OpenLB
Open Library of Bioscience
Advanced Search
Handbook of experimental pharmacology
2022;270 201-232.

Lipoprotein(a).

Florian Kronenberg
Author Information
  1. Florian Kronenberg: Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria. Florian.Kronenberg@i-med.ac.at. ORCID
PMID: 34196811 DOI: 10.1007/164_2021_504

Abstract

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein with a strong genetic regulation. Up to 90% of the concentrations are explained by a single gene, the LPA gene. The concentrations show a several-hundred-fold interindividual variability ranging from less than 0.1 mg/dL to more than 300 mg/dL. Lp(a) plasma concentrations above 30 mg/dL and even more above 50 mg/dL are associated with an increased risk for cardiovascular disease including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and all-cause mortality. Since concentrations above 50 mg/dL are observed in roughly 20% of the Caucasian population and in an even higher frequency in African-American and Asian-Indian ethnicities, it can be assumed that Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease.Carriers of genetic variants that are associated with high Lp(a) concentrations have a markedly increased risk for cardiovascular events. Studies that used these genetic variants as a genetic instrument to support a causal role for Lp(a) as a cardiovascular risk factor are called Mendelian randomization studies. The principle of this type of studies has been introduced and tested for the first time ever with Lp(a) and its genetic determinants.There are currently no approved pharmacologic therapies that specifically target Lp(a) concentrations. However, some therapies that target primarily LDL cholesterol have also an influence on Lp(a) concentrations. These are mainly PCSK9 inhibitors that lower LDL cholesterol by 60% and Lp(a) by 25-30%. Furthermore, lipoprotein apheresis lowers both, Lp(a) and LDL cholesterol, by about 60-70%. Some sophisticated study designs and statistical analyses provided support that lowering Lp(a) by these therapies also lowers cardiovascular events on top of the effect caused by lowering LDL cholesterol, although this was not the main target of the therapy. Currently, new therapies targeting RNA such as antisense oligonucleotides (ASO) or small interfering RNA (siRNA) against apolipoprotein(a), the main protein of the Lp(a) particle, are under examination and lower Lp(a) concentrations up to 90%. Since these therapies specifically lower Lp(a) concentrations without influencing other lipoproteins, they will serve the last piece of the puzzle whether a decrease of Lp(a) results also in a decrease of cardiovascular events.

Keywords

Apolipoprotein(a) Association study Cardiovascular disease Copy number variation Lipoprotein(a) Lp(a) Mendelian randomization Therapy

References

  1. Arsenault BJ, Boekholdt SM, Dube MP, Rheaume E, Wareham NJ, Khaw KT, Sandhu MS, Tardif JC (2014) Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet 7:304–310 [PMID: 24704946]
  2. Austin MA, Sandholzer C, Selby JV, Newman B, Krauss RM, Utermann G (1992) Lipoprotein(a) in women twins: heritability and relationship to apolipoprotein(a) phenotypes. Am J Hum Genet 51:829–840 [PMID: 1415225]
  3. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376:1670–1681 [PMID: 21067804]
  4. Bergmark C, Dewan A, Orsoni A, Merki E, Miller ER, Shin MJ, Binder CJ, Horkko S, Krauss RM, Chapman MJ, Witztum JL, Tsimikas S (2008) A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res 49:2230–2239 [PMID: 18594118]
  5. Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R, Edelberg JM, Fras Z, Goodman SG, Halvorsen S, Hanotin C, Harrington RA, Jukema JW, Loizeau V, Moriarty PM, Moryusef A, Pordy R, Roe MT, Sinnaeve P, Tsimikas S, Vogel R, White HD, Zahger D, Zeiher AM, Steg PG, Schwartz GG (2020) Effect of Alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 75:133–144 [PMID: 31948641]
  6. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W (2011) Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 365:2255–2267 [PMID: 22085343]
  7. Boffa MB, Koschinsky ML (2016) Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res 57:745–757 [PMID: 26647358]
  8. Boffa MB, Koschinsky ML (2019) Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease. Nat Rev Cardiol 16:305–318 [PMID: 30675027]
  9. Boffa MB, Stranges S, Klar N, Moriarty PM, Watts GF, Koschinsky ML (2018) Lipoprotein(a) and secondary prevention of atherothrombotic events: a critical appraisal. J Clin Lipidol 12:1358–1366 [PMID: 30316749]
