Markers of vascular inflammation are associated with the extent of atherosclerosis assessed as angiographic score and treadmill walking distances in patients with peripheral arterial occlusive disease
Free accessResearch articleFirst published online February, 2006
Markers of vascular inflammation are associated with the extent of atherosclerosis assessed as angiographic score and treadmill walking distances in patients with peripheral arterial occlusive disease
The importance of inflammation in atherosclerosis is well established in cardiovascular disease. However, limited data exist on the relationship between vascular inflammation and the severity of peripheral arterial occlusive disease (PAD). We investigated the relationship between biochemical markers of vascular inflammation and the diagnostic measures of PAD: ankle-brachial pressure index (ABI), maximum treadmill walking distance and angiographic score. In 127 patients (mean age 66 years; 64% males) with angiographically verified PAD, fasting blood samples were drawn for determination of selected soluble cell adhesion molecules, cytokines and chemokines. Tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and CD40 ligand (CD40L) were all significantly correlated with the angiographic score (p < 0.05 for all). After adjustment for relevant co-variates, MCP-1 and CD40L remained statistically significant (p < 0.01 for both). IL-6 was, independent of other risk factors, inversely correlated with the maximum treadmill walking distance (p < 0.01). Our cross-sectional study in PAD patients showed that the vascular inflammatory markers MCP-1, CD40L and IL-6 were significantly associated with the extent of atherosclerosis, assessed by angiographic score and maximum treadmill walking distance. These findings indicate that vascular inflammation is implicated in PAD, which might be of importance in future diagnosis and treatment of the disease.
Fowkes FGR, Housley E, Cawood EHH, MacIntyre CCA, Ruckley CV, Prescott RJ.Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemioly1991; 20: 383-392.
2.
Dormandy JA, Murray GD, Mahir M, Ascady G, Stranden E.The fate of the claudicant - a prospective study of 1969 claudicants. Eur J Vasc Surg1989; 30: 50-57.
3.
Selvin E, Erlinger TP.Prevalence of and risk factors for peripheral arterial disease in the United States. Circulation2004; 110: 738-743.
4.
Ross R.Atherosclerosis - an inflammatory disease. N Engl J Med1999; 340: 115-126.
Szmitko PE, Wang CH, Weisel RD.New markers of inflammation and endothelial cell activation: Part I. Circulation2003; 108: 1917-1923.
7.
Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM.C-reactive protein levels and outcomes after statin therapy. N Engl J Med2005; 352: 20-28.
8.
Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G.Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation2001; 104: 1336-1342.
9.
Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ.Plasma concentrations of soluble intercellular adhesion molecule 1 and risk of future myocardial infarction in apparently healthy men. Lancet1998; 351: 88-92.
10.
Hwang SJ, Ballantyne CM, Sharett AR, Smith LC, Davis CE.Circulating adhesion molecules VCAM-1, ICAM-1 and E-selectin in carotid atherosclerosis and incident coronary heart disease cases. The Atherosclerosis Risk in Communities (ARIC) study. Circulation1997; 96: 4219-4225.
11.
Danesh J, Wheeler JG, Hirschfield GM, Eda S.C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med2004; 350: 1387-1397.
12.
Kannel WB, McGee DL.Update on some epidemiologic features of intermittent claudication: the Framingham Study. J Am Geriatr Soc1985; 33: 13-18.
13.
Smith I, Franks PJ, Greenhalgh RM, Poulter NR, Powell JT.The influence of smoking cessation and hypertriglyceridaemia on the progression of peripheral arterial disease and the onset of critical ischemia. Eur J Vasc Endovasc Surg1996; 11: 402-408.
14.
Fowkes FG, Housley E, Riemersma RA, Macintyre CC.Smoking, lipids, glucose in-tolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am J Epidemoil1992; 135: 331-340.
15.
Drexel H, Steurer J, Muntwyler J, Meienberg S.Predictors of the presence and extent of peripheral arterial occlusive disease. Circulation1996; 94 (suppl 1): II-199-II-205.
16.
Jacobson UK, Dige-Pedersen H, Gyntelberg F, Svendsen UG.Risk factors and manifestations of arteriosclerosis in patients with intermittent claudication compared to normal persons. Dan Med Bull1984; 31: 145-148.
17.
Brand FN, Abbott RD, Kannel WB.Diabetes, intermittent claudication and risk of cardiovascular events. Diabetes1989; 38: 504-509.
18.
Graham IM, Daly LE, Refsum H, Robinson K.Plasma homocysteine as a risk factor for vascular disease. JAMA1997; 277: 1775-1779.
19.
McDermott MM, Liu K, Guralnik JM.The ankle brachial index independently predicts walking velocity and walking endurance in peripheral arterial disease. J Am Geriatr Soc1998; 46: 1355-1362.
20.
