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Current Cardiology Reports

, 21:102 | Cite as

Lp(a): Addressing a Target for Cardiovascular Disease Prevention

  • Nestor Vasquez
  • Parag H. JoshiEmail author
Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Lipid Abnormalities and Cardiovascular Prevention

Abstract

Purpose of Review

To review the current recommendations for lipoprotein(a) (Lp(a)) screening, the evidence behind the thresholds for increased cardiovascular disease (CVD) risk, and the available data supporting Lp(a) lowering.

Recent Findings

Lp(a) is almost entirely genetically determined and has an independent causal association with CVD. Measurement of Lp(a) is challenging given the structural heterogeneity of apolipoprotein a (apo(a)), for which isoform-insensitive immunoassays should be used. Current guidelines do not recommend treatment to lower Lp(a) but rather focus on intensified preventive measures including low-density lipoprotein cholesterol (LDL-C) lowering in patients with high Lp(a). Evidence suggests that levels higher than 50 mg/dL (125 nmol/L) identify significantly increased CVD risk. Mendelian randomization studies suggest that in order to have a clinically significant reduction in coronary heart disease, Lp(a) levels should be reduced by at least 60–70 mg/dL to attain a significant benefit. Ongoing studies of targeted therapy with antisense oligonucleotides (ASO) have shown promising reductions in Lp(a) up to 80%, but a cardiovascular outcomes trial is needed.

Summary

There is unquestionably an increased risk for CVD in patients with elevated Lp(a); however, measurement assay issues and the lack of Lp(a)-targeted therapies with proven outcome reduction limit the clinical utility of this important risk factor. Available evidence suggesting specific thresholds for clinically significant CVD risk are based on European or Caucasian populations, not accounting for important racial differences. Novel Lp(a)-targeted emerging therapies may need to account for an expected reduction of at least 60–70 mg/dL to achieve a clinically significant benefit.

Keywords

Lipoprotein(a) Cardiovascular disease Prevention Lipids 

Notes

Compliance with Ethical Standards

Conflict of Interest

Nestor Vasquez declares that he has no conflict of interest. Parag H. Joshi reports grant support from the AHA, Novo Nordisk, GlaxoSmithKline, Sanofi/Regeneron, AstraZeneca, and Pfizer; and personal fees from Regeneron and Bayer; and equity interest in the Global Genomics Group.

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.

