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| __NOTOC__
| | #Redirect [[High density lipoprotein natural history, complications and prognosis]] |
| {{High density lipoprotein}}
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| {{CMG}}; {{AE}} {{M.P}}
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| ==Overview==
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| The antiatherogenic actions of HDL-C through reverse cholesterol transport and the cardioprotective effect through endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects has been the basis trials to increase HDL and to determine prognosis. [[High-density lipoprotein]] (HDL) cholesterol levels are inversely related to risk for [[coronary artery disease]] (CAD), but because HDL particles are heterogeneous in size and composition, they may be differentially associated with other cardiovascular risk factors and with cardiovascular risk.
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| ==Prognosis and Complications==
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| Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risk.<ref name="pmid20425274">{{cite journal| author=Khera AV, Rader DJ| title=Future therapeutic directions in reverse cholesterol transport. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 1 | pages= 73-81 | pmid=20425274 | doi=10.1007/s11883-009-0080-0 | pmc=PMC3315100 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20425274 }} </ref><ref name="pmid19903920">{{cite journal| author=Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK et al.| title=Major lipids, apolipoproteins, and risk of vascular disease. | journal=JAMA | year= 2009 | volume= 302 | issue= 18 | pages= 1993-2000 | pmid=19903920 | doi=10.1001/jama.2009.1619 | pmc=PMC3284229 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19903920 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20157124 Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212] </ref> This strong negative association has lead to the development of the “HDL-C hypothesis” which proposes that pharmacological intervention to raise HDL-C will reduce cardiovascular risk; in fact, recent studies reports that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease. Some of the trials are :
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| * VA-HIT trial : The VA-HIT trial on 2531 with CHD who had an LDL-cholesterol (≤140 mg/dL or 3.6 mmol/L), an HDL-cholesterol (≤40 mg/dL or 1.0 mmol/L), and triglycerides ≤300 mg/dL (3.4 mmol/L), showed that cardiac death and nonfatal myocardial infarction occurred less often in the gemfibrozil treated group and strongly correlated with the serum HDL-cholesterol concentration achieved with gemfibrozil therapy, but was independent of changes in LDL-cholesterol or triglycerides.<ref name="pmid11268266">{{cite journal| author=Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ et al.| title=Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. | journal=JAMA | year= 2001 | volume= 285 | issue= 12 | pages= 1585-91 | pmid=11268266 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11268266 }} </ref>
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| * Trial of simvastatin plus niacin : In this study patients receiving simvastatin plus niacin were significantly less likely to sustain a cardiovascular event such as cardiac death, myocardial infarction or revascularization and experienced angiographic regression of the most significant coronary stenosis.<ref name="pmid11757504">{{cite journal| author=Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS et al.| title=Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 22 | pages= 1583-92 | pmid=11757504 | doi=10.1056/NEJMoa011090 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11757504 }} </ref>
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| * AIM-HIGH trial : A randomized trial comparing-extended release niacin (target dose 2000 mg per day) with placebo (100 to 200 mg of immediate release niacin) in 3414 patients with cardiovascular disease though increased levels of HDL-C and lowered levels of triglycerides and LDL-C was stopped early for futility after a mean follow-up of three years.<ref name="pmid22085343">{{cite journal| author=AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P et al.| title=Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. | journal=N Engl J Med | year= 2011 | volume= 365 | issue= 24 | pages= 2255-67 | pmid=22085343 | doi=10.1056/NEJMoa1107579 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22085343 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22508748 Review in: Ann Intern Med. 2012 Apr 17;156(8):JC4-08] </ref>
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| * ARBITER 2 study : A randomized trial that examined the effects of extended-release niacin 1000 mg daily in 167 patients with known CHD and an HDL-cholesterol concentration below 45 mg/dL who were already receiving a statin showed patients treated with niacin experienced a mean increase in HDL-cholesterol of 8 mg/dL (0.21 mmol/L) and had a trend toward decreased progression of carotid intima-media thickness.<ref name="pmid15537681">{{cite journal| author=Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA| title=Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. | journal=Circulation | year= 2004 | volume= 110 | issue= 23 | pages= 3512-7 | pmid=15537681 | doi=10.1161/01.CIR.0000148955.19792.8D | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15537681 }} </ref>
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| * Infusion of apo A-I Milano : A pilot trial of intravenous therapy with recombinant apo A-1 Milano phospholipid complexes (ETC-216) was conducted in 57 patients who were within two weeks of onset of an acute coronary syndrome and showed a significant decrease in the mean percentage of coronary artery volume occupied by atheroma.<ref name="pmid7923682">{{cite journal| author=Ameli S, Hultgardh-Nilsson A, Cercek B, Shah PK, Forrester JS, Ageland H et al.| title=Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. | journal=Circulation | year= 1994 | volume= 90 | issue= 4 | pages= 1935-41 | pmid=7923682 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7923682 }} </ref>
