Download PDF
Semin Vasc Med 2002; 02(3): 335-344
DOI: 10.1055/s-2002-35404
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

A Critical Evaluation of the Role of Lp(a) in Cardiovascular Disease: Can Lp(a) Be Useful in Risk Assessment?

Santica M. Marcovina1 , Marlys L. Koschinsky2
  • 1Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA
  • 2Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
Further Information

Publication History

Publication Date:
13 November 2002 (online)

    Permissions and Reprints

ABSTRACT

Lp(a) is a structurally complex particle which resembles LDL, but which also contains the distinctive glycoprotein apo(a). Apo(a) is characterized by a variable number of repeated kringle domains, which gives rise to differently-sized Lp(a) isoforms in the population. Although epidemiological studies indicate that elevated Lp(a) concentration and/or small apo(a) isoform sizes increase the risk of coronary heart disease (CHD), a causal role for Lp(a) in CHD remains unproven. This is largely due to the difficulty in establishing a relevant animal model to probe Lp(a) function, and the lack of intervention studies in which Lp(a) concentrations are lowered and outcomes followed. The accumulation of apo(a)/Lp(a) in arterial lesions has provided the rationale for numerous in vitro studies aimed at dissecting its function in this milieu. These studies have resulted in the proposal of numerous proatherogenic, prothrombotic and antifibrinolytic roles for both native and modified apo(a)/Lp(a). Although characterization of Lp(a) in the general population is not presently justified, Lp(a) analysis in patients at risk for CHD may be warranted.

