Medicine:Lipoprotein(a)

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Short description: Low-density lipoprotein containing apolipoprotein(a)


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.[1][2][3][4]

Lipoprotein(a) was discovered in 1963 by Kåre Berg.[5] The human gene encoding apolipoprotein(a) was successfully cloned in 1987.[6]

Structure

Lipoprotein(a) [Lp(a)] consists of an LDL-like particle and the specific apolipoprotein(a), which is bound covalently to the apoB contained in the outer shell of the particle. Lp(a) plasma concentrations are highly heritable and mainly controlled by the LPA gene located on chromosome 6q26-27. Apo(a) proteins vary in size due to a size polymorphism [KIV-2 VNTR], which is caused by a variable number of kringle IV repeats in the LPA gene. This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to more than 50 kringle IV repeats (each of the variable kringle IV consists of 114 amino acids).[6][7] These variable apo(a) sizes are known as "apo(a) isoforms".

There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration.[8] One theory explaining this correlation involves different rates of protein synthesis. Specifically, the larger the isoform, the more apo(a) precursor protein accumulates intracellularly in the endoplasmic reticulum. Lp(a) is not fully synthesised until the precursor protein is released from the cell, so the slower rate of production for the larger isoforms limits the plasma concentration.[9][10]

Populations

Lp(a) concentrations can vary by more than one thousand between individuals, from <0.2 to >200 mg/dL. This range of concentrations is observed in all populations studied by scientists so far. The mean and median concentrations differ among world populations. Most prominently, there is a two- to threefold higher mean Lp(a) plasma concentration in populations of African descent compared to Asian, Oceanic, or European populations. The general inverse correlation between apo(a) isoform size and Lp(a) plasma concentration is observed in all populations.[8] However, it was also discovered that mean Lp(a) associated with certain apo(a) isoforms varies between populations.

In addition to size effects, mutations in the LPA promoter may lead to a decreased apo(a) production.[11]

Function and pathology

Lp(a) is assembled at the hepatocyte cell membrane surface, which is similar to typical LDL particles. However, there are other possible locations of assembly. The particles mainly exist in plasma.[12][13][14][15]

Lp(a) contributes to the process of atherogenesis. The structure of apolipoprotein(a) is similar to plasminogen and tPA (tissue plasminogen activator) and it competes with plasminogen for its binding site, leading to reduced fibrinolysis. Also, because Lp(a) stimulates secretion of PAI-1, it leads to thrombogenesis.[16][17][18] It also may enhance coagulation by inhibiting the function of tissue factor pathway inhibitor.[19]

Moreover, Lp(a) carries atherosclerosis-causing cholesterol and binds atherogenic pro-inflammatory oxidised phospholipids as a preferential carrier of oxidised phospholipids in human plasma,[20] which attracts inflammatory cells to vessel walls and leads to smooth muscle cell proliferation.[21][22][23] Moreover, Lp(a) also is hypothesised to be involved in wound healing and tissue repair by interacting with components of the vascular wall and extracellular matrix.[24][25] Apo(a), a distinct feature of the Lp(a) particle, binds to immobilized fibronectin and endows Lp(a) with the serine-proteinase-type proteolytic activity.[26]

Nonetheless, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy.[citation needed] Thus, plasma Lp(a) is not vital, at least under normal environmental conditions.[citation needed] Since apo(a)/Lp(a) appeared rather recently in mammalian evolution – only old world monkeys and humans have been shown to harbour Lp(a) – its function might not be vital, but just evolutionarily advantageous under certain environmental conditions, e.g. in case of exposure to certain infectious diseases.[11]

Another possibility, suggested by Linus Pauling, is that Lp(a) is a primate adaptation to L-gulonolactone oxidase (GULO) deficiency, found only in certain lines of mammals. GULO is required for converting glucose to ascorbic acid (vitamin C), which is needed to repair arteries; following the loss of GULO, those primates who adopted diets less abundant in vitamin C may have used Lp(a) as an ascorbic-acid surrogate to repair arterial walls.[27]

Catabolism and clearance

The half-life of Lp(a) in circulation is approximately three to four days.[13] The mechanism and sites of Lp(a) catabolism are largely unknown. Uptake via the LDL receptor is not a major pathway of Lp(a) metabolism.[28][29] The kidney has been identified as playing a role in Lp(a) clearance from plasma.[30]

Disease

High Lp(a) in blood correlates with coronary heart disease (CHD), cardiovascular disease (CVD), atherosclerosis, thrombosis, and stroke.[31] However, the association between Lp(a) levels and stroke is not as strong as that between Lp(a) and cardiovascular disease.[1] Lp(a) concentrations may be affected by disease states (for example kidney failure), but are only slightly affected by diet, exercise, and other environmental factors.

