Modified and Dysfunctional Lipoproteins in Atherosclerosis: Effectors or Biomarkers?

Author(s): Alexander N. Orekhov*, Igor A. Sobenin.

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 9 , 2019

  Journal Home
Translate in Chinese
Submit Manuscript
Submit Proposal


Atherosclerotic diseases are the leading cause of mortality in industrialized countries. Correspondingly, studying the pathogenesis of atherosclerosis and developing new methods for its diagnostic and treatment remain in the focus of current medicine and health care. This review aims to discuss the mechanistic role of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in atherogenesis. In particular, the generally accepted hypothesis about the key role of oxidized LDL in atherogenesis is questioned, and an alternative concept of multiple modification of LDL is presented. The fundamental question discussed in this review is whether LDL and HDL are effectors or biomarkers, or both. This is important for understanding whether lipoproteins are a therapeutic target or just diagnostic indicators.

Keywords: Atherosclerosis, biomarker, desialylation, dysfunctional high-density lipoprotein, effector, modified low-density lipoprotein, multiple modification.

Dubland, J.A.; Francis, G.A. So much cholesterol: the unrecognized importance of smooth muscle cells in atherosclerotic foam cell formation. Curr. Opin. Lipidol., 2016, 27(2), 155-161.
Yu, X.H.; Fu, Y.C.; Zhang, D.W.; Yin, K.; Tang, C.K. Foam cells in atherosclerosis. Clin. Chim. Acta, 2013, 424, 245-252.
Yuan, Y.; Li, P.; Ye, J. Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis. Protein Cell, 2012, 3(3), 173-181.
Krauss, R.M. Lipoprotein subfractions and cardiovascular disease risk. Curr. Opin. Lipidol., 2010, 21(4), 305-311.
Orekhov, A.N.; Tertov, V.V.; Mukhin, D.N.; Koteliansky, V.E.; Glukhova, M.A.; Frid, M.G.; Sukhova, G.K.; Khashimov, K.A.; Smirnov, V.N. Insolubilization of low density lipoprotein induces cholesterol accumulation in cultured subendothelial cells of human aorta. Atherosclerosis, 1989, 79(1), 59-70.
Arnold, K.; Arnhold, J.; Zschörnig, O.; Wiegel, D.; Krumbiegel, M. Characterization of chemical modifications of surface properties of low density lipoproteins. Biomed. Biochim. Acta, 1989, 48(10), 735-742.
Desrumaux, C.; Athias, A.; Masson, D.; Gambert, P.; Lallemant, C.; Lagrost, L. Influence of the electrostatic charge of lipoprotein particles on the activity of the human plasma phospholipid transfer protein. J. Lipid Res., 1998, 39(1), 131-142.
Fogelman, A.M.; Shechter, I.; Seager, J.; Hokom, M.; Child, J.S.; Edwards, P.A. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc. Natl. Acad. Sci. USA, 1980, 77(4), 2214-2218.
Goldstein, J.L.; Ho, Y.K.; Basu, S.K.; Brown, M.S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc. Natl. Acad. Sci. USA, 1979, 76(1), 333-337.
Haberland, M.E.; Olch, C.L.; Folgelman, A.M. Role of lysines in mediating interaction of modified low density lipoproteins with the scavenger receptor of human monocyte macrophages. J. Biol. Chem., 1984, 259(18), 11305-11311.
Steinbrecher, U.P.; Parthasarathy, S.; Leake, D.S.; Witztum, J.L.; Steinberg, D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc. Natl. Acad. Sci. USA, 1984, 81(12), 3883-3887.
Vanderyse, L.; Devreese, A.M.; Baert, J.; Vanloo, B.; Lins, L.; Ruysschaert, J.M.; Rosseneu, M. Structural and functional properties of apolipoprotein B in chemically modified low density lipoproteins. Atherosclerosis, 1992, 97(2-3), 187-199.
Palinski, W.; Rosenfeld, M.E.; Ylä-Herttuala, S.; Gurtner, G.C.; Socher, S.S.; Butler, S.W.; Parthasarathy, S.; Carew, T.E.; Steinberg, D.; Witztum, J.L. Low density lipoprotein undergoes oxidative modification in vivo. Proc. Natl. Acad. Sci. USA, 1989, 86(4), 1372-1376.
Tertov, V.V.; Kaplun, V.V.; Dvoryantsev, S.N.; Orekhov, A.N. Apolipoprotein B-bound lipids as a marker for evaluation of low density lipoprotein oxidation in vivo. Biochem. Biophys. Res. Commun., 1995, 214(2), 608-613.
Avogaro, P.; Bon, G.B.; Cazzolato, G. Presence of a modified low density lipoprotein in humans. Arteriosclerosis, 1988, 8(1), 79-87.
Orekhov, A.N.; Bobryshev, Y.V.; Sobenin, I.A.; Melnichenko, A.A.; Chistiakov, D.A. Modified low density lipoprotein and lipoprotein-containing circulating immune complexes as diagnostic and prognostic biomarkers of atherosclerosis and type 1 diabetes macrovascular disease. Int. J. Mol. Sci., 2014, 15(7), 12807-12841.
