Lipoprotein(a) and cardiovascular disease
- Robert S Rosenson, MD
Robert S Rosenson, MD
- Professor of Medicine
- Mount Sinai School of Medicine
- Director, Cardiometabolic Disorders
- Mount Sinai Heart
- James H Stein, MD
James H Stein, MD
- Robert Turell Professor in Cardiovascular Research
- Director, Preventive Cardiology
- Department of Medicine, Cardiovascular Medicine Division
- University of Wisconsin School of Medicine and Public Health
- University of Wisconsin Hospital and Clinics
- Paul Durrington, MD
Paul Durrington, MD
- Professor of Medicine
- Physician to Manchester Royal Infirmary
- University of Manchester
Most trials of lipid-lowering therapy for the prevention of cardiovascular disease (CVD) focused on lowering low density lipoprotein cholesterol levels. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention".)
Although other dyslipidemias, such as an elevated level of lipoprotein(a), also may promote atherosclerosis, interventions directed toward altering these have only infrequently been evaluated in controlled clinical trials . Elevated serum lipoprotein(a), also referred to as Lp(a), is a risk factor for CVD. There is a causal relationship between Lp(a) excess and risk for myocardial infarction. (See 'Risk factor versus cause' below.)
This topic will review the genetics, structure, and function of Lp(a), as well as its association with atherosclerotic cardiovascular disease. Possible indications for screening and therapy will also be addressed. The association between Lp(a) and aortic valve sclerosis is discussed separately.(See "Aortic valve sclerosis and pathogenesis of calcific aortic stenosis", section on 'Pathogenesis of calcific aortic valve disease'.)
STRUCTURE AND FUNCTION
Lipoprotein(a) [Lp(a)] is a modified form of low density lipoprotein in which a large glycoprotein, apolipoprotein(a) [apo(a)] is covalently bound to apolipoprotein B by a disulfide bridge . The apo(a) chain contains five cysteine rich domains known as "kringles" . The fourth kringle is homologous with the fibrin-binding domain of plasminogen, a plasma protein that dissolves blood clots when activated. Because of this structural similarity to plasminogen, Lp(a) interferes with fibrinolysis by competing with plasminogen binding to molecules and cells. This impairs plasminogen activation, plasmin generation, and fibrinolysis [4,5]. Lp(a) also binds to macrophages via a high-affinity receptor that promotes foam cell formation and the deposition of cholesterol in atherosclerotic plaques .
Serum lipoprotein(a) [Lp(a)] levels are primarily genetically determined. In families without familial hypercholesterolemia, greater than 90 percent of the variability in Lp(a) levels can be explained by polymorphisms at the apolipoprotein(a) [apo(a)] gene locus (isoforms), also referred to as the LPA gene (Online Mendelian Inheritance in Man [MIM] 152200) . One important LPA polymorphism is the kringle IV type 2 size polymorphism, which results in a large number of differently sized isoforms of apo(a) . There is a strong inverse relationship between the size of the apo(a) isoforms and the Lp(a) concentrations [7,9-11]. A significant proportion (30 to 60 percent) of the population variation in Lp(a) levels is determined by this polymorphism .
- Rosenson RS. Beyond low-density lipoprotein cholesterol. A perspective on low high-density lipoprotein disorders and Lp(a) lipoprotein excess. Arch Intern Med 1996; 156:1278.
- Steyrer E, Durovic S, Frank S, et al. The role of lecithin: cholesterol acyltransferase for lipoprotein (a) assembly. Structural integrity of low density lipoproteins is a prerequisite for Lp(a) formation in human plasma. J Clin Invest 1994; 94:2330.
- McLean JW, Tomlinson JE, Kuang WJ, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 1987; 330:132.
- Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 1990; 10:240.
- Palabrica TM, Liu AC, Aronovitz MJ, et al. Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis. Nat Med 1995; 1:256.