Most commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Results using statin medications have been mixed in most trials, although a meta-analysis published in 2012 suggests that atorvastatin may be of benefit.[32]

Niacin (Vitamin B3) has been shown to reduce the levels of Lp(a) significantly in individuals with high levels of low-molecular weight Lp(a).[33][34]

High Lp(a) correlates with early atherosclerosis independently of other cardiac risk factors, including LDL. In patients with advanced cardiovascular disease, Lp(a) indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains that are very similar to plasminogen (PLG). Lp(a) accumulates in the vessel wall and inhibits the binding of PLG to the cell surface, reducing plasmin generation, which increases clotting. This inhibition of PLG by Lp(a) also promotes the proliferation of smooth muscle cells. These unique features of Lp(a) suggest that Lp(a) causes generation of clots and atherosclerosis.[35]

In one homogeneous tribal population of Tanzania, vegetarians have higher levels of Lp(a) than fish eaters, raising the possibility that pharmacologic amounts of fish oil supplements may help lower the levels of Lp(a).[36] Researchers in studies in 1995 and 1998 concluded that regular consumption of moderate amounts of alcohol led to a significant decline in plasma levels of Lp(a).[37] Other studies did not report this.

Diagnostic testing

Numerous studies confirming a strong correlation between elevated Lp(a) and heart disease have led to the consensus that Lp(a) is an important independent predictor of cardiovascular disease.[1] Animal studies have shown that Lp(a) may directly contribute to atherosclerotic damage by increasing plaque size, inflammation, instability, and smooth muscle cell growth.[38] Genetic data also support the theory that Lp(a) causes cardiovascular disease.[2]

The European Atherosclerosis Society currently recommends that patients with a moderate or high risk of cardiovascular disease should have their Lp(a) levels checked. Any patient with one of the following risk factors should be screened:

  • premature cardiovascular disease
  • familial hypercholesterolaemia
  • family history of premature cardiovascular disease
  • family history of elevated Lp(a)
  • recurrent cardiovascular disease despite statin treatment
  • ≥3% ten-year risk of fatal cardiovascular disease according to the European guidelines
  • ≥10% ten-year risk of fatal and/or non-fatal cardiovascular disease according to the U.S. guidelines[1]

If the level is elevated, treatment should be initiated to bring the level below 50 mg/dL. In addition, the patient's other cardiovascular risk factors (including LDL levels) should be managed optimally.[1] Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter as well.[39][40]

Prior studies of the relationship between Lp(a) and ethnicity have shown inconsistent results. Lp(a) levels seem to differ in different populations. For example, in some African populations, Lp(a) levels are higher on average than in other groups, so that using a risk threshold of 30 mg/dl could classify over 50% of the individuals as higher risk.[41][42][43][44] Some part of this complexity may be related to the different genetic factors involved in determining Lp(a) levels. One recent study showed that in different ethnic groups, different genetic alterations were associated with increased Lp(a) levels.[45]

More recent data suggest that prior studies were underpowered. The Atherosclerosis Risk in Communities (ARIC) Study followed 3467 African Americans and 9851 whites for 20 years. The researchers found that an elevated Lp(a) conferred the same risk in each group. African Americans had roughly three times the level of Lp(a), however, and Lp(a) also predicted an increased risk of stroke.[46]

Approximate levels of risk are indicated by the results below, although at present there are a variety of different methods by which to measure Lp(a). A standardized international reference material has been developed and is accepted by the WHO Expert Committee on Biological Standardization and the International Federation of Clinical Chemistry and Laboratory Medicine. Although further standardization is still needed, development of a reference material is an importance step toward standardizing results.[47][48]

Lipoprotein(a) - Lp(a)[49]

Desirable: <14 mg/dL (<35 nmol/L)
Borderline risk: 14–30 mg/dL (35–75 nmol/L)
High risk: 31–50 mg/dL (75–125 nmol/L)
Very high risk: >50 mg/dL (>125 nmol/L)