Tertov, V.V.; Bittolo-Bon, G.; Sobenin, I.A.; Cazzolato, G.; Orekhov, A.N.; Avogaro, P. Naturally occurring modified low density lipoproteins are similar if not identical: more electronegative and desialylated lipoprotein subfractions. Exp. Mol. Pathol., 1995, 62(3), 166-172.
Orekhov, A.N.; Ivanova, E.A.; Melnichenko, A.A.; Sobenin, I.A. Circulating desialylated low density lipoprotein. Cor Vasa, 2017, 159(2), e149-e156.
Trpkovic, A.; Resanovic, I.; Stanimirovic, J.; Radak, D.; Mousa, S.A.; Cenic-Milosevic, D.; Jevremovic, D.; Isenovic, E.R. Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases. Crit. Rev. Clin. Lab. Sci., 2015, 52(2), 70-85.
Arai, H. Oxidative modification of lipoproteins. Subcell. Biochem., 2014, 77, 103-114.
Steinberg, D.; Witztum, J.L. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 2010, 30(12), 2311-2316.
Fukuchi, M.; Watanabe, J.; Kumagai, K.; Baba, S.; Shinozaki, T.; Miura, M.; Kagaya, Y.; Shirato, K. Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary arteries. Lab. Invest., 2002, 82(10), 1437-1447.
Itabe, H.; Obama, T.; Kato, R. The dynamics of oxidized LDL during atherogenesis. J. Lipids, 2011, 2011, 418313.
Ylä-Herttuala, S.; Palinski, W.; Rosenfeld, M.E.; Steinberg, D.; Witztum, J.L. Lipoproteins in normal and atherosclerotic aorta. Eur. Heart J., 1990, 11(Suppl. E), 88-99.
Orekhov, A.N.; Tertov, V.V.; Kabakov, A.E.; Adamova, I.Y.; Pokrovsky, S.N.; Smirnov, V.N. Autoantibodies against modified low density lipoprotein. Nonlipid factor of blood plasma that stimulates foam cell formation. Arterioscler. Thromb., 1991, 11(2), 316-326.
Ivanova, E.A.; Bobryshev, Y.V.; Orekhov, A.N. LDL electronegativity index: a potential novel index for predicting cardiovascular disease. Vasc. Health Risk Manag., 2015, 11, 525-532.
Ivanova, E.A.; Myasoedova, V.A.; Melnichenko, A.A.; Grechko, A.V.; Orekhov, A.N. Small dense low-density lipoprotein as biomarker for atherosclerotic diseases. Oxid. Med. Cell. Longev., 2017, 2017, 1273042.
Ference, B.A.; Ginsberg, H.N.; Graham, I.; Ray, K.K.; Packard, C.J.; Bruckert, E.; Hegele, R.A.; Krauss, R.M.; Raal, F.J.; Schunkert, H.; Watts, G.F.; Borén, J.; Fazio, S.; Horton, J.D.; Masana, L.; Nicholls, S.J.; Nordestgaard, B.G.; van de Sluis, B.; Taskinen, M.R.; Tokgözoglu, L.; Landmesser, U.; Laufs, U.; Wiklund, O.; Stock, J.K.; Chapman, M.J.; Catapano, A.L. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European atherosclerosis society consensus panel. Eur. Heart J., 2017, 38(32), 2459-2472.
Akyol, S.; Lu, J.; Akyol, O.; Akcay, F.; Armutcu, F.; Ke, L.Y.; Chen, C.H. The role of electronegative low-density lipoprotein in cardiovascular diseases and its therapeutic implications. Trends Cardiovasc. Med., 2017, 27(4), 239-246.
Orekhov, A.N.; Sobenin, I.A. Modified lipoproteins as biomarkers of atherosclerosis. Front. Biosci., 2018, 23, 1422-1444.
Tertov, V.V.; Sobenin, I.A.; Orekhov, A.N.; Jaakkola, O.; Solakivi, T.; Nikkari, T. Characteristics of low density lipoprotein isolated from circulating immune complexes. Atherosclerosis, 1996, 122(2), 191-199.
Orekhov, A.N.; Tertov, V.V.; Mukhin, D.N.; Koteliansky, V.E.; Glukhova, M.A.; Khashimov, K.A.; Smirnov, V.N. Association of low-density lipoprotein with particulate connective tissue matrix components enhances cholesterol accumulation in cultured subendothelial cells of human aorta. Biochim. Biophys. Acta, 1987, 928(3), 251-258.
Garcia-Rios, A.; Nikolic, D.; Perez-Martinez, P.; Lopez-Miranda, J.; Rizzo, M.; Hoogeveen, R.C. LDL and HDL subfractions, dysfunctional HDL: treatment options. Curr. Pharm. Des., 2014, 20(40), 6249-6255.
J. S.. Monette; P. M., Hutchins; G. E., Ronsein; J., Wimberger; A. D., Irwin; C., Tang; J. D., Sara; B., Shao; T., Vaisar; A., Lerman; J. W. Heinecke patients with coronary endothelial dysfunction have impaired cholesterol efflux capacity and reduced HDL particle concentration. Circ. Res., 2016, 119(1), 83-90.
Ogura, M.; Hori, M.; Harada-Shiba, M. Association between cholesterol efflux capacity and atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol., 2016, 36(1), 181-188.
Rosenson, R.S.; Brewer, H.B., Jr; Ansell, B.J.; Barter, P.; Chapman, M.J.; Heinecke, J.W.; Kontush, A.; Tall, A.R.; Webb, N.R. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat. Rev. Cardiol., 2016, 13(1), 48-60.
