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  • Review Article
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Lipoprotein(a), platelet function and cardiovascular disease

Nature Reviews Cardiology volume 21, pages 299–311 (2024)Cite this article

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Abstract

Lipoprotein(a) (Lp(a)) is associated with atherothrombosis through several mechanisms, including putative antifibrinolytic properties. However, genetic association studies have not demonstrated an association between high plasma levels of Lp(a) and the risk of venous thromboembolism, and studies in patients with highly elevated Lp(a) levels have shown that Lp(a) lowering does not modify the clotting properties of plasma ex vivo. Lp(a) can interact with several platelet receptors, providing biological plausibility for a pro-aggregatory effect. Observational clinical studies suggest that elevated plasma Lp(a) concentrations are associated with worse long-term outcomes in patients undergoing revascularization. Furthermore, in these patients, those with elevated plasma Lp(a) levels derive more benefit from prolonged dual antiplatelet therapy than those with normal Lp(a) levels. The ASPREE trial in healthy older individuals treated with aspirin showed a reduction in ischaemic events in those who had a single-nucleotide polymorphism in LPA that is associated with elevated Lp(a) levels in plasma, without an increase in bleeding events. In this Review, we re-examine the role of Lp(a) in the regulation of platelet function and suggest areas of research to define further the clinical relevance to cardiovascular disease of the observed associations between Lp(a) and platelet function.

Key points

  • Lipoprotein(a) (Lp(a)) independently contributes to atherothrombosis through several mechanisms, including putative antifibrinolytic properties.

  • However, genetic association studies and experimental studies have not demonstrated an association between high Lp(a) levels in the plasma and the risk of venous thromboembolism or clot properties, respectively.

  • Oxidized phospholipids present in Lp(a) can interact with several platelet receptors, including protease-activated receptor 1 and CD36, which provides biological plausibility for a pro-aggregatory effect of Lp(a).

  • Observational studies suggest that elevated plasma Lp(a) concentrations are associated with worse long-term outcomes in patients undergoing revascularization and that prolonged dual antiplatelet therapy provides benefit to these patients.

  • The ASPREE trial in healthy older individuals treated with aspirin demonstrated a reduction in ischaemic events in those with genetically elevated Lp(a) levels in plasma, without an increase in bleeding events.

  • We propose a re-examination of the role of Lp(a) in regulating platelet function and suggest that future research should focus on defining the clinical relevance of the interaction between Lp(a) and platelets in cardiovascular disease.

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Fig. 1: Main platelet-activating ligands, platelet receptors and antiplatelet drugs.
Fig. 2: Potential lipoprotein(a) interactions with platelets and the coagulation system.
Fig. 3: Balance of pro-aggregatory and anti-aggregatory platelet effects of lipoprotein(a).
Fig. 4: Aspirin therapy, LPA genotype and primary prevention of cardiovascular disease.
Fig. 5: Oxidized phospholipids, lipoprotein(a) and acute coronary syndrome.
Fig. 6: Design of clinical trials of interventions targeting lipoprotein(a)-mediated cardiovascular risk.

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References

  1. Tsimikas, S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol. 69, 692–711 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Tsimikas, S. et al. NHLBI Working Group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J. Am. Coll. Cardiol. 71, 177–192 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. van der Valk, F. M. et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 134, 611–624 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kronenberg, F. et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur. Heart J. 22, 3925–3946 (2022).

    Article  Google Scholar 

  5. Clarke, R. et al. Oxidized phospholipids on apolipoprotein B-100 versus plasminogen and risk of coronary heart disease in the PROCARDIS study. Atherosclerosis 354, 15–22 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Boffa, M. B. & Koschinsky, M. L. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J. Lipid Res. 57, 745–757 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Loscalzo, J., Weinfeld, M., Fless, G. M. & Scanu, A. M. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 10, 240–245 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Etingin, O. R., Hajjar, D. P., Hajjar, K. A., Harpel, P. C. & Nachman, R. L. Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. J. Biol. Chem. 266, 2459–2465 (1991).

    Article  CAS  PubMed  Google Scholar 

  9. Palabrica, T. M. et al. Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis. Nat. Med. 1, 256–259 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Helgadottir, A. et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J. Am. Coll. Cardiol. 60, 722–729 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Kamstrup, P. R., Tybjaerg-Hansen, A. & Nordestgaard, B. G. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis. Arterioscler. Thromb. Vasc. Biol. 32, 1732–1741 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Dentali, F. et al. Lipoprotein(a) as a risk factor for venous thromboembolism: a systematic review and meta-analysis of the literature. Semin. Thromb. Hemost. 43, 614–620 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Boffa, M. B. et al. Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis. J. Lipid Res. 60, 2082–2089 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Belczewski, A. R. et al. Baboon lipoprotein(a) binds very weakly to lysine-agarose and fibrin despite the presence of a strong lysine-binding site in apolipoprotein(a) kringle IV type 10. Biochemistry 44, 555–564 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Tsimikas, S., Moriarty, P. M. & Stroes, E. S. Emerging RNA therapeutics to lower blood levels of Lp(a): JACC focus seminar 2/4. J. Am. Coll. Cardiol. 77, 1576–1589 (2021).

