AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. METHODS AND RESULTS: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ∼50 mg/dL). Treatment should primarily be niacin 1-3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a). CONCLUSION: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction.

Department of Clinical Biochemistry Herlev Hospital Copenhagen University Hospital University of Copenhagen DK 2730 Herlev Denmark

Zobrazit více v PubMed

Utermann G. Lipoprotein(a) In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. pp. 2753–2787.

Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–2339. PubMed

Erqou S, Kaptoge S, Perry PL, Di AE, 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;302:412–423. PubMed PMC

Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de FU, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518–2528. PubMed

Matthews KA, Sowers MF, Derby CA, Stein E, Miracle-McMahill H, Crawford SL, Pasternak RC. Ethnic differences in cardiovascular risk factor burden among middle-aged women: Study of Women's Health Across the Nation (SWAN) Am Heart J. 2005;149:1066–1073. PubMed

Cantin B, Gagnon F, Moorjani S, Despres JP, Lamarche B, Lupien PJ, Dagenais GR. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol. 1998;31:519–525. PubMed

Luc G, Bard JM, Arveiler D, Ferrieres J, Evans A, Amouyel P, Fruchart JC, Ducimetiere P. Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis. 2002;163:377–384. PubMed

Suk DJ, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. JAMA. 2006;296:1363–1370. PubMed

Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation. 2000;102:1082–1085. PubMed

Bennet A, Di AE, Erqou S, Eiriksdottir G, Sigurdsson G, Woodward M, Rumley A, Lowe GD, Danesh J, Gudnason V. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med. 2008;168:598–608. PubMed

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. PubMed

Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004;33:30–42. PubMed

Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001. pp. 2863–2913.

Tybjaerg-Hansen A, Steffensen R, Meinertz H, Schnohr P, Nordestgaard BG. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med. 1998;338:1577–1584. PubMed

Luke MM, Kane JP, Liu DM, Rowland CM, Shiffman D, Cassano J, Catanese JJ, Pullinger CR, Leong DU, Arellano AR, Tong CH, Movsesyan I, Naya-Vigne J, Noordhof C, Feric NT, Malloy MJ, Topol EJ, Koschinsky ML, Devlin JJ, Ellis SG. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler Thromb Vasc Biol. 2007;27:2030–2036. PubMed

Holmes DT, Schick BA, Humphries KH, Frohlich J. Lipoprotein(a) is an independent risk factor for cardiovascular disease in heterozygous familial hypercholesterolemia. Clin Chem. 2005;51:2067–2073. PubMed

Rader DJ, Cain W, Ikewaki K, Talley G, Zech LA, Usher D, Brewer HB., Jr. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate. J Clin Invest. 1994;93:2758–2763. PubMed PMC

Koschinsky ML, Marcovina SM. Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol. 2004;15:167–174. PubMed

Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem. 2003;49:1785–1796. PubMed

Koschinsky M, Marcovina SM. Lipoprotein(a) In: Ballantyne C, editor. Clinical Lipidology: A Companion to Braunwauld's Heart Disease. Philadelphia: Saunders Elsevier; 2009. pp. 130–143.

Nielsen LB. Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis. 1999;143:229–243. PubMed

Lundstam U, Hurt-Camejo E, Olsson G, Sartipy P, Camejo G, Wiklund O. Proteoglycans contribution to association of Lp(a) and LDL with smooth muscle cell extracellular matrix. Arterioscler Thromb Vasc Biol. 1999;19:1162–1167. PubMed

Bdeir K, Cane W, Canziani G, Chaiken I, Weisel J, Koschinsky ML, Lawn RM, Bannerman PG, Sachais BS, Kuo A, Hancock MA, Tomaszewski J, Raghunath PN, Ganz T, Higazi AA, Cines DB. Defensin promotes the binding of lipoprotein(a) to vascular matrix. Blood. 1999;94:2007–2019. PubMed

Boonmark NW, Lou XJ, Yang ZJ, Schwartz K, Zhang JL, Rubin EM, Lawn RM. Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice. J Clin Invest. 1997;100:558–564. PubMed PMC

Sotiriou SN, Orlova VV, Al-Fakhri N, Ihanus E, Economopoulou M, Isermann B, Bdeir K, Nawroth PP, Preissner KT, Gahmberg CG, Koschinsky ML, Chavakis T. Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin. FASEB J. 2006;20:559–561. PubMed

Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS, Witztum JL, Berger PB. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005;353:46–57. PubMed

Tsimikas S, Tsironis LD, Tselepis AD. New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2007;27:2094–2099. PubMed

Rouy D, Grailhe P, Nigon F, Chapman J, Angles-Cano E. Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator. In vitro studies in a plasma milieu. Arterioscler Thromb. 1991;11:629–638. PubMed

Feric NT, Boffa MB, Johnston SM, Koschinsky ML. Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation. J Thromb Haemost. 2008;6:2113–2120. PubMed

Pan S, Kleppe LS, Witt TA, Mueske CS, Simari RD. The effect of vascular smooth muscle cell-targeted expression of tissue factor pathway inhibitor in a murine model of arterial thrombosis. Thromb Haemost. 2004;92:495–502. PubMed

Hervio L, Chapman MJ, Thillet J, Loyau S, Angles-Cano E. Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis? Blood. 1993;82:392–397. PubMed

Erqou S, Thompson A, Di AE, Saleheen D, Kaptoge S, Marcovina S, Danesh J. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010;55:2160–2167. PubMed

Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, Egger G, Utermann G, Willeit J. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation. 1999;100:1154–1160. PubMed

von Eckardstein A, Schulte H, Cullen P, Assmann G. Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk. J Am Coll Cardiol. 2001;37:434–439. PubMed

Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J, De BG, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S, Scholte op RW, Weissberg P, Wood D, Yarnell J, Zamorano JL, Walma E, Fitzgerald T, Cooney MT, Dudina A, Vahanian A, Camm J, De CR, Dean V, Dickstein K, Funck-Brentano C, Filippatos G, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Hellemans I, Altiner A, Bonora E, Durrington PN, Fagard R, Giampaoli S, Hemingway H, Hakansson J, Kjeldsen SE, Larsen ML, Mancia G, Manolis AJ, Orth-Gomer K, Pedersen T, Rayner M, Ryden L, Sammut M, Schneiderman N, Stalenhoef AF, Tokgozoglu L, Wiklund O, Zampelas A. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J. 2007;28:2375–2414. PubMed

Grundy SM, Cleeman JI, Merz CN, Brewer HB, Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Jr, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004;24:e149–e161. PubMed

Nordestgaard BG. Does elevated C-reactive protein cause human atherothrombosis? Novel insights from genetics, intervention trials, and elsewhere. Curr Opin Lipidol. 2009;20:393–401. PubMed

Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis. 2010;210:353–361. PubMed

Carlson LA, Rosenhamer G. Reduction in mortality in the Stockholm Ischemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand. 1988;233:405–418. PubMed

Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245–1255. PubMed

Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA. 1990;264:3013–3017. PubMed

Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289–1298. PubMed

Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361:2113–2122. PubMed

Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther. 2010;126:314–345. PubMed

Tziomalos K, Athyros VG, Wierzbicki AS, Mikhailidis DP. Lipoprotein a: where are we now? Curr Opin Cardiol. 2009;24:351–357. PubMed

Gonbert S, Malinsky S, Sposito AC, Laouenan H, Doucet C, Chapman MJ, Thillet J. Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk. Atherosclerosis. 2002;164:305–311. PubMed

Suk DJ, Rifai N, Buring JE, Ridker PM. Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol. 2008;52:124–131. PubMed PMC

Maher VM, Brown BG, Marcovina SM, Hillger LA, Zhao XQ, Albers JJ. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a) JAMA. 1995;274:1771–1774. PubMed

Merki E, Graham MJ, Mullick AE, Miller ER, Crooke RM, Pitas RE, Witztum JL, Tsimikas S. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation. 2008;118:743–753. PubMed

Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, Baxter JD, Angelin B. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362:906–916. PubMed

Thompson GR. Recommendations for the use of LDL apheresis. Atherosclerosis. 2008;198:247–255. PubMed

Novel Phenotyping for Acute Heart Failure-Unsupervised Machine Learning-Based Approach

The Impact of the International Cooperation On Familial Hypercholesterolemia Screening and Treatment: Results from the ScreenPro FH Project

Maternal Cardiovascular Risk Assessment 3-to-11 Years Postpartum in Relation to Previous Occurrence of Pregnancy-Related Complications

Current practice in identifying and treating cardiovascular risk, with a focus on residual risk associated with atherogenic dyslipidaemia