSIS; BIOLOGICAL TRANSPORT; CARDIOVASCULAR DISEASES; CHOLESTEROL, HDL; HUMANS; MACROPHAGES; RISK FACTORS;

EID: 84952006045     PISSN: 15233804     EISSN: 15346242     Source Type: Journal    
DOI: 10.1007/s11883-015-0554-1     Document Type: Review

References (58)

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.
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.
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.
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.
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.
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.
7. Emerging Risk Factors, C et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993–2000.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
18. Rosenson RS et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125(15):1905–19.
19. Tall AR et al. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 2008;7(5):365–75.
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.
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.
22. Rohatgi A. High-density lipoprotein function measurement in human studies: focus on cholesterol efflux capacity. Prog Cardiovasc Dis. 2015;58(1):32–40.
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.
24. Khera AV et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364(2):127–35.
25. Bauer M et al. Carotid intima-media thickness as a biomarker of subclinical atherosclerosis. Swiss Med Wkly. 2012;142:w13705.
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.
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.
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.
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.
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.
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.
33. Ritsch A, Scharnagl H, Marz W. HDL cholesterol efflux capacity and cardiovascular events. N Engl J Med. 2015;372(19):1870–1.
34. Calabresi L, Franceschini G. Lecithin:cholesterol acyltransferase, high-density lipoproteins, and atheroprotection in humans. Trends Cardiovasc Med. 2010;20(2):50–3.
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.
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.
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.
38. Rousset X et al. Lecithin cholesterol acyltransferase: an anti- or pro-atherogenic factor? Curr Atheroscler Rep. 2011;13(3):249–56.
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.
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.
41. Mani P, Rohatgi A. Niacin therapy, HDL cholesterol, and cardiovascular disease: is the HDL hypothesis defunct? Curr Atheroscler Rep. 2015;17(8):521.
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.
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.
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.
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.
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.
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.
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.
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.
50. Krause BR, Remaley AT. Reconstituted HDL for the acute treatment of acute coronary syndrome. Curr Opin Lipidol. 2013;24(6):480–6.
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.
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.
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.
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.
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.
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.
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.
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.