  10. Brandt EJ, Mani A, Spatz ES, Desai NR, Nasir K (2020) Lipoprotein(a) levels and association with myocardial infarction and stroke in a nationally representative cross-sectional US cohort. J Clin Lipidol 14:695–706.e694 [PMID: 32739333]
  11. Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM, Nielsen SF, Willeit P, Young R, Surendran P, Karthikeyan S, Bolton TR, Peters JE, Kamstrup PR, Tybjaerg-Hansen A, Benn M, Langsted A, Schnohr P, Vedel-Krogh S, Kobylecki CJ, Ford I, Packard C, Trompet S, Jukema JW, Sattar N, Di Angelantonio E, Saleheen D, Howson JMM, Nordestgaard BG, Butterworth AS, Danesh J (2018) Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol 3:619–627 [PMID: 29926099]
  12. Cain WJ, Millar JS, Himebauch AS, Tietge UJ, Maugeais C, Usher D, Rader DJ (2005) Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. J Lipid Res 46:2681–2691 [PMID: 16150825]
  13. Cairns BJ, Coffey S, Travis RC, Prendergast B, Green J, Engert JC, Lathrop M, Thanassoulis G, Clarke R (2017) A replicated, genome-wide significant association of aortic stenosis with a genetic variant for lipoprotein(a): meta-analysis of published and novel data. Circulation 135:1181–1183 [PMID: 28320808]
  14. Capoulade R, Yeang C, Chan KL, Pibarot P, Tsimikas S (2018) Association of mild to moderate aortic valve stenosis progression with higher lipoprotein(a) and oxidized phospholipid levels: secondary analysis of a randomized clinical trial. JAMA Cardiol 3:1212–1217 [PMID: 30476957]
  15. Cegla J, Neely RDG, France M, Ferns G, Byrne CD, Halcox J, Datta D, Capps N, Shoulders C, Qureshi N, Rees A, Main L, Cramb R, Viljoen A, Payne J, Soran H (2019) HEART UK consensus statement on lipoprotein(a): a call to action. Atherosclerosis 291:62–70 [PMID: 31704552]
  16. Chen HY, Dufresne L, Burr H, Ambikkumar A, Yasui N, Luk K, Ranatunga DK, Whitmer RA, Lathrop M, Engert JC, Thanassoulis G (2018) Association of LPA variants with aortic stenosis: a large-scale study using diagnostic and procedural codes from electronic health records. JAMA Cardiol 3:18–23 [PMID: 29128868]
  17. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 361:2518–2528 [PMID: 20032323]
  18. Coassin S, Kronenberg F (2020) Mechanistic insights into lipoprotein(a): from infamous to ‘inflammous’. Eur Heart J 41:2272–2274 [PMID: 32445566]
  19. Coassin S, Erhart G, Weissensteiner H, de Eca Guimaraes AM, Lamina C, Schönherr S, Forer L, Haun M, Losso JL, Köttgen A, Schmidt K, Utermann G, Peters A, Gieger C, Strauch K, Finkenstedt A, Bale R, Zoller H, Paulweber B, Eckardt KU, Hüttenhofer A, Huber LA, Kronenberg F (2017) A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction. Eur Heart J 38:1823–1831 [PMID: 28444229]
  20. Coassin S, Schoenherr S, Weissensteiner H, Erhart G, Forer L, Losso JL, Lamina C, Haun M, Utermann G, Paulweber B, Specht G, Kronenberg F (2019) A comprehensive map of single base polymorphisms in the hypervariable LPA Kringle IV-2 copy number variation region. J Lipid Res 60:186–199 [PMID: 30413653]
  21. Cohen JC, Chiesa G, Hobbs HH (1993) Sequence polymorphisms in the apolipoprotein (a) gene. Evidence for dissociation between apolipoprotein(a) size and plasma lipoprotein(a) levels. J Clin Invest 91:1630–1636 [PMID: 8473506]
  22. Dahabreh IJ, Kent DM (2011) Index event bias as an explanation for the paradoxes of recurrence risk research. JAMA 305:822–823 [PMID: 21343582]
  23. Di Maio S, Grüneis R, Streiter G, Lamina C, Maglione M, Schoenherr S, Öfner D, Thorand B, Peters A, Eckardt K-U, Köttgen A, Kronenberg F, Coassin S (2020) Investigation of a nonsense mutation located in the complex KIV-2 copy number variation region of apolipoprotein(a) in 10,910 individuals. Genome Med 12:74 [PMID: 32825847]
  24. Dieplinger B, Lingenhel A, Baumgartner N, Poelz W, Dieplinger H, Haltmayer M, Kronenberg F, Mueller T (2007) Increased serum lipoprotein(a) concentrations and low molecular weight phenotypes of apolipoprotein(a) are associated with symptomatic peripheral arterial disease. Clin Chem 53:1298–1305 [PMID: 17525104]
  25. Erqou S, Kaptoge S, Perry PL, Di AE, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302:412–423 [PMID: 19622820]
  26. Erqou S, Thompson A, Di AE, Saleheen D, Kaptoge S, Marcovina S, Danesh J (2010) Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 55:2160–2167 [PMID: 20447543]
  27. Ford J, Lawson M, Fowler D, Maruyama N, Mito S, Tomiyasu K, Kinoshita S, Suzuki C, Kawaguchi A, Round P, Boyce M, Warrington S, Weber W, van Deventer S, Kastelein JJ (2014) Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Br J Clin Pharmacol 78:498–508 [PMID: 24628035]
  28. Frischmann ME, Kronenberg F, Trenkwalder E, Schaefer J, Schweer H, Dieplinger B, König P, Ikewaki K, Dieplinger H (2007) In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients. Kidney Int 71:1036–1043 [PMID: 17299521]