References

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

  1. 1.
    Berg K. A new serum type system in man--the Lp system. Acta Pathol Microbiol Scand. 1963;59:369–82.CrossRefGoogle Scholar
  2. 2.
    Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412–23.  https://doi.org/10.1001/jama.2009.1063.CrossRefGoogle Scholar
  3. 3.
    Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. 2013;61(11):1146–56.  https://doi.org/10.1016/j.jacc.2012.12.023.CrossRefPubMedGoogle Scholar
  4. 4.
    Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518–28.  https://doi.org/10.1056/NEJMoa0902604.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Consortium CAD, Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes TL, et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2013;45(1):25–33.  https://doi.org/10.1038/ng.2480.CrossRefGoogle Scholar
  6. 6.
    Zioncheck TF, Powell LM, Rice GC, Eaton DL, Lawn RM. Interaction of recombinant apolipoprotein(a) and lipoprotein(a) with macrophages. J Clin Invest. 1991;87(3):767–71.  https://doi.org/10.1172/JCI115079.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis. 1990;10(2):240–5.CrossRefGoogle Scholar
  8. 8.
    Palabrica TM, Liu AC, Aronovitz MJ, Furie B, Lawn RM, Furie BC. Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis. Nat Med. 1995;1(3):256–9.CrossRefGoogle Scholar
  9. 9.
    • Wilson DP, Jacobson TA, Jones PH, Koschinsky ML, McNeal CJ, Nordestgaard BG, et al. Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. Don P. Wilson, MD, on behalf of the Writing group. J Clin Lipidol. 2019.  https://doi.org/10.1016/j.jacl.2019.04.010 A recent statement on Lp(a) from the National Lipid Association with an in-depth summary of the latest data and recommendations. CrossRefGoogle Scholar
  10. 10.
    Lamon-Fava S, Jimenez D, Christian JC, Fabsitz RR, Reed T, Carmelli D, et al. The NHLBI Twin Study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a). Atherosclerosis. 1991;91(1–2):97–106.CrossRefGoogle Scholar
  11. 11.
    Austin MA, Sandholzer C, Selby JV, Newman B, Krauss RM, Utermann G. Lipoprotein(a) in women twins: heritability and relationship to apolipoprotein(a) phenotypes. Am J Hum Genet. 1992;51(4):829–40.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther. 2016;30(1):87–100.  https://doi.org/10.1007/s10557-016-6648-3.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Joshi PH, Krivitsky E, Qian Z, Vazquez G, Voros S, Miller J. Do we know when and how to lower lipoprotein(a)? Curr Treat Options Cardiovasc Med. 2010;12(4):396–407.CrossRefGoogle Scholar
  14. 14.
    Jacobson TA. Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin Proc. 2013;88(11):1294–311.  https://doi.org/10.1016/j.mayocp.2013.09.003.CrossRefPubMedGoogle Scholar
  15. 15.
    Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273(1):6–30.  https://doi.org/10.1111/j.1365-2796.2012.02592.x.CrossRefPubMedGoogle Scholar
  16. 16.
    Marcovina SM, Albers JJ. Lipoprotein (a) measurements for clinical application. J Lipid Res. 2016;57(4):526–37.  https://doi.org/10.1194/jlr.R061648.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995;41(2):246–55.PubMedGoogle Scholar
  18. 18.
    Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69(6):692–711.  https://doi.org/10.1016/j.jacc.2016.11.042.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844–53.  https://doi.org/10.1093/eurheartj/ehq386.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    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(11):1785–96.CrossRefGoogle Scholar
  21. 21.
    Tsimikas S, Fazio S, Ferdinand KC, Ginsberg HN, Koschinsky ML, Marcovina SM, et al. NHLBI Working Group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol. 2018;71(2):177–92.  https://doi.org/10.1016/j.jacc.2017.11.014.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2018;2018:CIR0000000000000625:e1082–143.  https://doi.org/10.1161/CIR.0000000000000625.CrossRefGoogle Scholar
  23. 23.
    Cook NR, Mora S, Ridker PM. Lipoprotein(a) and cardiovascular risk prediction among women. J Am Coll Cardiol. 2018;72(3):287–96.  https://doi.org/10.1016/j.jacc.2018.04.060.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37(39):2999–3058.  https://doi.org/10.1093/eurheartj/ehw272.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129(6):635–42.  https://doi.org/10.1161/CIRCULATIONAHA.113.004406.CrossRefPubMedGoogle Scholar
  26. 26.
    Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1575–9.  https://doi.org/10.1016/j.jacc.2013.06.051.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nestel PJ, Barnes EH, Tonkin AM, Simes J, Fournier M, White HD, et al. Plasma lipoprotein(a) concentration predicts future coronary and cardiovascular events in patients with stable coronary heart disease. Arterioscler Thromb Vasc Biol. 2013;33(12):2902–8.  https://doi.org/10.1161/ATVBAHA.113.302479.CrossRefPubMedGoogle Scholar
  28. 28.
    Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture P, Dawes M, et al. 2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2016;32(11):1263–82.  https://doi.org/10.1016/j.cjca.2016.07.510.CrossRefPubMedGoogle Scholar
  29. 29.
    Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301(22):2331–9.  https://doi.org/10.1001/jama.2009.801.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kostner GM, Avogaro P, Cazzolato G, Marth E, Bittolo-Bon G, Qunici GB. Lipoprotein Lp(a) and the risk for myocardial infarction. Atherosclerosis. 1981;38(1–2):51–61.CrossRefGoogle Scholar
  31. 31.
    Lee SR, Prasad A, Choi YS, Xing C, Clopton P, Witztum JL, et al. LPA gene, ethnicity, and cardiovascular events. Circulation. 2017;135(3):251–63.  https://doi.org/10.1161/CIRCULATIONAHA.116.024611.CrossRefPubMedGoogle Scholar
  32. 32.
