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Lipoprotein(a)

Lipoprotein(a) Clin Res Cardiol Suppl (2019) (Suppl) 14:1–4 https://doi.org/10.1007/s11789-019-00100-9 EDITORIAL 1 2 K. P. Mellwig ·A.Vogt © The Author(s) 2019 Lipoprotein(a) (LP(a))—discovered by Kare Berg [1]in Kringles are characterized by 2–40 repeats creating at 1963—is of increasing importance in clinical routine as re- least 30 polymorphous isoforms of Apo(a), which are dif- flected by the ESC/EAS Guidelines for the Management of ferent in terms of size and mass. Number and qualitative Dyslipidaemias and the recent AHA Guideline [2, 3]. These composition of kringle domains determine the atherogene- guidelines provide detailed recommendations for screening ity of Lp(a). The large isoforms with more kringle repeats and lipid analyses in the assessment of cardiovascular risk. seem to be less atherogenous than the smaller ones [9]. A consensus paper of the European Society of Cardiology summarizes basic principles, background as well as diag- nostic and therapeutic principles [4]. Synthesis and metabolism Apoprotein(a) is synthesized in the liver exclusively [10]. Structure—physiochemical characteristics How much Apo(a) is produced by the liver depends on the LPA gene and its amount remains more or less constant LP(a) is a lipid protein complex with a structure compared during a person’s lifetime. As Lp(a) in males rises only to to that of LDL (low density lipoprotein). Another apopro- a minor extent with increasing age, this parameter has to be tein, glycoprotein apoprotein(a) (Apo(a)) is bonded to the determined only once in a lifetime. In women however, the apoprotein B-100 (Apo B-100) of the LDL cholesterol via analysis should be done before and after menopause, as the a disulphide bridge [5]. Lp(a) level might markedly increase during menopause. It The presence of Apo(a) impairs the bond between Lp(a) is quite unclear where Lp(a) is produced, most probably on and the LDL receptor. An independent Lp(a) receptor has the surface of hepatocytes or in plasma. not been identified so far. Corresponding to the LDL choles- Catabolism of Lp(a) is independent of a functioning LDL terol (LDL-C), the Lp(a) molecule is coated by a layer of receptor [11]. The kidney seems to have a specific binding simple phospholipids, free cholesterol, and apoproteins. Its capacity for Lp(a) [12]. A reduced glomerular filtration rate core consists of triglycerides and esterified cholesterol [6]. (GFR) may lead to an increase in plasma concentration of Due to its structural similarity, Lp(a) competes with plas- Lp(a). Other factors are hypothyreosis or an acute phase minogen for bindings sites on endothelial cells thus block- reaction (e. g. acute myocardial infarction). Oestrogen ther- ing the development of plasmin [7]. This leads to a de- apy, pregnancy or aspirin uptake cause a non-significant or lay of fibrinolysis. Similar to plasminogen, Apo(a) contains relevant reduction [13]. a kringle domain [8]. Genetics This article is part of the special issue “Lp(a) – Update 2018” Apo(a) is encoded by a gene on chromosome 6q26-27 K. P. Mellwig akleemeyer@hdz-nrw.de [14]. Lp(a) plasma concentration is controlled by the Lp(a) gene locus; polymorphisms of the Apo(a) kringle IV-2 re- Klinik für Allgemeine und Interventionelle peats are responsible for the differences in plasma level. Of Kardiologie/Angiologie, Herz- und Diabeteszentrum 48 single nucleotide polymorphisms (SNPs) in the Lp(a) NRW, Universitätsklinik, Ruhr-Universität Bochum, gene region, seven SNPs show a significant association with Georgstr. 11, 32545 Bad Oeynhausen, Germany coronary heart disease [15]. The frequently used but slightly Medizinische Klinik und Poliklinik IV, Klinikum der arbitrary normal value of <30 mg/dl (1.6 mmol/l) is based Universität München, Ziemssenstr. 