  29. Grainger DJ, Kirschenlohr HL, Metcalfe JC, Weissberg PL, Wade DP, Lawn RM (1993) Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science 260:1655–1658 [PMID: 8503012]
  30. Guan W, Cao J, Steffen BT, Post WS, Stein JH, Tattersall MC, Kaufman JD, McConnell JP, Hoefner DM, Warnick R, Tsai MY (2015) Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 35:996–1001 [PMID: 25810300]
  31. Gurdasani D, Sjouke B, Tsimikas S, Hovingh GK, Luben RN, Wainwright NW, Pomilla C, Wareham NJ, Khaw KT, Boekholdt SM, Sandhu MS (2012) Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol 32:3058–3065 [PMID: 23065826]
  32. Hindy G, Aragam KG, Ng K, Chaffin M, Lotta LA, Baras A, Regeneron Genetics C, Drake I, Orho-Melander M, Melander O, Kathiresan S, Khera AV (2020) Genome-wide polygenic score, clinical risk factors, and long-term trajectories of coronary artery disease. Arterioscler Thromb Vasc Biol 40:2738–2746 [PMID: 32957805]
  33. Hoekstra M, Chen HY, Rong J, Dufresne L, Yao J, Guo X, Tsai MY, Tsimikas S, Post WS, Vasan RS, Rotter JI, Larson MG, Thanassoulis G, Engert JC (2021) Genome-wide association study highlights APOH as a novel locus for lipoprotein(a) levels. Arterioscler Thromb Vasc Biol 41:ATVBAHA120314965
  34. HPS3/TIMI55–REVEAL Collaborative Group, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, Collins R, Wiviott SD, Cannon CP, Braunwald E, Sammons E, Landray MJ (2017) Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 377:1217–1227
  35. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, Parhofer K, Ramlow W, Koch M, Utermann G, Labarrere CA, Seidel D (2009) 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 6:229–239 [PMID: 19234501]
  36. Julius U, Tselmin S, Schatz U, Fischer S, Birkenfeld AL, Bornstein SR (2019) Actual situation of lipoprotein apheresis in patients with elevated lipoprotein(a) levels. Atheroscler Suppl 40:1–7 [PMID: 31818437]
  37. Kamstrup PR, Nordestgaard BG (2016) Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population. J Am Coll Cardiol Heart Fail 4:78–87
  38. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG (2009) Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301:2331–2339 [PMID: 19509380]
  39. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2014) Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 63:470–477 [PMID: 24161338]
  40. Kannel WB, Dawber TR, Friedman GD, GLENNON WE, McNamara PM (1964) Risk factors in coronary heart disease.An evaluation of several serum lipids as predictors of coronary heart disease. The Framingham study. Ann Intern Med 61:888–899 [PMID: 14233810]
  41. Khan TZ, Hsu LY, Arai AE, Rhodes S, Pottle A, Wage R, Banya W, Gatehouse PD, Giri S, Collins P, Pennell DJ, Barbir M (2017) Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomized controlled cross-over trial. Eur Heart J 38:1561–1569 [PMID: 28453721]
  42. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, Mora S (2014) 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 129:635–642 [PMID: 24243886]
  43. Kiechl S, Willeit J, Mayr M, Viehweider B, Oberhollenzer F, Kronenberg F, Wiedermann CJ, Oberthaler S, Xu Q, Witztum JL, Tsimikas S (2007) Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol 27:1788–1795 [PMID: 17541022]
  44. Kinpara K, Okada H, Yoneyama A, Okubo M, Murase T (2011) Lipoprotein(a)-cholesterol: a significant component of serum cholesterol. Clin Chim Acta 412:1783–1787 [PMID: 21672532]
  45. Klarin D, Lynch J, Aragam K, Chaffin M, Assimes TL, Huang J, Lee KM, Shao Q, Huffman JE, Natarajan P, Arya S, Small A, Sun YV, Vujkovic M, Freiberg MS, Wang L, Chen J, Saleheen D, Lee JS, Miller DR, Reaven P, Alba PR, Patterson OV, DuVall SL, Boden WE, Beckman JA, Gaziano JM, Concato J, Rader DJ, Cho K, Chang KM, Wilson PWF, O'Donnell CJ, Kathiresan S, Tsao PS, Damrauer SM (2019) Genome-wide association study of peripheral artery disease in the million veteran program. Nat Med 25:1274–1279 [PMID: 31285632]
  46. Klezovitch O, Edelstein C, Scanu AM (2001) Stimulation of interleukin-8 production in human THP-1 macrophages by apolipoprotein (a): evidence for a critical involvement of elements in its C-terminal domain. J Biol Chem 276:46864–46869 [PMID: 11591715]
  47. Köchl S, Fresser F, Lobentanz E, Baier G, Utermann G (1997) Novel interaction of apolipoprotein(a) with b-2 glycoprotein I mediated by the kringle IV domain. Blood 90:1482–1489 [PMID: 9269765]
  48. Koschinsky ML, Marcovina SM (2004) Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol 15:167–174 [PMID: 15017359]