Khera, A.V.; Cuchel, M.; de la Llera-Moya, M.; Rodrigues, A.; Burke, M.F.; Jafri, K.; French, B.C.; Phillips, J.A.; Mucksavage, M.L.; Wilensky, R.L.; Mohler, E.R.; Rothblat, G.H.; Rader, D.J. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med., 2011, 364(2), 127-135.
Rohatgi, A.; Khera, A.; Berry, J.D.; Givens, E.G.; Ayers, C.R.; Wedin, K.E.; Neeland, I.J.; Yuhanna, I.S.; Rader, D.R.; de Lemos, J.A.; Shaul, P.W. HDL cholesterol efflux capacity and incident cardiovascular events. N. Engl. J. Med., 2014, 371(25), 2383-2393.
Frikke-Schmidt, R.; Nordestgaard, B.G.; Schnohr, P.; Steffensen, R.; Tybjaerg-Hansen, A. Mutation in ABCA1 predicted risk of ischemic heart disease in the Copenhagen City Heart Study Population. J. Am. Coll. Cardiol., 2005, 46(8), 1516-1520.
Santos, R.D.; Asztalos, B.F.; Martinez, L.R.; Miname, M.H.; Polisecki, E.; Schaefer, E.J. Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. J. Clin. Lipidol., 2008, 2(4), 237-247.
Frikke-Schmidt, R.; Nordestgaard, B.G.; Jensen, G.B.; Steffensen, R.; Tybjaerg-Hansen, A. Genetic variation in ABCA1 predicts ischemic heart disease in the general population. Arterioscler. Thromb. Vasc. Biol., 2008, 28(1), 180-186.
Bochem, A.E.; van Wijk, D.F.; Holleboom, A.G.; Duivenvoorden, R.; Motazacker, M.M.; Dallinga-Thie, G.M.; de Groot, E.; Kastelein, J.J.; Nederveen, A.J.; Hovingh, G.K.; Stroes, E.S. ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden. Eur. Heart J., 2013, 34(4), 286-291.
Frikke-Schmidt, R.; Nordestgaard, B.G.; Stene, M.C.; Sethi, A.A.; Remaley, A.T.; Schnohr, P.; Grande, P.; Tybjaerg-Hansen, A. 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(21), 2524-2532.
Johannsen, T.H.; Kamstrup, P.R.; Andersen, R.V.; Jensen, G.B.; Sillesen, H.; Tybjaerg-Hansen, A.; Nordestgaard, B.G. Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease. J. Clin. Endocrinol. Metab., 2009, 94(4), 1264-1273.
Haase, C.L.; Tybjærg-Hansen, A.; Grande, P.; Frikke-Schmidt, R. Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J. Clin. Endocrinol. Metab., 2010, 95(12), E500-E510.
Voight, B.F.; Peloso, G.M.; Orho-Melander, M.; Frikke-Schmidt, R.; Barbalic, M.; Jensen, M.K.; Hindy, G.; Hólm, H.; Ding, E.L.; Johnson, T.; Schunkert, H.; Samani, N.J.; Clarke, R.; Hopewell, J.C.; Thompson, J.F.; Li, M.; Thorleifsson, G.; Newton-Cheh, C.; Musunuru, K.; Pirruccello, J.P.; Saleheen, D.; Chen, L.; Stewart, A.; Schillert, A.; Thorsteinsdottir, U.; Thorgeirsson, G.; Anand, S.; Engert, J.C.; Morgan, T.; Spertus, J.; Stoll, M.; Berger, K.; Martinelli, N.; Girelli, D.; McKeown, P.P.; Patterson, C.C.; Epstein, S.E.; Devaney, J.; Burnett, M.S.; Mooser, V.; Ripatti, S.; Surakka, I.; Nieminen, M.S.; Sinisalo, J.; Lokki, M.L.; Perola, M.; Havulinna, A.; de Faire, U.; Gigante, B.; Ingelsson, E.; Zeller, T.; Wild, P.; de Bakker, P.I.; Klungel, O.H.; Maitland-van der Zee, A.H.; Peters, B.J.; de Boer, A.; Grobbee, D.E.; Kamphuisen, P.W.; Deneer, V.H.; Elbers, C.C.; Onland-Moret, N.C.; Hofker, M.H.; Wijmenga, C.; Verschuren, W.M.; Boer, J.M.; van der Schouw, Y.T.; Rasheed, A.; Frossard, P.; Demissie, S.; Willer, C.; Do, R.; Ordovas, J.M.; Abecasis, G.R.; Boehnke, M.; Mohlke, K.L.; Daly, M.J.; Guiducci, C.; Burtt, N.P.; Surti, A.; Gonzalez, E.; Purcell, S.; Gabriel, S.; Marrugat, J.; Peden, J.; Erdmann, J.; Diemert, P.; Willenborg, C.; König, I.R.; Fischer, M.; Hengstenberg, C.; Ziegler, A.; Buysschaert, I.; Lambrechts, D.; Van de Werf, F.; Fox, K.A.; El Mokhtari, N.E.; Rubin, D.; Schrezenmeir, J.; Schreiber, S.; Schäfer, A.; Danesh, J.; Blankenberg, S.; Roberts, R.; McPherson, R.; Watkins, H.; Hall, A.S.; Overvad, K.; Rimm, E.; Boerwinkle, E.; Tybjaerg-Hansen, A.; Cupples, L.A.; Reilly, M.P.; Melander, O.; Mannucci, P.M.; Ardissino, D.; Siscovick, D.; Elosua, R.; Stefansson, K.; O’Donnell, C.J.; Salomaa, V.; Rader, D.J.; Peltonen, L.; Schwartz, S.M.; Altshuler, D.; Kathiresan, S. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet, 2012, 380(9841), 572-580.