1, 80336 Munich, Germany on data which show that with an increasing value the car- K 2 K. P. Mellwig, A. Vogt diovascular risk increases without a given threshold value Registry data show that the degree of aortic valve steno- [16]. ESC recommends a threshold value of <50 mg/dl (80th sis rises with increasing Lp(a) levels [22]. percentile) [4]. Cerebrovascular and peripheral vascular disease, abdominal Thrombogenous and atherogenous characteristics aortic aneurysm In blood coagulation Lp(a) is the opponent of plasmino- Lp(a) is also discussed to be an independent risk factor for gen—the inactive preliminary enzyme stage of plas- cerebrovascular diseases. Particularly in young patients suf- min—which resolves fibrin clots. Lp(a) competes with fering from an apoplectic insult Lp(a) might be a causative plasminogen for the binding sites on endothelial cells thus factor [23]. Furthermore, Lp(a) seems to be a predictor for blocking plasmin formation [9]. This leads to a delay in an early recurrence [24]. fibrinolysis and to deposits on the vascular wall. High The manifestation of a peripheral arterial occlusive dis- concentrations of Lp(a) cause an increased thrombotic risk ease is also influenced by Lp(a) concentration and a low due to an inhibition of fibrinolytic mechanisms. molecular (NMW) Apo(a) phenotype [25]. The structure of Lp(a) contains about 30% of choles- Finally, numerous published reports on increased Lp(a) terol and cholesterol ester, in addition atherogenous, proim- levels in patients with documented abdominal aortic flammatoray oxidized phospholipids are bonded. This leads aneurysms should be mentioned. This might be an evi- to an accumulation of inflammatory cells in the vascular dence for Lp(a)-induced atherosclerotic processes in large wall with consecutive proliferation of smooth muscle cells. vessels [26]. Atherogenesis is thus induced and maintained. Screening Clinical relevance Coronary heart disease Presymptomatic patients with an increased cardiovascular risk are identified by the determination of classical risk The causative role of Lp(a) in the early manifestation of factors in established scores such as PROCAM, SCORE, coronary heart disease is becoming more and more evident. ASCVD. Earlier studies including meta-analyses have shown that The quality of these scores for risk assessment is not sat- an elevated Lp(a) concentration markedly increases the risk isfying. The sensitivities of these are <50% and the positive for coronary heart disease [17]. In addition, Mendelian ran- predictive value is at most 30% [27]. The establishment of domization has indicated that genetic mutations of Lp(a) new risk factors is therefore of high clinical relevance to in the form of polymorphisms of the Apo(a) kringle IV-2 improve the reliability of prognosis. Considering the ge- repeats are associated with a risk of coronary heart disease netic determination and hereditary burden Lp(a) might be [18]. Patients with a familial hypercholesterolemia (FH) a candidate. of a prospective cohort study, where 46,200 individuals of the Copenhagen General Population Study were enrolled, Therapy showed the highest risk of developing a coronary heart dis- ease in case of Lp(a)≥ 50 mg/dL (HR 5.3, 95% CI 3.6–7.6) [19]. In the GENESIS-PRAXY (GENdEr and Sex determi- So far lipoprotein apheresis is the only effective available nantS of cardiovascular disease) study, 939 young patients therapeutic option to reduce Lp(a) significantly, with a doc- admitted for an acute coronary syndrome (ACS) showed an umented effect on cardiac events [28]. association between high Lp(a) (>50 mg/dl) and high LDL- PCSK9 inhibitors reduce LDL cholesterol significantly C (>3.5 mmol/L) so that increased Lp(a) and high LDL-C and Lp(a) by about 25–30% [29]. In case of very high ini- represent an increased risk for ACS [20]. tial values of Lp(a), a favourable influence on athergenous events cannot be expected. A promising approach is the Aortic valve stenosis antisense oligonucleotide therapy. Phase 1 and 2 studies have shown reduction rates of Lp(a) of up to 80% with Aortic valve stenosis may be genetically induced as well a good tolerability [30]. If these results are reproducible as result