  49. Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL (1989) HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 80:1313–1319 [PMID: 2530005]
  50. Kraft HG, Menzel HJ, Hoppichler F, Vogel W, Utermann G (1989) Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis. J Clin Invest 83:137–142 [PMID: 2521341]
  51. Kraft HG, Köchl S, Menzel HJ, Sandholzer C, Utermann G (1992) The apolipoprotein(a) gene: a transcribed hypervariable locus controlling plasma lipoprotein(a) concentration. Hum Genet 90:220–230 [PMID: 1336760]
  52. Kraft HG, Lingenhel A, Köchl S, Hoppichler F, Kronenberg F, Abe A, Mühlberger V, Schönitzer D, Utermann G (1996) Apolipoprotein(a) Kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol 16:713–719 [PMID: 8640397]
  53. Kronenberg F (2014a) Lipoprotein(a) in various conditions: to keep a sense of proportions. Atherosclerosis 234:249–251 [PMID: 24612688]
  54. Kronenberg F (2014b) Lipoprotein(a): there's life in the old dog yet. Circulation 129:619–621 [PMID: 24515955]
  55. Kronenberg F (2016a) High-density lipoprotein cholesterol on a roller coaster: where will the ride end? Kidney Int 89:747–749 [PMID: 26994572]
  56. Kronenberg F (2016b) Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther 30:87–100 [PMID: 26896185]
  57. Kronenberg F (2019a) Prediction of cardiovascular risk by Lp(a) concentrations or genetic variants within the LPA gene region. Clin Res Cardiol Suppl 14:5–12 [PMID: 30859385]
  58. Kronenberg F (2019b) Therapeutic lowering of lipoprotein(a): how much is enough? Atherosclerosis 288:163–165 [PMID: 31327477]
  59. Kronenberg F, Tsimikas S (2019) The challenges of measuring Lp(a): a fight against Hydra? Atherosclerosis 289:181–183 [PMID: 31495537]
  60. Kronenberg F, Utermann G (2013) Lipoprotein(a) – resurrected by genetics. J Intern Med 273:6–30 [PMID: 22998429]
  61. Kronenberg F, Trenkwalder E, Lingenhel A, Friedrich G, Lhotta K, Schober M, Moes N, König P, Utermann G, Dieplinger H (1997) Renovascular arteriovenous differences in Lp(a) plasma concentrations suggest removal of Lp(a) from the renal circulation. J Lipid Res 38:1755–1763 [PMID: 9323585]
  62. Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, Egger G, Utermann G, Willeit J (1999) Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation 100:1154–1160 [PMID: 10484534]
  63. Kronenberg F, Lingenhel A, Lhotta K, Rantner B, Kronenberg MF, König P, Thiery J, Koch M, Von Eckardstein A, Dieplinger H (2004) Lipoprotein(a)- and low-density lipoprotein-derived cholesterol in nephrotic syndrome: impact on lipid-lowering therapy? Kidney Int 66:348–354 [PMID: 15200443]
  64. Lackner C, Boerwinkle E, Leffert CC, Rahmig T, Hobbs HH (1991) Molecular basis of apolipoprotein (a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis. J Clin Invest 87:2153–2161 [PMID: 1645755]
  65. Lackner C, Cohen JC, Hobbs HH (1993) Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet 2:933–940 [PMID: 8395942]
  66. Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, Baxter JD, Angelin B (2010) Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 362:906–916 [PMID: 20220185]
  67. Lamina C, Kronenberg F (2019) Estimation of the required lipoprotein(a)-lowering therapeutic effect size for reduction in coronary heart disease outcomes: a Mendelian randomization analysis. JAMA Cardiol 4:575–579 [PMID: 31017618]
  68. Lamon-Fava S, Jimenez D, Christian JC, Fabsitz RR, Reed T, Carmelli D, Castelli WP, Ordovas JM, Wilson PWF, Schaefer EJ (1991) The NHLBI twin study: heritability of apolipoprotein A-I and B, and low density lipoprotein subclasses and concordance for lipoprotein(a). Atherosclerosis 91:97–106 [PMID: 1839820]
  69. Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Luscher TF (2020) From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J 41:3884–3899 [PMID: 32350510]
  70. Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J (2014) Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 371:203–212 [PMID: 25014686]
  71. Langsted A, Kamstrup PR, Nordestgaard BG (2014) Lipoprotein(a): fasting and nonfasting levels, inflammation, and cardiovascular risk. Atherosclerosis 234:95–101 [PMID: 24632508]
  72. Langsted A, Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG (2016) High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol 4:577–587 [PMID: 27185354]
  73. Langsted A, Nordestgaard BG, Kamstrup PR (2019a) Elevated lipoprotein(a) and risk of ischemic stroke. J Am Coll Cardiol 74:54–66 [PMID: 31272552]
  74. Langsted A, Kamstrup PR, Nordestgaard BG (2019b) High lipoprotein(a) and high risk of mortality. Eur Heart J 40:2760–2770