Haase, C.L.; Tybjærg-Hansen, A.; Qayyum, A.A.; Schou, J.; Nordestgaard, B.G.; Frikke-Schmidt, R. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J. Clin. Endocrinol. Metab., 2012, 97(2), E248-E256.
Do, R.; Willer, C.J.; Schmidt, E.M.; Sengupta, S.; Gao, C.; Peloso, G.M.; Gustafsson, S.; Kanoni, S.; Ganna, A.; Chen, J.; Buchkovich, M.L.; Mora, S.; Beckmann, J.S.; Bragg-Gresham, J.L.; Chang, H.Y.; Demirkan, A.; Den Hertog, H.M.; Donnelly, L.A.; Ehret, G.B.; Esko, T.; Feitosa, M.F.; Ferreira, T.; Fischer, K.; Fontanillas, P.; Fraser, R.M.; Freitag, D.F.; Gurdasani, D.; Heikkilä, K.; Hyppönen, E.; Isaacs, A.; Jackson, A.U.; Johansson, A.; Johnson, T.; Kaakinen, M.; Kettunen, J.; Kleber, M.E.; Li, X.; Luan, J.; Lyytikäinen, L.P.; Magnusson, P.K.; Mangino, M.; Mihailov, E.; Montasser, M.E.; Müller-Nurasyid, M.; Nolte, I.M.; O’Connell, J.R.; Palmer, C.D.; Perola, M.; Petersen, A.K.; Sanna, S.; Saxena, R.; Service, S.K.; Shah, S.; Shungin, D.; Sidore, C.; Song, C.; Strawbridge, R.J.; Surakka, I.; Tanaka, T.; Teslovich, T.M.; Thorleifsson, G.; Van den Herik, E.G.; Voight, B.F.; Volcik, K.A.; Waite, L.L.; Wong, A.; Wu, Y.; Zhang, W.; Absher, D.; Asiki, G.; Barroso, I.; Been, L.F.; Bolton, J.L.; Bonnycastle, L.L.; Brambilla, P.; Burnett, M.S.; Cesana, G.; Dimitriou, M.; Doney, A.S.; Döring, A.; Elliott, P.; Epstein, S.E.; Eyjolfsson, G.I.; Gigante, B.; Goodarzi, M.O.; Grallert, H.; Gravito, M.L.; Groves, C.J.; Hallmans, G.; Hartikainen, A.L.; Hayward, C.; Hernandez, D.; Hicks, A.A.; Holm, H.; Hung, Y.J.; Illig, T.; Jones, M.R.; Kaleebu, P.; Kastelein, J.J.; Khaw, K.T.; Kim, E.; Klopp, N.; Komulainen, P.; Kumari, M.; Langenberg, C.; Lehtimäki, T.; Lin, S.Y.; Lindström, J.; Loos, R.J.; Mach, F.; McArdle, W.L.; Meisinger, C.; Mitchell, B.D.; Müller, G.; Nagaraja, R.; Narisu, N.; Nieminen, T.V.; Nsubuga, R.N.; Olafsson, I.; Ong, K.K.; Palotie, A.; Papamarkou, T.; Pomilla, C.; Pouta, A.; Rader, D.J.; Reilly, M.P.; Ridker, P.M.; Rivadeneira, F.; Rudan, I.; Ruokonen, A.; Samani, N.; Scharnagl, H.; Seeley, J.; Silander, K.; Stančáková, A.; Stirrups, K.; Swift, A.J.; Tiret, L.; Uitterlinden, A.G.; van Pelt, L.J.; Vedantam, S.; Wainwright, N.; Wijmenga, C.; Wild, S.H.; Willemsen, G.; Wilsgaard, T.; Wilson, J.F.; Young, E.H.; Zhao, J.H.; Adair, L.S.; Arveiler, D.; Assimes, T.L.; Bandinelli, S.; Bennett, F.; Bochud, M.; Boehm, B.O.; Boomsma, D.I.; Borecki, I.B.; Bornstein, S.R.; Bovet, P.; Burnier, M.; Campbell, H.; Chakravarti, A.; Chambers, J.C.; Chen, Y.D.; Collins, F.S.; Cooper, R.S.; Danesh, J.; Dedoussis, G.; de Faire, U.; Feranil, A.B.; Ferrières, J.; Ferrucci, L.; Freimer, N.B.; Gieger, C.; Groop, L.C.; Gudnason, V.; Gyllensten, U.; Hamsten, A.; Harris, T.B.; Hingorani, A.; Hirschhorn, J.N.; Hofman, A.; Hovingh, G.K.; Hsiung, C.A.; Humphries, S.E.; Hunt, S.C.; Hveem, K.; Iribarren, C.; Järvelin, M.R.; Jula, A.; Kähönen, M.; Kaprio, J.; Kesäniemi, A.; Kivimaki, M.; Kooner, J.S.; Koudstaal, P.J.; Krauss, R.M.; Kuh, D.; Kuusisto, J.; Kyvik, K.O.; Laakso, M.; Lakka, T.A.; Lind, L.; Lindgren, C.M.; Martin, N.G.; März, W.; McCarthy, M.I.; McKenzie, C.A.; Meneton, P.; Metspalu, A.; Moilanen, L.; Morris, A.D.; Munroe, P.B.; Njølstad, I.; Pedersen, N.L.; Power, C.; Pramstaller, P.P.; Price, J.F.; Psaty, B.M.; Quertermous, T.; Rauramaa, R.; Saleheen, D.; Salomaa, V.; Sanghera, D.K.; Saramies, J.; Schwarz, P.E.; Sheu, W.H.; Shuldiner, A.R.; Siegbahn, A.; Spector, T.D.; Stefansson, K.; Strachan, D.P.; Tayo, B.O.; Tremoli, E.; Tuomilehto, J.; Uusitupa, M.; van