Lipoprotein(a)

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{{cite journal | vauthors = Wade DP, Puckey LH, Knight BL, Acquati F, Mihalich A, Taramelli R | title = Characterization of multiple enhancer regions upstream of the apolipoprotein(a) gene | journal = The Journal of Biological Chemistry | volume = 272 | issue = 48 | pages = 30387–30399 | date = November 1997 | pmid = 9374529 | doi = 10.1074/jbc.272.48.30387 | doi-access = free }}{{cite journal | vauthors = Langsted A, Nordestgaard BG | title = Value of Genetic Testing for Lipoprotein(a) Variants | journal = Circulation. Genomic and Precision Medicine | volume = 15 | issue = 2 | pages = e003737 | date = April 2022 | pmid = 35311528 | doi = 10.1161/CIRCGEN.122.003737 | doi-access = free }} and mainly controlled by the LPA gene{{cite journal | vauthors = Coassin S, Chemello K, Khantalin I, Forer L, Döttelmayer P, Schönherr S, Grüneis R, Chong-Hong-Fong C, Nativel B, Ramin-Mangata S, Gallo A, Roche M, Muelegger B, Gieger C, Peters A, Zschocke J, Marimoutou C, Meilhac O, Lamina C, Kronenberg F, Blanchard V, Lambert G | title = Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk | journal = Circulation. Genomic and Precision Medicine | volume = 15 | issue = 2 | pages = e003489 | date = April 2022 | pmid = 35133173 | pmc = 9018215 | doi = 10.1161/CIRCGEN.121.003489 | doi-access = free }} located on chromosome 6q25.3–q26.{{cite web | title = Symbol report for LPA | url = https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/6667 | website = HGNC | publisher = Hugo Gene Nomenclature Committee | access-date = 19 June 2024 }} 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.{{Cite journal | vauthors = Scipione CA, Koschinsky ML, Boffa MB | title = Lipoprotein(a) in clinical practice: New perspectives from basic and translational science | journal = Critical Reviews in Clinical Laboratory Sciences | volume = 55 | issue = 1 | pages = 33–54 | date = 2018-01-02 | pmid = 29262744 | doi = 10.1080/10408363.2017.1415866 | url = https://www.tandfonline.com/doi/full/10.1080/10408363.2017.1415866 | language = en | issn = 1040-8363 | url-access = subscription }} 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).{{cite journal | vauthors = Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C | title = Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma | journal = The Journal of Clinical Investigation | volume = 80 | issue = 2 | pages = 458–465 | date = August 1987 | pmid = 2956279 | pmc = 442258 | doi = 10.1172/JCI113093 }} 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.{{cite journal | vauthors = Sandholzer C, Hallman DM, Saha N, Sigurdsson G, Lackner C, Császár A, Boerwinkle E, Utermann G | title = Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups | journal = Human Genetics | volume = 86 | issue = 6 | pages = 607–614 | date = April 1991 | pmid = 2026424 | doi = 10.1007/BF00201550 | s2cid = 19657929 }} 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 production rate for the larger isoforms limits the plasma concentration.{{cite journal | vauthors = Lobentanz EM, Krasznai K, Gruber A, Brunner C, Müller HJ, Sattler J, Kraft HG, Utermann G, Dieplinger H | title = Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells | journal = Biochemistry | volume = 37 | issue = 16 | pages = 5417–5425 | date = April 1998 | pmid = 9548923 | doi = 10.1021/bi972761t }}{{cite journal | vauthors = Brunner C, Lobentanz EM, Pethö-Schramm A, Ernst A, Kang C, Dieplinger H, Müller HJ, Utermann G | title = The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells | journal = The Journal of Biological Chemistry | volume = 271 | issue = 50 | pages = 32403–32410 | date = December 1996 | pmid = 8943305 | doi = 10.1074/jbc.271.50.32403 | doi-access = free }}