McDermott MM, Greenland P, Liu K, Guralnik JM.The ankle brachial index is associated with leg function and physical activity: the walking and leg circulation study. Ann Intern Med2002; 136: 873-883.
21.
Fowkes FGR.The measurement of atherosclerotic peripheral arterial disease in epidemiological surveys. Int J Epidemiol1988; 17: 248-254.
22.
McDermott M, Greenland P, Liu K, Guralnik JM.Asymptomatic arterial disease is independently associated with impaired lower extremity functioning: the women’s health and ageing study. Circulation2000; 101: 1007-1012.
23.
Knox WG, Finby N.Limitations of arteriography in determining operability for femoropopliteal occlusive disease. Ann Surg1965; 161: 509-515.
24.
Carter S.Clinical measurement of systolic pressures in limbs with arterial occlusive disease. JAMA1969; 297: 1869-1874.
25.
Meaney JFM.Stepping-table gladolinium-enhanced digital subtraction MR angiography of the aorta and lower extremity arteries: preliminary experience. Radiology1999; 211: 59-67.
26.
McDermott MM, Green D, Greenland P, Liu K, Criqui MH.Relation of levels of haemostatic factors and inflammatory markers to the ankle brachial index. Am J Cardiol2003; 92: 194-199.
27.
Santos S, Rooke TW, Bailey KR, McConnell JP, Kullo IJ.Relation of markers of inflammation (C-reactive protein, white blood cell count, and lipoprotein-associated phospholipase A2) to the ankle-brachial index. Vasc Med2004; 9: 171-176.
28.
Folsom AR, Pankow JS, Tracy RP, Amett DK, Peacock JM, Hong Y, Djousse L, Eckfeldt JH; Investigators of the NHBLI Family Heart Study. Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol2001; 88: 112-117.
29.
Delius W, Erikson U.Correlation between angiographic and hemodynamic findings in occlusions of arteries of extremities. J Vasc Surg1969; 3: 201-210.
30.
Lezack J, Carter SA.The relationship of distal systolic pressures to the clinical and angiographic findings in limbs with arterial occlusive disease. Scand J Clin Lab Invest1973; 31 (suppl. 128): 97-103.
31.
Kiekara O, Riekkinen H.Correlation of angiographically determined reduction of vascular lumen with lower-limb systolic pressures. Acta Chir Scand1985; 151: 437-440.
32.
Eickhoff JH, Engell HC.Diagnostic correctness of distal blood pressure measurements in patients with arterial insufficiency. Scand J Clin Lab Invest1980; 40: 647-652.
33.
Müller-Bühl U, Wiesemann A, Oser B, Kirchberger I.Correlaton of hemodynamic and functional variables with the angiographic extent of peripheral arterial occlusive disease. Vasc Med1999; 4: 247-251.
34.
Rollins BJ.Chemokines. Blood1997; 90: 909-928.
35.
Alam R.Chemokines in allergic inflammation. J Allergy Clin Immunol1997; 99: 273-277.
36.
Krishnaswamy G, Kelley J, Yerra L, Smith JK.Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease. J Interferon Cytokine Res1999; 19: 91-104.
37.
Schecter AD, Rollins BJ, Zhang YJ, Charo IF.Tissue factor is induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells. J Biol Chem1997; 272: 2868-2873.
38.
De Lemos JA.Associations between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes. Circulation2003; 107: 690-695.
39.
Schonbeck U, Libby P.CD40 signaling and plaque instability. Circ Res2001; 89: 1092-1103.
40.
Heeschen C, Dimmeler S, Hamm CW.Soluble CD40 ligand in acute coronary syndromes. N Engl J Med2003; 348: 1104-1111.
41.
Garlichs CD, John S, Schmeisser A.Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation2001; 104: 2395-2400.
42.
Varo N, Vincent D, Libby P.Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones. Circulation2003; 107: 2664-2669.
43.
McCarty MF.Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: downregulation with essential fatty acids, ethanol and pentoxifylline. Med Hypotheses1999; 52: 465-477.
Bollinger A, Breddin K, Hess H, Heystraten FM, Kollath J, Konttila A, Pouliadis G, Marshall M, Mey T, Mietaschk A, Roth FJ, Schoop W.Semi quantitative assessment of lower limb atherosclerosis from routine angiographic images. Atherosclerosis1981; 38: 339-346.
46.
Scott DJ, Hunt G, Beard JD, Hartnell GG, Horrocks M.Arteriogram scoring systems and pulse generated run-off in the assessment of patients with critical ischaemia for femorodistal bypass. Br J Surg1989; 76: 1202-1206.
47.
Gardner AW, Skinner JS, Cantwell BW, Smith K.Progressive vs single-stage treadmill tests for evaluation of claudication. Med Sci Sports Exerc1991; 23: 402-408.
