Soluble intercellular adhesion molecule-1 is associated with carotid and femoral atherosclerosis but not with intima-media thickness in a population-based sample

Atherosclerosis 164 (2002) 297
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Soluble intercellular adhesion molecule-1 is associated with carotid and femoral atherosclerosis but not with intima-media thickness in a population-based sample Vanina Bongard a, Antoine Elias b, Claire Bal dit Sollier c, Jean-Bernard Ruidavets a, Henri Boccalon b, Ludovic Drouet c, Jean Ferrie`res a,* a

Department of Epidemiology, INSERM U558, Faculte´ de Me´decine, 37 alle´es Jules Guesde, 31 073 Toulouse Cedex, France b Department of Vascular Medicine, Rangueil Hospital, Toulouse, France c Haematology Laboratory, Lariboisie`re Hospital, Paris, France Received 3 November 2001; received in revised form 18 February 2002; accepted 28 February 2002

Abstract Since inflammatory mechanisms seem to be involved in different stages of atherosclerosis, we analysed a random populationbased sample of 972 subjects to assess the relationships between soluble intercellular adhesion molecule-1 (sICAM-1), subclinical peripheral atherosclerosis and intima-media thickness (IMT). B-mode ultrasonography was used to assess the presence of carotid (common and internal) and femoral atherosclerotic plaques and to measure common carotid IMT (avoiding plaque sites). Mean sICAM-1 level was 287.4 (standard deviation: 102.8) and 255.2 (83.5) ng/ml, respectively, in subjects with and without carotid plaques (P B/0.0001). It equalled 286.7 (101.1) and 249.7 (79.7) ng/ml, respectively, in subjects with and without femoral plaques (P B/0.0001). Subjects beyond the 90th percentile of common carotid IMT had higher sICAM-1 levels than those below, but this was not significant (P/0.08). Multiple logistic regression analyses adjusted for age, gender and other cardiovascular risk factors showed that sICAM-1 was independently associated with the risk of having at least one carotid plaque (adjusted odds ratio for a 10 ng/ml increase in sICAM-1: OR/1.03, 95% confidence interval: [1.02
/1.05]) and with the risk of having at least one femoral plaque (adjusted OR/1.04 [1.02
/1.06]). On the other hand, no significant relationship was found in multivariate analysis between sICAM1 and common carotid IMT. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Soluble intercellular adhesion molecule-1; Inflammation; Carotid atherosclerosis; Femoral atherosclerosis; Intima-media thickness

1. Introduction Over the past decade, various published data have underlined the links between inflammatory mechanisms and atherosclerosis, particularly in the early stages of the atherosclerotic process. In response to pro-inflammatory cytokines, various adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) are expressed on the surface of endothelial cells and mediate the adhesion and migration of circulating leukocytes in subendothelial spaces, thus playing a critical role in the formation of foam cells and fatty streaks and in the early

* Corresponding author. Tel.: /33-561-52-1870; fax: /33-561-323332 E-mail address: [email protected] (J. Ferrie`res).

development of atherosclerosis [1]. A soluble form of ICAM-1 (sICAM-1), possibly resulting from shedding or cleavage from endothelial cells [2], can be found in plasma. Several prospective data have assessed the predictive value of sICAM-1 in the occurrence of myocardial infarction and coronary artery disease [3
/ 5], but the relationship of sICAM-1 with peripheral atherosclerosis has been less established. Indeed, contradictory data have been published regarding circulating ICAM-1 levels, various symptomatic forms of peripheral atherosclerosis and the severity and extent of peripheral vascular disease [6
/8]. Besides, early subclinical forms of carotid and femoral atherosclerosis have been scarcely studied, particularly in large population-based samples of apparently healthy subjects. The present study was performed in a random sample selected from the general population. Its aim was to

0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 2 ) 0 0 0 7 1 - 0

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determine the relationships of sICAM-1 plasma levels with ultrasound-assessed atherosclerotic plaques in the carotid and femoral arteries and with common carotid intima-media thickness (IMT).