Lp(a) concentrations can vary by more than one thousand between individuals, from <0.2 to >200 mg/dL. Scientists have found that this range of concentrations has been observed in all populations studied. 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.{{cite journal | vauthors = ((Patel AP, Wang (汪敏先) M, Pirruccello JP, Ellinor PT, Ng K, Kathiresan S, Khera AV)) | title = Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 41 | issue = 1 | pages = 465–474 | date = January 2021 | pmid = 33115266 | pmc = 7769893 | doi = 10.1161/ATVBAHA.120.315291 }}{{cite journal | vauthors = Kronenberg F, Mora S, Stroes ES, Ference BA, Arsenault BJ, Berglund L, Dweck MR, Koschinsky M, Lambert G, Mach F, McNeal CJ, Moriarty PM, Natarajan P, Nordestgaard BG, Parhofer KG, Virani SS, von Eckardstein A, Watts GF, Stock JK, Ray KK, Tokgözoğlu LS, Catapano AL | title = Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement | journal = European Heart Journal | volume = 43 | issue = 39 | pages = 3925–3946 | date = October 2022 | pmid = 36036785 | pmc = 9639807 | doi = 10.1093/eurheartj/ehac361 }} The general inverse correlation between apo(a) isoform size and Lp(a) plasma concentration is observed in all populations. However, it was also discovered that mean Lp(a) associated with certain apo(a) isoforms varies between populations.{{citation needed|date=November 2024}}

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

The Atherosclerosis Risk in Communities (ARIC) Study is a community-based cohort from 4 geographically diverse US communities. The ARIC Study found that the proportion of Atherosclerotic Cardiovascular Disease cases potentially attributable to elevated Lp(a) was 10.2% among Black adults compared with 4.7% among white adults. The population-attributable fraction ratio for Black adults compared with white adults was 2.30.

Because the hazard ratios for ASCVD associated with higher Lp(a) did not significantly differ between races, the ARIC study concluded that these differences appeared to be driven largely by racial differences in the distribution of Lp(a) levels.{{cite journal | vauthors = Grant JK, Martin SS, Zhang S, Matsushita K, Virani SS, Blumenthal RS, Hoogeveen RC, Boerwinkle E, Ballantyne CM, Coresh J, Ndumele CE | title = Racial Differences in the Burden of Atherosclerotic Cardiovascular Disease Related to Elevated Lipoprotein(a) Levels: The ARIC Study | journal = Circulation | volume = 150 | issue = 3 | pages = 250–252 | date = July 2024 | pmid = 39008561 | doi = 10.1161/CIRCULATIONAHA.124.069582 }}

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.{{cite journal | vauthors = White AL, Lanford RE | title = Cell surface assembly of lipoprotein(a) in primary cultures of baboon hepatocytes | journal = The Journal of Biological Chemistry | volume = 269 | issue = 46 | pages = 28716–28723 | date = November 1994 | pmid = 7961823 | doi = 10.1016/S0021-9258(19)61964-2 | doi-access = free }}{{cite journal | vauthors = Dieplinger H, Utermann G | title = The seventh myth of lipoprotein(a): where and how is it assembled? | journal = Current Opinion in Lipidology | volume = 10 | issue = 3 | pages = 275–283 | date = June 1999 | pmid = 10431664 | doi = 10.1097/00041433-199906000-00010 }}{{cite journal | vauthors = Koschinsky ML, Marcovina SM | title = Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity | journal = Current Opinion in Lipidology | volume = 15 | issue = 2 | pages = 167–174 | date = April 2004 | pmid = 15017359 | doi = 10.1097/00041433-200404000-00009 | s2cid = 45103589 }}

