Abstract
High-density lipoproteins (HDLs) have multiple pleiotropic effects against arteriosclerosis.
Most are independent of the cholesterol mass within HDL particles. Yet, HDL cholesterol
(HDL-C) remains a biomarker to assess cardiovascular risk. Whereas the epidemiological
association between HDL-C and cardiovascular risk is strong, graded and coherent across
populations, Mendelian randomization studies cast doubt on whether HDL-C is causally
related to atherosclerotic cardiovascular disease. The apparent failure of HDL-C-raising
therapies (fibrates, niacin, and cholesteryl ester transfer protein inhibitors) raises
questions about the HDL-C hypothesis. HDL particles are heterogeneous in lipid and
protein composition, and thus in size and function. Multiple factors related to oxidation
and inflammation might render HDL particles malfunctional or proatherogenic. HDL functionality
might be a preferred biomarker and therapeutic target. However, most of the beneficial
events of HDL particles occur in the subendothelial layer of arteries and not in plasma.
In this report, we review the complexity and controversies surrounding HDL and atherosclerotic
cardiovascular disease. Importantly, intimal HDL biogenesis, function, and egress
from the arterial wall might hold the key to unlocking the therapeutic potential of
HDL.
Résumé
Les lipoprotéines de haute densité (HDL) ont de multiples effets pléiotropiques contre
l’artériosclérose. La plupart sont indépendants de la masse de cholestérol des particules
HDL. Toutefois, le cholestérol HDL demeure un biomarqueur pour évaluer les risques
cardiovasculaires. Alors qu’il existe un lien épidémiologique fort, marqué et cohérent
entre le cholestérol HDL et les risques cardiovasculaires dans l’ensemble des populations,
les études à répartition aléatoire mendélienne remettent en question le lien causal
entre le cholestérol HDL et la maladie cardiovasculaire athérosclérotique. L’échec
apparent des traitements qui augmentent le cholestérol HDL (fibrates, niacine et inhibiteurs
de la protéine de transfert des esters de cholestérol) soulève des questions sur l’hypothèse
du cholestérol HDL. Les particules HDL sont hétérogènes quant à leur composition lipidique
et protéique et par conséquent, quant à leur taille et leur fonctionnement. De multiples
facteurs liés à l’oxydation et à l’inflammation pourraient entraîner un dysfonctionnement
des particules HDL ou les rendre pro-athérogènes. La fonctionnalité des HDL pourrait
constituer un biomarqueur et une cible thérapeutique privilégiés. Toutefois, la plupart
des manifestations bénéfiques des particules HDL se produisent dans la couche sous-endothéliale
des artères, et non dans le plasma. Dans le présent article, nous passons en revue
la complexité et les controverses qui entourent les HDL et la maladie cardiovasculaire
athérosclérotique. Notamment, la biogenèse intimale des HDL, leur fonctionnement et
leur évacuation de la paroi artérielle pourraient se révéler la clé de l’exploitation
du potentiel thérapeutique des HDL.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Canadian Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Ultracentrifugal studies of high density serum lipoproteins in clinically healthy adults.Am J Physiol. 1954; 179: 333-337
- Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease.Lancet. 1975; 1: 16-19
- High density lipoproteins: measurement techniques and potential biomarkers of cardiovascular risk.BBA Clin. 2015; 3: 175-188
- Unraveling the complexities of the HDL lipidome.J Lipid Res. 2013; 54: 2950-2963
- Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond.J Lipid Res. 2013; 54: 2575-2585
The Davidson/Shah Lab. HDL Proteome Watch. Available at: http://homepages.uc.edu/∼davidswm/HDLproteome.html. Accessed July 29, 2016.
- HDL, atherosclerosis, and emerging therapies.Cholesterol. 2013; 2013: 891403
- Cardioprotective functions of HDLs.J Lipid Res. 2014; 55: 168-179
- Chapter 45: lipoprotein disorders and CAD.in: Braunwald E. Libby P. Zipes D. Bonow R. Braunwald's Heart Disease. 10th Ed. Saunders, New York2014: 980-1000
- HDL and cardiovascular disease.Lancet. 2014; 384: 618-625
- The Tromso heart study. High-density lipoprotein and coronary heart-disease: a prospective case-control study.Lancet. 1977; 1: 965-968
- High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial.Circulation. 1986; 74: 1217-1225
- Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000
- Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.Circulation. 2013; 128: 1504-1512
- Genetics of cholesterol efflux.Curr Atheroscler Rep. 2012; 14: 235-246
- Discovery and refinement of loci associated with lipid levels.Nat Genet. 2013; 45: 1274-1283
- Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.JAMA. 2008; 299: 2524-2532
- Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.Lancet. 2012; 380: 572-580
- Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.Lancet. 2010; 375: 1875-1884
US Department of Health and Human Services. US Food and Drug Administration. Tricor (fenofibrate) tablets. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm342600.htm. Accessed July 30, 2016.
- Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N Engl J Med. 2011; 365: 2255-2267
- Effects of extended-release niacin with laropiprant in high-risk patients.N Engl J Med. 2014; 371: 203-212
- HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment.Eur Heart J. 2013; 34: 1279-1291
- 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult.Can J Cardiol. 2016; 32: 1263-1282
- Circulating cholesteryl ester transfer protein and coronary heart disease: mendelian randomization meta-analysis.Circ Cardiovasc Genet. 2015; 8: 114-121
- Effects of torcetrapib in patients at high risk for coronary events.N Engl J Med. 2007; 357: 2109-2122
- Effects of dalcetrapib in patients with a recent acute coronary syndrome.N Engl J Med. 2012; 367: 2089-2099
- Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: rationale and design of the ACCELERATE trial.Am Heart J. 2015; 170: 1061-1069
- Treatment options for low high-density lipoproteins.Curr Opin Endocrinol Diabetes Obes. 2014; 21: 134-139
- Novel apo E-derived ABCA1 agonist peptide (CS-6253) promotes reverse cholesterol transport and induces formation of prebeta-1 HDL in vitro.PLoS One. 2015; 10: e0131997
- Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial.JAMA. 2007; 297: 1675-1682
- ETC-216 for coronary artery disease.Expert Opin Biol Ther. 2011; 11: 387-394
- 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: 1111-1119
- HDL-targeted therapies: progress, failures and future.Nat Rev Drug Discov. 2014; 13: 445-464
- 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
- Lipoprotein remodeling generates lipid-poor apolipoprotein A-I particles in human interstitial fluid.Am J Physiol Endocrinol Metab. 2013; 304: E321-E328
- Dysfunctional HDL and atherosclerotic cardiovascular disease.Nat Rev Cardiol. 2016; 13: 48-60
- Functional and proteomic alterations of plasma high density lipoproteins in type 1 diabetes mellitus.Metabolism. 2016; 65: 1421-1431
- Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy.Transl Res. 2016; 173: 30-57
- Micro-RNAs and high-density lipoprotein metabolism.Arterioscler Thromb Vasc Biol. 2016; 36: 1076-1084
- MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins.Nat Cell Biol. 2011; 13: 423-433
- High-density lipoproteins: nature's multifunctional nanoparticles.ACS Nano. 2016; 10: 3015-3041
- The beta-chain of cell surface F(0)F(1) ATPase modulates apoA-I and HDL transcytosis through aortic endothelial cells.Arterioscler Thromb Vasc Biol. 2012; 32: 131-139
- Comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: colocalization of biglycan with apolipoproteins.Circulation. 1998; 98: 519-527
- Function and distribution of apolipoprotein A1 in the artery wall are markedly distinct from those in plasma.Circulation. 2013; 128: 1644-1655
- An abundant dysfunctional apolipoprotein A1 in human atheroma.Nat Med. 2014; 20: 193-203
- Macrophages in atherosclerosis: a dynamic balance.Nat Rev Immunol. 2013; 13: 709-721
- Macrophage phenotype and function in different stages of atherosclerosis.Circ Res. 2016; 118: 653-667
- Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.Circulation. 2012; 125: 1905-1919
- Molecular mechanisms of cellular cholesterol efflux.J Biol Chem. 2014; 289: 24020-24029
- So much cholesterol: the unrecognized importance of smooth muscle cells in atherosclerotic foam cell formation.Curr Opin Lipidol. 2016; 27: 155-161
- ATP-binding cassette transporter A1 expression and apolipoprotein A-I binding are impaired in intima-type arterial smooth muscle cells.Circulation. 2009; 119: 3223-3231
- Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis.Circulation. 2014; 129: 1551-1559
- Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL.Cell Metab. 2013; 17: 671-684
- Lymphatic transport of high-density lipoproteins and chylomicrons.J Clin Invest. 2014; 124: 929-935
- High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target.Circ Res. 2014; 114: 171-182
- Coronary artery disease: HDL and coronary heart disease–novel insights.Nat Rev Cardiol. 2014; 11: 559-560
- HDL cholesterol efflux capacity and incident cardiovascular events.N Engl J Med. 2014; 371: 2383-2393
Article info
Publication history
Published online: October 20, 2016
Accepted:
September 19,
2016
Received:
August 7,
2016
Footnotes
See page 332 for disclosure information.
Identification
Copyright
© 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.