Duijn, C.M.; Vollenweider, P.; Wallentin, L.; Wareham, N.J.; Whitfield, J.B.; Wolffenbuttel, B.H.; Altshuler, D.; Ordovas, J.M.; Boerwinkle, E.; Palmer, C.N.; Thorsteinsdottir, U.; Chasman, D.I.; Rotter, J.I.; Franks, P.W.; Ripatti, S.; Cupples, L.A.; Sandhu, M.S.; Rich, S.S.; Boehnke, M.; Deloukas, P.; Mohlke, K.L.; Ingelsson, E.; Abecasis, G.R.; Daly, M.J.; Neale, B.M.; Kathiresan, S. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet., 2013, 45(11), 1345-1352.
Holmes, M.V.; Asselbergs, F.W.; Palmer, T.M.; Drenos, F.; Lanktree, M.B.; Nelson, C.P.; Dale, C.E.; Padmanabhan, S.; Finan, C.; Swerdlow, D.I.; Tragante, V.; van Iperen, E.P.; Sivapalaratnam, S.; Shah, S.; Elbers, C.C.; Shah, T.; Engmann, J.; Giambartolomei, C.; White, J.; Zabaneh, D.; Sofat, R.; McLachlan, S.; Doevendans, P.A.; Balmforth, A.J.; Hall, A.S.; North, K.E.; Almoguera, B.; Hoogeveen, R.C.; Cushman, M.; Fornage, M.; Patel, S.R.; Redline, S.; Siscovick, D.S.; Tsai, M.Y.; Karczewski, K.J.; Hofker, M.H.; Verschuren, W.M.; Bots, M.L.; van der Schouw, Y.T.; Melander, O.; Dominiczak, A.F.; Morris, R.; Ben-Shlomo, Y.; Price, J.; Kumari, M.; Baumert, J.; Peters, A.; Thorand, B.; Koenig, W.; Gaunt, T.R.; Humphries, S.E.; Clarke, R.; Watkins, H.; Farrall, M.; Wilson, J.G.; Rich, S.S.; de Bakker, P.I.; Lange, L.A.; Davey Smith, G.; Reiner, A.P.; Talmud, P.J.; Kivimäki, M.; Lawlor, D.A.; Dudbridge, F.; Samani, N.J.; Keating, B.J.; Hingorani, A.D.; Casas, J.P. Mendelian randomization of blood lipids for coronary heart disease. Eur. Heart J., 2015, 36(9), 539-550.
Helgadottir, A.; Gretarsdottir, S.; Thorleifsson, G.; Hjartarson, E.; Sigurdsson, A.; Magnusdottir, A.; Jonasdottir, A.; Kristjansson, H.; Sulem, P.; Oddsson, A.; Sveinbjornsson, G.; Steinthorsdottir, V.; Rafnar, T.; Masson, G.; Jonsdottir, I.; Olafsson, I.; Eyjolfsson, G.I.; Sigurdardottir, O.; Daneshpour, M.S.; Khalili, D.; Azizi, F.; Swinkels, D.W.; Kiemeney, L.; Quyyumi, A.A.; Levey, A.I.; Patel, R.S.; Hayek, S.S.; Gudmundsdottir, I.J.; Thorgeirsson, G.; Thorsteinsdottir, U.; Gudbjartsson, D.F.; Holm, H.; Stefansson, K. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat. Genet., 2016, 48(6), 634-639.
Brunham, L.R. HDL as a Causal Factor in Atherosclerosis: Insights from Human Genetics. Curr. Atheroscler. Rep., 2016, 18(12), 71.
Glomset, J.A. The plasma lecithins: cholesterol acyltransferase reaction. J. Lipid Res., 1968, 9(2), 155-167.
Camont, L.; Chapman, M.J.; Kontush, A. Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol. Med., 2011, 17(10), 594-603.
Mineo, C.; Shaul, P.W. Novel biological functions of high-density lipoprotein cholesterol. Circ. Res., 2012, 111(8), 1079-1090.
Annema, W.; von Eckardstein, A.; Kovanen, P.T. HDL and atherothrombotic vascular disease. Handb. Exp. Pharmacol., 2015, 224, 369-403.