    Article  CAS  PubMed  Google Scholar 

  16. Kiefer, T. L. & Becker, R. C. Inhibitors of platelet adhesion. Circulation 120, 2488–2495 (2009).

    Article  PubMed  Google Scholar 

  17. Gurbel, P. A., Jeong, Y. H., Navarese, E. P. & Tantry, U. S. Platelet-mediated thrombosis: from bench to bedside. Circ. Res. 118, 1380–1391 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Coughlin, S. R. Protease activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800–1814 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Zimmerman, G. A., McIntyre, T. M., Prescott, S. M. & Stafforini, D. M. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit. Care Med. 30, S294–S301 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Tsironis, L. D., Mitsios, J. V., Milionis, H. J., Elisaf, M. & Tselepis, A. D. Effect of lipoprotein (a) on platelet activation induced by platelet-activating factor: role of apolipoprotein (a) and endogenous PAF-acetylhydrolase. Cardiovasc. Res. 63, 130–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Patrono, C. & Baigent, C. Role of aspirin in primary prevention of cardiovascular disease. Nat. Rev. Cardiol. 16, 675–686 (2019).

    Article  PubMed  Google Scholar 

  22. Malle, E., Ibovnik, A., Stienmetz, A., Kostner, G. M. & Sattler, W. Identification of glycoprotein IIb as the lipoprotein(a)-binding protein on platelets. Lipoprotein(a) binding is independent of an arginyl-glycyl-aspartate tripeptide located in apolipoprotein(a). Arterioscler. Thromb. 14, 345–352 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Ezratty, A., Simon, D. I. & Loscalzo, J. Lipoprotein(a) binds to human platelets and attenuates plasminogen binding and activation. Biochemistry 32, 4628–4633 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Martinez, C. et al. Binding of recombinant apolipoprotein(a) to human platelets and effect on platelet aggregation. Thromb. Haemost. 85, 686–693 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Rand, M. L. et al. Apolipoprotein(a) enhances platelet responses to the thrombin receptor-activating peptide SFLLRN. Arterioscler. Thromb. Vasc. Biol. 18, 1393–1399 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Podrez, E. A. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat. Med. 13, 1086–1095 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dou, H. et al. Oxidized phospholipids promote NETosis and arterial thrombosis in LNK(SH2B3) deficiency. Circulation 144, 1940–1954 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Malle, E. et al. Lysine modification of LDL or lipoprotein(a) by 4-hydroxynonenal or malondialdehyde decreases platelet serotonin secretion without affecting platelet aggregability and eicosanoid formation. Arterioscler. Thromb. Vasc. Biol. 15, 377–384 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Boonmark, N. W. & Lawn, R. M. The lysine-binding function of Lp(a). Clin. Genet. 52, 355–360 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Barre, D. E. Arginyl-glycyl-aspartyl (RGD) epitope of human apolipoprotein (a) inhibits platelet aggregation by antagonizing the IIb subunit of the fibrinogen (GPIIb/IIIa) receptor. Thromb. Res. 119, 601–607 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Bergmark, C. et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J. Lipid Res. 49, 2230–2239 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Leibundgut, G. et al. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J. Lipid Res. 54, 2815–2830 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sotiriou, S. N. et al. Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin. FASEB J. 20, 559–561 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Morrow, D. A. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404–1413 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Liu, H., Fu, D., Luo, Y. & Peng, D. Independent association of Lp(a) with platelet reactivity in subjects without statins or antiplatelet agents. Sci. Rep. 12, 16609 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Byun, Y. S. et al. Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial. J. Am. Coll. Cardiol. 65, 1286–1295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Byun, Y. S. et al. Oxidized phospholipids on apolipoprotein B-100 and recurrent ischemic events following stroke or transient ischemic attack. J. Am. Coll. Cardiol. 69, 147–158 (2017).