Lp(a) appears with different isoforms (per kringle repeats) of apolipoprotein; 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different isoforms. Lighter Lp(a) are also associated with disease. Thus, a test with simple quantitative results may not provide a complete assessment of risk.[50]

Treatment

The current simplest treatment for elevated Lp(a) is to take 1–3 grams of niacin daily, typically in an extended-release form. Niacin therapy may reduce Lp(a) levels by 20–30%.[51]

A meta-analysis suggested that atorvastatin may lower Lp(a) levels.[32] In severe cases, such as familial hypercholesterolemia or treatment-resistant hypercholesterolemia, LDL apheresis may dramatically reduce Lp(a). The goal of the treatment is to reduce levels to below 50 mg/dL. Cost is prohibitively high.[1]

A meta-analysis of six clinical trials confirmed that flaxseed supplementation modestly lowers Lp(a) levels.[52]

Testosterone is known to reduce Lp(a) levels.[53] Testosterone replacement therapy also appears to be associated with lower Lp(a) levels.[54][55] Estrogen replacement therapy in post-menopausal women will reduce Lp(a).[56] Raloxifene has not been shown to reduce Lp(a), while tamoxifen has.[57]

L-carnitine may also reduce Lp(a) levels. A systematic review and meta-analysis found a significant reduction with oral but not intravenous carnitine.[58] Other medications that are in various stages of development include thyromimetics, cholesterol-ester-transfer protein (CETP inhibitors), anti-sense oligonucleopeptides (such as Pelacarsen and Olpasiran), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.[59][60]

The American Academy of Pediatrics now recommends that all children between the ages of nine and eleven years old be screened for hyperlipidemia. Lp(a) levels should be considered in particular in children with a family history of early heart disease or high blood cholesterol levels. However, there have not been enough studies to determine which therapies might be beneficial.[61]

Interactions

Lp(a) has been shown to interact with calnexin,[62][63] fibronectin,[26] and fibrinogen beta chain.[64]

See also

  • Lipoprotein
  • Apolipoprotein
  • Very-low-density lipoprotein
  • Combined hyperlipidemia