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.{{cite journal | vauthors = Romagnuolo R, Scipione CA, Bazzi ZA, Boffa MB, Koschinsky ML | title = Inhibition of pericellular plasminogen activation by apolipoprotein(a): Roles of urokinase plasminogen activator receptor and integrins α_Mβ₂ and α_Vβ₃ | journal = Atherosclerosis | volume = 275 | pages = 11–21 | date = August 2018 | pmid = 29852400 | doi = 10.1016/j.atherosclerosis.2018.05.029 }}{{cite journal | vauthors = Romagnuolo R, DeMarco K, Scipione CA, Boffa MB, Koschinsky ML | title = Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen on the surface of vascular endothelial and smooth muscle cells | journal = Thrombosis Research | volume = 169 | pages = 1–7 | date = September 2018 | pmid = 29990619 | doi = 10.1016/j.thromres.2018.07.002 }} Also, because Lp(a) stimulates secretion of PAI-1, it leads to thrombogenesis.{{cite journal | vauthors = Banach M, Aronow WS, Serban C, Sahabkar A, Rysz J, Voroneanu L, Covic A | title = Lipids, blood pressure and kidney update 2014 | journal = Pharmacological Research | volume = 95-96 | pages = 111–125 | date = 2015 | pmid = 25819754 | pmc = 4696333 | doi = 10.1016/j.phrs.2015.03.009 }}{{cite journal | vauthors = Nordestgaard BG, Chapman MJ, Ray K, Borén 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, Tokgözoglu L, Tybjærg-Hansen A | title = Lipoprotein(a) as a cardiovascular risk factor: current status | journal = European Heart Journal | volume = 31 | issue = 23 | pages = 2844–2853 | date = December 2010 | pmid = 20965889 | pmc = 3295201 | doi = 10.1093/eurheartj/ehq386 }}{{cite journal | vauthors = Romagnuolo R, Scipione CA, Boffa MB, Marcovina SM, Seidah NG, Koschinsky ML | title = Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor | journal = The Journal of Biological Chemistry | volume = 290 | issue = 18 | pages = 11649–11662 | date = May 2015 | pmid = 25778403 | pmc = 4416867 | doi = 10.1074/jbc.M114.611988 | doi-access = free }} It also may enhance coagulation by inhibiting the function of tissue factor pathway inhibitor.{{cite journal | vauthors = Pan S, Kleppe LS, Witt TA, Mueske CS, Simari RD | title = The effect of vascular smooth muscle cell-targeted expression of tissue factor pathway inhibitor in a murine model of arterial thrombosis | journal = Thrombosis and Haemostasis | volume = 92 | issue = 3 | pages = 495–502 | date = September 2004 | pmid = 15351845 | doi = 10.1160/TH04-01-0006 | s2cid = 1212821 }}

Moreover, Lp(a) carries atherosclerosis-causing cholesterol and binds atherogenic pro-inflammatory oxidised phospholipids as a preferential carrier of oxidised phospholipids in human plasma,{{cite journal | vauthors = Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS, Witztum JL, Berger PB | title = Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease | journal = The New England Journal of Medicine | volume = 353 | issue = 1 | pages = 46–57 | date = July 2005 | pmid = 16000355 | doi = 10.1056/NEJMoa043175 | doi-access = free }} which attracts inflammatory cells to vessel walls and leads to smooth muscle cell proliferation.{{cite journal | vauthors = Banach M | title = Lipoprotein (a)-We Know So Much Yet Still Have Much to Learn ... | journal = Journal of the American Heart Association | volume = 5 | issue = 4 | pages = e003597 | date = April 2016 | pmid = 27108250 | pmc = 4859302 | doi = 10.1161/JAHA.116.003597 }}{{cite journal | vauthors = Gouni-Berthold I, Berthold HK | title = Lipoprotein(a): current perspectives | journal = Current Vascular Pharmacology | volume = 9 | issue = 6 | pages = 682–692 | date = November 2011 | pmid = 21529331 | doi = 10.2174/157016111797484071 }}{{cite journal | vauthors = Tsimikas S, Witztum JL | title = The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity | journal = Current Opinion in Lipidology | volume = 19 | issue = 4 | pages = 369–377 | date = August 2008 | pmid = 18607184 | doi = 10.1097/MOL.0b013e328308b622 | s2cid = 24081304 }} 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.{{cite journal | vauthors = Brown MS, Goldstein JL | title = Plasma lipoproteins: teaching old dogmas new tricks | journal = Nature | volume = 330 | issue = 6144 | pages = 113–114 | date = 1987 | pmid = 3670399 | doi = 10.1038/330113a0 | s2cid = 4322332 | doi-access = free }}{{cite journal | vauthors = Kostner GM, Bihari-Varga M | title = Is the atherogenicity of Lp(a) caused by its reactivity with proteoglycans? | journal = European Heart Journal | volume = 11 Suppl E | issue = Suppl E | pages = 184–189 | date = August 1990 | pmid = 2146124 | doi = 10.1093/eurheartj/11.suppl_e.184 }} 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.{{cite journal | vauthors = Salonen EM, Jauhiainen M, Zardi L, Vaheri A, Ehnholm C | title = Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it | journal = The EMBO Journal | volume = 8 | issue = 13 | pages = 4035–4040 | date = December 1989 | pmid = 2531657 | pmc = 401578 | doi = 10.1002/j.1460-2075.1989.tb08586.x }}

