Lp(a): der akzeptierte unabhängige Risikofaktor

Lipoprotein(a) (Lp(a)) besteht aus einem LDL-Partikel, an dem über das Apolipoprotein B100 des Partikels eine Disulfidbrücke zu einem Apolipoprotein(a) besteht ([ Abb. 1 ]). Obwohl Lp(a) bereits 1963 von Berg et al. erstmals als „lipoprotein associated antigen“ entdeckt [1] und schon früh ein Zusammenhang mit kardiovaskulären Ereignissen diskutiert wurde [2], konnten diese Annahmen der klinischen Eigenschaften erst deutlich später im Rahmen von epidemiologischen Evaluationen bestätigt werden [3], [4]. Ab einer Lp(a)-Konzentration von über 30 mg/dl (> 75 nmol/l) besteht ein nahezu linearer Zusammenhang zwischen dem Anstieg der Lp(a)-Konzentration und kardiovaskulären Ereignissen wie Myokardinfarkt und das Risiko für eine Aortenklappenstenose [3], [4].

• Literatur

• 1 Berg K. A New Serum Type System in Man--the Lp System. Acta Pathol Microbiol Scand 1963; 59: 369-382
• 2 Daae LN, Kierulf P, Landaas S, Urdal P. Cardiovascular risk factors: interactive effects of lipids, coagulation and fibrinolysis. Scand J Clin Lab Invest Suppl 1993; 215: 19-27
• 3 Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation 2008; 117: 176-184
• 4 Emerging Risk Factors Collaboration Erqou S, Kaptoge S, Perry PL. et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302: 412-423
• 5 Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 2016; 57: 1953-1975
• 6 Coassin S, Schonherr S, Weissensteiner H. et al. A comprehensive map of single-base polymorphisms in the hypervariable LPA kringle IV type 2 copy number variation region. J Lipid Res 2019; 60: 186-199
• 7 Clarke R, Peden JF, Hopewell JC. et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361: 2518-2528
• 8 Mack S, Coassin S, Rueedi R. et al. A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms. J Lipid Res 2017; 58: 1834-1844
• 9 Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol 2017; 69: 692-711
• 10 Romagnuolo R, Scipione CA, Bazzi ZA. et al. Inhibition of pericellular plasminogen activation by apolipoprotein(a): Roles of urokinase plasminogen activator receptor and integrins alphaMbeta2 and alphaVbeta3. Atherosclerosis 2018; 275: 11-21
• 11 McLean JW, Tomlinson JE, Kuang WJ. et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330: 132-137
• 12 Schettler VJ, Schulz EG, Hagenah GC, Neumann CL. Successful completion of pregnancy using apheresis and a balanced dose of coagulation factors in the presence of high thrombophilia and Lp(a) levels in a woman with two previous abortions. Clin Kidney J 2014; 7: 497-498
• 13 Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?. J Lipid Res 2016; 57: 745-757
• 14 Boffa MB, Koschinsky ML. Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease. Nat Rev Cardiol 2019; 16: 305-318
• 15 Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30: 2311-2316
• 16 Hartley A, Haskard D, Khamis R. Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis – Novel insights and future directions in diagnosis and therapy < sup/ >. Trends Cardiovasc Med 2019; 29: 22-26
• 17 Tsimikas S, Lau HK, Han KR. et al. Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein. Circulation 2004; 109: 3164-3170
• 18 Philippova M, Oskolkova OV, Bicker W. et al. Analysis of fragmented oxidized phosphatidylcholines in human plasma using mass spectrometry: Comparison with immune assays. Free Radic Biol Med 2019 May 26. pii: S0891-5849(18)32628–5 [Epub ahead of print]
• 19 Orso E, Schmitz G. Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies. Clin Res Cardiol Suppl 2017; 12: 31-37
• 20 Liu L, Craig AW, Meldrum HD. et al. Apolipoprotein(a) stimulates vascular endothelial cell growth and migration and signals through integrin alphaVbeta3. Biochem J 2009; 418: 325-336
• 21 Sage AP, Tsiantoulas D, Binder CJ, Mallat Z. The role of B cells in atherosclerosis. Nat Rev Cardiol 2019; 16: 180-196
• 22 Tsimikas S, Gordts P, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J 2019 May 20. pii: ehz310 [Epub ahead of print]
• 23 Tardif JC, Rheaume E, Rhainds D, Dube MP. Lipoprotein (a), arterial inflammation, and PCSK9 inhibition. Eur Heart J 2019; 40: 2782-2784
• 24 Graham MJ, Viney N, Crooke RM, Tsimikas S. Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans. J Lipid Res 2016; 57: 340-351
• 25 Schenck I, Keller C, Hailer S. et al. Reduction of Lp(a) by different methods of plasma exchange. Klin Wochenschr 1988; 66: 1197-1201
• 26 Armstrong VW, Schleef J, Thiery J. et al. Effect of HELP-LDL-apheresis on serum concentrations of human lipoprotein(a): kinetic analysis of the post-treatment return to baseline levels. Eur J Clin Invest 1989; 19: 235-240
• 27 Jaeger BR, Richter Y, Nagel D. et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med 2009; 6: 229-239
• 28 Leebmann J, Roeseler E, Julius U. et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation 2013; 128: 2567-2576
• 29 Roeseler E, Julius U, Heigl F. et al. Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease: Prospective 5 Years of Follow-Up and Apolipoprotein(a) Characterization. Arterioscler Thromb Vasc Biol 2016; 36: 2019-2027
• 30 Schettler VJJ, Neumann CL, Peter C. et al. Lipoprotein apheresis is an optimal therapeutic option to reduce increased Lp(a) levels. Clin Res Cardiol Suppl 2019; 14: 33-38
• 31 Khan TZ, Hsu LY, Arai AE. et al. Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomized controlled cross-over trial. Eur Heart J 2017; 38: 1561-1569
• 32 Khan TZ, Gorog DA, Arachchillage DJ. et al. Impact of lipoprotein apheresis on thrombotic parameters in patients with refractory angina and raised lipoprotein(a): Findings from a randomized controlled cross-over trial. J Clin Lipidol 2019 Jul 2. pii: S1933-2874(19)30229–6 [Epub ahead of print]
• 33 Sinzinger H, Steiner S, Derfler K. Pleiotropic effects of regular lipoprotein-apheresis. Atheroscler Suppl 2017; 30: 122-127
• 34 Wieland E, Schettler V, Armstrong VW. Highly effective reduction of C-reactive protein in patients with coronary heart disease by extracorporeal low density lipoprotein apheresis. Atherosclerosis 2002; 162: 187-191
• 35 Stefanutti C, Mazza F, Pasqualetti D. et al. Lipoprotein apheresis downregulates IL-1alpha, IL-6 and TNF-alpha mRNA expression in severe dyslipidaemia. Atheroscler Suppl 2017; 30: 200-208
• 36 Aday AW, Ridker PM. Targeting Residual Inflammatory Risk: A Shifting Paradigm for Atherosclerotic Disease. Front Cardiovasc Med 2019; 6: 16