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Lipoprotein(a) as a cardiovascular risk factor: current status". Eur. Heart J. 31 (23): 2844–53. December 2010. doi:10.1093/eurheartj/ehq386. PMID 20965889. 
  2. ↑ 2.0 2.1 "Lipoprotein(a) and risk of myocardial infarction--genetic epidemiologic evidence of causality". Scand. J. Clin. Lab. Invest. 71 (2): 87–93. April 2011. doi:10.3109/00365513.2010.550311. PMID 21231777. 
  3. ↑ "Lipoprotein (a) and stroke: a meta-analysis of observational studies". Stroke 38 (6): 1959–66. 2007. doi:10.1161/STROKEAHA.106.480657. PMID 17478739. 
  4. ↑ "Circulating lipoprotein (a) and all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis". European Journal of Epidemiology 38 (5): 485–499. May 2023. doi:10.1007/s10654-022-00956-4. PMID 36708412. 
  5. ↑ "A NEW SERUM TYPE SYSTEM IN MAN-THE Lp SYSTEM". Acta Pathol Microbiol Scand 59 (3): 369–82. 1963. doi:10.1111/j.1699-0463.1963.tb01808.x. PMID 14064818. 
  6. ↑ 6.0 6.1 "cDNA sequence of human apolipoprotein(a) is homologous to plasminogen". Nature 330 (6144): 132–7. 1987. doi:10.1038/330132a0. PMID 3670400. Bibcode: 1987Natur.330..132M. 
  7. ↑ "Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma". J. Clin. Invest. 80 (2): 458–65. August 1987. doi:10.1172/JCI113093. PMID 2956279. 
  8. ↑ 8.0 8.1 "Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups". Hum. Genet. 86 (6): 607–14. 1991. doi:10.1007/BF00201550. PMID 2026424. 
  9. ↑ "Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells". Biochemistry 37 (16): 5417–25. April 1998. doi:10.1021/bi972761t. PMID 9548923. 
  10. ↑ "The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells". J. Biol. Chem. 271 (50): 32403–10. 1996. doi:10.1074/jbc.271.50.32403. PMID 8943305. 
  11. ↑ 11.0 11.1 "Simultaneous mutations (A/G(-418) and C/T(-384)) in the apo(a) promoter of individuals with low Lp(a) levels". Molecular Genetics and Metabolism 69 (2): 165–7. February 2000. doi:10.1006/mgme.1999.2956. PMID 10720444. 
  12. ↑ "Cell surface assembly of lipoprotein(a) in primary cultures of baboon hepatocytes". The Journal of Biological Chemistry 269 (46): 28716–23. November 1994. doi:10.1016/S0021-9258(19)61964-2. PMID 7961823. 
  13. ↑ 13.0 13.1 "Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein (a) isoform is determined by the rate of lipoprotein(a) production". J. Clin. Invest. 91 (2): 443–7. February 1993. doi:10.1172/JCI116221. PMID 8432853. 
  14. ↑ "The seventh myth of lipoprotein(a): where and how is it assembled?". Current Opinion in Lipidology 10 (3): 275–83. June 1999. doi:10.1097/00041433-199906000-00010. PMID 10431664. 
  15. ↑ "Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity". Current Opinion in Lipidology 15 (2): 167–74. April 2004. doi:10.1097/00041433-200404000-00009. PMID 15017359. 
  16. ↑ "Lipids, blood pressure and kidney update 2014". Pharmacological Research 95-96: 111–25. 2015. doi:10.1016/j.phrs.2015.03.009. PMID 25819754. 
  17. ↑ "Lipoprotein(a) as a cardiovascular risk factor: current status". European Heart Journal 31 (23): 2844–53. December 2010. doi:10.1093/eurheartj/ehq386. PMID 20965889. 
  18. ↑ "Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor". The Journal of Biological Chemistry 290 (18): 11649–62. May 2015. doi:10.1074/jbc.M114.611988. PMID 25778403. 
  19. ↑ "The effect of vascular smooth muscle cell-targeted expression of tissue factor pathway inhibitor in a murine model of arterial thrombosis". Thrombosis and Haemostasis 92 (3): 495–502. September 2004. doi:10.1160/TH04-01-0006. PMID 15351845. 
  20. ↑ "Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease". The New England Journal of Medicine 353 (1): 46–57. July 2005. doi:10.1056/NEJMoa043175. PMID 16000355. 
  21. ↑ "Lipoprotein (a)-We Know So Much Yet Still Have Much to Learn …". Journal of the American Heart Association 5 (4): e003597. April 2016. doi:10.1161/JAHA.116.003597. PMID 27108250. 
  22. ↑ "Lipoprotein(a): current perspectives". Curr Vasc Pharmacol 9 (6): 682–92. November 2011. doi:10.2174/157016111797484071. PMID 21529331. 