    Article  CAS  PubMed  Google Scholar 

  38. Boullier, A. et al. The binding of oxidized low density lipoprotein to mouse CD36 is mediated in part by oxidized phospholipids that are associated with both the lipid and protein moieties of the lipoprotein. J. Biol. Chem. 275, 9163–9169 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Podrez, E. A. et al. Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J. Clin. Invest. 105, 1095–1108 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Boullier, A. et al. Phosphocholine as a pattern recognition ligand for CD36. J. Lipid Res. 46, 969–976 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Friedman, P., Horkko, S., Steinberg, D., Witztum, J. L. & Dennis, E. A. Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids. Importance of Schiff base formation and aldol condensation. J. Biol. Chem. 277, 7010–7020 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Seimon, T. A. et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 12, 467–482 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Consortium, C. A. D. et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25–33 (2013).

    Article  Google Scholar 

  44. Wang, W. et al. LNK/SH2B3 loss of function promotes atherosclerosis and thrombosis. Circ. Res. 119, e91–e103 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. MacFarlane, D. E., Gardner, S., Lipson, C. & Mills, D. C. Malondialdehyde production by platelets during secondary aggregation. Thromb. Haemost. 38, 1002–1009 (1977).

    Article  CAS  PubMed  Google Scholar 

  46. Tsironis, L. D. et al. Reduced PAF-acetylhydrolase activity associated with Lp(a) in patients with coronary artery disease. Atherosclerosis 177, 193–201 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Blencowe, C., Hermetter, A., Kostner, G. M. & Deigner, H. P. Enhanced association of platelet-activating factor acetylhydrolase with lipoprotein (a) in comparison with low density lipoprotein. J. Biol. Chem. 270, 31151–31157 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Tsimikas, S., Tsironis, L. D. & Tselepis, A. D. New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 27, 2094–2099 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Gries, A. et al. Lipoprotein(a) inhibits collagen-induced aggregation of thrombocytes. Arterioscler. Thromb. Vasc. Biol. 16, 648–655 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Barre, D. E. Apolipoprotein (a) mediates the lipoprotein (a)-induced biphasic shift in human platelet cyclic AMP. Thromb. Res. 112, 321–324 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Barre, D. E. Apoprotein (a) antagonises the GPIIB/IIIA receptor on collagen and ADP-stimulated human platelets. Front. Biosci. 9, 404–410 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Salsoso, R. et al. Relation of high lipoprotein (a) concentrations to platelet reactivity in individuals with and without coronary artery disease. Adv. Ther. 37, 4568–4584 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kille, A. et al. Association of lipoprotein(a) with intrinsic and on-clopidogrel platelet reactivity. J. Thromb. Thrombolysis 53, 1–9 (2022).

    Article  CAS  PubMed  Google Scholar 

  54. Suwa, S. et al. Impact of lipoprotein (a) on long-term outcomes in patients with coronary artery disease treated with statin after a first percutaneous coronary intervention. J. Atheroscler. Thromb. 24, 1125–1131 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu, H. H. et al. Association of lipoprotein(a) levels with recurrent events in patients with coronary artery disease. Heart 106, 1228–1235 (2020).

    Article  PubMed  Google Scholar 

  56. Yoon, Y.-H. et al. Association of lipoprotein(a) with recurrent ischemic events following percutaneous coronary intervention. JACC: Cardiovasc. Interv. 14, 2059–2068 (2021).

    PubMed  Google Scholar 

  57. Cui, K. et al. Benefit and risk of prolonged dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents in patients with elevated lipoprotein(a) concentrations. Front. Cardiovasc. Med. 8, 807925 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhu, P. et al. Association of lipoprotein(a) with platelet aggregation and thrombogenicity in patients undergoing percutaneous coronary intervention. Platelets 32, 684–689 (2021).

    Article  CAS  PubMed  Google Scholar 

  59. Ezhov, M. V., Safarova, M. S., Afanasieva, O. I., Kukharchuk, V. V. & Pokrovsky, S. N. Lipoprotein(a) level and apolipoprotein(a) phenotype as predictors of long-term cardiovascular outcomes after coronary artery bypass grafting. Atherosclerosis 235, 477–482 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Tsimikas, S. & Marcovina, S. M. Ancestry, lipoprotein(a), and cardiovascular risk thresholds: JACC review topic of the week. J. Am. Coll. Cardiol. 80, 934–946 (2022).

    Article  CAS  PubMed  Google Scholar 

  61. Chasman, D. I. et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 203, 371–376 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Lacaze, P. et al. Aspirin for primary prevention of cardiovascular events in relation to lipoprotein(a) genotypes. J. Am. Coll. Cardiol. 80, 1287–1298 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Akaike, M. et al. Effect of aspirin treatment on serum concentrations of lipoprotein(a) in patients with atherosclerotic diseases. Clin. Chem. 48, 1454–1459 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Ranga, G. S., Kalra, O. P., Tandon, H., Gambhir, J. K. & Mehrotra, G. Effect of aspirin on lipoprotein(a) in patients with ischemic stroke. J. Stroke Cerebrovasc. Dis. 16, 220–224 (2007).