from a lipid disorder and an Lp(a) increase. in a phase 3 study and cardiovascular events are reduced, A large-scale study has proved that an elevated Lp(a) and a specific drug therapy of high Lp(a) values might become a corresponding LP risk genotype (rs10455872, rs3798220, available for the first time. kringle IV type 2 repeat polymorphism) increase the risk The large number of publications during the past years for the development of aortic valve stenosis [21]. emphasizes the pathophysiological and clinical relevance K Lipoprotein(a) 3 10. Hoover-Plow J, Huang M (2013) Lipoprotein(a) metabolism: po- of Lp(a). The contributions to this supplement presented at tential sites for therapeutic targets. Metabolism 62(4):479–491. the Lp(a) Update 2018 meeting in Kassel are intended to https://doi.org/10.1016/j.metabol.2012.07.024 provide an overview and critical appraisal of cardiovascular 11. Hobbs HH, White AL (1999) Lipoprotein(a): intrigues and insights. risk factors for clinical routine. Curr Opin Lipidol 10(3):225–236 12. Kostner GM, Wo X, Frank S, Kostner K, Zimmermann R, Steyrer Conflict of interest K.P. Mellwig and A. Vogt declare that they have E (1997) Metabolism of Lp(a): assembly and excretion. Clin Genet no competing interests. 52(5):347–354 13. Kostner KM, Kostner GM (2017) Lipoprotein (a): a historical Open Access This article is distributed under the terms of the appraisal. J Lipid Res 58(1):1–14. https://doi.org/10.1194/jlr. Creative Commons Attribution 4.0 International License (http:// R071571 creativecommons.org/licenses/by/4.0/), which permits unrestricted 14. Frank SL, Klisak I, Sparkes RS, Mohandas T, Tomlinson JE, use, distribution, and reproduction in any medium, provided you give McLean JW, Lawn RM, Lusis AJ (1988) The apolipoprotein(a) appropriate credit to the original author(s) and the source, provide a gene resides on human chromosome 6q26-27, in close proximity to link to the Creative Commons license, and indicate if changes were the homologous gene for plasminogen. Hum Genet 79(4):352–356 made. 15. Mack S, Coassin S, Rueedi R, Yousri NA, Seppala I, Gieger C, Schonherr S, Forer L, Erhart G, Marques-Vidal P, Ried JS, Wae- ber G, Bergmann S, Dahnhardt D, Stockl A, Raitakari OT, Ka- References honen M, Peters A, Meitinger T, Strauch K, Group KO, Kedenko L, Paulweber B, Lehtimaki T, Hunt SC, Vollenweider P, Lamina 1. Berg K (1963) A new serum type system in man—the Lp system. C, Kronenberg F (2017) A genome-wide association meta-analy- Acta Pathol Microbiol Scand 59:369–382 sis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) 2. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, isoforms. J Lipid Res 58(9):1834–1844. https://doi.org/10.1194/jlr. Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, M076232 Reiner Z, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren 16. Scanu AM (1998) Atherothrombogenicity of lipoprotein(a): the de- WMM, Vlachopoulos C, Wood DA, Zamorano JL, Cooney MT bate. Am J Cardiol 82(9A):26Q–33Q (2016) 2016 ESC/EAS guidelines for the management of dyslip- 17. Gencer B, Kronenberg F, Stroes ES, Mach F (2017) Lipopro- idaemias. Eur Heart J 37(39):2999–3058. https://doi.org/10.1093/ tein(a): the revenant. Eur Heart J 38(20):1553–1560. https://doi. eurheartj/ehw272 org/10.1093/eurheartj/ehx033 3. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blu- 18. Kamstrup PR, Tybjaerg-Hansen A, Steffenssen R (2009) Geneti- menthal RS, Braun LT, Braun LT, de Ferranti S, Faiella-Tom- cally elevated lipoprotein(a) and increased risk of myocardial in- masino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, farction. JAMA 301(22):2331–2339 Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Or- 19. Langsted A, Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordest- ringer CE, Peralta CA, Saseen JJ, Smith SC Jr., Sperling L, Virani gaard BG (2016) High lipoprotein(a) as a possible cause of clinical SS, Yeboah J (2018) 2018 AHA/ACC/AACVPR/AAPA/ABC/ familial hypercholesterolaemia: a prospective cohort study. Lancet ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the Diabetes Endocrinol 4(7):577–587. https://doi.org/10.1016/S2213- management of blood cholesterol: executive summary: a report 8587(16)30042-0 of the American college of cardiology/American heart associa- 20. Afshar M, Pilote L, Dufresne L, Engert JC, Thanassoulis G (2016) tion task force on clinical practice guidelines. J Am Coll Cardiol. Lipoprotein(a) interactions with low-density lipoprotein choles- https://doi.org/10.1016/j.jacc.2018.11.002 terol and other cardiovascular risk factors in premature acute 4. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts coronary syndrome (ACS). J Am Heart Assoc. https://doi.org/10. GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, 1161/JAHA.115.003012 Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taski- 21. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2014) Ele- nen MR, Tokgozoglu L, Tybjaerg-Hansen A, European Atheroscle- vated lipoprotein(a) and risk of aortic valve stenosis in the general rosis Society Consensus P (2010) Lipoprotein(a) as a cardiovascu- population. J Am Coll Cardiol 63(5):470–477. https://doi.org/10. lar risk factor: current status. Eur Heart J 31(23):2844–2853. https:// 1016/j.jacc.2013.09.038 doi.org/10.1093/eurheartj/ehq386 22. Capoulade R, Chan KL, Yeang C, Mathieu P, Bosse Y, Dumesnil 5. Albers JJ, Kennedy H, Marcovina SM (1996) Evidence that Lp[a] JG, Tam JW, Teo KK, Mahmut A, Yang X, Witztum JL, Arsenault contains one molecule of apo[a] and one molecule of apoB: evalu- BJ, Despres JP, Pibarot P, Tsimikas S (2015) Oxidized phospho- ation of amino acid analysis data. J Lipid Res 37(1):192–196 lipids, lipoprotein(a), and progression of calcific aortic valve steno- 6. Scanu AM, Edelstein C, Klezovitch O (1999) Dominant role of the sis. J Am Coll Cardiol 66(11):1236–1246. https://doi.org/10.1016/ C-terminal domain in the binding of apolipoprotein(a) to the protein j.jacc.2015.07.020 core of proteoglycans and other members of the vascular matrix. 23. Nave AH, Lange KS, Leonards CO, Siegerink B, Doehner W, Trends Cardiovasc Med 9(7):196–200 Landmesser U, Steinhagen-Thiessen E, Endres M, Ebinger M 7. Scanu AM (2003) Lipoprotein(a) and the atherothrombotic process: (2015) Lipoprotein (a) as a risk factor for ischemic stroke: a meta- mechanistic insights and clinical implications. Curr Atheroscler analysis. Atherosclerosis 242(2):496–503. https://doi.org/10.1016/ Rep 5(2):106–113 j.atherosclerosis.2015.08.021 8. McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY, 24. Hong XW, Wu DM, Lu J, Zheng YL, Tu WJ, Yan J (2018) Lipopro- Fless GM, Scanu AM, Lawn RM (1987) cDNA sequence of hu- tein (a) as a predictor of early stroke recurrence in acute Ischemic man apolipoprotein(a) is homologous to plasminogen. Nature stroke. Mol Neurobiol 55(1):718–726. https://doi.org/10.1007/ 330(6144):132–137. https://doi.org/10.1038/330132a0 s12035-016-0346-9 9. Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, 25. Laschkolnig A, Kollerits B, Lamina C, Meisinger C, Rantner B, Seitz C (1987) Lp(a) glycoprotein phenotypes. Inheritance and Stadler M, Peters A, Koenig W, Stockl A, Dahnhardt D, Boger CA, relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest Kramer BK, Fraedrich G, Strauch K, Kronenberg F (2014) Lipopro- 80(2):458–465. https://doi.org/10.1172/JCI113093 tein (a) concentrations, apolipoprotein (a) phenotypes, and periph- K 4 K. P. Mellwig, A. Vogt eral arterial disease in three independent cohorts. Cardiovasc Res 128(24):2567–2576. https://doi.org/10.1161/CIRCULATIONAHA. 103(1):28–36. https://doi.org/10.1093/cvr/cvu107 113.002432 26. Kotani K, Sahebkar A, Serban MC, Ursoniu S, Mikhailidis DP, 29. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky Mariscalco G, Jones SR, Martin S, Blaha MJ, Toth PP, Rizzo M, E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Ceska Kostner K, Rysz J, Banach M (2017) Lipoprotein(a) levels in pa- R, Ezhov MV, Jukema JW, Jensen HK, Tokgozoglu SL, Mach tients with abdominal aortic aneurysm. Angiology 68(2):99–108. F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS https://doi.org/10.1177/0003319716637792 (2018) Lipoprotein(a), PCSK9 inhibition and cardiovascular risk: 27. von Eckardstein A, Schulte H, Assmann G (2005) Comparison insights from the FOURIER trial. Circulation. https://doi.org/10. of international recommendations for the recognition of asymp- 1161/circulationaha.118.037184 tomatic high risk patients for a heart attack in Germany. Z Kardiol 30. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu 94(1):52–60. https://doi.org/10.1007/s00392-005-0150-4 RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke 28. Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heut- ST, Witztum JL, Stroes ES, Tsimikas S (2016) Antisense oligonu- ling D, Breitenberger P, Maerz W, Lehmacher W, Heibges A, cleotides targeting apolipoprotein(a) in people with raised lipopro- Klingel R, ProLiFe Study G (2013) Lipoprotein apheresis in pa- tein(a): two randomised, double-blind, placebo-controlled, dose- tients with maximally tolerated lipid-lowering therapy, lipopro- ranging trials. Lancet 388(10057):2239–2253. https://doi.org/10. tein(a)-hyperlipoproteinemia, and progressive cardiovascular dis- 1016/s0140-6736(16)31009-1 ease: prospective observational multicenter study. Circulation http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Research in Cardiology Supplements Springer Journals

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Medicine & Public Health; Cardiology; Internal Medicine; Angiology; Cardiac Surgery; Diagnostic Radiology
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Abstract

Clin Res Cardiol Suppl (2019) (Suppl) 14:1–4 https://doi.org/10.1007/s11789-019-00100-9 EDITORIAL 1 2 K. P. Mellwig ·A.Vogt © The Author(s) 2019 Lipoprotein(a) (LP(a))—discovered by Kare Berg [1]in Kringles are characterized by 2–40 repeats creating at 1963—is of increasing importance in clinical routine as re- least 30 polymorphous isoforms of Apo(a), which are dif- flected by the ESC/EAS Guidelines for the Management of ferent in terms of size and mass. Number and qualitative Dyslipidaemias and the recent AHA Guideline [2, 3]. These composition of kringle domains determine the atherogene- guidelines provide detailed recommendations for screening ity of Lp(a). The large isoforms with more kringle repeats and lipid analyses in the assessment of cardiovascular risk. seem to be less atherogenous than the smaller ones [9]. A consensus paper of the European Society of Cardiology summarizes basic principles, background as well as diag- nostic and therapeutic principles [4]. Synthesis and metabolism Apoprotein(a) is synthesized in the liver exclusively [10]. Structure—physiochemical characteristics How much Apo(a) is produced by the liver depends on the LPA gene and its amount remains more or less constant LP(a) is a lipid protein complex with a structure compared during a person’s lifetime. As Lp(a) in males rises only to to that of LDL (low density lipoprotein). Another apopro- a minor extent with increasing age, this parameter has to be tein, glycoprotein apoprotein(a) (Apo(a)) is bonded to the determined only once in a lifetime. In women however, the apoprotein B-100 (Apo B-100) of the LDL cholesterol via analysis should be done before and after menopause, as the a disulphide bridge [5]. Lp(a) level might markedly increase during menopause. It The presence of Apo(a) impairs the bond between Lp(a) is quite unclear where Lp(a) is produced, most probably on and the LDL receptor. An independent Lp(a) receptor has the surface of hepatocytes or in plasma. not been identified so far. Corresponding to the LDL choles- Catabolism of Lp(a) is independent of a functioning LDL terol (LDL-C), the Lp(a) molecule is coated by a layer of receptor [11]. The kidney seems to have a specific binding simple phospholipids, free cholesterol, and apoproteins. Its capacity for Lp(a) [12]. A reduced glomerular filtration rate core consists of triglycerides and esterified cholesterol [6]. (GFR) may