  75. Laschkolnig A, Kollerits B, Lamina C, Meisinger C, Rantner B, Stadler M, Peters A, Koenig W, Stöckl A, Dähnhardt D, Böger CA, Krämer BK, Fraedrich G, Strauch K, Kronenberg F (2014) Lipoprotein(a) concentrations, apolipoprotein(a) phenotypes and peripheral arterial disease in three independent cohorts. Cardiovasc Res 103:28–36 [PMID: 24760552]
  76. Lee SR, Prasad A, Choi YS, Xing C, Clopton P, Witztum JL, Tsimikas S (2017) LPA gene, ethnicity, and cardiovascular events. Circulation 135:251–263 [PMID: 27831500]
  77. Leebmann J, Roseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breitenberger P, Maerz W, Lehmacher W, Heibges A, Klingel R (2013) Lipoprotein apheresis in patients with maximally tolerated lipid lowering therapy, Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease: prospective observational multicenter study. Circulation 128:2567–2576 [PMID: 24056686]
  78. Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, Yang X, Dennis E, Witztum JL, Koschinsky ML, Tsimikas S (2013) Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res 54:2815–2830 [PMID: 23828779]
  79. Li J, Lange LA, Sabourin J, Duan Q, Valdar W, Willis MS, Li Y, Wilson JG, Lange EM (2015) Genome- and exome-wide association study of serum lipoprotein (a) in the Jackson heart study. J Hum Genet 60:755–761 [PMID: 26377243]
  80. Lim ET, Wurtz P, Havulinna AS, Palta P, Tukiainen T, Rehnstrom K, Esko T, Magi R, Inouye M, Lappalainen T, Chan Y, Salem RM, Lek M, Flannick J, Sim X, Manning A, Ladenvall C, Bumpstead S, Hamalainen E, Aalto K, Maksimow M, Salmi M, Blankenberg S, Ardissino D, Shah S, Horne B, McPherson R, Hovingh GK, Reilly MP, Watkins H, Goel A, Farrall M, Girelli D, Reiner AP, Stitziel NO, Kathiresan S, Gabriel S, Barrett JC, Lehtimaki T, Laakso M, Groop L, Kaprio J, Perola M, McCarthy MI, Boehnke M, Altshuler DM, Lindgren CM, Hirschhorn JN, Metspalu A, Freimer NB, Zeller T, Jalkanen S, Koskinen S, Raitakari O, Durbin R, MacArthur DG, Salomaa V, Ripatti S, Daly MJ, Palotie A (2014) Distribution and medical impact of loss-of-function variants in the finnish founder population. PLoS Genet 10:e1004494 [PMID: 25078778]
  81. Mach F, Baigent C, Catapano AL, Koskina KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, Windecker S, Aboyans V, Collet JP, Dean V, Fitzsimons D, Gale CP, Grobbee D, Halvorsen S, Hindricks G, Iung B, Jüni P, Katus HA, Leclercq C, Lettino M, Lewis BS, Merkely B, Mueller C, Petersen S, Petronio AS, Roffi M, Shlyakhto E, Simpson IA, Sousa-Uva M, Touyz RM, Nibouche D, Zelveian PH, Siostrzonek P, Najafov R, van de Borne P, Pojskic B, Postadzhiyan A, Kypris L, Špinar J, Larsen ML, Eldin HS, Viigimaa M, Strandberg TE, Ferrières J, Agladze R, Laufs U, Rallidis L, Bajnok L, Gudjónsson T, Maher V, Henkin Y, Gulizia MM, Mussagaliyeva A, Bajraktari G, Kerimkulova A, Latkovskis G, Hamoui O, Slapikas R, Visser L, Dingli P, Ivanov V, Boskovic A, Nazzi M, Visseren F, Mitevska I, Retterstøl K, Jankowski P, Fontes-Carvalho R, Gaita D, Ezhov M, Foscoli M, Giga V, Pella D, Fras Z, Perez de Isla L, Hagström E, Lehmann R, Abid L, Ozdogan O, Mitchenko O, Patel RS (2019) ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis 290:140–205
  82. Mack S, Coassin S, Rueedi R, Yousri NA, Seppala I, Gieger C, Schoenherr S, Forer L, Erhart G, Marques-Vidal P, Ried JS, Waeber G, Bergmann S, Daehnhardt D, Stoeckl A, Raitakari OT, Khahonen M, Peters A, Meitinger T, Strauch K, Kedenko L, Paulweber B, Lehtimaki T, Hunt SC, Vollenweider P, Lamina C, Kronenberg F, Grp K-S (2017) A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms. J Lipid Res 58:1834–1844 [PMID: 28512139]
  83. Madsen CM, Kamstrup PR, Langsted A, Varbo A, Nordestgaard BG (2020) Lp(a) (lipoprotein[a])-lowering by 50 mg/dL (105 nmol/L) may be needed to reduce cardiovascular disease 20% in secondary prevention: a population-based study. Arterioscler Thromb Vasc Biol 40:255–266 [PMID: 31578080]
  84. McCormick SPA, Schneider WJ (2019) Lipoprotein(a) catabolism: a case of multiple receptors. Pathology 51:155–164 [PMID: 30595508]
  85. McLean JW, Tomlinson JE, Kuang W-J, Eaton DL, Chen EY, Fless GM, Scanu AM, Lawn RM (1987) cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 330:132–137 [PMID: 3670400]
  86. Miltiadous G, Saougos V, Cariolou M, Elisaf MS (2006) Plasma lipoprotein(a) levels and LDL-cholesterol lowering response to statin therapy in patients with heterozygous familial hypercholesterolemia. Ann Clin Lab Sci 36:353–355 [PMID: 16951279]
  87. Mooser V, Marcovina SM, White AL, Hobbs HH (1996) Kringle-containing fragments of apolipoprotein(a) circulate in human plasma and are excreted into the urine. J Clin Invest 98:2414–2424 [PMID: 8941661]