    Article  PubMed  Google Scholar 

  65. Maeda, S. et al. Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis 78, 145–150 (1989).

    Article  CAS  PubMed  Google Scholar 

  66. Mbewu, A. D., Durrington, P. N., Bulleid, S. & Mackness, M. I. The immediate effect of streptokinase on serum lipoprotein(a) concentration and the effect of myocardial infarction on serum lipoprotein(a), apolipoproteins A1 and B, lipids and C-reactive protein. Atherosclerosis 103, 65–71 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Tsimikas, S. et al. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J. Am. Coll. Cardiol. 41, 360–370 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Tsimikas, S. 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. Circulation 110, 1406–1412 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Waldmann, E. & Parhofer, K. G. Lipoprotein apheresis to treat elevated lipoprotein (a). J. Lipid Res. 57, 1751–1757 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lim, E. T. et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 10, e1004494 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Langsted, A., Nordestgaard, B. G. & Kamstrup, P. R. Low lipoprotein(a) levels and risk of disease in a large, contemporary, general population study. Eur. Heart J. 42, 1147–1156 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Koltai, K., Kesmarky, G., Feher, G., Tibold, A. & Toth, K. Platelet aggregometry testing: molecular mechanisms, techniques and clinical implications. Int. J. Mol. Sci. 18, 803 (2017).

    Article  Google Scholar 

  73. Gorog, D. A. & Becker, R. C. Point-of-care platelet function tests: relevance to arterial thrombosis and opportunities for improvement. J. Thromb. Thrombolysis 51, 1–11 (2021).

    Article  CAS  PubMed  Google Scholar 

  74. Bourguignon, A., Tasneem, S. & Hayward, C. P. Screening and diagnosis of inherited platelet disorders. Crit. Rev. Clin. Lab. Sci. 59, 405–444 (2022).

    Article  PubMed  Google Scholar 

  75. Chebbo, M. et al. Platelets purification is a crucial step for transcriptomic analysis. Int. J. Mol. Sci. 23, 3100 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Coppinger, J. A. et al. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 103, 2096–2104 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Parker, W. A. E. et al. Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome. Platelets 30, 148–157 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tsimikas, S., Reeves, R. R. & Patel, M. P. Always present, but now rediscovered: Lp(a) as a predictor of long-term outcomes in PCI. JACC Cardiovasc. Interv. 14, 2069–2072 (2021).

    Article  PubMed  Google Scholar 

  79. Tsimikas, S. et al. Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation 109, 3164–3170 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Fefer, P. et al. The role of oxidized phospholipids, lipoprotein (a) and biomarkers of oxidized lipoproteins in chronically occluded coronary arteries in sudden cardiac death and following successful percutaneous revascularization. Cardiovasc. Revasc. Med. 13, 11–19 (2012).

    Article  PubMed  Google Scholar 

  81. van Dijk, R. A. et al. Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions. J. Lipid Res. 53, 2773–2790 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Ravandi, A. et al. Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans. J. Am. Coll. Cardiol. 63, 1961–1971 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tsimikas, S., Bhatia, H. S. & Erlenge, D. Clinical trials to improve outcomes in patients with elevated Lp(a) undergoing PCI: the time has arrived. J. Clin. Lipidol. https://doi.org/10.1016/j.jacl.2023.06.005 (2023).

  84. Erlinge, D. et al. Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study. Lancet 397, 985–995 (2021).

    Article  CAS  PubMed  Google Scholar 

  85. Räber, L. et al. Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial. JAMA 327, 1771–1781 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Merki, E. et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J. Am. Coll. Cardiol. 57, 1611–1621 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Leibundgut, G. et al. Oxidized phospholipids are present on plasminogen, affect fibrinolysis, and increase following acute myocardial infarction. J. Am. Coll. Cardiol. 59, 1426–1437 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Schneider, M. et al. High-level lipoprotein [a] expression in transgenic mice: evidence for oxidized phospholipids in lipoprotein [a] but not in low density lipoproteins. J. Lipid Res. 46, 769–778 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Linton, M. F. et al. Transgenic mice expressing high plasma concentrations of human apolipoprotein B100 and lipoprotein(a). J. Clin. Invest. 92, 3029–3037 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Merki, E. et al. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation 118, 743–753 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Viney, N. J. et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 388, 2239–2253 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Tsimikas, S. et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N. Engl. J. Med. 382, 244–255 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Mohammadi-Shemirani, P. et al. Elevated lipoprotein(a) and risk of atrial fibrillation: an observational and Mendelian randomization study. J. Am. Coll. Cardiol. 79, 1579–1590 (2022).