lead to an increase in plasma concentration of Due to its structural similarity, Lp(a) competes with plas- Lp(a). Other factors are hypothyreosis or an acute phase minogen for bindings sites on endothelial cells thus block- reaction (e. g. acute myocardial infarction). Oestrogen ther- ing the development of plasmin [7]. This leads to a de- apy, pregnancy or aspirin uptake cause a non-significant or lay of fibrinolysis. Similar to plasminogen, Apo(a) contains relevant reduction [13]. a kringle domain [8]. Genetics This article is part of the special issue “Lp(a) – Update 2018” Apo(a) is encoded by a gene on chromosome 6q26-27 K. P. Mellwig akleemeyer@hdz-nrw.de [14]. Lp(a) plasma concentration is controlled by the Lp(a) gene locus; polymorphisms of the Apo(a) kringle IV-2 re- Klinik für Allgemeine und Interventionelle peats are responsible for the differences in plasma level. Of Kardiologie/Angiologie, Herz- und Diabeteszentrum 48 single nucleotide polymorphisms (SNPs) in the Lp(a) NRW, Universitätsklinik, Ruhr-Universität Bochum, gene region, seven SNPs show a significant association with Georgstr. 11, 32545 Bad Oeynhausen, Germany coronary heart disease [15]. The frequently used but slightly Medizinische Klinik und Poliklinik IV, Klinikum der arbitrary normal value of <30 mg/dl (1.6 mmol/l) is based Universität München, Ziemssenstr. 1, 80336 Munich, Germany on data which show that with an increasing value the car- K 2 K. P. Mellwig, A. Vogt diovascular risk increases without a given threshold value Registry data show that the degree of aortic valve steno- [16]. ESC recommends a threshold value of <50 mg/dl (80th sis rises with increasing Lp(a) levels [22]. percentile) [4]. Cerebrovascular and peripheral vascular disease, abdominal Thrombogenous and atherogenous characteristics aortic aneurysm In blood coagulation Lp(a) is the opponent of plasmino- Lp(a) is also discussed to be an independent risk factor for gen—the inactive preliminary enzyme stage of plas- cerebrovascular diseases. Particularly in young patients suf- min—which resolves fibrin clots. Lp(a) competes with fering from an apoplectic insult Lp(a) might be a causative plasminogen for the binding sites on endothelial cells thus factor [23]. Furthermore, Lp(a) seems to be a predictor for blocking plasmin formation [9]. This leads to a delay in an early recurrence [24]. fibrinolysis and to deposits on the vascular wall. High The manifestation of a peripheral arterial occlusive dis- concentrations of Lp(a) cause an increased thrombotic risk ease is also influenced by Lp(a) concentration and a low due to an inhibition of fibrinolytic mechanisms. molecular (NMW) Apo(a) phenotype [25]. The structure of Lp(a) contains about 30% of choles- Finally, numerous published reports on increased Lp(a) terol and cholesterol ester, in addition atherogenous, proim- levels in patients with documented abdominal aortic flammatoray oxidized phospholipids are bonded. This leads aneurysms should be mentioned. This might be an evi- to an accumulation of inflammatory cells in the vascular dence for Lp(a)-induced atherosclerotic processes in large wall with consecutive proliferation of smooth muscle cells. vessels [26]. Atherogenesis is thus induced and maintained. Screening Clinical relevance Coronary heart disease Presymptomatic patients with an increased cardiovascular risk are identified by the determination of classical risk The causative role of Lp(a) in the early manifestation of factors in established scores such as PROCAM, SCORE, coronary heart disease is becoming more and more evident. ASCVD. Earlier studies including meta-analyses have shown that The quality of these scores for risk assessment is not sat- an elevated Lp(a) concentration markedly increases the risk isfying. The sensitivities of these are <50% and the positive for coronary heart disease [17]. In addition, Mendelian ran- predictive value is at most 30% [27]. The establishment of domization has indicated that genetic mutations of Lp(a) new risk factors is