2. Materials and methods

2.1. Study population A sample of 972 subjects randomly selected from the general population to participate in the Third French MONICA cross-sectional Survey on cardiovascular risk factors was studied. The aim of the MONICA Project (MONItoring of trends and determinants in CArdiovascular disease) has already been extensively described elsewhere [9
/12]. Briefly, the project had to compare frequency, prognosis and management of coronary heart disease and cardiovascular risk factors between 37 centres from 21 countries in four continents. The Third French MONICA cross-sectional Survey on cardiovascular risk factors was carried out between December 1994 and July 1997. It was approved by an institutional review committee in agreement with the French law on human biomedical research. A population-based sample of middle-aged men and women (35
/ 64 years) living in the Toulouse area (South-western France) was randomly recruited. Polling lists available in each town hall of the survey area were used for sampling in order to carry out a random selection of the general population. The informed consent to participate in the study was obtained from each subject before the beginning of the survey. The participation rate was 66%.

2.2. Questionnaires and measurement of clinical parameters Extensive questionnaires were completed by the participants with the help of a trained and certified medical staff. Data concerning their socio-economic level, medical history, drug intake, cardiovascular risk factors and life style were recorded. Education level was assessed by a report of completed years of schooling (from the beginning of primary school until graduation or school drop out). Smoking habits were estimated in pack-years. Alcohol consumption was quantified in grams of alcohol per day with a 7-day recall method. Height, weight and arterial blood pressure (mean of two measurements performed with a standard sphygmomanometer in a sitting position after a 5-min rest at least) were measured according to standardised protocols by the medical staff. Body mass index was calculated as weight divided by height squared (kg/m2).

2.3. Laboratory methods Blood samples were taken after at least 10 h of overnight fasting. Soluble ICAM-1 levels were assessed using an immunoenzymatic method (Immunotech, Marseille, France). Between-series coefficient of variation (maximum value) was 6.9%. Serum total cholesterol and triglycerides were measured by enzymatic assays (Boehringer, Mannheim, Germany). High density lipoprotein cholesterol (HDL-c) measurement was done after sodium phosphotungstate
/magnesium chloride precipitation of apo B-containing lipoproteins. Low density lipoprotein cholesterol (LDL-c) was determined by Friedewald formula [13]. Glucose and fibrinogen levels were measured using conventional clinical chemical methods. Von Willebrand factor activity levels were assessed using a platelet aggregation technique (Dade Behring Marburg GmbH, Marburg, Germany). 2.4. Ultrasonography High-resolution B-mode ultrasonography was used to identify atherosclerotic plaques in carotid and femoral artery beds and to measure common carotid IMT. An ATL UM9 system (Advanced Technology Laboratories Ultramark 9 High Definition Imaging) was used with a 7.4 MHz transducer. The potential presence of atherosclerotic plaques was investigated in the right and left common carotid arteries, internal carotid arteries (including carotid bulbs) and femoral arteries (including femoral bifurcations). A plaque was defined as a distinct zone identified with either a focal area of hyperechogenicity relative to adjacent segments or a focal protrusion into the lumen of the vessel, composed of only calcified deposits or a combination of calcified and non calcified material [14]. The reproducibility of plaque measurement was evaluated in a sample of 40 randomly selected subjects submitted to a second ultrasound scan. The percentage of agreement and the kappa coefficient for the assessment of atherosclerotic plaques were 0.88 and 0.64 (P B/0.0001), respectively. Common carotid IMT was defined as the distance between the media
/adventitia interface and the lumen
/ intima interface, avoiding plaque sites. IMT measurements were performed on the right and left common carotid arteries, on the far wall exclusively. Three points at two locations (proximal and middle, with about 10
/ 15 mm intervals, the most cranial point being about 15
/ 20 mm from the bifurcation) were measured on each artery, giving a total of 12 points. The values at the 12 sites were combined to obtain an overall mean common carotid IMT (Eurequa, TSA Company, Meudon, France) [15]. The inter- and intra-observer variabilities of the common carotid artery IMT associated with the functions of the Eurequa software have been previously reported [15]. Furthermore, in 26 subjects submitted to a