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| * Infusion of reconstituted HDL : The ERASE trial on 183 CHD patients with reconstituted human HDL estimating the coronary atheroma volume was associated with a high incidence of liver function test abnormalities, which led to early study discontinuation in this group.<ref name="pmid17387133">{{cite journal| author=Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM et al.| title=Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. | journal=JAMA | year= 2007 | volume= 297 | issue= 15 | pages= 1675-82 | pmid=17387133 | doi=10.1001/jama.297.15.jpc70004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17387133 }} </ref>
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| * Theobromine study : Theobromine, as found in cocoa, has been associated with an increase in HDL-C and has been associated with a decreased risk of cardiovascular disease in observational studies.<ref name="pmid17344491">{{cite journal| author=Baba S, Osakabe N, Kato Y, Natsume M, Yasuda A, Kido T et al.| title=Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. | journal=Am J Clin Nutr | year= 2007 | volume= 85 | issue= 3 | pages= 709-17 | pmid=17344491 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17344491 }} </ref><ref name="pmid23595874">{{cite journal| author=Neufingerl N, Zebregs YE, Schuring EA, Trautwein EA| title=Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial. | journal=Am J Clin Nutr | year= 2013 | volume= 97 | issue= 6 | pages= 1201-9 | pmid=23595874 | doi=10.3945/ajcn.112.047373 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23595874 }} </ref>
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| * CETP inhibition : Torcetrapib, anacetrapib, evacetrapib, and dalcetrapib inhibit cholesteryl ester transfer protein (CETP) and raise HDL-cholesterol levels. Though investigation of torcetrapib and dalcetrapib has stopped due to the finding of an increased risk of cardiovascular events in the ILLUMINATE trial and dal-OUTCOMES, Anacetrapib in the DEFINE study has shown to increase HDL, but the overall safety in CHD is yet to be proved.<ref name="pmid21082868">{{cite journal| author=Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM et al.| title=Safety of anacetrapib in patients with or at high risk for coronary heart disease. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 25 | pages= 2406-15 | pmid=21082868 | doi=10.1056/NEJMoa1009744 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21082868 }} </ref>
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| ====Current Trends====
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| =====HDL-P as an alternative to HDL-C=====
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| * Few studies have evaluated HDL-P associations with CHD risk, and we know of none that evaluated it jointly with HDL-C and LDL-P.
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| ** Multi-Ethnic Study of Atherosclerosis (MESA) study on multi-ethnic men and women without clinical CVD or lipid-lowering medication use at baseline showed HDL-C (cholestrol content of HDL) associations with carotid intima-media thickness (cIMT) and its CHD incidence to be substantially attenuated by adjusting for atherogenic lipoproteins, particularly LDL-P. In contrast, HDL-P (particle concentrations) associations with cIMT and incident CHD were relatively unaffected by adjusting for atherogenic lipoproteins, HDL-C, and mean HDL particle size.<ref name="pmid22796256">{{cite journal| author=Mackey RH, Greenland P, Goff DC, Lloyd-Jones D, Sibley CT, Mora S| title=High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). | journal=J Am Coll Cardiol | year= 2012 | volume= 60 | issue= 6 | pages= 508-16 | pmid=22796256 | doi=10.1016/j.jacc.2012.03.060 | pmc=PMC3411890 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22796256 }} </ref>
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| ** Multiple Risk Factor Intervention Trial (MRFIT) : Low HDL-P levels predicted CHD death over 18 years of follow-up among men with metabolic syndrome in the MRFIT cohort. In the MRFIT, high levels of HDL-P and especially medium HDL-P were associated with a reduced risk of CHD<ref name="pmid17011566">{{cite journal| author=Kuller LH, Grandits G, Cohen JD, Neaton JD, Prineas R, Multiple Risk Factor Intervention Trial Research Group| title=Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome. | journal=Atherosclerosis | year= 2007 | volume= 195 | issue= 1 | pages= 122-8 | pmid=17011566 | doi=10.1016/j.atherosclerosis.2006.09.001 | pmc=PMC2098784 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17011566 }} </ref>
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| ** EPIC-Norfolk Study : In this study lower HDL-P levels predicted incident events independent of age, sex, apoB, triglycerides, mean HDL particle size, smoking, myeloperoxidase, paraoxonase-1, and hsCRP.<ref name="pmid19153411">{{cite journal| author=El Harchaoui K, Arsenault BJ, Franssen R, Després JP, Hovingh GK, Stroes ES et al.| title=High-density lipoprotein particle size and concentration and coronary risk. | journal=Ann Intern Med | year= 2009 | volume= 150 | issue= 2 | pages= 84-93 | pmid=19153411 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19153411 }} </ref>
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| ** VA-HIT Study : In this study lower levels of baseline and on-trial HDL-P predicted CHD events among men with low HDL-C randomized to gemfibrozil vs. placebo.<ref name="pmid16534013">{{cite journal| author=Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, McNamara JR et al.| title=Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. | journal=Circulation | year= 2006 | volume= 113 | issue= 12 | pages= 1556-63 | pmid=16534013 | doi=10.1161/CIRCULATIONAHA.105.565135 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16534013 }} </ref>