  88. Morgan BM, Brown AN, Deo N, Harrop TWR, Taiaroa G, Mace PD, Wilbanks SM, Merriman TR, Williams MJA, McCormick SPA (2020) Nonsynonymous SNPs in LPA homologous to plasminogen deficiency mutants represent novel null apo(a) alleles. J Lipid Res 61:432–444 [PMID: 31806727]
  89. Moriarty PM, Gray JV, Gorby LK (2019) Lipoprotein apheresis for lipoprotein(a) and cardiovascular disease. J Clin Lipidol 13:894–900 [PMID: 31753721]
  90. Nicholls SJ, Ruotolo G, Brewer HB, Wang MD, Liu L, Willey MB, Deeg MA, Krueger KA, Nissen SE (2016) Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients. J Clin Lipidol 10:519–527 [PMID: 27206939]
  91. Nordestgaard BG, Langsted A (2016) Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 57:1953–1975 [PMID: 27677946]
  92. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 31:2844–2853 [PMID: 20965889]
  93. Nowak-Gottl U, Junker R, Hartmeier M, Koch HG, Munchow N, Assmann G, Von Eckardstein A (1999) Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood. Circulation 100:743–748 [PMID: 10449697]
  94. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira PA, Wasserman SM, Ceska R, Ezhov MV, Jukema JW, Jensen HK, Tokgozoglu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS (2019) Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 139:1483–1492 [PMID: 30586750]
  95. Ober C, Nord AS, Thompson EE, Pan L, Tan Z, Cusanovich D, Sun Y, Nicolae R, Edelstein C, Schneider DH, Billstrand C, Pfaffinger D, Phillips N, Anderson RL, Philips B, Rajagopalan R, Hatsukami TS, Rieder MJ, Heagerty PJ, Nickerson DA, Abney M, Marcovina S, Jarvik GP, Scanu AM, Nicolae DL (2009) Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J Lipid Res 50:798–806 [PMID: 19124843]
  96. O'Donoghue ML, Morrow DA, Tsimikas S, Sloan S, Ren AF, Hoffman EB, Desai NR, Solomon SD, Domanski M, Arai K, Chiuve SE, Cannon CP, Sacks FM, Sabatine MS (2014) Lipoprotein(a) for risk assessment in patients with established coronary artery disease. J Am Coll Cardiol 63:520–527 [PMID: 24161323]
  97. Pare G, Caku A, McQueen M, Anand SS, Enas E, Clarke R, Boffa MB, Koschinsky M, Wang X, Yusuf S (2019) Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups. Circulation 139:1472–1482 [PMID: 30667276]
  98. Parson W, Kraft HG, Niederstatter H, Lingenhel AW, Kochl S, Fresser F, Utermann G (2004) A common nonsense mutation in the repetitive Kringle IV-2 domain of human apolipoprotein(a) results in a truncated protein and low plasma Lp(a). Hum Mutat 24:474–480 [PMID: 15523644]
  99. Patel AP, Wang M, Pirruccello JP, Ellinor PT, Ng K, Kathiresan S, Khera AV (2021) Lp(a) (lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank. Arterioscler Thromb Vasc Biol 41:465–474 [PMID: 33115266]
  100. Perombelon YFN, Soutar AK, Knight BL (1994) Variation in lipoprotein(a) concentration associated with different apolipoprotein(a) alleles. J Clin Invest 93:1481–1492 [PMID: 8163653]
  101. Perrot N, Theriault S, Dina C, Chen HY, Boekholdt SM, Rigade S, Despres AA, Poulin A, Capoulade R, Le TT, Messika-Zeitoun D, Trottier M, Tessier M, Guimond J, Nadeau M, Engert JC, Khaw KT, Wareham NJ, Dweck MR, Mathieu P, Pibarot P, Schott JJ, Thanassoulis G, Clavel MA, Bosse Y, Arsenault BJ (2019) Genetic variation in LPA, calcific aortic valve stenosis in patients undergoing cardiac surgery, and familial risk of aortic valve microcalcification. JAMA Cardiol 4:620–627 [PMID: 31141105]
  102. Poon M, Zhang XX, Dunsky KG, Taubman MB, Harpel PC (1997) Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation 96:2514–2519 [PMID: 9355887]
  103. Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, Lachmann RH, Gaudet D, Tan JL, Chasan-Taber S, Tribble DL, Flaim JD, Crooke ST (2010) Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375:998–1006 [PMID: 20227758]
  104. Rader DJ, Cain W, Ikewaki K, Talley G, Zech LA, Usher D, Brewer HB (1994) The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate. J Clin Invest 93:2758–2763 [PMID: 8201014]
  105. Ray KK, Stoekenbroek RM, Kallend D, Leiter LA, Landmesser U, Scott Wright R, Wijngaard P, Kastelein JJP (2018) Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins: prespecified secondary end points in Orion 1. Circulation 138:1304–1316 [PMID: 29735484]
  106. Ray KK, Vallejo-Vaz AJ, Ginsberg HN, Davidson MH, Louie MJ, Bujas-Bobanovic M, Minini P, Eckel RH, Cannon CP (2019) Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis 288:194–202 [PMID: 31253441]
  107. Ripatti S, Tikkanen E, Orho-Melander M, Havulinna AS, Silander K, Sharma A, Guiducci C, Perola M, Jula A, Sinisalo J, Lokki ML, Nieminen MS, Melander O, Salomaa V, Peltonen L, Kathiresan S (2010) A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 376:1393–1400 [PMID: 20971364]
