American Journal of Cardiology
Volume 101, Issue 12, Supplement , Pages S11-S22 , 16 June 2008

Lipoprotein-Associated Phospholipase A2: A Risk Marker or a Risk Factor?

  • Amir Lerman, MD

      Affiliations

    • Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    • Corresponding Author InformationAddress for reprints: Amir Lerman, MD, Department of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
    • ,
  • Joseph P. McConnell, PhD

      Affiliations

    • Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
    • Department of Laboratory Medicine and Immunochemical Core Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

References 

  1. Garza CA, Montori VM, McConnell JP, Somers VK, Kullo IJ, Lopez-Jimenz F. Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin Proc. 2007;82:159–165
  2. McConnell JP, Hoefner DM. Lipoprotein-associated phospholipase A2 [review]. Clin Lab Med. 2006;26:679–697
  3. Macphee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA, et al. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem J. 1999;338:479–487
  4. Tjoelker LW, Wilder C, Eberhardt C, Stafforini DM, Dietsch G, Schimpf B, et al Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature. 1995;374:549–553
  5. Min JH, Jain MK, Wilder C, Paul L, Apitz-Castro R, Spleaf DC, et al. Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase. Biochemistry. 1999;38:12935–12942
  6. Stafforini DM, Tjoelker LW, McCormick PA, Vaitkus D, McIntyre TM, Gray PW, et al. Molecular basis of the interaction between plasma platelet activating factor acetylhydrolase and low density lipoprotein. J Biol Chem. 1999;274:7018–7024
  7. Snyder MR, Mullins JL, Ninova D, Hartman SJ, Wolfert RL, Jaffe AS, et al. Distribution of Lp-PLA2 among lipoprotein fractions and association with atherosclerotic risk markers (Abstract C-132). Clin Chem. 2006;52(6 Suppl):A120–A121
  8. Tselepis AD, Karabina SA, Stengel D, Piedagnel R, Chapman MJ, Ninio E. N-linked glycosylation of macrophage derived PAF-AH is a major determinant of enzyme association with plasma HDL. J Lipid Res. 2001;42:1645–1654
  9. Marathe GK, Zimmerman GA, McIntyre TM. Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the oxidized phospholipids hydrolase of high density lipoprotein particles. J Biol Chem. 2003;278:3937–3947
  10. Karabina SA, Liapikos TA, Grekas G, Goudevenos J, Tselepis AD. Distribution of PAF-acetylhydrolase activity in human plasma low-density subfractions. Biochim Biophysics Acta. 1994;1213:34–38
  11. Gazi I, Lourida ES, Filippatos T, Tsimihodimos V, Tselepis EM. Lipoprotein-associated phospholipase A2 activity is a marker of small, dense LDL particles in human plasma. Clin Chem. 2005;51:2264–2273
  12. Hodis HN, Kramsch DM, Avogaro P, Bittolo-Ban G, Cazzolato G, Hwang J, et al. Biochemical and cytotoxic characteristics of an in vivo circulation oxidized low density lipoprotein (LDL). J Lipid Res. 1994;35:669–677
  13. Yang CY, Raya JL, Chen HH, Chen CH, Abe Y, Pownall HJ, et al. Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low density lipoproteins. Arterioscler Thromb Vasc Biol. 2003;23:1083–1090
  14. Kiechl S, Willeit J, Mayr M, Viehweider B, Oberhollenzer M, Kronenberg F, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol. 2007;27:1788–1795
  15. Macphee CH, Tew DG, Rice SQJ, Lawrence GMP, Southan CD, Milliner KJ, et al. A novel phospholipase A2 has been cloned that is responsible for the increased lyso-phosphatidylcholine content of oxidatively modified LDL. Atherosclerosis. 1995;115:S33
  16. Glass CK, Witztum JL. Atherosclerosis: the road ahead [review]. Cell. 2001;104:503–516
  17. Hakkinen T, Luoma JS, Hiltunen MO, MacPhee CH, Milliner KJ, Patel L, et al. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 1999;19:2909–2917
  18. Tselepis AD, Chapman M. Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase. Atheroscler Suppl. 2002;3:57–68
  19. Sudhir K. Clinical review: lipoprotein-associated phospholipase A2, a novel inflammatory biomarker and independent risk predictor for cardiovascular disease. J Clin Endocrinol Metab. 2005;90:3100–3105
  20. Lavi S, McConnell JP, Rihal CS, Prasad A, Mathew V, Lerman LO, et al. Local production of lipoprotein-associated phospholipase A2 and lysophosphatidylcholine in the coronary circulation: association with early coronary atherosclerosis and endothelial dysfunction in humans. Circulation. 2007;115:2715–2721