- Zioncheck TF, Powell LM, Rice GC, et al. Interaction of recombinant apolipoprotein(a) and lipoprotein(a) with macrophages. J Clin Invest 1991; 87:767.
- Boerwinkle E, Leffert CC, Lin J, et al. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992; 90:52.
- Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009; 301:2331.
- Bowden JF, Pritchard PH, Hill JS, Frohlich JJ. Lp(a) concentration and apo(a) isoform size. Relation to the presence of coronary artery disease in familial hypercholesterolemia. Arterioscler Thromb 1994; 14:1561.
- Kraft HG, Lingenhel A, Köchl S, et al. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol 1996; 16:713.
- Sandholzer C, Saha N, Kark JD, et al. Apo(a) isoforms predict risk for coronary heart disease. A study in six populations. Arterioscler Thromb 1992; 12:1214.
- Thanassoulis G, O'Donnell CJ. Mendelian randomization: nature's randomized trial in the post-genome era. JAMA 2009; 301:2386.
- Bostom AG, Gagnon DR, Cupples LA, et al. A prospective investigation of elevated lipoprotein (a) detected by electrophoresis and cardiovascular disease in women. The Framingham Heart Study. Circulation 1994; 90:1688.
- Bostom AG, Cupples LA, Jenner JL, et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. JAMA 1996; 276:544.
- Marcovina SM, Albers JJ, Wijsman E, et al. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res 1996; 37:2569.
- Dahlén G, Ericson C, Furberg C, et al. Studies on an extra pre-beta lipoprotein fraction. Acta Med Scand Suppl 1972; 531:1.
- Superko HR. Beyond LDL cholesterol reduction. Circulation 1996; 94:2351.
- 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.
- Marcovina SM, Albers JJ, Scanu AM, et al. Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem 2000; 46:1956.
- Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302:412.
- Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102:1082.
- Dangas G, Ambrose JA, D'Agate DJ, et al. Correlation of serum lipoprotein(a) with the angiographic and clinical presentation of coronary artery disease. Am J Cardiol 1999; 83:583.
- Schaefer EJ, Lamon-Fava S, Jenner JL, et al. Lipoprotein(a) levels and risk of coronary heart disease in men. The lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994; 271:999.
- Nguyen TT, Ellefson RD, Hodge DO, et al. Predictive value of electrophoretically detected lipoprotein(a) for coronary heart disease and cerebrovascular disease in a community-based cohort of 9936 men and women. Circulation 1997; 96:1390.
- Wald NJ, Law M, Watt HC, et al. Apolipoproteins and ischaemic heart disease: implications for screening. Lancet 1994; 343:75.
- Cremer P, Nagel D, Labrot B, et al. Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen, LDL cholesterol and other risk factors: results from the prospective Göttingen Risk Incidence and Prevalence Study (GRIPS). Eur J Clin Invest 1994; 24:444.
- Schwartzman RA, Cox ID, Poloniecki J, et al. Elevated plasma lipoprotein(a) is associated with coronary artery disease in patients with chronic stable angina pectoris. J Am Coll Cardiol 1998; 31:1260.
- Ariyo AA, Thach C, Tracy R, Cardiovascular Health Study Investigators. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med 2003; 349:2108.
- Shai I, Rimm EB, Hankinson SE, et al. Lipoprotein (a) and coronary heart disease among women: beyond a cholesterol carrier? Eur Heart J 2005; 26:1633.
- Coleman MP, Key TJ, Wang DY, et al. A prospective study of obesity, lipids, apolipoproteins and ischaemic heart disease in women. Atherosclerosis 1992; 92:177.
- Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993; 270:2195.
- Jauhiainen M, Koskinen P, Ehnholm C, et al. Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants. Atherosclerosis 1991; 89:59.
- Cantin B, Gagnon F, Moorjani S, et al. Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. J Am Coll Cardiol 1998; 31:519.