Phillips, M.C. Molecular mechanisms of cellular cholesterol efflux. J. Biol. Chem., 2014, 289(35), 24020-24029.
Wang, N.; Lan, D.; Chen, W.; Matsuura, F.; Tall, A.R. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc. Natl. Acad. Sci. USA, 2004, 101(26), 9774-9779.
Larrede, S.; Quinn, C.M.; Jessup, W.; Frisdal, E.; Olivier, M.; Hsieh, V.; Kim, M.J.; Van Eck, M.; Couvert, P.; Carrie, A.; Giral, P.; Chapman, M.J.; Guerin, M.; Le Goff, W. Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arterioscler. Thromb. Vasc. Biol., 2009, 29(11), 1930-1936.
Tarling, E.J.; Edwards, P.A. ATP binding cassette transporter G1 (ABCG1) is an intracellular sterol transporter. Proc. Natl. Acad. Sci. USA, 2011, 108(49), 19719-19724.
Liu, Y.; Tang, C. Regulation of ABCA1 functions by signaling pathways. Biochim. Biophys. Acta, 2012, 1821(3), 522-529.
Michell, D.L.; Vickers, K.C. Lipoprotein carriers of microRNAs. Biochim. Biophys. Acta, 2016, 1861(12 Pt B), 2069-2074.
Vickers, K.C.; Palmisano, B.T.; Shoucri, B.M.; Shamburek, R.D.; Remaley, A.T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol., 2011, 13(4), 423-433.
Temel, R.E.; Brown, J.M. A new model of reverse cholesterol transport: enTICEing strategies to stimulate intestinal cholesterol excretion. Trends Pharmacol. Sci., 2015, 36(7), 440-451.
Jakulj, L.; van Dijk, T.H.; de Boer, J.F.; Kootte, R.S.; Schonewille, M.; Paalvast, Y.; Boer, T.; Bloks, V.W.; Boverhof, R.; Nieuwdorp, M.; Beuers, U.H.; Stroes, E.S.; Groen, A.K. Transintestinal cholesterol transport is active in mice and humans and controls Ezetimibe-induced fecal neutral sterol excretion. Cell Metab., 2016, 24(6), 783-794.
Rader, D.J.; Hovingh, G.K. HDL and cardiovascular disease. Lancet, 2014, 384(9943), 618-625.
Bruckert, E.; Labreuche, J.; Amarenco, P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis, 2010, 210(2), 353-361.
Bruckert, E.; Labreuche, J.; Amarenco, P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis, 2010, 210(2), 353-361.
Jun, M.; Foote, C.; Lv, J.; Neal, B.; Patel, A.; Nicholls, S.J.; Grobbee, D.E.; Cass, A.; Chalmers, J.; Perkovic, V. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet, 2010, 375(9729), 1875-1884.
Administration FaD. Withdrawal of approval of indications related to the coadministration with statins in applications for niacin extended-release tablets and fenofibric acid delayed- release capsules. Fed. Reg., 2016, 81(74)
Administration FaD. Withdrawal of approval of new drug applications for Advicor and Simcor. Fed. Reg., 2016, 81(74)
Li, C.; Zhang, W.; Zhou, F.; Chen, C.; Zhou, L.; Li, Y.; Liu, L.; Pei, F.; Luo, H.; Hu, Z.; Cai, J.; Zeng, C. Cholesteryl ester transfer protein inhibitors in the treatment of dyslipidemia: a systematic review and meta-analysis. PLoS One, 2013, 8(10), e77049.
März, W.; Kleber, M.E.; Scharnagl, H.; Speer, T.; Zewinger, S.; Ritsch, A.; Parhofer, K.G.; von Eckardstein, A.; Landmesser, U.; Laufs, U. HDL cholesterol: reappraisal of its clinical relevance. Clin. Res. Cardiol., 2017, 106(9), 663-675. Epub ahead of print
Bowman, L.; Hopewell, J.C.; Chen, F.; Wallendszus, K.; Stevens, W.; Collins, R.; Wiviott, S.D.; Cannon, C.P.; Braunwald, E.; Sammons, E.; Landray, M.J. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med., 2017, 377(13), 1217-1227.
Silbernagel, G.; Schöttker, B.; Appelbaum, S.; Scharnagl, H.; Kleber, M.E.; Grammer, T.B.; Ritsch, A.; Mons, U.; Holleczek, B.; Goliasch, G.; Niessner, A.; Boehm, B.O.; Schnabel, R.B.; Brenner, H.; Blankenberg, S.; Landmesser, U.; März, W. High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur. Heart J., 2013, 34(46), 3563-3571.
Annema, W.; von Eckardstein, A. Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy. Transl. Res., 2016, 173, 30-57.
Nissen, S.E.; Tsunoda, T.; Tuzcu, E.M.; Schoenhagen, P.; Cooper, C.J.; Yasin, M.; Eaton, G.M.; Lauer, M.A.; Sheldon, W.S.; Grines, C.L.; Halpern, S.; Crowe, T.; Blankenship, J.C.; Kerensky, R. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA, 2003, 290(17), 2292-2300.
Tardif, J.C.; Grégoire, J.; L’Allier, P.L.; Ibrahim, R.; Lespérance, J.; Heinonen, T.M.; Kouz, S.; Berry, C.; Basser, R.; Lavoie, M.A.; Guertin, M.C.; Rodés-Cabau, J. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA, 2007, 297(15), 1675-1682.