  108. Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breitenberger P, Leebmann J, Lehmacher W, Kamstrup PR, Nordestgaard BG, Maerz W, Noureen A, Schmidt K, Kronenberg F, Heibges A, Klingel R (2016) Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) characterization. Arterioscler Thromb Vasc Biol 36:2019–2027 [PMID: 27417585]
  109. Romagnuolo R, Scipione CA, Bazzi ZA, Boffa MB, Koschinsky ML (2018) Inhibition of pericellular plasminogen activation by apolipoprotein(a): roles of urokinase plasminogen activator receptor and integrins aMb2 and aVb3. Atherosclerosis 275:11–21 [PMID: 29852400]
  110. Safarova MS, Ezhov MV, Afanasieva OI, Matchin YG, Atanesyan RV, Adamova IY, Utkina EA, Konovalov GA, Pokrovsky SN (2013) Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography. Atheroscler Suppl 14:93–99 [PMID: 23357149]
  111. Saleheen D, Haycock PC, Zhao W, Rasheed A, Taleb A, Imran A, Abbas S, Majeed F, Akhtar S, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Mallick NH, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Frossard P, Tsimikas S, Witztum JL, Marcovina S, Sandhu M, Rader DJ, Danesh J (2017) Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol 5:524–533 [PMID: 28408323]
  112. Samaha FF, McKenney J, Bloedon LT, Sasiela WJ, Rader DJ (2008) Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med 5:497–505 [PMID: 18506154]
  113. Sandholzer C, Saha N, Kark JD, Rees A, Jaross W, Dieplinger H, Hoppichler F, Boerwinkle E, Utermann G (1992) Apo(a) isoforms predict risk for coronary heart disease: a study in six populations. Arterioscler Thromb 12:1214–1226 [PMID: 1390593]
  114. Scanu AM, Hinman J (2002) Issues concerning the monitoring of statin therapy in hypercholesterolemic subjects with high plasma lipoprotein(a) levels. Lipids 37:439–444 [PMID: 12056584]
  115. Scharnagl H, Stojakovic T, Dieplinger B, Dieplinger H, Erhart G, Kostner GM, Hermann M, März W, Grammer TB (2019) Comparison of lipoprotein(a) serum concentrations measured by six commercially available immunoassays. Atherosclerosis 289:206–213 [PMID: 31493849]
  116. Smits LJ, van Kuijk SM, Leffers P, Peeters LL, Prins MH, Sep SJ (2013) Index event bias-a numerical example. J Clin Epidemiol 66:192–196 [PMID: 23257150]
  117. Stiekema LCA, Stroes ESG, Verweij SL, Kassahun H, Chen L, Wasserman SM, Sabatine MS, Mani V, Fayad ZA (2019) Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. Eur Heart J 40:2775–2781 [PMID: 30561610]
  118. Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, Kroon J, Schnitzler JG, Dzobo KE, Cupido AJ, Tsimikas S, Stroes ESG, de Winther MPJ, Bahjat M (2020) Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a). Eur Heart J 41:2262–2271 [PMID: 32268367]
  119. Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, Kerr KF, Pechlivanis S, Budoff MJ, Harris TB, Malhotra R, O’Brien KD, Kamstrup PR, Nordestgaard BG, Tybjaerg-Hansen A, Allison MA, Aspelund T, Criqui MH, Heckbert SR, Hwang SJ, Liu Y, Sjogren M, van der Pals J, Kalsch H, Muhleisen TW, Nothen MM, Cupples LA, Caslake M, Di AE, Danesh J, Rotter JI, Sigurdsson S, Wong Q, Erbel R, Kathiresan S, Melander O, Gudnason V, O’Donnell CJ, Post WS (2013) Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 368:503–512 [PMID: 23388002]
  120. Thomas T, Zhou H, Karmally W, Ramakrishnan R, Holleran S, Liu Y, Jumes P, Wagner JA, Hubbard B, Previs SF, Roddy T, Johnson-Levonas AO, Gutstein DE, Marcovina SM, Rader DJ, Ginsberg HN, Millar JS, Reyes-Soffer G (2017) CETP (cholesteryl ester transfer protein) inhibition with anacetrapib decreases production of lipoprotein(a) in mildly hypercholesterolemic subjects. Arterioscler Thromb Vasc Biol 37:1770–1775 [PMID: 28729361]
  121. Tomlinson JE, McLean JW, Lawn RM (1989) Rhesus monkey apolipoprotein(a). Sequence, evolution, and sites of synthesis. J Biol Chem 264:5957–5965 [PMID: 2925643]
  122. Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS, Witztum JL, Berger PB (2005) Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 353:46–57 [PMID: 16000355]
  123. Tsimikas S, Mallat Z, Talmud PJ, Kastelein JJ, Wareham NJ, Sandhu MS, Miller ER, Benessiano J, Tedgui A, Witztum JL, Khaw KT, Boekholdt SM (2010) Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events. J Am Coll Cardiol 56:946–955 [PMID: 20828647]
  124. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker BF, Burkey JL, Yang Q, Marcovina SM, Geary RS, Crooke RM, Witztum JL (2015) Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386:1472–1483 [PMID: 26210642]
  125. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L, Witztum JL (2020a) Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 382:244–255 [PMID: 31893580]