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299

Fig. 1. Distribution of common carotid IMT.

second common carotid IMT assessment, mean differences between visits were small (/0.007 mm for the right common carotid artery and /0.022 mm for the left common carotid artery) and the intra-class correlation coefficients between visits were 0.64 (P B/0.001) for the right common carotid artery and 0.53 (P B/0.01) for the left common carotid artery [16]. 2.5. Statistical analysis Statistical analysis was performed using SAS statistical software (SAS Institute Inc., Cary, NC, USA). In bivariate analysis, qualitative variables were compared with x2-test (or bilateral Fisher’s exact test when necessary). Student’s t-test was used to compare qualitative data with quantitative data. When the distribution of continuous variables was skewed, log transformed data were used in statistical tests. Common carotid IMT was studied as a dichotomous variable, the 90th percentile being chosen as the cutoff point. However, to improve the validity of our results, analyses were also performed using the 75th and 95th percentiles as cutoff points. A multivariate logistic regression analysis was performed. Three multiple logistic models were constructed. The first one assessed the odds ratios (OR) independently associated with the risk of having at least one atherosclerotic plaque in the explored sites of the carotid arteries (right and left common carotids, internal carotids and carotid bulbs). The second one assessed the odds ratios independently associated with the risk of having at least one atherosclerotic plaque in the explored sites of the femoral arteries (right and left femoral arteries and femoral bifurcations). Lastly, the third model assessed the odds ratios independently associated with the risk of being beyond the 90th

percentile of common carotid IMT. The independent variables of the logistic models were determined by backward analysis among the studied variables. Only those significantly associated with the dependent variable (P B/0.05) after backward analysis were maintained in the final logistic models. However, a systematic adjustment was performed for gender and for antihypertensive, hypocholesterolaemic and hypoglycaemic drug intake since these variables correspond to major cardiovascular risk factors. Interactions between sICAM-1 and adjustment variables were tested in all final models. None of them was significant.

3. Results The sample was composed of 458 women (47.1%) and 514 men (52.9%). At least one carotid plaque was found in 279 subjects (28.7%), whereas 387 (39.8%) presented with at least one femoral plaque. The distribution of common carotid IMT in the sample is shown in Fig. 1. Values ranged from 0.39 to 1.31 mm and mean common carotid IMT equalled 0.59 mm (standard deviation: 0.10 mm). The 75th, 90th and 95th percentiles of common carotid IMT were, respectively, 0.64, 0.71 and 0.77 mm. Levels of sICAM-1 were significantly higher in subjects with carotid and femoral plaques than in subjects without plaque (Table 1). Mean sICAM-1 was higher in subjects beyond the 90th percentile of common carotid IMT than in those below, but this difference was not significant (P /0.08) (Table 1). Other characteristics of subjects according to the presence of carotid and femoral atherosclerotic plaques and to the value of common carotid IMT are shown in Table 1. Presence of plaques and high common carotid IMT were

300

Table 1 Characteristics of subjects according to the presence of carotid and femoral atherosclerotic plaques and to the value of common carotid IMT (percentage or mean (standard deviation)) Carotid artery explored sites No plaque (n 693)

] 1 plaque (n  279)

Pa

53.0%

32.6%

10.1% 9.5% 2.2% 10.7% 48.2 (8.2) 12.9 (3.8) 11.3 (17.8) 15.9 (21.7) 24.8 (3.9) 128 (16) 78.5 (9.8) 5.77 (0.98) 1.48 (0.43) 3.80 (0.94) 1.09 (0.55) 5.59 (0.87) 3.36 (0.69) 113 (49) 255.2 (83.5)

