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| __NOTOC__
| | #Redirect [[High density lipoprotein natural history, complications and prognosis]] |
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| {{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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| ===Coronary Heart Disease===
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| ====Cardio Protective Effect====
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| The mature spherical HDL particle is composed of enzymes, such as paraoxonase, platelet-activating factor acetylhydrolase (PAF-AH or Lp-PLA2), lecithin-cholesterol acyl transferase (LCAT), [[apolipoproteins]] (apoA-I and apoA-II), lipid molecules, such as [[triglyceride]], [[cholesterol]], [[phospholipids]] and bioactive lipid molecules, including sphingosine 1-phosphate (S1P) and related lysosphingolipids.<ref name="pmid18716026">{{cite journal| author=Scanu AM, Edelstein C| title=HDL: bridging past and present with a look at the future. | journal=FASEB J | year= 2008 | volume= 22 | issue= 12 | pages= 4044-54 | pmid=18716026 | doi=10.1096/fj.08-117150 | pmc=PMC2614615 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18716026 }} </ref> The antiatherogenic actions of HDL-C are complex and are mediated through the some of the aforementioned components. HDL-C plays a major role in reverse cholesterol transport, mobilizing cholesterol from the periphery to the liver. In addition, cardioprotective effects of HDL-C include endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects and maintenance of low blood viscosity through a permissive action on red cell deformability.
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| * Apo A-I :
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| **Several studies have shown that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. Macrophage cholesterol efflux is a process whereby excess cholesterol in cells and in atherosclerotic plaques is removed. Current data indicate that the plasma HDL associated apolipoprotein M (apoM) levels modulate the ability of plasma to mobilize cellular cholesterol and protects against experimental atherosclerosis.<ref name="pmid24046869">{{cite journal| author=Elsøe S, Christoffersen C, Luchoomun J, Turner S, Nielsen LB| title=Apolipoprotein M promotes mobilization of cellular cholesterol in vivo. | journal=Biochim Biophys Acta | year= 2013 | volume= 1831 | issue= 7 | pages= 1287-92 | pmid=24046869 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24046869 }} </ref>
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| **Animal models have shown that the somatic gene transfer of human apo A-I can prevent the development of atherosclerosis or reverse preexisting atherosclerosis or its role in the anti-endotoxin function of HDL.<ref name="pmid9884386">{{cite journal| author=Benoit P, Emmanuel F, Caillaud JM, Bassinet L, Castro G, Gallix P et al.| title=Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. | journal=Circulation | year= 1999 | volume= 99 | issue= 1 | pages= 105-10 | pmid=9884386 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9884386 }} </ref><ref name="pmid10534470">{{cite journal| author=Tangirala RK, Tsukamoto K, Chun SH, Usher D, Puré E, Rader DJ| title=Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. | journal=Circulation | year= 1999 | volume= 100 | issue= 17 | pages= 1816-22 | pmid=10534470 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10534470 }} </ref><ref name="pmid11804981">{{cite journal| author=Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G et al.| title=Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. | journal=Circulation | year= 2002 | volume= 105 | issue= 3 | pages= 290-2 | pmid=11804981 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11804981 }} </ref><ref name="pmid15188057">{{cite journal| author=Ma J, Liao XL, Lou B, Wu MP| title=Role of apolipoprotein A-I in protecting against endotoxin toxicity. | journal=Acta Biochim Biophys Sin (Shanghai) | year= 2004 | volume= 36 | issue= 6 | pages= 419-24 | pmid=15188057 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15188057 }} </ref>
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| **Current data suggest that, ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in [[endothelial cells]], and the scavenger receptor B type 1 mediate multiple intracellular signaling pathways as well as the efflux of cholesterol and/or oxysterols in response to apoA-I/HDL.<ref name="pmid22488423">{{cite journal| author=Prosser HC, Ng MK, Bursill CA| title=The role of cholesterol efflux in mechanisms of endothelial protection by HDL. | journal=Curr Opin Lipidol | year= 2012 | volume= 23 | issue= 3 | pages= 182-9 | pmid=22488423 | doi=10.1097/MOL.0b013e328352c4dd | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22488423 }} </ref>