KEYWORDS

Lipoprotein(a) - apolipoprotein(a) - coronary heart disease - atherosclerosis

REFERENCES

  • 1 Berg K. A new serum type system in man: the Lp system.  Acta Pathol Microbiol Scand . 1963;  59 362-382
    PubMedSearch in Google Scholar
  • 2 Cheng S W, Ting A C, Wong J. Lipoprotein(a) and its relationship to risk factors and severity of atherosclerotic peripheral vascular disease.  Eur Vasc Endovasc Surg . 1997;  14 17-23
    PubMedSearch in Google Scholar
  • 3 Peng D Q, Zhao S P, Wang J L. Lipoprotein(a) and apolipoprotein E epsilon 4 as independent risk factors for ischemic stroke.  J Cardiovasc Risk . 1999;  6 1-6
    PubMedSearch in Google Scholar
  • 4 Marcovina S M, Hegele R A, Koschinsky M L. Lipoprotein(a) and coronary heart disease risk.  Curr Cardiol Rep . 1999;  1 105-111
    PubMedSearch in Google Scholar
  • 5 Marcovina S M, Koschinsky M L. Lipoprotein(a) as a risk factor for coronary artery disease.  Am J Cardiol . 1998;  82 57U-66U
    CrossrefPubMedSearch in Google Scholar
  • 6 Craig W Y, Neveux L M, Palomaki G E. Lipoprotein(a) as a risk factor for ischemic heart disease: meta-analysis of prospective studies.  Clin Chem . 1998;  44 2301-2306
    PubMedSearch in Google Scholar
  • 7 Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies.  Circulation . 2000;  102 1082-1085
    CrossrefPubMedSearch in Google Scholar
  • 8 Armstrong V W, Cremer P, Eberle E. The association between serum Lp(a) concentrations and angiographically-assessed coronary atherosclerosis. Dependence on serum LDL levels.  Atherosclerosis . 1986;  62 249-257
    PubMedSearch in Google Scholar
  • 9 Maher V M, Brown B G, Marcovina S M. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).  JAMA . 1995;  274 1771-1774
    CrossrefPubMedSearch in Google Scholar
  • 10 Hopkins P N, Wu L L, Hunt S C. Lipoprotein(a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease.  Arterioscler Thromb Vasc Biol . 1997;  17 2783-2792
    PubMedSearch in Google Scholar
  • 11 Cantin B, Gagnon F, Moorjani S. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men?.  <~>The Quebec Cardiovascular Study. J Am Coll Cardiol . 1998;  31 519-525
    PubMedSearch in Google Scholar
  • 12 Kronenberg F, Kronenberg M F, Kiechl S. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck Study.  Circulation . 1999;  100 1154-1160
    PubMedSearch in Google Scholar
  • 13 van Eckardstein A, Schulte H, Cullen P. Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk.  J Am Coll Cardiol . 2001;  37 434-439
    CrossrefPubMedSearch in Google Scholar
  • 14 Marcovina S M, Koschinsky M L. Lipoprotein(a): Structure, measurement, and clinical significance. In: Rifai, N, Warnick, GR, Dominiczak MH, eds. Handbook of Lipoprotein Testing, Ed 2. Washington, DC AACC Press 345-385
  • 15 Angelin B. Therapy for lowering lipoprotein(a) levels.  Curr Opin Lipidol . 1997;  8 337-341
    PubMedSearch in Google Scholar
  • 16 Albers J J, Kennedy H, Marcovina S M. Evidence that Lp(a) contains one molecule of apo(a) and one molecule of apo B: evaluation of amino acid analysis data.  J Lipid Res . 1996;  37 192-196
    PubMedSearch in Google Scholar
  • 17 Koschinsky M L, Côté G P, Gabel B R. Identification of the cysteine residue in apolipoprotein(a) that mediates extracellular coupling with apolipoprotein B-100.  J Biol Chem . 1993;  268 19819-19825
    PubMedSearch in Google Scholar
  • 18 Callow M J, Rubin E M. Site-specific mutagenesis demonstrates that cysteine 4326 of apolipoprotein B is required for covalent linkage with apolipoprotein(a) in vivo J Biol Chem .  1995;  270 23914-23917
    PubMedSearch in Google Scholar
  • 19 Trieu V N, McConathy W J. A two-step model for lipoprotein(a) formation.  J Biol Chem . 1995;  270 15471-15474
    CrossrefPubMedSearch in Google Scholar
  • 20 Gabel B R, Koschinsky M L. Sequences within apolipoprotein(a) kringle IV types 6-8 bind directly to low-density lipoprotein and mediate noncovalent association of apolipoprotein(a) with apolipoprotein B-100.  Biochemistry . 1998;  37 7892-7898
    CrossrefPubMedSearch in Google Scholar
  • 21 Becker L, McLeod, R, Marcovina S M. Identification of a critical lysine residue in apolipoprotein B-100 that mediates noncovalent interaction with apolipoprotein(a) (in press).  J Biol Chem.
    PubMed
  • 22 Xu S. Apolipoprotein(a) binds to low density lipoprotein at two distant sites in lipoprotein(a).  Biochemistry . 1998;  37 9284-9294
    CrossrefPubMedSearch in Google Scholar