Nonetheless, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy.{{Citation needed|date=November 2023}} Thus, plasma Lp(a) is not vital, at least under normal environmental conditions.{{Citation needed|date=November 2023}} 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.{{cite journal | vauthors = Pati N, Rouf A, Pati U | title = Simultaneous mutations (A/G(-418) and C/T(-384)) in the apo(a) promoter of individuals with low Lp(a) levels | journal = Molecular Genetics and Metabolism | volume = 69 | issue = 2 | pages = 165–167 | date = February 2000 | pmid = 10720444 | doi = 10.1006/mgme.1999.2956 }}

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.{{cite journal | vauthors = Pauling L, Rath M | title = A Unified Theory of Human Cardiovascular Disease | journal = Journal of Orthomolecular Medicine | volume = 7 | issue = 1 | year = 1992 | url = http://orthomolecular.org/library/jom/1992/pdf/1992-v07n01-p005.pdf | s2cid = 37023416 | access-date = 2012-01-09 | archive-date = 2018-12-26 | archive-url = https://web.archive.org/web/20181226010738/http://orthomolecular.org/library/jom/1992/pdf/1992-v07n01-p005.pdf | url-status = live }}

The half-life of Lp(a) in circulation is approximately three to four days.{{cite journal | vauthors = Rader DJ, Cain W, Zech LA, Usher D, Brewer HB | title = Variation in lipoprotein(a) concentrations among individuals with the same apolipoprotein (a) isoform is determined by the rate of lipoprotein(a) production | journal = The Journal of Clinical Investigation | volume = 91 | issue = 2 | pages = 443–447 | date = February 1993 | pmid = 8432853 | pmc = 287951 | doi = 10.1172/JCI116221 }} The mechanism and sites of Lp(a) catabolism are largely unknown. The LDL receptor has been reported as a receptor for Lp(a) clearance, but is not a major pathway of Lp(a) metabolism under normal or hypercholesterolemic conditions.{{cite journal | vauthors = Knight BL, Perombelon YF, Soutar AK, Wade DP, Seed M | title = Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects | journal = Atherosclerosis | volume = 87 | issue = 2–3 | pages = 227–237 | date = April 1991 | pmid = 1830206 | doi = 10.1016/0021-9150(91)90025-X }}{{cite journal | vauthors = Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, Hoeg JM, Davignon J, Lupien P, Grossman M | title = The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans | journal = The Journal of Clinical Investigation | volume = 95 | issue = 3 | pages = 1403–1408 | date = March 1995 | pmid = 7883987 | pmc = 441483 | doi = 10.1172/JCI117794 }} The kidney has been identified as playing a role in Lp(a) clearance from plasma.{{cite journal | vauthors = Albers JJ, Koschinsky ML, Marcovina SM | title = Evidence mounts for a role of the kidney in lipoprotein(a) catabolism | journal = Kidney International | volume = 71 | issue = 10 | pages = 961–962 | date = May 2007 | pmid = 17495935 | doi = 10.1038/sj.ki.5002240 | doi-access = free }}

High Lp(a) in blood correlates with coronary heart disease (CHD), cardiovascular disease (CVD), atherosclerosis, thrombosis, and stroke.{{cite book | vauthors = Wilde C | title = Hidden Causes of Heart Attack and Stroke: Inflammation, Cardiology's New Frontier | pages = 182–183 | year = 2003 | publisher = Abigon Press | isbn = 978-0-9724959-0-5 }} However, the association between Lp(a) levels and stroke is not as strong as that between Lp(a) and cardiovascular disease. 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.{{citation needed|date=November 2024}}

