The ARIC Carotid MRI Study of Blood Cellular Markers: An Inverse Association of Monocyte Myeloperoxidase Content With Peripheral Arterial Disease

Abstract

We evaluated the association of blood monocyte and platelet activation markers with the risk of peripheral artery disease (PAD) in a multicenter study of atherosclerosis among African American and Caucasian patients. Flow cytometric analysis of blood cells was performed in 1791 participants (209 cases with PAD and 1582 noncases) from the cross-sectional Atherosclerosis Risk in Communities Carotid Magnetic Resonance Imaging ([MRI] ARIC Carotid MRI) Study to assess platelet glycoproteins IIb and IIIa, P-selectin, CD40 ligand, platelet—leukocyte aggregates, monocyte lipopolysaccharide receptor, toll-like receptors (TLRs) 2 and 4, P-selectin glycoprotein ligand 1, cyclooxygenase 2, and myeloperoxidase. Multivariate regression analyses evaluated the association of cellular markers with the risk of PAD. After adjusting for age, race, and gender, platelet CD40L, and monocyte myeloperoxidase (mMPO) levels were significantly lower (P < .001), and monocyte TLR-4 levels were higher (P = .03) in patients with PAD. With additional adjustments for conventional risk factors, mMPO remained inversely and independently associated with the risk of PAD (odds ratio [OR]: 0.35, P = .01).

Keywords

peripheral arterial disease monocytes myeloperoxidase platelets flow cytometry multicenter study

Get full access to this article

View all access options for this article.

References

Ouriel K. Peripheral arterial disease. Lancet. 2001;358(9289): 1257-1264.

Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999;340(2):115-126.

Libby P. Inflammation in atherosclerosis. Nature. 2002 ; 420(6917):868-874.

Hansson GK Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352(16):1685-1695.

Elkind MS , Cheng J. , Boden-Albala B. , Paik MC , Sacco RL Elevated white blood cell count and carotid plaque thickness: the northern Manhattan stroke study. Stroke. 2001;32(4):842-849.

Lee CD , Folsom AR , Nieto FJ , Chambless LE , Shahar E. , Wolfe DA White blood cell count and incidence of coronary heart disease and ischemic stroke and mortality from cardiovascular disease in African-American and White men and women: atherosclerosis risk in communities study. Am J Epidemiol. 2001;154(8):758-764.

The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives . Am J Epidemiol. 1989;129(4):687-702.

Folsom AR , Aleksic N. , Sanhueza A. , Boerwinkle E. Risk factor correlates of platelet and leukocyte markers assessed by flow cytometry in a population-based sample. Atherosclerosis. 2008; 205(1):272-278.

Catellier DJ , Aleksic N. , Folsom AR , Boerwinkle E. Atherosclerosis Risk in Communities (ARIC) Carotid MRI Flow Cytometry study of monocyte and platelet markers: intraindividual variability and reliability. Clin Chem. 2008;54(8):1363-1371.

10.

Warrino DE , DeGennaro LJ , Hanson M. , Swindells S. , Pirruccello SJ , Ryan WL Stabilization of white blood cells and immunologic markers for extended analysis using flow cytometry. J Immunol Methods. 2005 ;305(2):107-119.

11.

Buffon A. , Biasucci LM , Liuzzo G. , D’Onofrio G. , Crea F. , Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med. 2002;347(1):5-12.

12.

Zhang R. , Brennan ML , Fu X. , et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA. 2001;286(17):2136-2142.

13.

Baldus S. , Heeschen C. , Meinertz T. , et al, CAPTURE Investigators. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation . 2003;108(12):1440-1445.

14.

Kutter D. , Devaquet P. , Vanderstocken G. , Paulus JM , Marchal V. , Gothot A. Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit ? Acta Haematol. 2000;104(1):10-15.

15.

Sugiyama S. , Okada Y. , Sukhova GK , Virmani R. , Heinecke JW , Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol. 2001;158(3):879-891.

16.

van Leeuwen M. , Gijbels MJ , Duijvestijn A. , et al. Accumulation of myeloperoxidase-positive neutrophils in atherosclerotic lesions in LDLR-/- mice. Arterioscler Thromb Vasc Biol. 2008;28(1): 84-89.

17.

Nicholls SJ , Hazen SL Myeloperoxidase and cardiovascular disease . Arterioscler Thromb Vasc Biol. 2005;25(6):1102-1111.

18.

Bos A. , Wever R. , Roos D. Characterization and quantification of the peroxidase in human monocytes. Biochim Biophys Acta. 1978; 525(1):37-44.

19.

Brevetti G. , Schiano V. , Laurenzano E. , et al. Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease. Eur Heart J. 2008;29(2):224-230.

20.

Monaco C. , Rossi E. , Milazzo D. , et al. Persistent systemic inflammation in unstable angina is largely unrelated to the atherothrombotic burden. J Am Coll Cardiol . 2005;45(2):238-243.

21.

Nasir K. , Guallar E. , Navas-Acien A. , Criqui MH , Lima JA Relationship of monocyte count and peripheral arterial disease: results from the National Health and Nutrition Examination Survey 1999-2002. Arterioscler Thromb Vasc Biol. 2005;25(9):1966-1971.

22.

Luu NT , Madden J. , Calder PC , et al. Comparison of the pro-inflammatory potential of monocytes from healthy adults and those with peripheral arterial disease using an in vitro culture model. Atherosclerosis. 2007;193(2):259-268.

23.

Edfeldt K. , Swedenborg J. , Hansson GK , Yan ZQ Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation. 2002;105(10): 1158-1161.

24.

Mullick AE , Tobias PS , Curtiss LK Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest. 2005;115(11):3149-3156.

25.

Vainas T. , Stassen FR , Bruggeman CA , et al. Synergistic effect of Toll-like receptor 4 and CD14 polymorphisms on the total atherosclerosis burden in patients with peripheral arterial disease . J Vasc Surg. 2006;44(2):326-332.

26.

Young RS , Naseem KM , Pasupathy S. , Ahilathirunayagam S. , Chaparala RP , Homer-Vanniasinkam S. Platelet membrane CD154 and sCD154 in progressive peripheral arterial disease: a pilot study. Atherosclerosis. 2007;190(2):452-458.

27.

Blann AD , Tan KT , Tayebjee MH , Davagnanam I. , Moss M. , Lip GY Soluble CD40L in peripheral artery disease. Relationship with disease severity, platelet markers and the effects of angioplasty. Thromb Haemost . 2005;93(3):578-583.

28.

Rajagopalan S. , Mckay I. , Ford I. , Bachoo P. , Greaves M. , Brittenden J. Platelet activation increases with the severity of peripheral arterial disease: implications for clinical management. J Vasc Surg. 2007;46(3):485-490.

29.

Robless PA , Okonko D. , Lintott P. , Mansfield AO , Mikhailidis DP , Stansby GP Increased platelet aggregation and activation in peripheral arterial disease . Eur J Vasc Endovasc Surg. 2003; 25(1):16-22.

30.

McBane RD 2nd , Karnicki K. , Miller RS , Owen WG The impact of peripheral arterial disease on circulating platelets. Thromb Res. 2004 ;113(2):137.

31.

Kullo IJ , Bailey KR , Kardia SL , Mosley TH Jr , Boerwinkle E. , Turner ST Ethnic differences in peripheral arterial disease in the NHLBI Genetic Epidemiology Network of Arteriopathy (GENOA) study. Vasc Med. 2003;8(4):237-242.