Waksman, R.; Torguson, R. Kent. K. M.; Pichard, A. D.; Suddath, W. O.; Satler, L. F.; Martin, B. D.; Perlman, T. J.; Maltais, J. A.; Weissman, N. J.; Fitzgerald, P. J.; Brewer, H. B. Jr. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous deliidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J. Am. Coll. Cardiol., 2010, 55(24), 2727-2735.
Shamburek, R.D.; Bakker-Arkema, R.; Auerbach, B.J.; Krause, B.R.; Homan, R.; Amar, M.J.; Freeman, L.A.; Remaley, A.T. Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement. J. Clin. Lipidol., 2016, 10(2), 356-367.
Gordon, T.; Castelli, W.P.; Hjortland, M.C.; Kannel, W.B.; Dawber, T.R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med., 1977, 62(5), 707-714.
Genest, J.J.; McNamara, J.R.; Salem, D.N.; Schaefer, E.J. Prevalence of risk factors in men with premature coronary artery disease. Am. J. Cardiol., 1991, 67(15), 1185-1189.
Di Angelantonio, E.; Sarwar, N.; Perry, P.; Kaptoge, S.; Ray, K.K.; Thompson, A.; Wood, A.M.; Lewington, S.; Sattar, N.; Packard, C.J.; Collins, R.; Thompson, S.G.; Danesh, J. Major lipids, apolipoproteins, and risk of vascular disease. JAMA, 2009, 302(18), 1993-2000.
van der Steeg, W.A.; Holme, I.; Boekholdt, S.M.; Larsen, M.L.; Lindahl, C.; Stroes, E.S.; Tikkanen, M.J.; Wareham, N.J.; Faergeman, O.; Olsson, A.G.; Pedersen, T.R.; Khaw, K.T.; Kastelein, J.J. 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), 634-642.
Bowe, B.; Xie, Y.; Xian, H.; Balasubramanian, S.; Zayed, M.A.; Al-Aly, Z. High density lipoprotein cholesterol and the risk of all-cause mortality among U.S. veterans. Clin. J. Am. Soc. Nephrol., 2016, 11(10), 1784-1793.
Bartlett, J.; Predazzi, I.M.; Williams, S.M.; Bush, W.S.; Kim, Y.; Havas, S.; Toth, P.P.; Fazio, S.; Miller, M. Is isolated low high-density lipoprotein cholesterol a cardiovascular disease risk factor? New insights from the Framingham offspring study. Circ. Cardiovasc. Qual. Outcomes, 2016, 9(3), 206-212.
Di Angelantonio, E.; Gao, P.; Pennells, L.; Kaptoge, S.; Caslake, M.; Thompson, A.; Butterworth, A.S.; Sarwar, N.; Wormser, D.; Saleheen, D.; Ballantyne, C.M.; Psaty, B.M.; Sundström, J.; Ridker, P.M.; Nagel, D.; Gillum, R.F.; Ford, I.; Ducimetiere, P.; Kiechl, S.; Koenig, W.; Dullaart, R.P.; Assmann, G.; D’Agostino, R.B., Sr; Dagenais, G.R.; Cooper, J.A.; Kromhout, D.; Onat, A.; Tipping, R.W.; Gómez-de-la-Cámara, A.; Rosengren, A.; Sutherland, S.E.; Gallacher, J.; Fowkes, F.G.; Casiglia, E.; Hofman, A.; Salomaa, V.; Barrett-Connor, E.; Clarke, R.; Brunner, E.; Jukema, J.W.; Simons, L.A.; Sandhu, M.; Wareham, N.J.; Khaw, K.T.; Kauhanen, J.; Salonen, J.T.; Howard, W.J.; Nordestgaard, B.G.; Wood, A.M.; Thompson, S.G.; Boekholdt, S.M.; Sattar, N.; Packard, C.; Gudnason, V.; Danesh, J. Lipid-related markers and cardiovascular disease prediction. JAMA, 2012, 307(23), 2499-2506.
Chapman, M.J.; Ginsberg, H.N.; Amarenco, P.; Andreotti, F.; Borén, J.; Catapano, A.L.; Descamps, O.S.; Fisher, E.; Kovanen, P.T.; Kuivenhoven, J.A.; Lesnik, P.; Masana, L.; Nordestgaard, B.G.; Ray, K.K.; Reiner, Z.; Taskinen, M.R.; Tokgözoglu, L.; Tybjærg-Hansen, A.; Watts, G.F. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart J., 2011, 32(11), 1345-1361.
Brotman, D.J.; Walker, E.; Lauer, M.S.; O’Brien, R.G. In search of fewer independent risk factors. Arch. Intern. Med., 2005, 165(2), 138-145.
Stone, N.J.; Robinson, J.G.; Lichtenstein, A.H.; Bairey Merz, C.N.; Blum, C.B.; Eckel, R.H.; Goldberg, A.C.; Gordon, D.; Levy, D.; Lloyd-Jones, D.M.; McBride, P.; Schwartz, J.S.; Shero, S.T.; Smith, S.C., Jr; Watson, K.; Wilson, P.W.; Eddleman, K.M.; Jarrett, N.M.; LaBresh, K.; Nevo, L.; Wnek, J.; Anderson, J.L.; Halperin, J.L.; Albert, N.M.; Bozkurt, B.; Brindis, R.G.; Curtis, L.H.; DeMets, D.; Hochman, J.S.; Kovacs, R.J.; Ohman, E.M.; Pressler, S.J.; Sellke, F.W.; Shen, W.K.; Smith, S.C., Jr; Tomaselli, G.F. 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.
