Skip to main content
Log in

Screening for and Management of Elevated Lp(a)

  • Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

While lipoprotein(a) (Lp(a)) has long been an intriguing subject for basic researchers and clinicians alike, it is only recently that this unique cardiovascular risk factor has begun to be broadly utilized as part of risk prediction. This has dovetailed with the recognition, from genetic studies, that Lp(a) is indeed causal for atherothrombotic disease rather than being merely a marker. Yet, significant questions remain the subject of ongoing study including: what patients groups benefit the most from determination of plasma Lp(a) concentrations; how can elevated plasma Lp(a) concentrations be most effectively managed; does reduction in plasma Lp(a) concentrations reduce risk for atherothrombotic events; and what is the molecular mechanism or mechanisms underlying the risk attributed to elevated Lp(a)? This review summarizes recent progress in genetic studies, basic laboratory research, and epidemiology with a focus on how Lp(a) might be incorporated into clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Berg K. A new serum type system in man: the Lp system. Acta Pathol Microbiol Scand. 1963;59:362–82.

    Google Scholar 

  2. Grundy, SM (Panel Chair). Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc. 2001;285:2486–97.

    Google Scholar 

  3. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273:6–30.

    Article  PubMed  CAS  Google Scholar 

  4. Kamstrup PR, Nordestgaard BG. Lipoprotein(a) should be taken much more seriously. Clin Chem. 2010;56:1252–60.

    Article  PubMed  Google Scholar 

  5. Fless GM, Rolih CA, Scanu AM. Heterogeneity of human plasma lipoprotein (a). Isolation and characterization of the lipoprotein subspecies and their apoproteins. J Biol Chem. 1984;259:11470–8.

    PubMed  CAS  Google Scholar 

  6. McLean JW, Tomlinson JE, Kuang WJ, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987;330:132–7.

    Article  PubMed  CAS  Google Scholar 

  7. Gabel BR, Koschinsky ML. Analysis of the proteolytic activity of a recombinant form of apolipoprotein(a). Biochemistry. 1995;34:15777–84.

    Article  PubMed  CAS  Google Scholar 

  8. van der Hoek YY, Wittekoek ME, Beisiegel U, et al. The apolipoprotein(a) kringle IV repeats which differ from the major repeat kringle are present in variably sized isoforms. Hum Mol Genet. 1993;2:361–6.

    Article  PubMed  Google Scholar 

  9. Lackner C, Cohen JC, Hobbs HH. Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet. 1993;2:933–40.

    Article  PubMed  CAS  Google Scholar 

  10. Marcovina SM, Hobbs HH, Albers JJ. Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature. Clin Chem. 1996;42:436–9.

    PubMed  CAS  Google Scholar 

  11. Marcovina SM, Albers JJ, Wijsman, et al. Differences in Lp(a) concentrations and apo(a) polymorphs between back and white Americans. J Lipid Res. 1996;37:2569–985.

    PubMed  CAS  Google Scholar 

  12. Brunner C, Lobentanz EM, Petho-Schramm A, et al. The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells. J Biol Chem. 1996;271:32403–10.

    Article  PubMed  CAS  Google Scholar 

  13. Utermann G. The mysteries of lipoprotein(a). Science. 1989;246:904–10.

    Article  PubMed  CAS  Google Scholar 

  14. Boffa MB, Marcovina SM, Koschinsky ML. Lipoprotein(a) as an emerging risk factor for atherothrombosis: principles from bench to bedside. In: Davidson M, Toth P, Maki KC, editors. Therapeutic Lipidology. New York: Springer (Humana Press); 2007. p. 241–66.

    Google Scholar 

  15. Rifai N, Ma J, Sacks FM, et al. Apolipoprotein(a) size and lipoprotein(a) concentrations and future risk of angina pectoris with evidence of severe coronary atherosclerosis in men: the Physician’s Health Study. Clin Chem. 2004;50:1364–71.

    Article  PubMed  CAS  Google Scholar 

  16. Suk Danik J, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006;296:1363–70.

    Article  PubMed  CAS  Google Scholar 

  17. Bennet A, Di Angelantonio E, Erqou S, et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med. 2008;168:598–608.

    Article  PubMed  CAS  Google Scholar 

  18. Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation. 2008;117:176–84.