  126. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL (2020b) Statin therapy increases lipoprotein(a) levels. Eur Heart J 41:2275–2284 [PMID: 31111151]
  127. Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL (2020c) Statins and increases in Lp(a): an inconvenient truth that needs attention. Eur Heart J 41:192–193 [PMID: 31893480]
  128. Utermann G (1989) The mysteries of lipoprotein(a). Science 246:904–910 [PMID: 2530631]
  129. Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C (1987) Lp(a) glycoprotein phenotypes: inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest 80:458–465 [PMID: 2956279]
  130. Utermann G, Hoppichler F, Dieplinger H, Seed M, Thompson G, Boerwinkle E (1989) Defects in the low density lipoprotein receptor gene affect lipoprotein (a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci U S A 86:4171–4174 [PMID: 2524837]
  131. van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, Nieuwdorp M, Joosten LA, Netea MG, Koschinsky ML, Witztum JL, Tsimikas S, Riksen NP, Stroes ES (2016) Oxidized phospholipids on lipoprotein(a) elicit Arterial Wall inflammation and an inflammatory monocyte response in humans. Circulation 134:611–624 [PMID: 27496857]
  132. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke ST, Witztum JL, Stroes ES, Tsimikas S (2016) Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 388:2239–2253 [PMID: 27665230]
  133. Virani SS, Brautbar A, Davis BC, Nambi V, Hoogeveen RC, Sharrett AR, Coresh J, Mosley TH, Morrisett JD, Catellier DJ, Folsom AR, Boerwinkle E, Ballantyne CM (2012) Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the atherosclerosis risk in communities (ARIC) study. Circulation 125:241–249 [PMID: 22128224]
  134. Vongpromek R, Bos S, Ten Kate GJ, Yahya R, Verhoeven AJ, De Feyter PJ, Kronenberg F, van Lennep JE, Sijbrands EJ, Mulder MT (2015) Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia. J Intern Med 278:166–173 [PMID: 25487646]
  135. Vuorio A, Watts GF, Kovanen PT (2019) Lipoprotein(a) as a risk factor for calcific aortic valvulopathy in heterozygous familial hypercholesterolemia. Atherosclerosis 281:25–30 [PMID: 30616181]
  136. Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, Kronenberg F, Drechsler C, Wanner C, Mora S, Lesogor A, Tsimikas S (2018) Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 392:1311–1320 [PMID: 30293769]
  137. Yahya R, Berk K, Verhoeven A, Bos S, van der Zee L, Touw J, Erhart G, Kronenberg F, Timman R, Sijbrands E, van Roeters LJ, Mulder M (2019) Statin treatment increases lipoprotein(a) levels in subjects with low molecular weight apolipoprotein(a) phenotype. Atherosclerosis 289:201–205 [PMID: 31327478]
  138. Yeang C, Witztum JL, Tsimikas S (2021) Novel method for quantification of lipoprotein(a)-cholesterol: implications for improving accuracy of LDL-C measurements. J Lipid Res 62:100053. https://doi.org/10.1016/j.jlr.2021.100053
  139. Zhang J, Du R, Peng K, Wu X, Hu C, Li M, Xu Y, Xu M, Wang S, Bi Y, Wang W, Lu J, Chen Y (2019) Serum lipoprotein (a) is associated with increased risk of stroke in Chinese adults: a prospective study. Atherosclerosis 289:8–13 [PMID: 31437611]

MeSH Term

Blood Component Removal
Cardiovascular Diseases
Cholesterol, LDL
Humans
Lipoprotein(a)
Proprotein Convertase 9
Risk Factors

Chemicals

Cholesterol, LDL
Lipoprotein(a)
PCSK9 protein, human
Proprotein Convertase 9
Journal Article
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0LpconcentrationscardiovasculargenetictherapiesriskdiseaseLDLcholesterolLipoproteineventstargetalsolowerlipoprotein90%geneeven50 mg/dLassociatedincreasedSincevariantssupportMendelianrandomizationstudiesspecificallylowersstudyloweringmainRNAdecrease[Lp]atherogenicstrongregulationexplainedsingleLPAshowseveral-hundred-foldinterindividualvariabilityrangingless01 mg/dL300 mg/dLplasma30 mg/dLincludingmyocardialinfarctionstrokeaorticvalvestenosisheartfailureperipheralarterialall-causemortalityobservedroughly20%CaucasianpopulationhigherfrequencyAfrican-AmericanAsian-IndianethnicitiescanassumedoneimportantgeneticallydeterminedfactorsCarriershighmarkedlyStudiesusedinstrumentcausalrolefactorcalledprincipletypeintroducedtestedfirsttimeeverdeterminantsTherecurrentlyapprovedpharmacologicHoweverprimarilyinfluencemainlyPCSK9inhibitors60%25-30%Furthermoreapheresis60-70%sophisticateddesignsstatisticalanalysesprovidedtopeffectcausedalthoughtherapyCurrentlynewtargetingantisenseoligonucleotidesASOsmallinterferingsiRNAapolipoproteinproteinparticleexaminationwithoutinfluencinglipoproteinswillservelastpiecepuzzlewhetherresultsApolipoproteinAssociationCardiovascularCopynumbervariationTherapy

Similar Articles

Cited By