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| * ApoA-I/SR-BI :
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| **[[HDL]] also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling.<ref name="pmid20089950">{{cite journal| author=Saddar S, Mineo C, Shaul PW| title=Signaling by the high-affinity HDL receptor scavenger receptor B type I. | journal=Arterioscler Thromb Vasc Biol | year= 2010 | volume= 30 | issue= 2 | pages= 144-50 | pmid=20089950 | doi=10.1161/ATVBAHA.109.196170 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20089950 }} </ref> Recent studies have shown that SR-BI is also expressed in endothelial cells (ECs) and mediates HDL-associated apoA-I-induced stimulation of endothelial nitric oxide synthase (eNOS), inhibition of monocyte adhesion to endothelial cells, vasorelaxation, and re-endothelialization following perivascular electric injury.<ref name="pmid18753704">{{cite journal| author=Okajima F, Sato K, Kimura T| title=Anti-atherogenic actions of high-density lipoprotein through sphingosine 1-phosphate receptors and scavenger receptor class B type I. | journal=Endocr J | year= 2009 | volume= 56 | issue= 3 | pages= 317-34 | pmid=18753704 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18753704 }} </ref><ref name="pmid17574123">{{cite journal| author=Mineo C, Shaul PW| title=Role of high-density lipoprotein and scavenger receptor B type I in the promotion of endothelial repair. | journal=Trends Cardiovasc Med | year= 2007 | volume= 17 | issue= 5 | pages= 156-61 | pmid=17574123 | doi=10.1016/j.tcm.2007.03.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17574123 }} </ref><ref name="pmid20105136">{{cite journal| author=Kimura T, Sato K, Tomura H, Okajima F| title=Cross-talk between exogenous statins and endogenous high-density lipoprotein in anti-inflammatory and anti-atherogenic actions. | journal=Endocr Metab Immune Disord Drug Targets | year= 2010 | volume= 10 | issue= 1 | pages= 8-15 | pmid=20105136 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20105136 }} </ref>
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| **It is also proposed that the anti-apoptotic and proliferative effects of apoA-I are mediated through F1-ATPase-catalysed ADP production and subsequent P2Y13 receptor stimulation, thus contributing to the atheroprotective functions.<ref name="pmid19372457">{{cite journal| author=Radojkovic C, Genoux A, Pons V, Combes G, de Jonge H, Champagne E et al.| title=Stimulation of cell surface F1-ATPase activity by apolipoprotein A-I inhibits endothelial cell apoptosis and promotes proliferation. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 7 | pages= 1125-30 | pmid=19372457 | doi=10.1161/ATVBAHA.109.187997 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19372457 }} </ref>
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| ** HDL promotes the production of signaling molecule [[nitric oxide]] (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). Studies have shown the ability of recombiant HDL (rHDL) or reconstituted apoA-I with phospholipids but without cholesterol to stimulate eNOS activation and to repair damaged endothelium and to enhance ischemia-induced angiogenesis through stimulation of endothelial progenitor cells (EPCs) in vivo.<ref name="pmid16528007">{{cite journal| author=Tso C, Martinic G, Fan WH, Rogers C, Rye KA, Barter PJ| title=High-density lipoproteins enhance progenitor-mediated endothelium repair in mice. | journal=Arterioscler Thromb Vasc Biol | year= 2006 | volume= 26 | issue= 5 | pages= 1144-9 | pmid=16528007 | doi=10.1161/01.ATV.0000216600.37436.cf | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16528007 }} </ref><ref name="pmid17272742">{{cite journal| author=Sumi M, Sata M, Miura S, Rye KA, Toya N, Kanaoka Y et al.| title=Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis. | journal=Arterioscler Thromb Vasc Biol | year= 2007 | volume= 27 | issue= 4 | pages= 813-8 | pmid=17272742 | doi=10.1161/01.ATV.0000259299.38843.64 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17272742 }} </ref> The enhancement of SR-BI expression by [[simvastatin]] results in enhancement of HDL- and rHDL-induced eNOS activation and subsequent inhibition of adhesion molecule expression, which supports the role of SR-BI in HDL-induced anti-inflammatory actions.<ref name="pmid18981156">{{cite journal| author=Kimura T, Mogi C, Tomura H, Kuwabara A, Im DS, Sato K et al.| title=Induction of scavenger receptor class B type I is critical for simvastatin enhancement of high-density lipoprotein-induced anti-inflammatory actions in endothelial cells. | journal=J Immunol | year= 2008 | volume= 181 | issue= 10 | pages= 7332-40 | pmid=18981156 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18981156 }} </ref>
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| * Sphingosine 1-phosphate (S1P) :