    Article  PubMed  CAS  Google Scholar 

  19. • Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. 2013;61:1146–56. Analysis of the large Copenhagen City Heart Study showing that including Lp(a) in patients with of this lipoprotein above the 80th percentile improves prediction of their risk; previous studies in this vein that reached different conclusions had examined all individuals, rather than focusing on those with the highest levels.

    Article  PubMed  CAS  Google Scholar 

  20. Craig WY, Neveux LM, Palomaki GE, et al. Lipoprotein(a) as a risk factor for ischemic heart disease: meta-analysis of prospective studies. Clin Chem. 1998;44:2301–6.

    PubMed  CAS  Google Scholar 

  21. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation. 2000;102:1082–5.

    Article  PubMed  CAS  Google Scholar 

  22. Erqou S, Kaptoge S, Perry P, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–23.

    Article  PubMed  CAS  Google Scholar 

  23. • Virani SS, Brautbar A, Davis BC, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2012;125:241–9. Highly powered study showing that blacks with elevated Lp(a) are indeed at greater cardiovascular risk, suggesting a common pathophysiological link regardless of ethnicity but highlighting the need to use cut points appropriate for the different distributions of Lp(a) concentrations in specific ethnic groups.

    Article  PubMed  CAS  Google Scholar 

  24. Ridker PM. Lipoprotein(a), ethnicity and cardiovascular risk: erasing a paradox and filling a clinical gap. Circulation. 2012;125:207–9.

    Article  PubMed  Google Scholar 

  25. Boerwinkle E, Leffert CC, Lin J, et al. Apolipoprotein(a) gene accounts for greater than 90 % of the variation in plasma lipoprotein(a) concentrations. J Clin Invest. 1990;90:52–60.

    Article  Google Scholar 

  26. Luke MM, Kane JP, Liu DM, et al. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler Thromb Vasc Biol. 2007;27:2030–6.

    Article  PubMed  CAS  Google Scholar 

  27. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518–28.

    Article  PubMed  CAS  Google Scholar 

  28. Sandholzer C, Boerwinkle E, Saha N, et al. Apolipoprotein(a) phenotypes, Lp(a) concentration and plasma lipid levels in relation to coronary heart disease in a Chinese population: evidence for the role of the apo(a) gene in coronary heart disease. J Clin Invest. 1992;89:1040–6.

    Article  PubMed  CAS  Google Scholar 

  29. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–9.

    Article  PubMed  CAS  Google Scholar 

  30. Boffa MB, Marcovina SM, Koschinsky ML. Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models. Clin Biochem. 2004;37:333–43.

    Article  PubMed  CAS  Google Scholar 

  31. Hoover-Plow JL, Miles LA, Fless GM, et al. Comparison of the lysine binding functions of lipoprotein(a) and plasminogen. Biochemistry. 1993;32:13681–7.

    Article  PubMed  CAS  Google Scholar 

  32. Sangrar W, Bajzar L, Nesheim ME, Koschinsky ML. Antifibrinolytic effect of recombinant apolipoprotein(a) in vitro is primarily due to attenuation of tPA-mediated Glu-plasminogen activation. Biochemistry. 1995;34:5151–7.

    Article  PubMed  CAS  Google Scholar 

  33. Hancock MA, Boffa MB, Marcovina SM, et al. Inhibition of plasminogen activation by lipoprotein(a). Critical domains in apolipoprotein(a) and mechanism of inhibition on fibrin and degraded fibrin surfaces. J Biol Chem. 2003;278:23260–9.

    Article  PubMed  CAS  Google Scholar 

  34. Pellegrino M, Furmaniak-Kazmierczak E, LeBlanc JC, et al. The apolipoprotein(a) component of lipoprotein(a) stimulates actin stress fiber formation and loss of cell-cell contact in cultured endothelial cells. J Biol Chem. 2004;279:6526–33.

    Article  PubMed  CAS  Google Scholar 

  35. Cho T, Romagnuolo R, Scipione C, et al. Apolipoprotein(a) stimulates nuclear translocation of β-catenin: a novel pathogenic mechanism for lipoprotein(a). Mol Biol Cell. 2013;24:210–21.