- Nishino M, Malloy MJ, Naya-Vigne J, et al. Lack of association of lipoprotein(a) levels with coronary calcium deposits in asymptomatic postmenopausal women. J Am Coll Cardiol 2000; 35:314.
- Cobbaert C, Jukema JW, Zwinderman AH, et al. Modulation of lipoprotein(a) atherogenicity by high density lipoprotein cholesterol levels in middle-aged men with symptomatic coronary artery disease and normal to moderately elevated serum cholesterol. Regression Growth Evaluation Statin Study (REGRESS) Study Group. J Am Coll Cardiol 1997; 30:1491.
- 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.
- Willeit P, Kiechl S, Kronenberg F, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 2014; 64:851.
- Bennet A, Di Angelantonio E, Erqou S, et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med 2008; 168:598.
- Genest JJ Jr, Martin-Munley SS, McNamara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992; 85:2025.
- Stubbs P, Seed M, Lane D, et al. Lipoprotein(a) as a risk predictor for cardiac mortality in patients with acute coronary syndromes. Eur Heart J 1998; 19:1355.
- Erqou S, Thompson A, Di Angelantonio E, et al. 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.
- Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol 2013; 61:1146.
- Ohira T, Schreiner PJ, Morrisett JD, et al. Lipoprotein(a) and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2006; 37:1407.
- Smolders B, Lemmens R, Thijs V. Lipoprotein (a) and stroke: a meta-analysis of observational studies. Stroke 2007; 38:1959.
- Sechi LA, Kronenberg F, De Carli S, et al. Association of serum lipoprotein(a) levels and apolipoprotein(a) size polymorphism with target-organ damage in arterial hypertension. JAMA 1997; 277:1689.
- 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.
- Argraves KM, Kozarsky KF, Fallon JT, et al. The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. J Clin Invest 1997; 100:2170.
- Dangas G, Mehran R, Harpel PC, et al. Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation. J Am Coll Cardiol 1998; 32:2035.
- Salonen EM, Jauhiainen M, Zardi L, et al. Lipoprotein(a) binds to fibronectin and has serine proteinase activity capable of cleaving it. EMBO J 1989; 8:4035.
- Schachinger V, Halle M, Minners J, et al. Lipoprotein(a) selectively impairs receptor-mediated endothelial vasodilator function of the human coronary circulation. J Am Coll Cardiol 1997; 30:927.
- Schlaich MP, John S, Langenfeld MR, et al. Does lipoprotein(a) impair endothelial function? J Am Coll Cardiol 1998; 31:359.
- Takami S, Yamashita S, Kihara S, et al. Lipoprotein(a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells. Circulation 1998; 97:721.
- Haberland ME, Fless GM, Scanu AM, Fogelman AM. Malondialdehyde modification of lipoprotein(a) produces avid uptake by human monocyte-macrophages. J Biol Chem 1992; 267:4143.
- Poon M, Zhang X, Dunsky KG, et al. Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation 1997; 96:2514.
- Riis Hansen P, Kharazmi A, Jauhiainen M, Ehnholm C. Induction of oxygen free radical generation in human monocytes by lipoprotein(a). Eur J Clin Invest 1994; 24:497.
- Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 2005; 353:46.
- Deb A, Caplice NM. Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis. Clin Cardiol 2004; 27:258.
- Braeckman L, De Bacquer D, Rosseneu M, De Backer G. Determinants of lipoprotein(a) levels in a middle-aged working population. Eur Heart J 1996; 17:1808.
- Glader CA, Boman J, Saikku P, et al. The proatherogenic properties of lipoprotein(a) may be enhanced through the formation of circulating immune complexes containing Chlamydia pneumoniae-specific IgG antibodies. Eur Heart J 2000; 21:639.
- Kullo IJ, Bailey KR, Bielak LF, et al. Lack of association between lipoprotein(a) and coronary artery calcification in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Mayo Clin Proc 2004; 79:1258.
