nach oben

Current Atherosclerosis Reports

Erschienen in:

01.01.2016 | Coronary Heart Disease (S. Virani and S. Naderi, Section Editors)

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

verfasst von: Anish Bhatt, Anand Rohatgi

Erschienen in: Current Atherosclerosis Reports | Ausgabe 1/2016

Einloggen, um Zugang zu erhalten

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.

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.CrossRefPubMed

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.CrossRef

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

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

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.CrossRefPubMed

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

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

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRef

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

18.

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

19.

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

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.PubMedCentralPubMed

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.CrossRefPubMed

22.

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

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.PubMedCentralPubMed

24.

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

25.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

33.

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

34.

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

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.PubMedCentralCrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

38.

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

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

41.

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

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

50.

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

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.CrossRefPubMed

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.PubMedCentralCrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.

Titel: HDL Cholesterol Efflux Capacity: Cardiovascular Risk Factor and Potential Therapeutic Target
verfasst von: Anish Bhatt
Anand Rohatgi
Publikationsdatum: 01.01.2016
Verlag: Springer US
Erschienen in: Current Atherosclerosis Reports / Ausgabe 1/2016
Print ISSN: 1523-3804
Elektronische ISSN: 1534-6242
DOI: https://doi.org/10.1007/s11883-015-0554-1

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

25.04.2024 | Hypotonie | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

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

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Update Innere Medizin

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2016

The Link Between Inflammatory Disorders and Coronary Heart Disease: a Look at Recent Studies and Novel Drugs in Development

Dual Antiplatelet Therapy in Patients with Stable Ischemic Heart Disease

The Link Between Obstructive Sleep Apnea and Cardiovascular Disease

Aspirin for the Primary Prevention of Cardiovascular Disease: In Need of Clarity

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Update Innere Medizin