    Article  PubMed  CAS  Google Scholar 

  36. Haque NS, Zhang X, French DL, et al. The CC Chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells. Circulation. 2000;102:786–92.

    Article  PubMed  CAS  Google Scholar 

  37. Etingin OR, Hajjar DP, Hajjar KA, et al. Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. J Biol Chem. 1991;266:2459–65.

    PubMed  CAS  Google Scholar 

  38. Edelstein C, Pfaffinger D, Hinman J, et al. Lysine-physphatidylcholine adducts in kringle V impart unique immunological and protein pro-inflammatory properties to human apolipoprotein(a). J Biol Chem. 2003;278:52841–7.

    Article  PubMed  CAS  Google Scholar 

  39. Rand ML, Sangrar W, Hancock MA, et al. Apolipoprotein(a) enhances platelet responses to the thrombin receptor-activating peptide SFLLRN. Arterioscler Thromb Vasc Biol. 1998;18:1393–9.

    Article  PubMed  CAS  Google Scholar 

  40. Liu L, Craig AW, Meldrum HD, et al. Apolipoprotein(a) stimulates vascular endothelial cell growth and migration and signals through integrin alphaVbeta3. Biochem J. 2009;418:325–36.

    Article  PubMed  CAS  Google Scholar 

  41. Berliner JA, Leitinger N, Tsimikas S. The role of oxidized phospholipids in atherosclerosis. J Lipid Res. 2009;50(Suppl):S207–12.

    PubMed  Google Scholar 

  42. Boyd HC, Gown AM, Wolfbauer G, Chait A. Direct evidence for a protein recognized by a monoclonal antibody against oxidatively modified LDL in atherosclerotic lesions from a Watanabe heritable hyperlipidemic rabbit. Am J Pathol. 1989;135:815–25.

    PubMed  CAS  Google Scholar 

  43. Tsimikas S, Witztum JL, Miller ER, et al. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Circulation. 2004;110:1406–12.

    Article  PubMed  CAS  Google Scholar 

  44. Palinski W, Hörkkö S, Miller E, et al. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Invest. 1996;98:800–14.

    Article  PubMed  CAS  Google Scholar 

  45. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49:2230–9.

    Article  PubMed  CAS  Google Scholar 

  46. Tsimikas S, Kiechl S, Willeit J, et al. Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study. J Am Coll Cardiol. 2006;47:2219–28.

    Article  PubMed  CAS  Google Scholar 

  47. Fraley AE, Tsimikas S. Clinical applications of circulating oxidized low-density lipoprotein biomarkers in cardiovascular disease. Curr Opin Lipidol. 2006;17:502–9.

    Article  PubMed  CAS  Google Scholar 

  48. Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005;353:46–57.

    Article  PubMed  CAS  Google Scholar 

  49. Kiechl S, Willeit J, Mayr M, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol. 2007;27:1788–95.

    Article  PubMed  CAS  Google Scholar 

  50. Ravandi A, Boekholdt SM, Mallat Z, et al. Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study. J Lipid Res. 2001;52:1829–36.

    Article  Google Scholar 

  51. • Seimon TA, Nadolski MJ, Liao X, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010;12:467–82. Elegant study that is the first to convincingly demonstrate that the oxPL on apo(a) can negatively impact macrophage phenotype.

    Article  PubMed  CAS  Google Scholar 

  52. Rodger EJ, Suetani RJ, Jones GT, et al. Proteomic analysis of aortae from human lipoprotein(a) transgenic mice shows an early metabolic response independent of atherosclerosis. PLoS One. 2012;7:e30383.

    Article  PubMed  CAS  Google Scholar 

  53. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–53.

    Article  PubMed  CAS  Google Scholar 

  54. Goldhaber SZ. European Atherosclerosis Society screening recommendations for lipoprotein(a) and high-sensitivity C-reactive protein: double standard or failure of evidence-based medicine? Clin Chem. 2010;56:1544–6.

    Article  PubMed  CAS  Google Scholar 

  55. Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5:338–67.

    Article  PubMed  Google Scholar 

  56. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National Heart, Lung, and Blood Institute Workshop on lipoprotein(a) and cardiovascular disease: recent advances and future directions. Clin Chem. 2003;49:1785–96.