- Desmarais RL, Sarembock IJ, Ayers CR, et al. Elevated serum lipoprotein(a) is a risk factor for clinical recurrence after coronary balloon angioplasty. Circulation 1995; 91:1403.
- Ribichini F, Steffenino G, Dellavalle A, et al. Plasma lipoprotein(a) is not a predictor for restenosis after elective high-pressure coronary stenting. Circulation 1998; 98:1172.
- Giovanetti F, Gargiulo M, Laghi L, et al. Lipoprotein(a) and other serum lipid subfractions influencing primary patency after infrainguinal percutaneous transluminal angioplasty. J Endovasc Ther 2009; 16:389.
- Miwa K, Nakagawa K, Yoshida N, et al. Lipoprotein(a) is a risk factor for occurrence of acute myocardial infarction in patients with coronary vasospasm. J Am Coll Cardiol 2000; 35:1200.
- Stein JH, Rosenson RS. Lipoprotein Lp(a) excess and coronary heart disease. Arch Intern Med 1997; 157:1170.
- Maher VM, Brown BG. Lipoprotein (a) and coronary heart disease. Curr Opin Lipidol 1995; 6:229.
- Thompson GR, Maher VM, Matthews S, et al. Familial Hypercholesterolaemia Regression Study: a randomised trial of low-density-lipoprotein apheresis. Lancet 1995; 345:811.
- Rader DJ, Brewer HB Jr. Lipoprotein(a). Clinical approach to a unique atherogenic lipoprotein. JAMA 1992; 267:1109.
- Børresen AL, Berg K, Dahlén G, et al. The effect of Gemfibrozil on human serum apolipoproteins and on serum reserve cholesterol binding capacity (SRCBC). Artery 1981; 9:77.
- Jones PH, Pownall HJ, Patsch W, et al. Effect of gemfibrozil on levels of lipoprotein[a] in type II hyperlipoproteinemic subjects. J Lipid Res 1996; 37:1298.
- Maggi FM, Biasi GM, Catapano AL. Reduction of Lp(a) plasma levels by bezafibrate. Atherosclerosis 1993; 100:127.
- Bimmermann A, Boerschmann C, Schwartzkopff W, et al. Effective therapeutic measures for reducing lipoprotein(a) in patients with dyslipidemia. Lipoprotein(a) reduction with sustained-release bezafibrate. Curr Ther Res 1991; 49:635.
- Sacks FM, McPherson R, Walsh BW. Effect of postmenopausal estrogen replacement on plasma Lp(a) lipoprotein concentrations. Arch Intern Med 1994; 154:1106.
- Kim CJ, Min YK, Ryu WS, et al. Effect of hormone replacement therapy on lipoprotein(a) and lipid levels in postmenopausal women. Influence of various progestogens and duration of therapy. Arch Intern Med 1996; 156:1693.
- Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335:453.
- Espeland MA, Marcovina SM, Miller V, et al. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Circulation 1998; 97:979.
- Carlson LA, Hamsten A, Asplund A. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med 1989; 226:271.
- Guyton JR, Blazing MA, Hagar J, et al. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. Arch Intern Med 2000; 160:1177.
- Keller C. Apheresis in coronary heart disease with elevated Lp (a): a review of Lp (a) as a risk factor and its management. Ther Apher Dial 2007; 11:2.
- Gurakar A, Hoeg JM, Kostner G, et al. Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis 1985; 57:293.
- Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014; 63:1278.
- Chasman DI, Shiffman D, Zee RY, et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 2009; 203:371.
- STRUCTURE AND FUNCTION
- Measurement of serum Lp(a) concentration
- CVD RISK
- Cerebrovascular disease
- Patients with hypertension
- Risk factor versus cause
- MECHANISMS OF CVD RISK
- Myocardial infarction due to vasospasm
- Aggressive LDL-C reduction
- Lp(a) reduction
- - Lipid-lowering drugs
- - Apheresis
- SUMMARY AND RECOMMENDATIONS