    Article  CAS  PubMed  Google Scholar 

  94. Erqou, S. et al. Emerging risk factors collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. J. Am. Med. Assoc. 302, 412–423 (2009).

    Article  CAS  Google Scholar 

  95. Emdin, C. A. et al. Phenotypic characterization of genetically lowered human lipoprotein(a) levels. J. Am. Coll. Cardiol. 68, 2761–2772 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Marcovina, S. M. et al. Development of an LC–MS/MS proposed candidate reference method for the standardization of analytical methods to measure lipoprotein(a). Clin. Chem. 67, 490–499 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Cobbaert, C. M. et al. Towards an SI-traceable reference measurement system for seven serum apolipoproteins using bottom-up quantitative proteomics: conceptual approach enabled by cross-disciplinary/cross-sector collaboration. Clin. Chem. 67, 478–489 (2021).

    Article  PubMed  Google Scholar 

  98. Marcovina, S. M. et al. Development and validation of an isoform-independent monoclonal antibody-based ELISA for measurement of lipoprotein(a). J. Lipid Res. 63, 100239 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhao, S. P. & Xu, D. Y. Oxidized lipoprotein(a) enhanced the expression of P-selectin in cultured human umbilical vein endothelial cells. Thromb. Res. 100, 501–510 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. 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 296, 121–133 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Barre, D. E. Lipoprotein (a) reduces platelet aggregation via apo(a)-mediated decreases in thromboxane A(2)production. Platelets 9, 93–96 (1998).

    Article  CAS  PubMed  Google Scholar 

  102. Xu, D. Y., Zhao, S. P. & Peng, W. P. Elevated plasma levels of soluble P-selectin in patients with acute myocardial infarction and unstable angina. An inverse link to lipoprotein(a). Int. J. Cardiol. 64, 253–258 (1998).

    Article  CAS  PubMed  Google Scholar 

  103. Dai, W. et al. Intracellular tPA–PAI-1 interaction determines VLDL assembly in hepatocytes. Science 381, eadh5207 (2023).

    Article  CAS  PubMed  Google Scholar 

  104. Kronenberg, F. et al. Apolipoprotein(a) phenotypes predict the risk for carotid atherosclerosis in patients with end-stage renal disease. Arterioscler. Thromb. 14, 1405–1411 (1994).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

H.S.B. is partially supported by NIH grants 1K08HL166962, 1KL2TR001444 and 5T32HL079891. P.L. is supported by a National Heart Foundation Future Leader Fellowship (10260). S.T. is supported by NHLBI R01 HL159156 and R01 HL170224.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA, USA

    Harpreet S. Bhatia, Mitul Patel & Sotirios Tsimikas

  2. Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Richard C. Becker

  3. Division of Cardiology, University Hospital of Basel, Basel, Switzerland

    Gregor Leibundgut

  4. Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

    Paul Lacaze & Andrew Tonkin

  5. Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jagat Narula

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  1. Harpreet S. Bhatia
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  2. Richard C. Becker
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Contributions

H.S.B., G.L. and S.T. researched data for the article and wrote the manuscript. H.S.B., R.C.B., G.L. and S.T. provided substantial contribution to discussion of content. H.S.B., R.C.B., G.L., M.P., P.L., A.T. and J.N. reviewed and/or edited the manuscript before submission.

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Correspondence to Sotirios Tsimikas.

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Competing interests

H.S.B. has received consulting fees from Kaneka Medical and Novartis. R.C.B. is a member of the Data Safety Monitoring Board (DSMB) for Ionis and Novartis and is on the scientific advisory board for Basking Biosciences. A.T. has received honoraria for lectures or DSMB participation from Amgen, Boehringer-Ingelheim, Merck, The Medicines Company, Novartis and Pfizer. S.T. is a co-inventor and has received royalties from patents owned by the University of California San Diego, is a co-founder of and has an equity interest in Kleanthi Diagnostics and Oxitope and has a dual appointment at the University of California San Diego and Ionis Pharmaceuticals. The other authors declare no competing interests.

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Nature Reviews Cardiology thanks Pia Kamstrup and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Bhatia, H.S., Becker, R.C., Leibundgut, G. et al. Lipoprotein(a), platelet function and cardiovascular disease. Nat Rev Cardiol 21, 299–311 (2024). https://doi.org/10.1038/s41569-023-00947-2

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