    Article  PubMed  CAS  Google Scholar 

  57. Marcovina SM, Albers JJ, Scanu AM, et al. Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem. 2000;46:1956–67.

    PubMed  CAS  Google Scholar 

  58. Tziomalos K, Athyros VG, Wierzbicki AS, Mikhailidis DP. Lipoprotein a: where are we now? Curr Opin Cardiol. 2009;24:351–7.

    Article  PubMed  Google Scholar 

  59. • Brown WV, Ballantyne CM, Jones PH, Marcovina S. Management of Lp(a). J Clin Lipidol. 2010;4:240–7. A wide-ranging and highly readable overview of current thinking on the clinical utility, and challenges, of Lp(a).

    Article  PubMed  Google Scholar 

  60. Kronenberg F, Kronenberg MF, Kiechl S, et al. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation. 1999;100:1154–60.

    Article  PubMed  CAS  Google Scholar 

  61. Erqou S, Thrompson A, Di Angelantonio E, et al. Apolipoprotein(a) isoforms and the risk of vascular disease. J Am Coll Cardiol. 2010;55:2160–7.

    Article  PubMed  CAS  Google Scholar 

  62. Crouse III JR. New developments in the use of niacin for treatment of hyperlipidemia: new considerations in the use of an old drug. Coron Artery Dis. 1996;7:321–6.

    Article  PubMed  Google Scholar 

  63. Investigators AIM-HIGH, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  Google Scholar 

  64. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279–91.

    Google Scholar 

  65. Akaike M, Azuma H, Kagawa A, et al. Effect of aspirin treatment on serum concentrations of lipoprotein(a) in patients with atherosclerotic diseases. Clin Chem. 2002;48:1454–9.

    PubMed  CAS  Google Scholar 

  66. Chasman DI, Shiffman D, Zee RY, et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. 2009;203:371–6.

    Article  PubMed  CAS  Google Scholar 

  67. • Visser ME, Witztum JL, Stroes ES, Kastelein JJ. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J. 2012;33:1451–8. One of a quartet of papers revealing novel modalities to lower plasma Lp(a) concentrations, although all of them have beneficial effects on other aspects of the lipid profile.

    Article  PubMed  CAS  Google Scholar 

  68. • Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–18. One of a quartet of papers revealing novel modalities to lower plasma Lp(a) concentrations, although all of them have beneficial effects on other aspects of the lipid profile.

    Article  PubMed  CAS  Google Scholar 

  69. • McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344–53. One of a quartet of papers revealing novel modalities to lower plasma Lp(a) concentrations, although all of them have beneficial effects on other aspects of the lipid profile.

    Article  PubMed  CAS  Google Scholar 

  70. • Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363:2406–15. One of a quartet of papers revealing novel modalities to lower plasma Lp(a) concentrations, although all of them have beneficial effects on other aspects of the lipid profile.

    Article  PubMed  CAS  Google Scholar 

  71. Jaeger BR, Richter Y, Nagel D, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med. 2009;6:229–39.

    Article  PubMed  CAS  Google Scholar 

  72. Safarova MS, Ezhov MV, Afanasieva OI, et al. Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography. Atheroscler Suppl. 2013;14:93–9.

    Article  PubMed  CAS  Google Scholar 

  73. Cantin B, Gagnon F, Moorjani S, et al. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol. 1998;31:519–25.

    Article  PubMed  CAS  Google Scholar 

  74. Luc G, Bard JM, Arveiler D, PRIME Study Group, et al. Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis. 2002;163:377–84.

    Article  PubMed  CAS  Google Scholar 

  75. Maher VM, Brown BG, Marcovina SM, et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). J Am Med Assoc. 1995;274:1771–4.

    Article  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Michael B. Boffa declares that he has no conflict of interest.

Marlys L. Koschinsky declares that she has no conlfict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marlys L. Koschinsky.

Additional information

This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boffa, M.B., Koschinsky, M.L. Screening for and Management of Elevated Lp(a). Curr Cardiol Rep 15, 417 (2013). https://doi.org/10.1007/s11886-013-0417-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-013-0417-8

Keywords

Navigation