  • 23 White A L, Rainwater D L, Lanford R E. Intracellular maturation of apolipoprotein(a) and assembly of lipoprotein(a) in primary baboon hepatocytes.  J Lipid Res . 1993;  34 509-517
    PubMedSearch in Google Scholar
  • 24 Frank S, Krasznai K, Durovic S. High-level expression of various apolipoprotein(a) isoforms by ``transferrinfection'': the role of kringle IV sequences in the extracellular association with low-density lipoprotein.  Biochemistry . 1994;  33 12329-12339
    CrossrefPubMedSearch in Google Scholar
  • 25 White A L, Lanford R E. Cell surface assembly of lipoprotein(a) in primary cultures of baboon hepatocytes.  J Biol Chem . 1994;  269 28716-28723
    PubMedSearch in Google Scholar
  • 26 Fless G M, ZumMallen M E, Scanu A M. Physicochemical properties of apolipoprotein(a) and lipoprotein(a-) derived from the dissociation of human plasma lipoprotein(a).  J Biol Chem . 1986;  261 8712-8718
    PubMedSearch in Google Scholar
  • 27 Kraft H G, Menzel H J, Hopplichler F. Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis.  J Clin Invest . 1989;  83 137-140
    PubMedSearch in Google Scholar
  • 28 McLean J W, Tomlinson J E, Kuang W-J. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.  Nature . 1987;  330 132-137
    CrossrefPubMedSearch in Google Scholar
  • 29 Lackner C, Cohen J C, Hobbs H H. Molecular definition of the extreme size polymorphism in apolipoprotein(a).  Hum Mol Genet . 1993;  2 933-940
    CrossrefPubMedSearch in Google Scholar
  • 30 van der Hoek Y Y, Wittekoek M E, Beisiegel U. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably-sized isoforms.  Hum Mol Genet . 1993;  2 361-366
    PubMedSearch in Google Scholar
  • 31 Sangrar W, Marcovina S M, Koschinsky M L. Expression and characterization of apolipoprotein(a) kringle IV types 1, 2 and 10 in mammalian cells.  Protein Eng . 1993;  7 723-731
    PubMedSearch in Google Scholar
  • 32 Gabel B R, May L F, Marcovina S M. Lipoprotein(a) Assembly. Quantitative assessment of the role of apo(a) kringle IV types 2-10 in particle formation.  Arterioscler Thromb Vasc Biol . 1996;  16 1559-1567
    PubMedSearch in Google Scholar
  • 33 Ernst A, Helmhold M, Brunner C. Identification of two functionally distinct lysine-binding sites in kringle 37 and in kringles 32-36 of human apolipoprotein(a).  J Biol Chem . 1994;  270 6227-6234
    PubMedSearch in Google Scholar
  • 34 Utermann G, Menzel H J, Kraft H G. Lp(a) glycoprotein phenotypes: inheritance and relation to Lp(a)-lipoprotein concentrations in plasma.  J Clin Invest . 1987;  80 458-465
    PubMedSearch in Google Scholar
  • 35 Brunner C, Lobentanz E M, Petho-Schramm A. The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells.  J Biol Chem . 1996;  13 32403-32410
    PubMedSearch in Google Scholar
  • 36 Gaw A, Brown E A, Ford I. Impact of apo(a) length polymorphism and the control of plasma Lp(a) concentrations: evidence for a threshold effect.  Arterioscler Thromb Vasc Biol . 1998;  18 1870-1876
    PubMedSearch in Google Scholar
  • 37 Rath M, Niendorf A, Reblin T. Detection and quantification of lipoprotein(a) in the arterial wall of 107 coronary bypass patients.  Arteriosclerosis . 1989;  9 579-592
    PubMedSearch in Google Scholar
  • 38 Fan J, Shimoyamada H, Sun H. Transgenic rabbits expressing human apolipoprotein(a) develop more extensive atherosclerotic lesions in response to a cholesterol-rich diet.  Arterioscler Thromb Vasc Biol . 2001;  21 88-94
    PubMedSearch in Google Scholar
  • 39 Dangas G, Mehran R, Harpel P C. Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation.  J Am Coll Cardiol . 1998;  32 2035-2042
    CrossrefPubMedSearch in Google Scholar
  • 40 Hoff H F, O'Neil J, Yashiro A. Partial characterization of lipoproteins containing apo(a) in human atherosclerotic lesions.  J Lipid Res . 1993;  34 789-798
    PubMedSearch in Google Scholar
  • 41 Scanu A M. Proteolytic modifications of lipoprotein(a): potential relevance to its postulated atherothrombogenic role.  J Investig Med . 1998;  46 359-363
    PubMedSearch in Google Scholar
  • 42 Edelstein C, Italia J A, Scanu A M. Polymorphonuclear cells isolated from human peripheral blood cleave lipoprotein(a) and apolipoprotein(a) at multiple interkringle sites via the enzyme elastase.  J Biol Chem . 1997;  272 11079-11087
    CrossrefPubMedSearch in Google Scholar
  • 43 Edelstein C, Shapiro S D, Klezovitch O. Matrix metalloelastase, MMP-12, cleaves human apolipoprotein(a) in the linker region between kringles IV-4 and IV-5.  J Biol Chem . 1999;  274 10019-10023
    CrossrefPubMedSearch in Google Scholar
