The role of Lp(a) in cardiovascular diseases and treatment options
Abstract
Based on Centers for Disease Control and Prevention and World Health Organization statistics, cardiovascular disease (CVD) is the leading cause of death globally, especially in developed countries. Atherosclerosis, associated with inflammation and endothelial dysfunction, is one of the major causes of cardiovascular disease, and several studies have tried to identify risk factors for atherosclerosis. Lipoprotein (a) [Lp(a)] has become increasingly appreciated in the past decades as a strong independent risk factor. Although there are several clinical trials on lipidlowering drugs to reduce the risk of CVD, most drugs not only fail to drop Lp(a) levels significantly but also do not specifically target Lp(a). While PCSK9 inhibitors are currently regarded as the best therapeutic drug for elevated Lp(a), recently, the development of novel drugs targeting the RNA of the Lp(a) gene (LPA), small interfering RNAs and antisense oligonucleotides, has progressed rapidly, and they have been assessed for their clinical efficacy. The objective of this case study/focused review is to review what Lp(a) is, why it has clinical significance in developing CVD, and more importantly how its level is controlled.
Keywords: Lipoprotein (a), cardiovascular diseases, atherosclerosis, PCSK9 inhibitors, antisense oligonucleotides, small interfering RNA.
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References
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25. Korneva, V.A., T.Y. Kuznetsova, and U. Julius, Modern Approaches to Lower Lipoprotein(a) Concentrations and Consequences for Cardiovascular Diseases. Biomedicines, 2021, 9(9).
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27. Grabie, M., C.H. Tai, and W.H. Frishman, Is Anacetrapib Better Than Its CETP Inhibitor Counterparts? Cardiol Rev, 2019, 27(5): p. 242-248.
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29. Landmesser, U., W. Poller, S. Tsimikas, et al., From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J, 2020, 41(40): p. 3884-3899.
30. Nissen, S.E., K. Wolski, C. Balog, et al., 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): p. 1679-1687.
2. McLean, J.W., J.E. Tomlinson, W.-J. Kuang, et al., cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature, 1987, 330(6144): p. 132-137.
3. Kraft, H.G., A. Lingenhel, S. Köchl, et al., Apolipoprotein(a) Kringle IV Repeat Number Predicts Risk for Coronary Heart Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 1996, 16(6): p. 713-719.
4. Marcovina, S.M. and M.D. Shapiro, Measurement of Lipoprotein(a). Journal of the American College of Cardiology, 2022, 79(7): p. 629-631.
5. Cegla, J., M. France, S.M. Marcovina, et al., Lp(a): When and how to measure it. Ann Clin Biochem, 2021, 58(1): p. 16-21.
6. Kostner, K.M. and G.M. Kostner, Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus. Int J Mol Sci, 2022, 23(7).
7. Krempler, F., G. Kostner, K. Bolzano, et al., Lipoprotein (a) is not a metabolic product of other lipoproteins containing apolipoprotein B. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1979, 575(1): p. 63-70.
8. McCormick, S.P., Lipoprotein(a): biology and clinical importance. Clin Biochem Rev, 2004, 25(1): p. 69-80.
9. Hrzenjak, A., S. Frank, X. Wo, et al., Galactose-specific asialoglycoprotein receptor is involved in lipoprotein (a) catabolism. Biochem J, 2003, 376(Pt 3): p. 765-71.
10. Kronenberg, F., G. Utermann, and H. Dieplinger, Lipoprotein(a) in renal disease. Am J Kidney Dis, 1996, 27(1): p. 1-25.
11. Cauza, E., J. Kletzmaier, G. Bodlaj, et al., Relationship of non-LDL-bound apo(a), urinary apo(a) fragments and plasma Lp(a) in patients with impaired renal function. Nephrology Dialysis Transplantation, 2003, 18(8): p. 1568-1572.
12. Kaiser, Y., M. Daghem, E. Tzolos, et al., Association of Lipoprotein(a) With Atherosclerotic Plaque Progression. Journal of the American College of Cardiology, 2022, 79(3): p. 223-233.
13. Guan, W., J. Cao, B.T. Steffen, et al., 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, 2015, 35(4): p. 996-1001.
14. Patel, A.P., M. Wang, J.P. Pirruccello, et al., Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank. Arterioscler Thromb Vasc Biol, 2021, 41(1): p. 465-474.
15. Tsimikas, S., A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol, 2017, 69(6): p. 692-711.
16. Takami, S., S. Yamashita, S. Kihara, et al., Lipoprotein(a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells. Circulation, 1998, 97(8): p. 721-8.
17. Bihari-Varga, M., E. Gruber, M. Rotheneder, et al., Interaction of lipoprotein Lp(a) and low density lipoprotein with glycosaminoglycans from human aorta. Arteriosclerosis, 1988, 8(6): p. 851-7.
18. van der Valk, F.M., S. Bekkering, J. Kroon, et al., Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation, 2016, 134(8): p. 611-24.
19. Boffa, M.B., T.T. Marar, C. Yeang, et al., Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis. J Lipid Res, 2019, 60(12): p. 2082-2089.
20. Nguyen, S., L. Ilano, N. Oluoha, et al., Lipoprotein(a) a Risk Factor for Venous Thrombosis and Pulmonary Embolism in Patients Younger Than 50 Years of Age. Blood, 2018, 132(Supplement 1): p. 5055-5055.
21. Chasman, D.I., D. Shiffman, R.Y. Zee, et al., Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis, 2009, 203(2): p. 371-6.
22. Ooi, E.M., G.F. Watts, D.C. Chan, et al., Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol, 2015, 35(12): p. 2686-93.
23. Chennamsetty, I., K.M. Kostner, T. Claudel, et al., Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice. J Lipid Res, 2012, 53(11): p. 2405-12.
24. Mefford, M.T., S.M. Marcovina, V. Bittner, et al., PCSK9 loss-of-function variants and Lp(a) phenotypes among black US adults. J Lipid Res, 2019, 60(11): p. 1946-1952.
25. Korneva, V.A., T.Y. Kuznetsova, and U. Julius, Modern Approaches to Lower Lipoprotein(a) Concentrations and Consequences for Cardiovascular Diseases. Biomedicines, 2021, 9(9).
26. Gaudet, D., G.F. Watts, J.G. Robinson, et al., Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (from the Phase 3 ODYSSEY Program). Am J Cardiol, 2017, 119(1): p. 40-46.
27. Grabie, M., C.H. Tai, and W.H. Frishman, Is Anacetrapib Better Than Its CETP Inhibitor Counterparts? Cardiol Rev, 2019, 27(5): p. 242-248.
28. Pokrovsky, S.N., O.I. Afanasieva, and M.V. Ezhov, Therapeutic Apheresis for Management of Lp(a) Hyperlipoproteinemia. Curr Atheroscler Rep, 2020, 22(11): p. 68.
29. Landmesser, U., W. Poller, S. Tsimikas, et al., From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J, 2020, 41(40): p. 3884-3899.
30. Nissen, S.E., K. Wolski, C. Balog, et al., 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): p. 1679-1687.
Published
2022-10-21
How to Cite
May, H., & Shurmur, S. (2022). The role of Lp(a) in cardiovascular diseases and treatment options. The Southwest Respiratory and Critical Care Chronicles, 10(45), 48-53. https://doi.org/10.12746/swrccc.v10i45.1079
Section
Case Report and Focused Review
Copyright (c) 2022 Harry May, Scott Shurmur
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
