Lipoprotein(a): from Causality to Treatment

Overview

Journal Curr Atheroscler Rep

Publisher Springer

Specialty Cardiology & Vascular Diseases

Date 2024 Jan 22

PMID 38252372

Authors

Florian Kronenberg

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: This paper reviews the evidence why lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease and how high Lp(a) concentrations should be managed now and with an outlook to the future.

Review Findings: No optimal and widely available animal models exist to study the causality of the association between Lp(a) and cardiovascular disease. This has been a major handicap for the entire field. However, genetic studies turned the page. Already in the early 1990s, the principle of Mendelian randomization studies was applied for the first time ever (even if they were not named so at that time). Genetic variants of the LPA gene such as the apolipoprotein(a) isoform size, the number and sum of kringle IV repeats and later single nucleotide polymorphisms are strongly associated with life-long exposure to high Lp(a) concentrations as well as cardiovascular outcomes. This evidence provided a basis for the development of specific Lp(a)-lowering drugs that are currently in clinical testing phase. Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease. With the specific Lp(a)-lowering therapies, we might get tools to fight this common risk factor in case the outcome trials will be positive.

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References

Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, Marcovina S . Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010; 55(19):2160-7. DOI: 10.1016/j.jacc.2009.10.080. View

Stankov S, Cuchel M . Gene editing for dyslipidemias: New tools to "cut" lipids. Atherosclerosis. 2023; 368:14-24. PMC: 10493168. DOI: 10.1016/j.atherosclerosis.2023.01.010. View

Sandholzer C, Boerwinkle E, Saha N, Tong M, Utermann G . Apolipoprotein(a) phenotypes, Lp(a) concentration and plasma lipid levels in relation to coronary heart disease in a Chinese population: evidence for the role of the apo(a) gene in coronary heart disease. J Clin Invest. 1992; 89(3):1040-6. PMC: 442954. DOI: 10.1172/JCI115645. View

Coassin S, Erhart G, Weissensteiner H, Eca Guimaraes de Araujo M, Lamina C, Schonherr S . A novel but frequent variant in LPA KIV-2 is associated with a pronounced Lp(a) and cardiovascular risk reduction. Eur Heart J. 2017; 38(23):1823-1831. PMC: 5837733. DOI: 10.1093/eurheartj/ehx174. View

Kronenberg F, Utermann G . Lipoprotein(a): resurrected by genetics. J Intern Med. 2012; 273(1):6-30. DOI: 10.1111/j.1365-2796.2012.02592.x. View

Koschinsky M, Kronenberg F . The long journey of lipoprotein(a) from cardiovascular curiosity to therapeutic target. Atherosclerosis. 2022; 349:1-6. DOI: 10.1016/j.atherosclerosis.2022.04.017. View

Perombelon Y, Soutar A, Knight B . Variation in lipoprotein(a) concentration associated with different apolipoprotein(a) alleles. J Clin Invest. 1994; 93(4):1481-92. PMC: 294162. DOI: 10.1172/JCI117126. View

Kostner G, AVOGARO P, Cazzolato G, Marth E, Bittolo-Bon G, Qunici G . Lipoprotein Lp(a) and the risk for myocardial infarction. Atherosclerosis. 1981; 38(1-2):51-61. DOI: 10.1016/0021-9150(81)90103-9. View

Kronenberg F, Mora S, Stroes E, Ference B, Arsenault B, Berglund L . Frequent questions and responses on the 2022 lipoprotein(a) consensus statement of the European Atherosclerosis Society. Atherosclerosis. 2023; 374:107-120. DOI: 10.1016/j.atherosclerosis.2023.04.012. View

10.

Nissen S, Wolski K, Balog C, Swerdlow D, Scrimgeour A, Rambaran C . Single Ascending Dose Study of a Short Interfering RNA Targeting Lipoprotein(a) Production in Individuals With Elevated Plasma Lipoprotein(a) Levels. JAMA. 2022; 327(17):1679-1687. PMC: 8978050. DOI: 10.1001/jama.2022.5050. View

11.

Landmesser U, Poller W, Tsimikas S, Most P, Paneni F, Luscher T . From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J. 2020; 41(40):3884-3899. DOI: 10.1093/eurheartj/ehaa229. View

12.

Koschinsky M, Beisiegel U, Henne-Bruns D, Eaton D, Lawn R . Apolipoprotein(a) size heterogeneity is related to variable number of repeat sequences in its mRNA. Biochemistry. 1990; 29(3):640-4. DOI: 10.1021/bi00455a007. View

13.

Brunner C, Lobentanz E, Ernst A, Kang C, Dieplinger H, Muller H . The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells. J Biol Chem. 1996; 271(50):32403-10. DOI: 10.1074/jbc.271.50.32403. View

14.

Kraft H, Lingenhel A, Kochl S, Hoppichler F, Kronenberg F, Abe A . Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol. 1996; 16(6):713-9. DOI: 10.1161/01.atv.16.6.713. View

15.

Schwartz G, Ballantyne C . Existing and emerging strategies to lower Lipoprotein(a). Atherosclerosis. 2022; 349:110-122. DOI: 10.1016/j.atherosclerosis.2022.04.020. View

16.

Lackner C, Boerwinkle E, Leffert C, Rahmig T, Hobbs H . Molecular basis of apolipoprotein (a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis. J Clin Invest. 1991; 87(6):2153-61. PMC: 296974. DOI: 10.1172/JCI115248. View

17.

Perrot N, Verbeek R, Sandhu M, Boekholdt S, Hovingh G, Wareham N . Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: The EPIC-Norfolk prospective population study. Atherosclerosis. 2016; 256:47-52. PMC: 5321848. DOI: 10.1016/j.atherosclerosis.2016.11.010. View

18.

Utermann G, Menzel H, Kraft H, Duba H, Kemmler H, Seitz C . Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest. 1987; 80(2):458-65. PMC: 442258. DOI: 10.1172/JCI113093. View

19.

Laschkolnig A, Kollerits B, Lamina C, Meisinger C, Rantner B, Stadler M . Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts. Cardiovasc Res. 2014; 103(1):28-36. PMC: 4065111. DOI: 10.1093/cvr/cvu107. View

20.

Nordestgaard B, Chapman M, Ray K, Boren J, Andreotti F, Watts G . Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010; 31(23):2844-53. PMC: 3295201. DOI: 10.1093/eurheartj/ehq386. View