  • 44 Scanu A M, Edelstein C, Klezovitch O. Dominant role of the C-terminal domain in the binding of apolipoprotein(a) to the protein core of proteoglycans and other members of the vascular matrix.  Trends Cardiovasc Med . 1999;  9 196-200
    CrossrefPubMedSearch in Google Scholar
  • 45 Mooser V, Marcovina S M, White A L. Kringle-containing fragments of apolipoprotein(a) circulate in human plasma and are excreted into the urine.  J Clin Invest . 1996;  98 2414-2424
    PubMedSearch in Google Scholar
  • 46 Mooser V, Seabra M C, Abedin M. Apolipoprotein(a) kringle 4-containing fragments in human urine.  J Clin Invest . 1996;  97 858-864
    PubMedSearch in Google Scholar
  • 47 Kostner K M, Maurer G, Huber K. Urinary excretion of apo(a) fragments. Role in apo(a) catabolism.  Arterioscler Thromb Vasc Biol . 1996;  16 905-911
    PubMedSearch in Google Scholar
  • 48 Haberland M E, Fless G M, Scanu A M. Malondialdehyde modification of lipoprotein(a) produces avid uptake by human monocyte-macrophages.  J Biol Chem . 1992;  267 4143-4151
    PubMedSearch in Google Scholar
  • 49 Naruszewicz M, Selinger E, Davignon J. Oxidative modification of lipoprotein(a) and the effect of beta-carotene.  Metabolism . 1992;  41 1215-1224
    CrossrefPubMedSearch in Google Scholar
  • 50 Sattler W, Kostner G M, Waeg G. Oxidation of lipoprotein Lp(a). A comparison with low density lipoproteins.  Biochim Biophys Acta . 1991;  1081 65-74
    PubMedSearch in Google Scholar
  • 51 Jurgens G, Chen Q, Esterbauer H. Immunostaining of human autopsy aortas with antibodies to modified apolipoprotein B and apolipoprotein(a).  Arterioscler Thromb . 1993;  13 1689-1699
    PubMedSearch in Google Scholar
  • 52 Scanu A M. Atherothrombogenicity of lipoprotein(a): the debate.  Am J Cardiol . 1998;  82 26Q-33Q
    PubMedSearch in Google Scholar
  • 53 Hoover-Plow J, Khaitan A, Fless G M. Phospholipase A2 modification enhances lipoprotein(a) binding to the subendothelial matrix.  Thromb Haemost . 1998;  79 640-648
    PubMedSearch in Google Scholar
  • 54 Carmeliet P, Collen D. Gene manipulation and transfer of the plasminogen and coagulation system in mice.  Semin Thromb Hemost . 1996;  22 525-542
    PubMedSearch in Google Scholar
  • 55 Sangrar W, Bajzar L, Nesheim M E. The antifibrinolytic effect of recombinant apolipoprotein(a) in vitro is primarily due to attenuation of tPA-mediated Glu-plasminogen activation.  Biochemistry . 1995;  34 5151-5157
    CrossrefPubMedSearch in Google Scholar
  • 56 Palabrica T M, Liu A C, Aronovitz M J. Antifibrinolytic effect of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis.  Nat Med . 1995;  1 256-259
    PubMedSearch in Google Scholar
  • 57 Biemond B J, Friederich P W, Koschinsky M L. Apolipoprotein(a) attenuates fibrinolysis in the rabbit jugular vein thrombosis model in vivo.  Circulation . 1997;  96 1612-1615
    CrossrefPubMedSearch in Google Scholar
  • 58 Rand M L, Sangrar W, Hancock M A. Apolipoprotein(a) enhances platelet responses to the thrombin receptor-activating peptide, SFLLRN.  Arterioscler Thromb Vasc Biol . 1998;  18 1393-1399
    PubMedSearch in Google Scholar
  • 59 Etingen O R, Hajjar D P, Hajjar K A. Lipoprotein(a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis.  J Biol Chem . 1991;  266 2459-2465
    PubMedSearch in Google Scholar
  • 60 Li X N, Grenett H E, Benza R L. Genotype-specific transcriptional regulation of PAI-1 expression by hypertriglyceridemic VLDL and Lp(a) in cultured human endothelial cells.  Arterioscler Thromb Vasc Biol . 1997;  17 3215-3223
    PubMedSearch in Google Scholar
  • 61 Buechler C, Ullrich H, Ritter M. Lipoprotein(a) up-regulates the expression of the plasminogen activator inhibitor 2 in human blood monocytes.  Blood . 2001;  97 981-986
    CrossrefPubMedSearch in Google Scholar
  • 62 Kojima S, Harpel P C, Rifkin D B. Lipoprotein(a) inhibits the generation of transforming growth factor beta: an endogenous inhibitor of smooth muscle cell migration.  J Cell Biol . 1991;  113 1439-1445
    CrossrefPubMedSearch in Google Scholar
  • 63 Grainger D J, Kirschenlohr H L, Metcalfe J C. The proliferation of human smooth muscle cells is promoted by lipoprotein(a).  Science . 1993;  260 1655-1658
    CrossrefPubMedSearch in Google Scholar
  • 64 Grainger D J, Kemp P R, Liu A C. Activation of transforming growth factor beta is inhibited in transgenic apolipoprotein(a) mice.  Nature . 1994;  370 460-462
    CrossrefPubMedSearch in Google Scholar
  • 65 Desmaris R L, Sarembock I J, Ayers C R. Elevated serum lipoprotein(a) is a risk factor for clinical recurrence after coronary balloon angioplasty.  Circulation . 1995;  91 1403-1409