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| **Fractionation by density gradient centrifugation has shown that sphingosine 1-phosphate (S1P) is concentrated in the lipoprotein fraction with a rank order of [[HDL]] > [[LDL]] > [[VLDL]], and to a lesser extent, in the lipoprotein-deficient albumin fraction when expressed as pmol/mg protein. Thus, HDL-S1P has been proposed to mediate a variety of HDL-induced actions.<ref name="pmid11104690">{{cite journal| author=Murata N, Sato K, Kon J, Tomura H, Yanagita M, Kuwabara A et al.| title=Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. | journal=Biochem J | year= 2000 | volume= 352 Pt 3 | issue= | pages= 809-15 | pmid=11104690 | doi= | pmc=PMC1221521 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11104690 }} </ref>
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| **S1P has been shown to improve ischemia/reperfusion-induced injury in vivo and in vitro with inhibition of inflammatory [[neutrophil]] recruitment and cardiomyocyte [[apoptosis]] in the infarcted area.<ref name="pmid12003800">{{cite journal| author=Jin ZQ, Zhou HZ, Zhu P, Honbo N, Mochly-Rosen D, Messing RO et al.| title=Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKC epsilon knockout mouse hearts. | journal=Am J Physiol Heart Circ Physiol | year= 2002 | volume= 282 | issue= 6 | pages= H1970-7 | pmid=12003800 | doi=10.1152/ajpheart.01029.2001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12003800 }} </ref><ref name="pmid19247197">{{cite journal| author=Karliner JS| title=Sphingosine kinase and sphingosine 1-phosphate in cardioprotection. | journal=J Cardiovasc Pharmacol | year= 2009 | volume= 53 | issue= 3 | pages= 189-97 | pmid=19247197 | doi=10.1097/FJC.0b013e3181926706 | pmc=PMC2835544 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19247197 }} </ref><ref name="pmid16982942">{{cite journal| author=Theilmeier G, Schmidt C, Herrmann J, Keul P, Schäfers M, Herrgott I et al.| title=High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. | journal=Circulation | year= 2006 | volume= 114 | issue= 13 | pages= 1403-9 | pmid=16982942 | doi=10.1161/CIRCULATIONAHA.105.607135 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16982942 }} </ref>
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| **The pro-atherogenic adhesion molecule expression elicited by S1P disappears in the presence of physiological concentrations of HDL in a manner sensitive to SR-BI.<ref name="pmid17046831">{{cite journal| author=Kimura T, Tomura H, Mogi C, Kuwabara A, Damirin A, Ishizuka T et al.| title=Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells. | journal=J Biol Chem | year= 2006 | volume= 281 | issue= 49 | pages= 37457-67 | pmid=17046831 | doi=10.1074/jbc.M605823200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17046831 }} </ref>
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| * Paraoxonase 1 (PON1) :
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| ** Paraoxonase is an esterase enzyme that is synthesized by the [[liver]] and it is associated with HDL in the blood. There is considerable evidence to prove the fact that the antioxidant activity of HDL is largely due to the PON1 which is located on it.<ref name="pmid23908111">{{cite journal| author=Huang Y, Wu Z, Riwanto M, Gao S, Levison BS, Gu X et al.| title=Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. | journal=J Clin Invest | year= 2013 | volume= 123 | issue= 9 | pages= 3815-28 | pmid=23908111 | doi=10.1172/JCI67478 | pmc=PMC3754253 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23908111 }} </ref> A atorvastatin study demonstrating HDL-related antioxidant activity as well as lipid-lowering properties proves PON1 action of prevents LDL oxidation and inactivates LDL-derived oxidized phospholipids.<ref name="pmid24024670">{{cite journal| author=Sozer V, Uzun H, Gelisgen R, Kaya M, Kalayci R, Tabak O et al.| title=The effects of atorvastatin on oxidative stress in L-NAME-treated rats. | journal=Scand J Clin Lab Invest | year= 2013 | volume= | issue= | pages= | pmid=24024670 | doi=10.3109/00365513.2013.828241 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24024670 }} </ref>
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| ** Studies have suggested that serum antioxidant activity of PON1 was an important factor which provided protection from oxidative stress and lipid peroxidation in [[CAD]].<ref name="pmid23998046">{{cite journal| author=Shekhanawar M, Shekhanawar SM, Krisnaswamy D, Indumati V, Satishkumar D, Vijay V et al.| title=The role of 'paraoxonase-1 activity' as an antioxidant in coronary artery diseases. | journal=J Clin Diagn Res | year= 2013 | volume= 7 | issue= 7 | pages= 1284-7 | pmid=23998046 | doi=10.7860/JCDR/2013/5144.3118 | pmc=PMC3749616 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23998046 }} </ref> Thus, evaluating the effects of PON 1 for CAD patients may be promising in the treatment and prognosis of CAD.