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.{{cite journal | vauthors = Takagi H, Umemoto T | title = Atorvastatin decreases lipoprotein(a): a meta-analysis of randomized trials | journal = International Journal of Cardiology | volume = 154 | issue = 2 | pages = 183–186 | date = January 2012 | pmid = 21996415 | doi = 10.1016/j.ijcard.2011.09.060 }}

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).{{cite journal | vauthors = Sahebkar A, Reiner Ž, Simental-Mendía LE, Ferretti G, Cicero AF | title = Effect of extended-release niacin on plasma lipoprotein(a) levels: A systematic review and meta-analysis of randomized placebo-controlled trials | journal = Metabolism: Clinical and Experimental | volume = 65 | issue = 11 | pages = 1664–1678 | date = November 2016 | pmid = 27733255 | doi = 10.1016/j.metabol.2016.08.007 }}{{cite journal | vauthors = Artemeva NV, Safarova MS, Ezhov MV, Afanasieva OI, Dmitrieva OA, Pokrovsky SN | title = Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype | journal = Atherosclerosis. Supplements | volume = 18 | pages = 53–58 | date = May 2015 | pmid = 25936305 | doi = 10.1016/j.atherosclerosissup.2015.02.008 }}

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 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.{{cite journal | vauthors = Caplice NM, Panetta C, Peterson TE, Kleppe LS, Mueske CS, Kostner GM, Broze GJ, Simari RD | title = Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis | journal = Blood | volume = 98 | issue = 10 | pages = 2980–2987 | date = November 2001 | pmid = 11698280 | doi = 10.1182/blood.V98.10.2980 | doi-access = free }}

In a homogeneous tribal population in 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).{{cite journal | vauthors = Marcovina SM, Kennedy H, Bittolo Bon G, Cazzolato G, Galli C, Casiglia E, Puato M, Pauletto P | title = Fish intake, independent of apo(a) size, accounts for lower plasma lipoprotein(a) levels in Bantu fishermen of Tanzania: The Lugalawa Study | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 19 | issue = 5 | pages = 1250–1256 | date = May 1999 | pmid = 10323776 | doi = 10.1161/01.ATV.19.5.1250 | doi-access = free }} 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).{{cite journal | vauthors = Sharpe PC, Young IS, Evans AE | title = Effect of moderate alcohol consumption on lp(a) lipoprotein concentrations. Reduction is supported by other studies | journal = BMJ | location = Clinical Research Ed. | volume = 316 | issue = 7145 | pages = 1675 | date = May 1998 | pmid = 9603764 | pmc = 1113249 | doi = 10.1136/bmj.316.7145.1675 }} Other studies did not report this.

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. Animal studies have shown that Lp(a) may directly contribute to atherosclerotic damage by increasing plaque size, inflammation, instability, and smooth muscle cell growth.{{cite journal | vauthors = Kamstrup PR, Nordestgaard BG | title = Lipoprotein(a) should be taken much more seriously | journal = Biomarkers in Medicine | volume = 3 | issue = 5 | pages = 439–441 | date = October 2009 | pmid = 20477514 | doi = 10.2217/bmm.09.57 | doi-access = free }} Genetic data also support the theory that Lp(a) causes cardiovascular disease.

The European Atherosclerosis Society 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

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. Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter as well.{{cite journal | vauthors = Klausen IC, Sjøl A, Hansen PS, Gerdes LU, Møller L, Lemming L, Schroll M, Faergeman O | title = Apolipoprotein(a) isoforms and coronary heart disease in men: a nested case-control study | journal = Atherosclerosis | volume = 132 | issue = 1 | pages = 77–84 | date = July 1997 | pmid = 9247362 | doi = 10.1016/S0021-9150(97)00071-3 }}{{cite journal | vauthors = Paultre F, Pearson TA, Weil HF, Tuck CH, Myerson M, Rubin J, Francis CK, Marx HF, Philbin EF, Reed RG, Berglund L | title = High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 20 | issue = 12 | pages = 2619–2624 | date = December 2000 | pmid = 11116062 | doi = 10.1161/01.ATV.20.12.2619 | s2cid = 12507462 | doi-access = free }}