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| ** Women’s Health Study : This large study showed the inverse association of HDL-P with incident CVD over an 11 year follow-up was not significant.<ref name="pmid19204302">{{cite journal| author=Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM| title=Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. | journal=Circulation | year= 2009 | volume= 119 | issue= 7 | pages= 931-9 | pmid=19204302 | doi=10.1161/CIRCULATIONAHA.108.816181 | pmc=PMC2663974 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19204302 }} </ref> However, HDL-P was inversely associated with incident CHD among postmenopausal women in the Women’s Health Initiative Hormone Trial, adjusted for treatment arm, and the inverse association of HDL-P with cIMT was statistically significant for women in the current study.<ref name="pmid18599797">{{cite journal| author=Hsia J, Otvos JD, Rossouw JE, Wu L, Wassertheil-Smoller S, Hendrix SL et al.| title=Lipoprotein particle concentrations may explain the absence of coronary protection in the women's health initiative hormone trials. | journal=Arterioscler Thromb Vasc Biol | year= 2008 | volume= 28 | issue= 9 | pages= 1666-71 | pmid=18599797 | doi=10.1161/ATVBAHA.108.170431 | pmc=PMC2701372 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18599797 }} </ref>
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| =====Challenging HDL-C hypothesis=====
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| * The theory of HDL-C levels to predict CVD risk has been challenged in clinical trials where LDL-C has reached a very low level. The recent failure of the large the following trials raised questions about the benefits of this therapeutic strategy to raise HDL.<ref name="pmid22294855">{{cite journal| author=Cook C, Sheets C| title=Clinical equipoise and personal equipoise: two necessary ingredients for reducing bias in manual therapy trials. | journal=J Man Manip Ther | year= 2011 | volume= 19 | issue= 1 | pages= 55-7 | pmid=22294855 | doi=10.1179/106698111X12899036752014 | pmc=PMC3172958 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22294855 }} </ref>
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| ** In the ILLUMINATE study adverse events caused by torcetrapib were likely to represent off-target effects of the drug but raised question about the value of raising HDL-C. Attempts to decrease cardiovascular risk in statin-treated patients with the CETP inhibitor torcetrapib have failed, despite an increase in HDL-C by 72%. The failure of torcetrapib and dalcetrapib may be explained by off-target adverse effects and weak CETP inhibition, respectively.<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165 }} </ref>
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| ** The dal-OUTCOMES trial using dalcetrapib raised HDL-C by 31 to 40% but had no effects on cardiovascular events.<ref name="pmid23126252">{{cite journal| author=Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J et al.| title=Effects of dalcetrapib in patients with a recent acute coronary syndrome. | journal=N Engl J Med | year= 2012 | volume= 367 | issue= 22 | pages= 2089-99 | pmid=23126252 | doi=10.1056/NEJMoa1206797 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23126252 }} </ref>
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| ** Niacin, used at pharmacological doses (up to 2gm/day), led to a neutrality of results in terms of cardiovascular outcomes in the AIM-HIGM. This study was also criticized for having a relatively small sample size.<ref name="pmid22085343">{{cite journal| author=AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P et al.| title=Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. | journal=N Engl J Med | year= 2011 | volume= 365 | issue= 24 | pages= 2255-67 | pmid=22085343 | doi=10.1056/NEJMoa1107579 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22085343 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22508748 Review in: Ann Intern Med. 2012 Apr 17;156(8):JC4-08] </ref>
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| ** The recent failure of the large (>25,000 subjects) HPS2-THRIVE trial with niacin raised questions about the benefits of this therapeutic strategy to raise HDL..<ref name="pmid23444397">{{cite journal| author=HPS2-THRIVE Collaborative Group| title=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. | journal=Eur Heart J | year= 2013 | volume= 34 | issue= 17 | pages= 1279-91 | pmid=23444397 | doi=10.1093/eurheartj/eht055 | pmc=PMC3640201 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23444397 }} </ref>
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| Attention is focusing on specific HDL subfractions and on biomarkers of HDL function (reflecting its pleiotropic effects) as potential therapeutic targets for cardiovascular protection. Such studies have reinforced the need for validated assays of HDL function rather than static measurement of HDL-C. A variety of HDL/apoA-I-based therapies are currently under investigation. To better understand the relation between HDL and atherosclerosis, we should consider developing and measuring better markers of HDL function, rather than the cholesterol mass within HDL particles.
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| ==References==
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| {{Reflist|2}}
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| {{Lipopedia}}
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| [[Category:Lipopedia]]
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| [[Category:Lipid disorders]]
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| [[Category:Cardiology]]
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| [[Category:Lipoproteins]]
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