  23. ↑ "The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity". Curr. Opin. Lipidol. 19 (4): 369–77. August 2008. doi:10.1097/MOL.0b013e328308b622. PMID 18607184. 
  24. ↑ "Plasma lipoproteins: teaching old dogmas new tricks". Nature 330 (6144): 113–4. 1987. doi:10.1038/330113a0. PMID 3670399. 
  25. ↑ "Is the atherogenicity of Lp(a) caused by its reactivity with proteoglycans?". European Heart Journal 11 Suppl E: 184–9. August 1990. doi:10.1093/eurheartj/11.suppl_e.184. PMID 2146124. 
  26. ↑ 26.0 26.1 "Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it". The EMBO Journal 8 (13): 4035–40. December 1989. doi:10.1002/j.1460-2075.1989.tb08586.x. PMID 2531657. 
  27. ↑ "A Unified Theory of Human Cardiovascular Disease". Journal of Orthomolecular Medicine 7 (1). 1992. http://orthomolecular.org/library/jom/1992/pdf/1992-v07n01-p005.pdf. 
  28. ↑ "Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects". Atherosclerosis 87 (2–3): 227–37. 1991. doi:10.1016/0021-9150(91)90025-X. PMID 1830206. 
  29. ↑ "The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans". J. Clin. Invest. 95 (3): 1403–8. March 1995. doi:10.1172/JCI117794. PMID 7883987. 
  30. ↑ "Evidence mounts for a role of the kidney in lipoprotein(a) catabolism". Kidney Int. 71 (10): 961–2. 2007. doi:10.1038/sj.ki.5002240. PMID 17495935. 
  31. ↑ Christian Wilde (2003). Hidden Causes of Heart Attack and Stroke: Inflammation, Cardiology's New Frontier. Abigon Press. pp. 182–183. ISBN 978-0-9724959-0-5. 
  32. ↑ 32.0 32.1 "Atorvastatin decreases lipoprotein(a): a meta-analysis of randomized trials". Int. J. Cardiol. 154 (2): 183–6. January 2012. doi:10.1016/j.ijcard.2011.09.060. PMID 21996415. 
  33. ↑ "Effect of extended-release niacin on plasma lipoprotein(a) levels: A systematic review and meta-analysis of randomized placebo-controlled trials". Metabolism: Clinical and Experimental 65 (11): 1664–1678. 2016. doi:10.1016/j.metabol.2016.08.007. PMID 27733255. 
  34. ↑ "Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype". Atherosclerosis. Supplements 18: 53–8. May 2015. doi:10.1016/j.atherosclerosissup.2015.02.008. PMID 25936305. 
  35. ↑ "Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis". Blood 98 (10): 2980–7. 2001. doi:10.1182/blood.V98.10.2980. PMID 11698280. 
  36. ↑ "Fish intake, independent of apo(a) size, accounts for lower plasma lipoprotein(a) levels in Bantu fishermen of Tanzania: The Lugalawa Study". Arterioscler. Thromb. Vasc. Biol. 19 (5): 1250–6. May 1999. doi:10.1161/01.ATV.19.5.1250. PMID 10323776. 
  37. ↑ "Effect of moderate alcohol consumption on lp(a) lipoprotein concentrations. Reduction is supported by other studies". BMJ 316 (7145): 1675. May 1998. doi:10.1136/bmj.316.7145.1675. PMID 9603764. 
  38. ↑ "Lipoprotein(a) should be taken much more seriously". Biomark Med 3 (5): 439–41. October 2009. doi:10.2217/bmm.09.57. PMID 20477514. 
  39. ↑ "Apolipoprotein(a) isoforms and coronary heart disease in men: a nested case-control study". Atherosclerosis 132 (1): 77–84. July 1997. doi:10.1016/S0021-9150(97)00071-3. PMID 9247362. 
  40. ↑ "High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men". Arterioscler. Thromb. Vasc. Biol. 20 (12): 2619–24. 2000. doi:10.1161/01.ATV.20.12.2619. PMID 11116062. 
  41. ↑ "Contribution of the apo[a] phenotype to plasma Lp[a] concentrations shows considerable ethnic variation". J. Lipid Res. 32 (12): 1919–28. 1991. doi:10.1016/S0022-2275(20)41895-4. PMID 1840066. 
  42. ↑ "Serum LP(a) levels in African aboriginal Pygmies and Bantus, compared with Caucasian and Asian population samples". J Clin Epidemiol 50 (9): 1045–53. 1997. doi:10.1016/S0895-4356(97)00129-7. PMID 9363039. https://pure.eur.nl/en/publications/d6c7d723-d6d3-42a5-a824-df09d1376d60. 
  43. ↑ "Genetics of the Lp(a)/apo(a) system in an autochthonous Black African population from the Gabon". Eur. J. Hum. Genet. 14 (2): 190–201. 2006. doi:10.1038/sj.ejhg.5201512. PMID 16267501. 
  44. ↑ "The importance of the relation between lipoprotein(a) and lipids for development of atherosclerosis and cardiovascular disease". J. Intern. Med. 250 (3): 265–7. 2001. doi:10.1046/j.1365-2796.2001.00889.x. PMID 11555135. 
