Lipoprotein (a): Kardiyovasküler Risk Değerlendirmesinde Kritik Bir Lipoprotein
Özet
Kardiyovasküler risk faktörlerini hedef alan tedavilere rağmen, aterosklerotik hastalıklar önemli sayıda ölümden sorumlu olmaya devam etmektedir. Bundan dolayı ek risk faktörlerinin saptanması önem kazanmaktadır. Lipoprotein(a) kardiyovasküler hastalık riski ile belirgin bir şekilde ilişkilidir. Lp(a)’nın patofizyolojik etkileri ve enflamatuvar süreçler, aterogeneze katkıda bulunan ortak biyolojik yolları paylaşmaktadır.
Apolipoprotein(a) (Apo(a)) ile düşük yoğunluklu lipoproteine (LDL) benzeri bir partikülden oluşan Lp(a) seviyeleri genetik faktörler tarafından belirlenir, diyet veya yaşam tarzından önemli ölçüde etkilenmez. Ancak Lp(a), LDL’den daha aterojeniktir çünkü LDL’nin tüm proaterojenik bileşenlerinin yanı sıra apo(a)’yı da içerir. Apo(a), enflamasyon dahil olmak üzere ek mekanizmalar yoluyla aterotrombozu güçlendirir.
Çocuklardaki Lp(a) düzeyleri iyi belirlenmemiştir. Bu nedenle, pediyatrik referans aralıkları ve erken KVH riski taşıyan pediyatrik hastalar için cut off belirlenmelidir. Ayrıca, çocukluk çağında Lp(a) testi için kılavuzlar, risk tarama grupları hazırlanmalıdır.
Klinisyenler, özellikle mevcut risk faktörleri olan hastalarda Lp(a) ölçümlerini rutin kardiyovasküler risk değerlendirme protokollerine dahil etmeyi düşünmelidir. Kişiselleştirilmiş tedavi olanakları ile KVH’nın gelecekteki yönetimi, Lp(a) gibi öne çıkan biyobelirteçlere bağlı olacaktır.
Despite therapies targeting cardiovascular risk factors, atherosclerotic diseases remain responsible for a significant number of deaths. It is therefore important to identify additional risk factors. Lipoprotein(a) is significantly associated with cardiovascular disease risk. The pathophysiological effects of Lp(a) and inflammatory processes share common biological pathways that contribute to atherogenesis.
Composed of apolipoprotein(a) (Apo(a)) and a low-density lipoprotein (LDL)-like particle, Lp(a) levels are determined by genetic factors and are not significantly affected by diet or lifestyle. However, Lp(a) is more atherogenic than LDL because it contains all the proatherogenic components of LDL as well as apo(a). Apo(a) potentiates atherothrombosis through additional mechanisms, including inflammation.
Lp(a) levels in children are not well established. Therefore, pediatric reference ranges and cut-offs for pediatric patients at risk of early CVD should be established. Furthermore, guidelines for Lp(a) testing in childhood and risk screening groups should be developed.
Clinicians should consider incorporating Lp(a) measurements into routine cardiovascular risk assessment protocols, especially in patients with existing risk factors. The future management of CVD with personalized treatment opportunities will depend on prominent biomarkers such as Lp(a).
Referanslar
Berg,K. A new serum type system in man-the lp system. Acta Pathol.Microbiol.scand 1963; 59: 369-382.
Rrenninger W, G Wendtt, P Nawrocki and H Weigand. The association of elevated lipo(a) with early miyokardial infarction (MI). Humangenetik 1965; 1: 658-667.
Albers JJ, Cabana G V, Warnick GR and Hazzard WR. Lp(a) lipoprotein: relationship to sinking pre-beta lipoprotein, hyperlipoproteinemia, and apolipoprotein B. Metabolism 1975; 24: 1047-1054.
Gaubatz JW, Ghanem KI, Guvera J, Nava LM, Patsch W. Polymorphic form of human apolipoprotein (a): inheritance and relationship of their moleculer weights to plasma levels of lipoprotein(a). J. lipid Res 1990; 31: 603-613.
Uhlén, M., et al. (2015). proteomics. Nature, 525(7568), 192-197. doi:10.1038/nature15390.
Tsimikas, S. (2017). The emerging role of lipoprotein(a) and apolipoprotein(a) in atherosclerotic cardiovascular disease. Clin Chem.63(1), 138-141.
Schnitzler, J.G.; Hoogeveen, R.M.; Ali, L.; Prange, K.H.M.; Waissi, F.; van Weeghel, M.; Bachmann, J.C.; Versloot, M.; Borrelli, M.J.;Yeang, C.; et al. Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflamma-tion and Leukocyte Extravasation. Circ. Res. 2020, 126, 1346–1359.
Sotiriou, S.N.; Orlova, V.V.; Al-Fakhri, N.; Ihanus, E.; Economopoulou, M.; Isermann, B.; Bdeir, K.; Nawroth, P.P.; Preissner, K.T.; Gahmberg, C.G.; et al. Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin. FASEB J. 2006, 20, 559–561.