    PubMedSearch in Google Scholar
  • 66 Miyata M, Biro S, Arima S. High serum concentration of lipoprotein(a) is a risk factor for restenosis after percutaneous transluminal coronary angioplasty in Japanese patients with single-vessel disease.  Am Heart J . 1996;  130 269-273
    PubMedSearch in Google Scholar
  • 67 Adams M R, Kinlay S, Blake C J. Atherogenic lipids and endothelial dysfunction: mechanisms in the genesis of ischemic disorders.  Annu Rev Med . 2000;  51 149-167
    CrossrefPubMedSearch in Google Scholar
  • 68 Haque N, Zhang X, French D L. CC chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells.  Circulation . 2000;  102 786-792
    PubMedSearch in Google Scholar
  • 69 Allen S, Khan S, Tam S-P. Expression of adhesion molecules by Lp(a): a potential novel mechanism for its atherogenicity.  FASEB J . 1998;  12 1765-1776
    PubMedSearch in Google Scholar
  • 70 Zhao S P, Xu D Y. Oxidized lipoprotein(a) enhanced the expression of P-selectin in cultured human umbilical vein endothelial cells.  Thromb Res . 2000;  100 501-510
    CrossrefPubMedSearch in Google Scholar
  • 71 Takami S, Yamashita S, Kihara S. Lipoprotein(a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells.  Circulation . 1998;  97 721-728
    PubMedSearch in Google Scholar
  • 72 Zhao S P, Xu D Y. Oxidized lipoprotein(a) increases the expression of platelet-derived growth factor-B in human umbilical vein endothelial cells.  Clin Chim Acta . 2000;  296 121-133
    CrossrefPubMedSearch in Google Scholar
  • 73 Galle J, Schneider R, Heinloth A. Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: role of oxidative stress.  Kidney Int . 1999;  55 1450-1461
    CrossrefPubMedSearch in Google Scholar
  • 74 Schachinger V, Halle M, Minners J. Lipoprotein(a) selectively impairs receptor-mediated endothelial vasodilator function of the human coronary circulation.  J Am Coll Cardiol . 1997;  30 927-934
    CrossrefPubMedSearch in Google Scholar
  • 75 Moeslinger T, Friedl T, Volf I. Inhibition of inducible nitric oxide synthesis by oxidized lipoprotein(a) in a murine macrophage cell line.  FEBS Lett . 2000;  478 95-99
    CrossrefPubMedSearch in Google Scholar
  • 76 Zampoulakis J D, Kyriakousi A A, Poralis K A. Lipoprotein(a) is related to the extent of lesions in the coronary vasculature and to unstable coronary syndromes.  Clin Cardiol . 2000;  23 895-900
    PubMedSearch in Google Scholar
  • 77 Ganne F, Vasse M, Beaudeux J L. Increased expression of u-PA and u-PAR on monocytes by LDL and Lp(a) lipoproteins-consequences for plasmin generation and monocyte adhesion.  Thromb Haemost . 1999;  81 594-600
    PubMedSearch in Google Scholar
  • 78 Fortunato J E, Bassiouny H S, Song R H. Apolipoprotein(a) fragments in relation to human carotid plaque instability.  J Vasc Surg . 2000;  32 555-563
    PubMedSearch in Google Scholar
  • 79 Kraft H G, Lingenhel A, Kochl S. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary artery disease.  Arterioscler Thromb Vasc Biol . 1996;  16 713-719
    PubMedSearch in Google Scholar
  • 80 Linden T, Taddei-Peters W, Wilhelmsen L. Serum lipids, lipoprotein(a) and apo(a) isoforms in patients with established coronary artery disease and their relation to disease and prognosis after coronary by-pass surgery.  Atherosclerosis . 1998;  137 175-186
    CrossrefPubMedSearch in Google Scholar
  • 81 Marcovina S M, Albers J J, Wijsman E. Differences in Lp(a) concentrations and apo(a) polymorphs between Black and White Americans.  J Lipid Res . 1996;  37 2569-2585
    PubMedSearch in Google Scholar
  • 82 Paultre F, Pearson T A, Weil H F. High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men.  Arterioscler Thromb Vasc Biol . 2000;  20 2619-2624
    PubMedSearch in Google Scholar
  • 83 Wild S H, Fortmann S P, Marcovina S M. A prospective case-control study of lipoprotein levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants.  Arterioscler Thromb Vasc Biol . 1997;  17 239-245
    PubMedSearch in Google Scholar
  • 84 Hervio L, Girard-Globa A, Durlach A. The antifibrinolytic effect of lipoprotein(a) in heterozygous subjects is modulated by the relative concentrations of each of the apolipoprotein(a) isoforms and their affinity for fibrin.  Eur J Clin Invest . 1996;  26 411-417
    CrossrefPubMedSearch in Google Scholar
  • 85 Koschinsky M L, Marcovina S M. The effect of hormone replacement therapy on lipoprotein(a) levels in post-menopausal women.  Cardiovascular Rev Rep . 1999;  7 387-394
    PubMedSearch in Google Scholar