  21. Safaya R, Chai H, Kougias P, Lin P, Lumsden A, Yao Q, et al. Effect of lysophosphatidylcholine on vasomotor functions of porcine coronary arteries. J Surg Res. 2005;126:182–188
  22. Inoue N, Takeshita S, Gao D, Ishida T, Kawashima S, Akita H, et al. Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells. Atherosclerosis. 2001;155:45–52
  23. Takahashi M, Okazaki H, Ogata Y, Takeuchi K, Ikeda U, Shimada K. Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen-activated protein kinase-dependent mechanism. Atherosclerosis. 2002;161:387–394
  24. Chadhuri P, Colles SM, Damron DS, Graham LM. Lysophosphatidylcholine inhibits endothelial cell migration by increasing intracellular calcium and activating calpain. Arterioscler Thromb Vasc Biol. 2003;23:218–223
  25. Kolodgie FD, Burke AP, Skorija KS, Ladich E, Kutys R, Makuria AT, et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:2523–2529
  26. Vickers KC, Maguire C, Wolfert RL, Insull W, Holvoet P, Morrisett J. Quantitation and distribution of lipoprotein-associated phospholipase A2 and oxidized low-density lipoprotein in atherosclerotic lesions of carotid endarterectomy tissues [abstract]. J Am Coll Cardiol. 2006;47(suppl A):346A
  27. Johnson A, Zalewski A, Janmohamed S, Sawyer J, Rolfe T, Staszkiewicz W, et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, an emerging CV risk marker, can be inhibited in atherosclerotic lesions and plasma by novel pharmacologic intervention: the results of a multicenter clinical study [abstract]. Circulation. 2004;110:590
  28. Shi Y, Zhang P, Zhang L, Osman H, Mohler ER, Macphee C, et al. Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses. Atherosclerosis. 2007;191:54–62
  29. Zhang P, Zhang L, Carabasi A, Diehl J, Dimuzio PJ, Dimatteo C, et al. Oxidized LDL-induced upregulation of IL-18 in monocytes/macrophages is modulated by lipoprotein-associated phospholipase A2: potential mechanism of inflammatory burden in atherosclerosis. Circulation. 2006;114:II-24;Abstract 258
  30. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–671
  31. Targonski PV, Bonetti PO, Pumper GM, Higano ST, Holmes DR, Lerman A. Coronary endothelial dysfunction is associated with an increased risk of cerebrovascular events. Circulation. 2003;107:2805–2809
  32. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111:363–368
  33. Yang EH, McConnell JP, Lennon RJ, Barsness GW, Pumper G, Hartman SJ, et al. Lipoprotein-associated phospholipase A2 is an independent marker for coronary endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol. 2006;26:106–111
  34. Iribarren C, Gross MD, Darbinian JA, Jacobs DR, Sidney S, Loria CM. Association of lipoprotein-associated phospholipase A2 mass and activity with calcified coronary plaque in young adults: the CARDIA study. Arterioscler Thromb Vasc Biol. 2005;25:216–221
  35. Kardys I, Oei HH, Hofman A, Oudkerk M, Witteman JC. Lipoprotein-associated phospholipase A2 and coronary calcification: the Rotterdam Coronary Calcification Study. Atherosclerosis. 2007;191:377–383
  36. Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB. Association of lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur Heart J. 2005;26:137–144
  37. Wolfert RL, Kim NW, Selby RG, Sarno MJ, Warnick RG, Sudhir K. Biological variability and specificity of lipoprotein-associated phospholipase A2 (Lp-PLA2), a novel marker of cardiovascular risk [abstract]. Circulation. 2004;110(suppl 3):309
  38. Cederholm A, Svenungsson E, Stengel D, Fei GZ, Pockley AG, Ninio E, et al. Platelet-activating factor-acetylhydrolase and other novel risk and protective factors for cardiovascular disease in systemic lupus erythematosus. Arthritis Rheum. 2004;50:2869–2876
  39. Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function and hemodynamic stress (KAROLA). Arterioscler Thromb Vasc Biol. 2006;26:1586–1593
  40. McLaughlin TM, Abbasi F, Wolfert R, Lamendola C, Reaven G, Reaven P. Lipoprotein-associated phospholipase A2 is not increased in association with insulin resistance [abstract]. Arterioscler Thromb Vasc Biol. 2004;24:E-67
  41. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, Criqui M, et al Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511
