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(Circulation. 2004;109:837-842.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Lipoprotein-Associated Phospholipase A₂, High-Sensitivity C-Reactive Protein, and Risk for Incident Coronary Heart Disease in Middle-Aged Men and Women in the Atherosclerosis Risk in Communities (ARIC) Study

Christie M. Ballantyne, MD; Ron C. Hoogeveen, PhD; Heejung Bang, PhD; Josef Coresh, MD, PhD; Aaron R. Folsom, MD, MPH; Gerardo Heiss, MD, PhD; A. Richey Sharrett, MD, DrPH

From the Section of Atherosclerosis and Lipoprotein Research, Department of Medicine, Baylor College of Medicine, and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, Tex (C.M.B., R.C.H.); the Departments of Biostatistics (H.B.) and Epidemiology (G.H.), School of Public Health, the University of North Carolina at Chapel Hill; the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md (J.C., A.R.S.); and the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (A.R.F.).

Correspondence to Christie M. Ballantyne, Baylor College of Medicine, 6565 Fannin, M.S. A-601, Houston, TX 77030. E-mail cmb{at}bcm.tmc.edu

Received August 27, 2003; revision received November 18, 2003; accepted November 20, 2003.

Background— Measuring C-reactive protein (CRP) has been recommended to identify patients at high risk for coronary heart disease (CHD) with low LDL cholesterol (LDL-C). Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a proinflammatory enzyme associated primarily with LDL.

Methods and Results— In a prospective, case cohort study in 12 819 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities study, the relation between Lp-PLA₂, CRP, traditional risk factors, and risk for CHD events over a period of 6 years was examined in a proportional hazards model, stratified by LDL-C. Lp-PLA₂ and CRP levels were higher in the 608 cases than the 740 noncases. Both Lp-PLA₂ and CRP were associated with incident CHD after adjustment for age, sex, and race with a hazard ratio of 1.78 for the highest tertile of Lp-PLA₂ and 2.53 for the highest category of CRP versus the lowest categories. Lp-PLA₂ correlated positively with LDL-C (r=0.36) and negatively with HDL-C (r=-0.33) but not with CRP (r=-0.05). In a model adjusted for traditional risk factors including LDL-C, the association of Lp-PLA₂ with CHD was attenuated and not statistically significant. For individuals with LDL-C below the median (130 mg/dL), Lp-PLA₂ and CRP were both significantly and independently associated with CHD in fully adjusted models. For individuals with LDL-C <130 mg/dL, those with both Lp-PLA₂ and CRP levels in the highest tertile were at the greatest risk for a CHD event.

Conclusions— Lp-PLA₂ and CRP may be complementary in identifying individuals at high CHD risk who have low LDL-C.

Key Words: Key Words: • coronary disease • epidemiology • inflammation • risk factors

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				M. Cushman Leukocyte Count in Vascular Risk Prediction Arch Intern Med, March 14, 2005; 165(5): 487 - 488. [Full Text] [PDF]

				A. Chait, C. Y. Han, J. F. Oram, and J. W. Heinecke Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? J. Lipid Res., March 1, 2005; 46(3): 389 - 403. [Abstract] [Full Text] [PDF]

				K. Winkler, B. R. Winkelmann, H. Scharnagl, M. M. Hoffmann, A. B. Grawitz, M. Nauck, B. O. Bohm, and W. Marz Platelet-Activating Factor Acetylhydrolase Activity Indicates Angiographic Coronary Artery Disease Independently of Systemic Inflammation and Other Risk Factors: The Ludwigshafen Risk and Cardiovascular Health Study Circulation, March 1, 2005; 111(8): 980 - 987. [Abstract] [Full Text] [PDF]

				H.-H. S. Oei, I. M. van der Meer, A. Hofman, P. J. Koudstaal, T. Stijnen, M. M.B. Breteler, and J. C.M. Witteman Lipoprotein-Associated Phospholipase A2 Activity Is Associated With Risk of Coronary Heart Disease and Ischemic Stroke: The Rotterdam Study Circulation, February 8, 2005; 111(5): 570 - 575. [Abstract] [Full Text] [PDF]

				I. J. Kullo and C. M. Ballantyne Conditional Risk Factors for Atherosclerosis Mayo Clin. Proc., February 1, 2005; 80(2): 219 - 230. [Abstract] [PDF]

				P. M Ridker, C. P. Cannon, D. Morrow, N. Rifai, L. M. Rose, C. H. McCabe, M. A. Pfeffer, E. Braunwald, and the Pravastatin or Atorvastatin Evaluation and Inf C-Reactive Protein Levels and Outcomes after Statin Therapy N. Engl. J. Med., January 6, 2005; 352(1): 20 - 28. [Abstract] [Full Text] [PDF]

				C. H. Macphee and J. J. Nelson An evolving story of lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular risk prediction Eur. Heart J., January 2, 2005; 26(2): 107 - 109. [Full Text] [PDF]

				E. S. Brilakis, J. P. McConnell, R. J. Lennon, A. A. Elesber, J. G. Meyer, and P. B. Berger 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., January 2, 2005; 26(2): 137 - 144. [Abstract] [Full Text] [PDF]

				J. T. Wu and L. L. Wu Association of Soluble Markers with Various Stages and Major Events of Atherosclerosis Ann. Clin. Lab. Sci., January 1, 2005; 35(3): 240 - 250. [Abstract] [Full Text] [PDF]

				C. Iribarren, M. D. Gross, J. A. Darbinian, D. R. Jacobs Jr, S. Sidney, and C. M. Loria Association of Lipoprotein-Associated Phospholipase A2 Mass and Activity With Calcified Coronary Plaque in Young Adults: The CARDIA Study Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 216 - 221. [Abstract] [Full Text] [PDF]

				J. K. Pai, T. Pischon, J. Ma, J. E. Manson, S. E. Hankinson, K. Joshipura, G. C. Curhan, N. Rifai, C. C. Cannuscio, M. J. Stampfer, et al. Inflammatory Markers and the Risk of Coronary Heart Disease in Men and Women N. Engl. J. Med., December 16, 2004; 351(25): 2599 - 2610. [Abstract] [Full Text] [PDF]

				W. Koenig, N. Khuseyinova, H. Lowel, G. Trischler, and C. Meisinger 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 Circulation, October 5, 2004; 110(14): 1903 - 1908. [Abstract] [Full Text] [PDF]

				R. J. Glynn, N. R. Cook, P. Libby, J. T. Willerson, E. Braunwald, J. M. Foody, A. M. Gotto, N. Wenger, P. M. Ridker, W. Koenig, et al. C-Reactive Protein and Coronary Heart Disease N. Engl. J. Med., July 15, 2004; 351(3): 295 - 298. [Full Text] [PDF]

				P. M Ridker, N. J. Brown, D. E. Vaughan, D. G. Harrison, and J. L. Mehta Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events Circulation, June 29, 2004; 109(25_suppl_1): IV-6 - IV-19. [Full Text] [PDF]

				P. M Ridker, P. W.F. Wilson, and S. M. Grundy Should C-Reactive Protein Be Added to Metabolic Syndrome and to Assessment of Global Cardiovascular Risk? Circulation, June 15, 2004; 109(23): 2818 - 2825. [Abstract] [Full Text] [PDF]

				R. SoRelle Cardiovascular News Circulation, February 24, 2004; 109 (7): e9012 - e9012. [Full Text]