  45. ↑ "Variation in LPA is associated with Lp(a) levels in three populations from the Third National Health and Nutrition Examination Survey". PLOS ONE 6 (1): e16604. 2011. doi:10.1371/journal.pone.0016604. PMID 21305047. Bibcode: 2011PLoSO...616604D. 
  46. ↑ "Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study". Circulation 125 (2): 241–9. January 2012. doi:10.1161/CIRCULATIONAHA.111.045120. PMID 22128224. 
  47. ↑ "Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a)". Clin. Chem. 46 (12): 1956–67. 2000. doi:10.1093/clinchem/46.12.1956. PMID 11106328. 
  48. ↑ "First WHO/IFCC International Reference Reagent for Lipoprotein(a) for Immunoassay--Lp(a) SRM 2B". Clin. Chem. Lab. Med. 42 (6): 670–6. 2004. doi:10.1515/CCLM.2004.114. PMID 15259385. 
  49. ↑ Ryan, George M; Julius Torelli (2005). Beyond cholesterol: 7 life-saving heart disease tests that your doctor may not give you. New York: St. Martin's Griffin. p. 91. ISBN 978-0-312-34863-2. https://archive.org/details/beyondcholestero00tore/page/91. 
  50. ↑ "Genetics of the quantitative Lp(a) lipoprotein trait. III. Contribution of Lp(a) glycoprotein phenotypes to normal lipid variation". Hum. Genet. 82 (1): 73–8. April 1989. doi:10.1007/BF00288277. PMID 2523852. 
  51. ↑ "The therapeutic role of niacin in dyslipidemia management". J. Cardiovasc. Pharmacol. Ther. 19 (2): 141–58. 2014. doi:10.1177/1074248413514481. PMID 24363242. 
  52. ↑ "Flaxseed supplementation reduces plasma lipoprotein(a) levels: A meta-analysis". Altern Ther Health Med 27 (3): 50–53. May 2021. PMID 31634874. 
  53. ↑ "Testosterone decreases lipoprotein(a) in men". The American Journal of Cardiology 77 (14): 1244–7. 1996. doi:10.1016/S0002-9149(96)00174-9. PMID 8651107. 
  54. ↑ "Testosterone decreases lipoprotein(a) in men". The American Journal of Cardiology 77 (14): 1244–7. 1996. doi:10.1016/S0002-9149(96)00174-9. PMID 8651107. 
  55. ↑ "Lipoprotein(a): medical treatment options for an elusive molecule". Curr. Pharm. Des. 17 (9): 871–6. 2011. doi:10.2174/138161211795428777. PMID 21476974. 
  56. ↑ "The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: A systematic review and meta-analysis". Maturitas 99: 27–36. May 2017. doi:10.1016/j.maturitas.2017.02.009. PMID 28364865. 
  57. ↑ "The Effects of Tamoxifen on Plasma Lipoprotein(a) Concentrations: Systematic Review and Meta-Analysis". Drugs 77 (11): 1187–1197. 2017. doi:10.1007/s40265-017-0767-4. PMID 28573436. 
  58. ↑ "Impact of L-carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials". Scientific Reports 6: 19188. January 2016. doi:10.1038/srep19188. PMID 26754058. Bibcode: 2016NatSR...619188S. 
  59. ↑ "Lipoprotein(a): medical treatment options for an elusive molecule". Current Pharmaceutical Design 17 (9): 871–6. 2011. doi:10.2174/138161211795428777. PMID 21476974. 
  60. ↑ "New Therapeutic Approaches to the Treatment of Dyslipidemia 2: LDL-C and Lp(a)". Journal of Lipid and Atherosclerosis 12 (1): 37–46. January 2023. doi:10.12997/jla.2023.12.1.37. PMID 36761062. 
  61. ↑ Expert Panel on Integrated Guidelines for Cardiovascular Health Risk Reduction in Children Adolescents; National Heart, Lung (December 2011). "Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report". Pediatrics 128 (Suppl 5): S213–56. doi:10.1542/peds.2009-2107C. PMID 22084329. 
  62. ↑ "Inhibition of N-linked glycosylation results in retention of intracellular apo[a] in hepatoma cells, although nonglycosylated and immature forms of apolipoprotein[a] are competent to associate with apolipoprotein B-100 in vitro". J. Lipid Res. 39 (8): 1629–40. August 1998. doi:10.1016/S0022-2275(20)32192-1. PMID 9717723. 
  63. ↑ "Apolipoprotein[a] secretion from hepatoma cells is regulated in a size-dependent manner by alterations in disulfide bond formation". J. Lipid Res. 44 (4): 816–27. April 2003. doi:10.1194/jlr.M200451-JLR200. PMID 12562843. 
  64. ↑ "Mapping of a minimal apolipoprotein(a) interaction motif conserved in fibrin(ogen) beta - and gamma -chains". J. Biol. Chem. 275 (49): 38206–12. December 2000. doi:10.1074/jbc.M003640200. PMID 10980194. 

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