Common carotid IMT

] 1 plaque (n  387)

Pa

B 0.001b 57.6%

31.3%

22.9% 23.3% 5.4% 12.2%

B 0.001b B 0.001b B 0.01b 0.50b

8.7% 7.3% 1.4% 11.2%

54.2 (8.0) 12.2 (3.8) 18.4 (25.6) 22.4 (26.8) 26.6 (4.2) 139 (18) 82.5 (10.6) 6.01 (1.01) 1.38 (0.43) 4.05 (0.94) 1.27 (0.65) 5.83 (1.14) 3.50 (0.75) 118 (53) 287.4 (102.8)

B 0.0001 B 0.01 B 0.01 B 0.001 B 0.0001 B 0.0001 B 0.0001 B 0.001 B 0.01 B 0.0001 B 0.0001 B 0.0001 B 0.01 0.12 B 0.0001

47.4 (8.2) 13.2 (3.8) 9.2 (15.4) 14.5 (20.3) 24.6 (3.8) 127 (16) 77.6 (9.6) 5.70 (1.00) 1.51 (0.45) 3.72 (0.95) 1.04 (0.53) 5.52 (0.73) 3.34 (0.67) 114 (49) 249.7 (79.7)

No plaque (n 585)

 90th percentile (n  106)

Pa

B 0.001b 49.2%

30.2%

B 0.001b

21.4% 22.7% 5.7% 11.1%

B 0.001b B 0.001b B 0.001b 0.99b

11.0% 12.0% 2.1% 10.7%

36.8% 25.2% 11.3% 15.1%

B 0.001b B 0.001b B 0.001c 0.18b

53.6 (7.9) 11.9 (3.7) 19.6 (25.3) 22.6 (26.8) 26.5 (4.1) 137 (18) 82.8 (10.4) 6.05 (0.95) 1.37 (0.39) 4.10 (0.89) 1.28 (0.64) 5.86 (1.21) 3.49 (0.75) 116 (52) 286.7 (101.1)

B 0.0001 B 0.0001 B 0.0001 B 0.001 B 0.0001 B 0.0001 B 0.0001 B 0.0001 B 0.0001 B 0.0001 B 0.0001 B 0.0001 B 0.001 0.52 B 0.0001

49.1 (8.5) 12.9 (3.8) 12.3 (19.0) 17.0 (22.7) 25.1 (3.9) 129 (17) 79.1 (10.0) 5.81 (1.00) 1.47 (0.43) 3.83 (0.95) 1.11 (0.57) 5.61 (0.90) 3.39 (0.71) 114 (50) 262.6 (89.0)

56.9 (6.4) 11.1 (3.5) 21.9 (29.3) 23.7 (28.1) 27.3 (4.6) 144 (18) 84.0 (10.8) 6.08 (0.93) 1.29 (0.42) 4.18 (0.82) 1.34 (0.72) 6.08 (1.32) 3.52 (0.73) 121 (52) 279.0 (102.4)

B 0.0001 B 0.0001 B 0.05 0.14 B 0.0001 B 0.0001 B 0.0001 B 0.01 B 0.0001 B 0.001 B 0.0001 B 0.0001 0.06 0.13 0.08

B 90th percentile (n 866)

d

Percentage of subjects using : Antihypertensive drug(s) Hypocholesterolaemic drug(s) Hypoglycaemic drug(s) Anti-inflammatory drug(s) or antibiotic(s) Age (years) Education level (years) Smoking (pack-years)e Alcohol consumption (g/day)e Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mmol/l) HDL-c (mmol/l) LDL-c (mmol/l) Triglycerides (mmol/l)e Fasting glucose (mmol/l)e Fibrinogen (g/l) von Willebrand factor activity (%)e sICAM-1 (ng/ml) a b c d e

Student’s t -test P -value. x2-test P -value. Bilateral Fisher’s exact test P -value. Use of antihypertensive, hypocholesterolaemic or hypoglycaemic drug(s) during the last 12 months. Use of anti-inflammatory drug(s) or antibiotic(s) during the last 15 days. Computed from log transformed data.