    Virani SS, Brautbar A, Davis BC, Nambi V, Hoogeveen RC, Sharrett AR, 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(2):241–9.  https://doi.org/10.1161/CIRCULATIONAHA.111.045120.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lanktree MB, Anand SS, Yusuf S, Hegele RA, Investigators S. Comprehensive analysis of genomic variation in the LPA locus and its relationship to plasma lipoprotein(a) in South Asians, Chinese, and European Caucasians. Circ Cardiovasc Genet. 2010;3(1):39–46.  https://doi.org/10.1161/CIRCGENETICS.109.907642.CrossRefPubMedGoogle Scholar
  34. 34.
    Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388(10057):2239–53.  https://doi.org/10.1016/S0140-6736(16)31009-1.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ference BA. How to use Mendelian randomization to anticipate the results of randomized trials. Eur Heart J. 2018;39(5):360–2.  https://doi.org/10.1093/eurheartj/ehx462.CrossRefPubMedGoogle Scholar
  36. 36.
    • Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM, Nielsen SF, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–27.  https://doi.org/10.1001/jamacardio.2018.1470 A large Mendelian randomization study using genetic variants to estimate the required Lp(a) reduction to reach significant coronary heart disease risk reduction. Findings suggest the amount of reduction needed may be as high as 100 mg/dL. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Lamina C, Kronenberg F, Lp GC. Estimation of the required lipoprotein(a)-lowering therapeutic effect size for reduction in coronary heart disease outcomes: a Mendelian randomization analysis. JAMA Cardiol. 2019;4:575.  https://doi.org/10.1001/jamacardio.2019.1041.CrossRefPubMedGoogle Scholar
  38. 38.
    Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81.  https://doi.org/10.1016/S0140-6736(10)61350-5.CrossRefGoogle Scholar
  39. 39.
    Fraley AE, Schwartz GG, Olsson AG, Kinlay S, Szarek M, Rifai N, et al. Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: results from the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial. J Am Coll Cardiol. 2009;53(23):2186–96.  https://doi.org/10.1016/j.jacc.2009.02.041.CrossRefPubMedGoogle Scholar
  40. 40.
    Choi SH, Chae A, Miller E, Messig M, Ntanios F, DeMaria AN, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol. 2008;52(1):24–32.  https://doi.org/10.1016/j.jacc.2008.02.066.CrossRefPubMedGoogle Scholar
  41. 41.
    Investigators A-H, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.  https://doi.org/10.1056/NEJMoa1107579.CrossRefGoogle Scholar
  42. 42.
    Group HTC, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–12.  https://doi.org/10.1056/NEJMoa1300955.CrossRefGoogle Scholar
  43. 43.
    Parish S, Hopewell JC, Hill MR, Marcovina S, Valdes-Marquez E, Haynes R, et al. Impact of apolipoprotein(a) isoform size on lipoprotein(a) lowering in the HPS2-THRIVE Study. 2018;11(2):e001696.  https://doi.org/10.1161/CIRCGEN.117.001696.
  44. 44.
    Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Blom D, Seidah NG, et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res. 2016;57(6):1086–96.  https://doi.org/10.1194/jlr.P065334.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Gaudet D, Watts GF, Robinson JG, Minini P, Sasiela WJ, Edelberg J, et al. Effect of alirocumab on lipoprotein(a) over >/=1.5 years (from the phase 3 ODYSSEY Program). Am J Cardiol. 2017;119(1):40–6.  https://doi.org/10.1016/j.amjcard.2016.09.010.CrossRefPubMedGoogle Scholar
  46. 46.
    • O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. 2019;139(12):1483–92.  https://doi.org/10.1161/CIRCULATIONAHA.118.037184 A landmark trial on secondary prevention population using PCSK9 inhibitors in addition to maximally tolerated statins showing significant residual risk associated with Lp(a) at low LDL-C levels and greater clinical benefit in treating groups with higher Lp(a). CrossRefGoogle Scholar
  47. 47.
    Bittner V, Szarek M, Aylward P, Bhatt D, Diaz R, Edelberg J, et al. Lipoprotein(a) lowering by alirocumab contributes to total events reduction independent of low-density lipoprotein cholesterol in the ODYSSEY OUTCOMES Trial, vol. 2019. New Orleans: ACC; 2019; 03/18/19.Google Scholar
  48. 48.
    Tsimikas S, Karwatowska-Prokopezuk E, Gouni-Berthold I, Tardif J, Baum S, Steinhagen-Thiessen E et al. Safety and efficacy of AKCEA-APO(a)-LRx to lower lipoprotein(a) levels in patients with established cardiovascular disease: a phase 2 dose-ranging trial. AHA Scientific Sessions; 11/10/2018; Chicago2018.Google Scholar
  49. 49.
    Gotoh T, Kuroda T, Yamasawa M, Nishinaga M, Mitsuhashi T, Seino Y, et al. Correlation between lipoprotein(a) and aortic valve sclerosis assessed by echocardiography (the JMS Cardiac Echo and Cohort Study). Am J Cardiol. 1995;76(12):928–32.CrossRefGoogle Scholar
  50. 50.
    Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997;29(3):630–4.CrossRefGoogle Scholar
  51. 51.
    Glader CA, Birgander LS, Soderberg S, Ildgruben HP, Saikku P, Waldenstrom A, et al. Lipoprotein(a), chlamydia pneumoniae, leptin and tissue plasminogen activator as risk markers for valvular aortic stenosis. Eur Heart J. 2003;24(2):198–208.  https://doi.org/10.1016/s0195-668x(02)00385-8.CrossRefPubMedGoogle Scholar
  52. 52.
    Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368(6):503–12.  https://doi.org/10.1056/NEJMoa1109034.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol. 2014;63(5):470–7.  https://doi.org/10.1016/j.jacc.2013.09.038.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Capoulade R, Chan KL, Yeang C, Mathieu P, Bosse Y, Dumesnil JG, et al. Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis. J Am Coll Cardiol. 2015;66(11):1236–46.  https://doi.org/10.1016/j.jacc.2015.07.020.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Division of Cardiology, Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasUSA

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