  42. Cook NR. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation. 2007;115:928–935
  43. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, et al Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355:2631–2639
  44. Gerber Y, McConnell JP, Jaffe AS, Weston SA, Killian JM, Roger VL. Lipoprotein-associated phospholipase A2 and prognosis after myocardial infarction in the community. Arterioscler Thromb Vasc Biol. 2006;26:2517–2522
  45. Winkler K, Hoffmann MM, Winkelmann BR, Friedrich I, Schafer G, Seelhorst U, et al. Lipoprotein-associated phospholipase A2 predicts 5-year mortality independently of established risk factors and adds prognostic information in patients with low and medium high-sensitivity C-reactive protein (the Ludwigshafen Risk and Cardiovascular Health Study). Clin Chem. 2007;53:1440–1447
  46. Blake GJ, Dada N, Fox JC, Manson JE, Ridker PM. Prospective evaluation of lipoprotein-associated phospholipase A2 levels and the risk of future cardiovascular events in women. J Am Coll Cardiol. 2001;38:1302–1306
  47. Ballantyne C, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Heiss G, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109:837–842
  48. Packard CJ, O‘Reilly DSJ, Caslake MJ, McMahan AD, Ford I, Cooney J, et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. N Engl J Med. 2000;343:1148–1155
  49. Blankenberg S, Stengel D, Rupprecht HJ, Bickel C, Meyer J, Cambien F, et al. Plasma PAF-acetylhydrolase in patients with coronary artery disease: results of a cross-sectional analysis. J Lipid Res. 2003;44:1381–1386
  50. Koenig W, Khuseyinova N, Löwel H, Trischler G, Meisinger C. Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany (MONICA-Augsburg). Circulation. 2004;110:1903–1908
  51. Winkler K, Abletshauser C, Friedrich I, Hoffmann MM, Wieland H, März W. Fluvastatin slow-release lowers platelet-activating factor acetyl hydrolase activity: a placebo-controlled trial in patients with type 2 diabetes. J Clin Endocrinol Metab. 2004;89:1153–1159
  52. Oei H-HS, van der Meer IM, Hofman A, Koudstaal PJ, Stijnen T, Breteler MMB, et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischaemic stroke: the Rotterdam Study. Circulation. 2005;111:570–575
  53. Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Chambless LE, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. 2005;165:2479–2484
  54. Winkler K, Winkelmann BR, Scharnagl H, Hoffmann MM, Grawitz AB, Nauck M, et al. Platelet-activating factor acetylhydrolase activity indicates angiographic coronary artery disease independently of systemic inflammation and other risk factors. Circulation. 2005;111:980–987
  55. Khuseyinova N, Imhof A, Rothenbacher D, Trischler G, Kuelb S, Scharnagl H, et al. Association between Lp-PLA2 and coronary artery disease: focus on its relationship with lipoproteins and markers of inflammation and hemostasis. Atherosclerosis. 2005;182:181–188
  56. May HT, Horne BD, Anderson JL, Wolfert RL, Muhlestein JB, Renlund DG, et al. Lipoprotein-associated phospholipase A2 independently predicts the angiographic diagnosis of coronary artery disease and coronary death. Am Heart J. 2006;152:997–1003
  57. Caslake MJ, Cooney J, Murray E, Bedford D, Robertson M, Nelson JJ, Packard CJ. Lipoprotein-associated phospholipase A2 as a risk factor for coronary vascular disease in the elderly (PROSPER). Proceedings from the XIV International Symposium on Atherosclerosis; June 18–22, 2006; Rome, Italy. Abstract page 484.
  58. Elkind MS, Tai W, Coates K, Paik MC, Sacco RL. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med. 2006;166:2073–2080
  59. O'Donoghue M, Morrow DA, Sabatine MS, Murphy SA, McCabe CH, Cannon CP, et al. Lp-PLA2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT–TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction) trial. Circulation. 2006;113:1745–1752
  60. Jenny NS, Solomon C, Cushman M, Nelson JJ, Tracy RP, Psaty BM, et al. Lipoprotein-associated phospholipase A2 and cardiovascular disease: results from the Cardiovascular Health Study [abstract]. Circulation. 2006;113:E-332
  61. Corsetti JP, Rainwater DL, Moss AJ, Zareba W, Sparks CE. High lipoprotein-associated phospholipase A2 is a risk factor for recurrent coronary events in postinfarction patients. Clin Chem. 2006;52:1331–1338