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Percentage of women

Femoral artery explored sites

V. Bongard et al. / Atherosclerosis 164 (2002) 297
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both significantly linked to major cardiovascular risk factors. In multivariate analysis, hypocholesterolaemic drug intake, male gender, age, smoking, systolic blood pressure and sICAM-1 were independently and positively related to carotid plaques (Table 2). These variables were also independently related to femoral plaques as well as antihypertensive drug intake and LDL-c. The odds ratio independently associated with a 10 ng/ml increase in sICAM-1 levels was 1.03 (95% confidence interval: [1.02
/1.05]) for the risk of having at least one carotid plaque and it was 1.04 [1.02
/1.06] for the risk of having at least one femoral plaque. Both of these odds ratios were highly significant (P B/0.0001). On the other hand, sICAM-1 was not associated in multivariate analysis with the risk of being beyond the 90th percentile of common carotid IMT (0.71 mm) (Table 3). In backward analysis the variable sICAM-1 was early deleted from the logistic model, and when sICAM-1 was forced in the model, the corresponding odds ratio was far from the significance level (P /0.63) (Table 3, model 2). Similar results were obtained when the 95th (0.77 mm) and 75th (0.64 mm) percentiles were chosen as cutoff points (data not shown): whatever the cutoff point, sICAM-1 was not significantly associated with common carotid IMT.

4. Discussion These results concerning various stages and locations of the atherosclerotic process, provide additional information to previous data on adhesion molecules and atherosclerosis. We showed that circulating ICAM-1 levels were independently related to the presence of

301

carotid and femoral atherosclerotic plaques in asymptomatic middle-aged subjects, whereas no relationship was found between sICAM-1 and common carotid IMT. Although the exact significance of circulating forms of ICAM-1 still remains to be fully determined, these results may suggest some differences in the involvement of adhesion molecules in the mechanisms of intimamedia thickening and plaque development. Most of the previously published data on sICAM-1 in atherosclerosis have considered symptomatic forms of coronary artery and peripheral vascular diseases whereas early stages of the atherosclerotic process have been less studied [3,5
/8]. However, the identification of potential markers of subclinical atherosclerosis could be useful to detect persons at risk of the development of further symptomatic cardiovascular disease in order to provide them early adequate health care and advice. From this point of view, it is interesting to search for correlations between sICAM-1 and carotid IMT. Indeed, intima-media thickening may be an expression of early atherosclerosis and it has been consistently associated with atherogenic profiles. It has been notably related to conventional cardiovascular risk factors [16
/18] and to various locations of atherosclerosis [19
/22]. In addition, its predictive value in the occurrence of further coronary artery disease has been assessed by several authors [23
/27]. In the present study, common carotid IMT was analysed as a dichotomous variable. The choice of the 90th percentile as cutoff point was of course arbitrary since abnormal values of IMT are not clearly defined. Actually, IMT is strongly dependent on gender and age, with greater values in men and the elderly [17]. There is no agreement between studies about the threshold beyond which IMT should be considered as pathologic

Table 2 Odds ratios independently associated with the risk of having at least one atherosclerotic plaque in the carotid and femoral artery explored sites

Use of drug(s) c: Antihypertensive drug(s) Hypocholesterolaemic drug(s) Gender (men in reference) Age (1 year) Smoking (1 pack-year) Systolic blood pressure (1 mm Hg) LDL-c (1 mmol/l) sICAM-1 (10 ng/ml)

Model (1)a carotid artery explored sites

Model (2)b femoral artery explored sites

OR [95% CI]

P

OR [95% CI]