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.{{cite journal | vauthors = Helmhold M, Bigge J, Muche R, Mainoo J, Thiery J, Seidel D, Armstrong VW | title = Contribution of the apo[a] phenotype to plasma Lp[a] concentrations shows considerable ethnic variation | journal = Journal of Lipid Research | volume = 32 | issue = 12 | pages = 1919–1928 | date = December 1991 | pmid = 1840066 | doi = 10.1016/S0022-2275(20)41895-4 | doi-access = free }}{{cite journal | vauthors = Cobbaert C, Mulder P, Lindemans J, Kesteloot H | title = Serum LP(a) levels in African aboriginal Pygmies and Bantus, compared with Caucasian and Asian population samples | journal = Journal of Clinical Epidemiology | volume = 50 | issue = 9 | pages = 1045–1053 | date = September 1997 | pmid = 9363039 | doi = 10.1016/S0895-4356(97)00129-7 | url = https://pure.eur.nl/en/publications/d6c7d723-d6d3-42a5-a824-df09d1376d60 | access-date = 2023-11-30 | url-status = live | hdl-access = free | s2cid = 2188933 | archive-date = 2024-06-11 | archive-url = https://web.archive.org/web/20240611070416/https://pure.eur.nl/en/publications/serum-lpa-levels-in-african-aboriginal-pygmies-and-bantus-compare | hdl = 1765/68815 }}{{cite journal | vauthors = Schmidt K, Kraft HG, Parson W, Utermann G | title = Genetics of the Lp(a)/apo(a) system in an autochthonous Black African population from the Gabon | journal = European Journal of Human Genetics | volume = 14 | issue = 2 | pages = 190–201 | date = February 2006 | pmid = 16267501 | doi = 10.1038/sj.ejhg.5201512 | doi-access = free }}{{cite journal | vauthors = Dahlén GH, Ekstedt B | title = The importance of the relation between lipoprotein(a) and lipids for development of atherosclerosis and cardiovascular disease | journal = Journal of Internal Medicine | volume = 250 | issue = 3 | pages = 265–267 | date = September 2001 | pmid = 11555135 | doi = 10.1046/j.1365-2796.2001.00889.x | s2cid = 44679184 | doi-access = free }} 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.{{cite journal | vauthors = Dumitrescu L, Glenn K, Brown-Gentry K, Shephard C, Wong M, Rieder MJ, Smith JD, Nickerson DA, Crawford DC | veditors = Kloss-Brandstaetter A | title = Variation in LPA is associated with Lp(a) levels in three populations from the Third National Health and Nutrition Examination Survey | journal = Plos One | volume = 6 | issue = 1 | pages = e16604 | date = January 2011 | pmid = 21305047 | pmc = 3030597 | doi = 10.1371/journal.pone.0016604 | doi-access = free | bibcode = 2011PLoSO...616604D }}

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, Lp(a) also predicted an increased risk of stroke.{{cite journal | vauthors = 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 | title = Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study | journal = Circulation | volume = 125 | issue = 2 | pages = 241–249 | date = January 2012 | pmid = 22128224 | pmc = 3760720 | doi = 10.1161/CIRCULATIONAHA.111.045120 }}

Approximate levels of risk are indicated by the results below, although at present, there are various 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, the development of a reference material is an important step toward standardizing results.{{cite journal | vauthors = Marcovina SM, Albers JJ, Scanu AM, Kennedy H, Giaculli F, Berg K, Couderc R, Dati F, Rifai N, Sakurabayashi I, Tate JR, Steinmetz A | title = 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) | journal = Clinical Chemistry | volume = 46 | issue = 12 | pages = 1956–1967 | date = December 2000 | pmid = 11106328 | doi = 10.1093/clinchem/46.12.1956 | doi-access = free }}{{cite journal | vauthors = Dati F, Tate JR, Marcovina SM, Steinmetz A | title = First WHO/IFCC International Reference Reagent for Lipoprotein(a) for Immunoassay--Lp(a) SRM 2B | journal = Clinical Chemistry and Laboratory Medicine | volume = 42 | issue = 6 | pages = 670–676 | year = 2004 | pmid = 15259385 | doi = 10.1515/CCLM.2004.114 | s2cid = 24696473 }}