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| ** Studies have shown pomegranate to be a potent anti-atherogenic agent because of its antioxidants which have the ability to increase the activity of the HDL-associated paraoxonase 1 (PON1), which breaks down harmful oxidized lipids in lipoproteins, in macrophages, and in atherosclerotic plaques.<ref name="pmid23908863">{{cite journal| author=Aviram M, Rosenblat M| title=Pomegranate for your cardiovascular health. | journal=Rambam Maimonides Med J | year= 2013 | volume= 4 | issue= 2 | pages= e0013 | pmid=23908863 | doi=10.5041/RMMJ.10113 | pmc=PMC3678830 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23908863 }} </ref>
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| * Indirect cardioprotective actions :
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| ** It includes, HDL capacities to promote pancreatic β-cell [[insulin]] secretion, to protect pancreatic β cells from apoptosis, and to enhance [[glucose]] uptake by skeletal muscle myocytes. Studies have shown that inhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre-incubated with LDL was restored by co-treatment with HDL.<ref name="pmid23437184">{{cite journal| author=Carey AL, Siebel AL, Reddy-Luthmoodoo M, Natoli AK, D'Souza W, Meikle PJ et al.| title=Skeletal muscle insulin resistance associated with cholesterol-induced activation of macrophages is prevented by high density lipoprotein. | journal=PLoS One | year= 2013 | volume= 8 | issue= 2 | pages= e56601 | pmid=23437184 | doi=10.1371/journal.pone.0056601 | pmc=PMC3578940 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23437184 }} </ref>
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| ** In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and [[platelets]] HDL is antithrombotic. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of [[thrombosis]].<ref name="pmid16763172">{{cite journal| author=Mineo C, Deguchi H, Griffin JH, Shaul PW| title=Endothelial and antithrombotic actions of HDL. | journal=Circ Res | year= 2006 | volume= 98 | issue= 11 | pages= 1352-64 | pmid=16763172 | doi=10.1161/01.RES.0000225982.01988.93 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16763172 }} </ref>
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| ** Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties.<ref name="pmid23023510">{{cite journal| author=Mineo C, Shaul PW| title=Novel biological functions of high-density lipoprotein cholesterol. | journal=Circ Res | year= 2012 | volume= 111 | issue= 8 | pages= 1079-90 | pmid=23023510 | doi=10.1161/CIRCRESAHA.111.258673 | pmc=PMC3500606 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23023510 }} </ref>
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| Many of these numerous actions of HDL have been observed not only in cell culture and animal models but also in human studies, and assessments of these functions are now being applied to patient populations to better-elucidate which actions of HDL may contribute to its cardioprotective potential and how they can be quantified and targeted. Further work on the many mechanisms of HDL action promises to reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health. 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 negative association that is strong, graded, and coherent across population studied, has led to the development of the “HDL-C hypothesis,” which proposes that pharmacological intervention to raise HDL-C will reduce cardiovascular risk.
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| Recently studies have found 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 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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| =====Challening 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:Lipoproteins]]
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