P

1.43 1.82 0.47 1.07 1.01 1.02
/ 1.03

0.13 B 0.01 B 0.0001 B 0.0001 B 0.05 B 0.001
/ B 0.0001

1.87 2.39 0.37 1.08 1.02 1.01 1.25 1.04

B 0.05 B 0.0001 B 0.0001 B 0.0001 B 0.0001 B 0.05 B 0.01 B 0.0001

[0.90
/2.26] [1.20
/2.77] [0.33
/0.66] [1.05
/1.10] [1.00
/1.02] [1.01
/1.03] [1.02
/1.05]

[1.15
/3.02] [1.52
/3.74] [0.26
/0.51] [1.06
/1.10] [1.01
/1.03] [1.00
/1.02] [1.06
/1.48] [1.02
/1.06]

a Model (1): Odds ratios independently associated with the risk of having at least one atherosclerotic plaque in the carotid artery explored sites. The model is also adjusted for use of hypoglycaemic drug(s) during the last 12 months (OR 0.70, P  0.42). Hosmer and Lemeshow goodness-of-fit test: P 0.41. b Model (2): Odds ratios independently associated with the risk of having at least one atherosclerotic plaque in the femoral artery explored sites. The model is also adjusted for use of hypoglycaemic drug(s) during the last 12 months (OR 1.48, P  0.44). Hosmer and Lemeshow goodness-of-fit test: P 0.31. c Use of antihypertensive or hypocholesterolaemic drug(s) during the last 12 months.

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302

Table 3 Odds ratios independently associated with the risk of being beyond the 90th percentile of common carotid IMT Model (1)a

c

Use of antihypertensive drug(s) Age (1 year) Smoking (1 pack-year) Systolic blood pressure (1 mm Hg) HDL-c (1 mmol/l) sICAM-1 (10 ng/ml)

Model (2)b

OR [95% CI]

P

OR [95% CI]

P

2.23 1.10 1.01 1.02 0.42

B 0.01 B 0.0001 B 0.01 B 0.01 B 0.01

2.25 1.10 1.01 1.01 0.43 1.01

B 0.01 B 0.0001 B 0.05 B 0.01 B 0.05 0.63

[1.28
/3.87] [1.07
/1.14] [1.00
/1.02] [1.01
/1.03] [0.22
/0.81]

a

[1.29
/3.92] [1.07
/1.14] [1.00
/1.02] [1.01
/1.03] [0.22
/0.82] [0.98
/1.03]

Model (1): The model is also adjusted for gender (OR 0.69 (men in reference), P  0.17) and for use of P  0.36) and hypoglycaemic drug(s) (OR 1.43, P  0.43) during the last 12 months. Hosmer and Lemeshow b Model (2): The model is also adjusted for gender (OR 0.68 (men in reference), P 0.16) and for use of P  0.36) and hypoglycaemic drug(s) (OR 1.42, P  0.45) during the last 12 months. Hosmer and Lemeshow c Use of antihypertensive drug(s) during the last 12 months.

intima-media thickening, but most of the authors have used thresholds ranging from 0.75 to 1 mm [17]. In our sample, we observed relatively low values of IMT compared with those described in American or Northern European populations of the same age [17,23,28]. This is in accordance with the well-known low cardiovascular risk in subjects living in South Europe. Indeed, data collected by the MONICA registries of acute myocardial infarction have shown that the population of South-western France has one of the lowest rates of coronary heart disease mortality [12]. A common carotid IMT of 0.75 mm was ranked in our sample between the 90th and the 95th percentile, whereas less than 1% of the subjects were presenting with an IMT higher than 1 mm. This observation led us to use the 90th percentile (e.g. 0.71 mm) as cutoff point in IMT analysis. This limit was close to the thresholds usually used in previous studies and it allowed a sufficient number of subjects in each class of IMT. Nevertheless, since this choice was partly arbitrary, we reiterated the analysis of IMT using other cutoff points (95th and 75th percentiles, e.g. 0.77 and 0.64 mm). In all cases, no significant association was found between sICAM-1 levels and common carotid IMT. Two previous published studies have analysed the relationship between IMT and sICAM-1. The first one was performed in a sample of 105 hypercholesterolaemic subjects and healthy controls randomly selected from the Swedish general population [29]. In agreement with our results, the authors failed to find any independent association between sICAM-1 and IMT. The second one was a cross-sectional study including 92 subjects [30]. Age-adjusted sICAM-1 levels increased in a stepwise fashion across common carotid IMT tertiles and a significant difference in mean sICAM-1 was assessed between the first and the third tertile. The adjustment for cardiovascular risk factors had minimal impact on this result. The apparent discrepancy between these findings and ours probably results from differences in