therefore of high clinical relevance to in the form of polymorphisms of the Apo(a) kringle IV-2 improve the reliability of prognosis. Considering the ge- repeats are associated with a risk of coronary heart disease netic determination and hereditary burden Lp(a) might be [18]. Patients with a familial hypercholesterolemia (FH) a candidate. of a prospective cohort study, where 46,200 individuals of the Copenhagen General Population Study were enrolled, Therapy showed the highest risk of developing a coronary heart dis- ease in case of Lp(a)≥ 50 mg/dL (HR 5.3, 95% CI 3.6–7.6) [19]. In the GENESIS-PRAXY (GENdEr and Sex determi- So far lipoprotein apheresis is the only effective available nantS of cardiovascular disease) study, 939 young patients therapeutic option to reduce Lp(a) significantly, with a doc- admitted for an acute coronary syndrome (ACS) showed an umented effect on cardiac events [28]. association between high Lp(a) (>50 mg/dl) and high LDL- PCSK9 inhibitors reduce LDL cholesterol significantly C (>3.5 mmol/L) so that increased Lp(a) and high LDL-C and Lp(a) by about 25–30% [29]. In case of very high ini- represent an increased risk for ACS [20]. tial values of Lp(a), a favourable influence on athergenous events cannot be expected. A promising approach is the Aortic valve stenosis antisense oligonucleotide therapy. Phase 1 and 2 studies have shown reduction rates of Lp(a) of up to 80% with Aortic valve stenosis may be genetically induced as well a good tolerability [30]. If these results are reproducible as result from a lipid disorder and an Lp(a) increase. in a phase 3 study and cardiovascular events are reduced, A large-scale study has proved that an elevated Lp(a) and a specific drug therapy of high Lp(a) values might become a corresponding LP risk genotype (rs10455872, rs3798220, available for the first time. kringle IV type 2 repeat polymorphism) increase the risk The large number of publications during the past years for the development of aortic valve stenosis [21]. emphasizes the pathophysiological and clinical relevance K Lipoprotein(a) 3 10. Hoover-Plow J, Huang M (2013) Lipoprotein(a) metabolism: po- of Lp(a). The contributions to this supplement presented at tential sites for therapeutic targets. Metabolism 62(4):479–491. the Lp(a) Update 2018 meeting in Kassel are intended to https://doi.org/10.1016/j.metabol.2012.07.024 provide an overview and critical appraisal of cardiovascular 11. Hobbs HH, White AL (1999) Lipoprotein(a): intrigues and insights. risk factors for clinical routine. Curr Opin Lipidol 10(3):225–236 12. Kostner GM, Wo X, Frank S, Kostner K, Zimmermann R, Steyrer Conflict of interest K.P. Mellwig and A. Vogt declare that they have E (1997) Metabolism of Lp(a): assembly and excretion. Clin Genet no competing interests. 52(5):347–354 13. Kostner KM, Kostner GM (2017) Lipoprotein (a): a historical Open Access This article is distributed under the terms of the appraisal. J Lipid Res 58(1):1–14. https://doi.org/10.1194/jlr. Creative Commons Attribution 4.0 International License (http:// R071571 creativecommons.org/licenses/by/4.0/), which permits unrestricted 14. Frank SL, Klisak I, Sparkes RS, Mohandas T, Tomlinson JE, use, distribution, and reproduction in any medium, provided you give McLean JW, Lawn RM, Lusis AJ (1988) The apolipoprotein(a) appropriate credit to the original author(s) and the source, provide a gene resides on human chromosome 6q26-27, in close proximity to link to the Creative Commons license, and indicate if changes were the homologous gene for plasminogen. Hum Genet 79(4):352–356 made. 15. Mack S, Coassin S, Rueedi R, Yousri NA, Seppala I, Gieger C, Schonherr S, Forer L, Erhart G, Marques-Vidal P, Ried JS, Wae- ber G, Bergmann S, Dahnhardt D, Stockl A, Raitakari OT, Ka- References honen M, Peters A, Meitinger T, Strauch K, Group KO, Kedenko L, Paulweber B, Lehtimaki T, Hunt SC, Vollenweider P, Lamina 1. Berg K (1963) A new serum type system in man—the Lp system. 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