Lipoprotein(a) — Lp(a){{cite book | vauthors = Ryan GM, Torelli J | title = Beyond cholesterol: 7 life-saving heart disease tests that your doctor may not give you | location = New York | pages = [https://archive.org/details/beyondcholestero00tore/page/91 91] | year = 2005 | publisher = St. Martin's Griffin | isbn = 978-0-312-34863-2 | url = https://archive.org/details/beyondcholestero00tore/page/91 }}

: 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.{{cite journal | vauthors = Boerwinkle E, Menzel HJ, Kraft HG, Utermann G | title = Genetics of the quantitative Lp(a) lipoprotein trait. III. Contribution of Lp(a) glycoprotein phenotypes to normal lipid variation | journal = Human Genetics | volume = 82 | issue = 1 | pages = 73–78 | date = April 1989 | pmid = 2523852 | doi = 10.1007/BF00288277 | s2cid = 912295 }}

The US FDA has given the Tina-quant® lipoprotein Lp(a) RxDx assay from Roche a Breakthrough Device Designation. The assay is designed to identify patients who may benefit from therapies aimed at decreasing Lp(a) levels.{{Cite web | title = FDA Grants Breakthrough Device Designation to Blood Test Measuring Lp(a) | date = 2024-05-22 | url = https://www.hcplive.com/view/fda-grants-breakthrough-device-designation-blood-test-measuring-lp-a- | access-date = 2024-06-11 | website = HCP Live | language = en | archive-date = 2024-05-26 | archive-url = https://web.archive.org/web/20240526025857/https://www.hcplive.com/view/fda-grants-breakthrough-device-designation-blood-test-measuring-lp-a- | url-status = live }}

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%.{{cite journal | vauthors = Boden WE, Sidhu MS, Toth PP | title = The therapeutic role of niacin in dyslipidemia management | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 19 | issue = 2 | pages = 141–158 | date = March 2014 | pmid = 24363242 | doi = 10.1177/1074248413514481 | s2cid = 5134822 }} However more recent research suggests that the inflammatory effects of the breakdown products of excess niacin lead to an increase in risk of major adverse cardiovascular event.{{cite journal | vauthors = Ferrell M, Wang Z, Anderson JT, Li XS, Witkowski M, DiDonato JA, Hilser JR, Hartiala JA, Haghikia A, Cajka T, Fiehn O, Sangwan N, Demuth I, Konig M, Steinhagen-Thiessen E, Landmesser U, Tang WH, Allayee H, Hazen SL | title = A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular risk | journal = Nature Medicine | volume = 30 | issue = 2 | pages = 424–434 | date = February 2024 | pmid = 38374343 | pmc = 11841810 | doi = 10.1038/s41591-023-02793-8 }}

A meta-analysis suggested that atorvastatin may lower Lp(a) levels. 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.

A meta-analysis of six clinical trials confirmed that flaxseed supplementation modestly lowers Lp(a) levels.{{cite journal | vauthors = Sahebkar A, Katsiki N, Ward N, Reiner Ž | title = Flaxseed Supplementation Reduces Plasma Lipoprotein(a) Levels: A Meta-Analysis | journal = Alternative Therapies in Health and Medicine | volume = 27 | issue = 3 | pages = 50–53 | date = May 2021 | pmid = 31634874 }}