hypocholesterolaemic (OR 1.29, goodness-of-fit test: P  0.16. hypocholesterolaemic (OR 1.29, goodness-of-fit test: P  0.14.

population characteristics. Indeed, the sample analysed by Rohde et al. was not representative of the general population since it was composed of outpatients referred for a transthoracic echocardiogram. In addition, subjects were older than 50 years. As a consequence, mean IMT (0.90 mm) was higher than in previously described younger and healthier samples [17,23,28]. Thus, as mentioned by the authors, the generalisation of their data may be limited and their findings should be considered in the context of their study population characteristics. In fact, we probably studied an earlier stage of the atherosclerosis disease than Rohde et al. did. This may explain why they found an association between IMT and sICAM-1, whereas in younger and apparently healthier subjects with thinner IMT we failed to find any significant relationship. Actually, beyond a certain value, intima-media thickening is strongly associated with atherosclerosis, and the difference between areas of thickening and fully developed atherosclerotic plaques is not always very clear. In the analysis of a subsample of the ARIC study, Hwang et al. used high values of IMT as a surrogate for carotid atherosclerosis instead of studying well-defined atherosclerotic plaques [4]. Based on this approximation, the authors concluded that sICAM-1 was an independent correlate of subclinical carotid atherosclerosis. Compared with previously published data, one of the main interests in our study is that we differentiated intimamedia thickening from well-defined carotid atherosclerotic plaques, thus providing information on various stages of atherosclerosis. Furthermore, since we examined both carotid and femoral artery beds, we also provided information on various locations of atherosclerosis. To our knowledge, our study is the only one that considered the link between circulating ICAM-1 and atherosclerosis in all these different subclinical expressions of peripheral vascular disease. A result of prime importance is the consistent association we found between sICAM-1 and asymptomatic atherosclerotic

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plaques whatever the location of plaques. This suggests that sICAM-1 might be a relevant marker of generalised asymptomatic atherosclerosis and might be useful for detecting patients before the onset of symptoms relative to peripheral vascular diseases. Although intercellular adhesion molecules are not exclusively produced by vascular wall components, sICAM-1 may reflect low grade vascular inflammatory states and may be more specific for plaque detection than general markers of inflammation such as C-reactive protein which is produced by the liver and raised in a wide range of situations. However, the respective contribution of these various markers of inflammation remains to be determined. In conclusion, our data support the role played by endothelial inflammation which may contribute to the early development of peripheral atherosclerotic plaques, or at least, may reflect the processes occurring in the early development of plaques. However, our data underline differences between the occurrence of asymptomatic atherosclerotic plaques and intima-media thickening. While sICAM-1 might be useful in middle-aged subjects as an easily assessable and inexpensive marker of subclinical atherosclerosis in both carotid and femoral arteries, we failed to find any significant association between sICAM-1 and common carotid IMT in this large sample with low cardiovascular risk and thin IMT. Additional data are now needed to determine beyond which values sICAM-1 should be considered as abnormal and to determine whether sICAM-1 may actively affect plaque development and its complications.

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