O’Neil, C.H.; Boffa, M.B.; Hancock, M.A.; Pickering, J.G.; Koschinsky, M.L. Stimulation of vascular smooth muscle cell proliferationand migration by apolipoprotein(a) is dependent on inhibition of transforming growth factor-beta activation and on the presence of kringle IV type 9. J. Biol. Chem. 2004, 279, 55187–55195.
Xue, S.; Green, M.A.; LoGrasso, P.V.; Boettcher, B.R.; Madison, E.L.; Curtiss, L.K.; Miles, L.A. Comparison of the effects of Apo(a) kringle IV-10 and plasminogen kringles on the inter-actions of lipoprotein(a) with regulatory molecules. Thromb. Haemost. 1999, 81, 428–435.
Hajjar, K.A.; Gavish, D.; Breslow, J.L.; Nachman, R.L. Lipoprotein(a) modulation of endothe-lial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989, 339, 303–305.
Caplice, N.M.; Panetta, C.; Peterson, T.E.; Kleppe, L.S.; Mueske, C.S.; Kostner, G.M.; Broze GJJr Simari, R.D. Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: A novel link between lipoproteins and thrombosis. Blood 2001, 98, 2980–2987.
Schmidt K, Noureen A, Kronenberg F, et al. Structure, function, and genetics of lipoprotein (a). J Lipid Res 2016;57:1339–59.
Marcovina SM, Albers JJ, Gabel B, et al. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem 1995;41:246–55.
Baris Gencer, Florian Kronenberg, Erik S. Stroes, François Mach, Lipoprotein(a): the revenant, Eur Heart J, Volume 38, Issue 20, 21 May 2017, Pages 1553–1560.
Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther 2016;30:87-100.
Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med 2013;273:6–30.
Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, et al. Genetically Elevated Lipoprotein(a) and Increased Risk of Myocardial Infarction. JAMA 2009;301(22):2331-2339.
Clarke R, Peden JF, Hopewell JC, et al. Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease. N Engl J Med 2009 Dec;361(26):2518-2528
Vinci P, Di Girolamo FG, Panizon E, et al. Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives. Int J Environ Res Public Health. 2023 Sep 6;20(18):6721.
Marlys L. Koschinsky, Archna Bajaj, Michael B. Boffa, et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice J Clin LipidolVolume 18, Issue 3,2024 30:87–100.
Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022 Oct 14;43(39):3925-3946.
Pearson, G.J, Thanassoulis, G, et al., 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults, Can J Cardiol , 2021, 37, 1129-1150
Patel AP, Wang M, Pirruccello JP, et al. Lp(a) (Lipoprotein[a]) Concentrations and Incident Atherosclerotic Cardiovascular Disease: New Insights From a Large National Biobank. Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):465-474.
B. G. Nordestgaard, A. Langsted, "Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology," J Lipid Resvol. 57, no. 11, pp. 1953-1975, 2016, doi: 10.1194/jlr.R071233
Emerging Risk Factors Collaboration; Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009 Jul 22;302(4):412-23. doi: 10.1001/jama.2009.1063.
P. R. Kamstrup, A. Tybjaerg-Hansen, R. Steffensen, and B. G. Nordestgaard, "Genetically elevated lipoprotein(a) and increased risk of myocardial infarction," JAMA, vol. 301, no. 22, pp. 2331-9, Jun 10 2009, doi: 10.1001/jama.2009.801.
A. Vuorio, G. F. Watts, W. J. Schneider, S. Tsimikas, and P. T. Kovanen, "Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities," J Intern Med, vol. 287, no. 1, pp. 2-18, 2020, doi: https://doi.org/10.1111/joim.12981.
G. Reyes-Soffer, "The impact of race and ethnicity on lipoprotein(a) levels and cardiovascular risk," (in eng), Curr Opin Lipidol, vol. 32, no. 3, pp. 163-166, Jun 1 2021, doi: 10.1097/mol.0000000000000753.
Rao, M. N., et al. (2016). Lipoprotein(a) and the risk of cardiovascular disease: A review. J Clin Lipidol10(1), 15-24.
Boffa, M. B., & Koschinsky, M. L. (2020). Lipoprotein(a) and cardiovascular disease: Current understanding and future directions. Clin Chem Clinical Chemistry, 66(8), 1070-1080.
D. S. Hippe et al., "Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report," Arterioscler Thromb Vasc Biol, vol. 38, no. 3, pp. 673-678, Mar 2018, doi: 10.1161/atvbaha.117.310368.
L. M. de Boer et al., "Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis," Eur J Prev Cardiol, vol. 29, no. 5, pp. 779-792, 2021, doi: 10.1093/eurjpc/zwab171.
S. Tsimikas, "A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies," (in eng), J Am Coll Cardiol, vol. 69, no. 6, pp. 692-711, Feb 14 2017, doi: 10.1016/j.jacc.2016.11.042.
S. Burgess et al., "Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis," JAMA Cardiol., vol. 3, no. 7, pp. 619-627, 2018, doi: 10.1001/jamacardio.2018.1470.