Testosterone is known to reduce Lp(a) levels.{{cite journal | vauthors = Zmunda JM, Thompson PD, Dickenson R, Bausserman LL | title = Testosterone decreases lipoprotein(a) in men | journal = The American Journal of Cardiology | volume = 77 | issue = 14 | pages = 1244–1247 | date = June 1996 | pmid = 8651107 | doi = 10.1016/S0002-9149(96)00174-9 | doi-access = free }} Testosterone replacement therapy also appears to be associated with lower Lp(a) levels.{{cite journal | vauthors = Parhofer KG | title = Lipoprotein(a): medical treatment options for an elusive molecule | journal = Current Pharmaceutical Design | volume = 17 | issue = 9 | pages = 871–876 | year = 2011 | pmid = 21476974 | doi = 10.2174/138161211795428777 | doi-broken-date = 1 November 2024 }} Estrogen replacement therapy in post-menopausal women will reduce Lp(a).{{cite journal | vauthors = Anagnostis P, Galanis P, Chatzistergiou V, Stevenson JC, Godsland IF, Lambrinoudaki I, Theodorou M, Goulis DG | title = The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: A systematic review and meta-analysis | journal = Maturitas | volume = 99 | pages = 27–36 | date = May 2017 | pmid = 28364865 | doi = 10.1016/j.maturitas.2017.02.009 | hdl-access = free | hdl = 10044/1/48763 }} Raloxifene has not been shown to reduce Lp(a), while tamoxifen has.{{cite journal | vauthors = Sahebkar A, Serban MC, Penson P, Gurban C, Ursoniu S, Toth PP, Jones SR, Lippi G, Kotani K, Kostner K, Rizzo M, Rysz J, Banach M | title = The Effects of Tamoxifen on Plasma Lipoprotein(a) Concentrations: Systematic Review and Meta-Analysis | journal = Drugs | volume = 77 | issue = 11 | pages = 1187–1197 | date = July 2017 | pmid = 28573436 | pmc = 5501893 | doi = 10.1007/s40265-017-0767-4 }}

L-carnitine may also reduce Lp(a) levels. A systematic review and meta-analysis found a significant reduction with oral but not intravenous carnitine.{{cite journal | vauthors = Serban MC, Sahebkar A, Mikhailidis DP, Toth PP, Jones SR, Muntner P, Blaha MJ, Andrica F, Martin SS, Borza C, Lip GY, Ray KK, Rysz J, Hazen SL, Banach M | title = Impact of L-carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials | journal = Scientific Reports | volume = 6 | pages = 19188 | date = January 2016 | pmid = 26754058 | pmc = 4709689 | doi = 10.1038/srep19188 | bibcode = 2016NatSR...619188S }} 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.{{cite journal | vauthors = Kim KA, Park HJ | title = New Therapeutic Approaches to the Treatment of Dyslipidemia 2: LDL-C and Lp(a) | journal = Journal of Lipid and Atherosclerosis | volume = 12 | issue = 1 | pages = 37–46 | date = January 2023 | pmid = 36761062 | pmc = 9884549 | doi = 10.12997/jla.2023.12.1.37 }}

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 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.{{cite journal | title = Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report | journal = Pediatrics | volume = 128 Suppl 5 | issue = Suppl 5 | pages = S213–S256 | date = December 2011 | pmid = 22084329 | pmc = 4536582 | doi = 10.1542/peds.2009-2107C }}

In March 2025, Eli Lilly announced that an experimental drug, lepodisiran, showed promising results in significantly lowering Lp(a) levels for months with a single injection.

https://www.nytimes.com/2025/03/30/health/heart-attack-lpa-protein.html

Lp(a) has been shown to interact with calnexin,{{cite journal | vauthors = Bonen DK, Nassir F, Hausman AM, Davidson NO | title = 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 | journal = Journal of Lipid Research | volume = 39 | issue = 8 | pages = 1629–1640 | date = August 1998 | pmid = 9717723 | doi = 10.1016/S0022-2275(20)32192-1 | doi-access = free }}{{cite journal | vauthors = Nassir F, Xie Y, Davidson NO | title = Apolipoprotein[a] secretion from hepatoma cells is regulated in a size-dependent manner by alterations in disulfide bond formation | journal = Journal of Lipid Research | volume = 44 | issue = 4 | pages = 816–827 | date = April 2003 | pmid = 12562843 | doi = 10.1194/jlr.M200451-JLR200 | doi-access = free }} fibronectin, and fibrinogen beta chain.{{cite journal | vauthors = Klose R, Fresser F, Kochl S, Parson W, Kapetanopoulos A, Fruchart-Najib J, Baier G, Utermann G | title = Mapping of a minimal apolipoprotein(a) interaction motif conserved in fibrin(ogen) beta — and gamma -chains | journal = The Journal of Biological Chemistry | volume = 275 | issue = 49 | pages = 38206–38212 | date = December 2000 | pmid = 10980194 | doi = 10.1074/jbc.M003640200 | doi-access = free }}

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Category:Apolipoproteins

Category:Lipid disorders

Category:Cardiology