Catapano, A.L.; Graham, I.; De Backer, G.; Wiklund, O.; Chapman, M.J.; Drexel, H.; Hoes, A.W.; Jennings, C.S.; Landmesser, U.; Pedersen, T.R.; Reiner, Ž.; Riccardi, G.; Taskinen, M.R.; Tokgozoglu, L.; Verschuren, W.M.M.; Vlachopoulos, C.; Wood, D.A.; Zamorano, J.L.; Cooney, M.T. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur. Heart J., 2016, 37(39), 2999-3058.
Graham, I.M.; Catapano, A.L.; Wong, N.D. Current guidelines on prevention with a focus on dyslipidemias. Cardiovasc. Diagn. Ther., 2017, 7(Suppl. 1), S4-S10.
Kooter, A.J.; Kostense, P.J.; Groenewold, J.; Thijs, A.; Sattar, N.; Smulders, Y.M. Integrating information from novel risk factors with calculated risks: the critical impact of risk factor prevalence. Circulation, 2011, 124(6), 741-745.
Ioannidis, J.P.; Tzoulaki, I. Minimal and null predictive effects for the most popular blood biomarkers of cardiovascular disease. Circ. Res., 2012, 110(5), 658-662.
Gilstrap, L.G.; Wang, T.J. Biomarkers and cardiovascular risk assessment for primary prevention: an update. Clin. Chem., 2012, 58(1), 72-82.
Tzoulaki, I.; Siontis, K.C.; Evangelou, E.; Ioannidis, J.P. Bias in associations of emerging biomarkers with cardiovascular disease. JAMA Intern. Med., 2013, 173(8), 664-671.
Tsimikas, S.; Miller, Y.I. Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr. Pharm. Des., 2011, 17(1), 27-37.
Leopold, J.A. Antioxidants and coronary artery disease: from pathophysiology to preventive therapy. Coron. Artery Dis., 2015, 26(2), 176-183.
Lichtenstein, A.H.; Appel, L.J.; Brands, M.; Carnethon, M.; Daniels, S.; Franch, H.A.; Franklin, B.; Kris-Etherton, P.; Harris, W.S.; Howard, B.; Karanja, N.; Lefevre, M.; Rudel, L.; Sacks, F.; Van Horn, L.; Winston, M.; Wylie-Rosett, J. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation, 2006, 114(1), 82-96.
Sampson, U.K.; Fazio, S.; Linton, M.F. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr. Atheroscler. Rep., 2012, 14(1), 1-10.
Fulcher, J.; O’Connell, R.; Voysey, M.; Emberson, J.; Blackwell, L.; Mihaylova, B.; Simes, J.; Collins, R.; Kirby, A.; Colhoun, H.; Braunwald, E.; La Rosa, J.; Pedersen, T.R.; Tonkin, A.; Davis, B.; Sleight, P.; Franzosi, M.G.; Baigent, C.; Keech, A. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet, 2015, 385(9976), 1397-1405.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 1994, 344(8934), 1383-1389.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med., 1998, 339(19), 1349-1357.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet, 2002, 360(9326), 7-22.
Downs, J.R.; Clearfield, M.; Weis, S.; Whitney, E.; Shapiro, D.R.; Beere, P.A.; Langendorfer, A.; Stein, E.A.; Kruyer, W.; Gotto, A.M., Jr Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA, 1998, 279(20), 1615-1622.
Sacks, F.M.; Pfeffer, M.A.; Moye, L.A.; Rouleau, J.L.; Rutherford, J.D.; Cole, T.G.; Brown, L.; Warnica, J.W.; Arnold, J.M.; Wun, C.C.; Davis, B.R.; Braunwald, E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N. Engl. J. Med., 1996, 335(14), 1001-1009.
Shepherd, J.; Cobbe, S.M.; Ford, I.; Isles, C.G.; Lorimer, A.R.; MacFarlane, P.W.; McKillop, J.H.; Packard, C.J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med., 1995, 333(20), 1301-1307.
Baigent, C.; Keech, A.; Kearney, P.M.; Blackwell, L.; Buck, G.; Pollicino, C.; Kirby, A.; Sourjina, T.; Peto, R.; Collins, R.; Simes, R. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 2005, 366(9493), 1267-1278.
Chen, Z.; Peto, R.; Collins, R.; MacMahon, S.; Lu, J.; Li, W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ, 1991, 303(6797), 276-282.
Sacks, F.M.; Tonkin, A.M.; Shepherd, J.; Braunwald, E.; Cobbe, S.; Hawkins, C.M.; Keech, A.; Packard, C.; Simes, J.; Byington, R.; Furberg, C.D. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation, 2000, 102(16), 1893-1900.
Collinson, P. Evidence and cost effectiveness requirements for recommending new biomarkers. EJIFCC, 2015, 26(3), 183-189.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [1512 - 1524]
Pages: 13
DOI: 10.2174/0929867325666180320121137
Price: $58

Article Metrics

PDF: 24