  62. Sabatine MS, Morrow DA, O'Donoghue M, Jablonski KA, Rice MM, Solomon S, et al. Prognostic utility of lipoprotein-associated phospholipase A2 for cardiovascular outcomes in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol. 2007;27:2463–2469
  63. Daniels LB, Barrett-Connor E, Sarno M, Laughlin GA, Bettencourt R, Wolfert RL. Lipoprotein-associated phospholipase A2 (Lp-PLA2) independently predicts incident coronary heart disease (CHD) in an apparently healthy older population: the Rancho Bernardo Study [abstract]. Circulation. 2006;114:II-870
  64. Oldgren J, James SK, Siegbahn A, Wallentin L. Lipoprotein-associated phospholipase A2 does not predict mortality or new ischaemic events in acute coronary syndrome patients. Eur Heart J. 2007;28:699–704
  65. Persson M, Hedblad B, Nelson JJ, Berglund G. Elevated Lp-PLA2 levels add prognostic information to the metabolic syndrome on incidence of cardiovascular events among middle-aged nondiabetic subjects. Arterioscler Thromb Vasc Biol. 2007;27:1411–1416
  66. Mockel M, Muller R, Vollert JO, Muller C, Danne O, Gareis R, et al. Lipoprotein-associated phospholipase A2 for early risk stratification in patients with suspected acute coronary syndrome: a multi-marker approach: the North Wuerttemberg and Berlin Infarction Study-II (NOBIS-II). Clin Res Cardiol. 2007;96:604–612
  67. Robins SJ, Collins D, Nelson JJ, Bloomfield HE, Asztalos BF. Cardiovascular events with increased lipoprotein-associated phospholipase A2 and low high-density lipoprotein-cholesterol (The Veterans Affairs HDL Intervention Trial). Arterioscler Thromb Vasc Biol. 2008;28:DOI:10.1161/ATVBAHA.107.160739
  68. Furie KL, Parides MK, Greer DM, Camargo ECS, Singhal AB, Lederer M, et al Lipoprotein-associated phospholipase A2 activity predicts early stroke recurrence [abstract]. Stroke. 2007;382s:458
  69. Wassertheil-Smoller S, Kooperberg C, McGinn AP, Kaplan RC, Hsia J, Hendrix SL, et al. Lipoprotein-associated phospholipase A2, hormone use, and the risk of ischemic stroke in postmenopausal women. Hypertension. 2008;51(4):1115–1122
  70. Ballantyne C, Nambi V, Chambless L, Hu Y, Coresh J, Ni J, et al. Inflammatory biomarkers Lp-PLA2 and CRP for prediction of first ischemic stroke [abstract]. Vasc Med. 2007;12:146
  71. Lanman RB, Wolfert RL, Fleming JK, Jaffe AS, Roberts WL, Warnick GR, et al. Lipoprotein-associated phospholipase A2: review and recommendation of a clinical cut point for adults. Prev Cardiol. 2006;9:138–143
  72. Libby P, Sasiela W. Plaque stabilization: can we turn theory into evidence?. Am J Cardiol. 2006;98(suppl):26P–33P
  73. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110:3512–3517
  74. Zhao XQ, Yuan C, Hatsukami TS, Frechette EH, Kang XJ, Maravilla KR, et al. Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler Thromb Vasc Biol. 2001;21:1623–1629
  75. Albert MA, Glynn RJ, Wolfert RL, Ridker PM. The effect of statin therapy on lipoprotein associated phospholipase A2 levels. Atherosclerosis. 2005;182:193–198
  76. Muhlestein JB, May HT, Jensen JR, Horne BD, Lanman RB, Lavasani F, et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia. J Am Coll Cardiol. 2006;48:396–401
  77. Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, et al. Differential effect of hypolipidemic drugs on lipoprotein-associated phospholipase A2. Arterioscler Thromb Vasc Biol. 2007;27:2236–2243
  78. Schaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, et al. Effects of atorvastatin versus other statins on fasting and postprandial C-reactive protein and lipoprotein-associated phospholipase A2 in patients with coronary heart disease versus control subjects. Am J Cardiol. 2005;95:1025–1032
  79. Shalwitz RA, Maki KV, Doyle RT, Ballantyne CM. Lipoprotein subfraction responses differentially predict changes in lipoprotein-associated phospholipase A2 during prescription omega-3 therapy [abstract]. Arterioscler Thromb Vasc Biol. 2007;27:e93–e94
  80. Kuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelsstiel CD, et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol. 2006;98:743–745

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9149(08)00685-1

doi: 10.1016/j.amjcard.2008.04.014

American Journal of Cardiology
Volume 101, Issue 12, Supplement , Pages S11-S22 , 16 June 2008

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