Elevated ICAM-1 and MCP-1 Plasma Levels in Subjects at High Cardiovascular Risk Are Diminished by Atorvastatin Treatment

Luis Miguel Blanco-Colio, PhD; Jose Luis Martín-Ventura, PhD; Eduardo de Teresa, MD, FESC; Csaba Farsang, MD, DSc; Allan Gaw, MD, PhD, MRCPath, MFPM; GianFranco Gensini, MD; Lawrence A. Leiter, MD, FRCP, FACP; Anatoly Langer, MD; Pierre Martineau, MSc, PharmD, BCPS; Jesús Egido, MD, PhD

Am Heart J. 2007;153(5):881-888. 

Abstract and Introduction

Background: Plasma levels of soluble intercellular adhesion molecule 1 (sICAM-1) and monocyte chemoattractant protein 1 (sMCP-1) are associated with increased risk for future coronary events. However, the effect of statins on these inflammatory markers has hardly been studied. We analyzed whether treatment with the different doses of atorvastatin affects sICAM-1 and sMCP-1 plasma levels in subjects at high cardiovascular risk.
Methods: Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration was a 12-week, prospective, multicenter, open-label trial that enrolled a total of 2117 subjects with coronary heart disease (CHD), CHD equivalent (defined as diabetes, peripheral vascular disease, or cerebrovascular disease), or a 10-year CHD risk >20%. Subjects with low-density-lipoprotein cholesterol between 100 and 220 mg/dL (2.6-5.7 mmol/L) and triglycerides <600 mg/dL (6.8 mmol/L) were assigned to atorvastatin (10-80 mg/d) based on low-density-lipoprotein cholesterol at screening. The Atorvastatin on Inflammatory Markers study included statin-free patients (N = 1078).
Results: At baseline, 52%, 14%, 12%, and 22% of subjects were assigned to doses of 10, 20, 40, and 80 mg, respectively. Levels of sICAM-1 [geometric mean (95% confidence interval); 283.8 (278.1-289.6) vs 131.9 (127.2-136.6) ng/mL, P < .0001] and sMCP-1 [164.1 (159.9-168.2) vs 131.1 (123.1-139.6 pg/mL, P < .0001] were increased in subjects at high cardiovascular risk compared to healthy subjects (n = 130). In the whole population, sICAM-1 and sMCP-1 levels were reduced by atorvastatin [% change (95% confidence interval); -2.2 (-3.8 to -0.6); -4.1 (-6.1 to -2); P = .006 and P = .0002, respectively]. All doses of atorvastatin diminished sICAM-1 and sMCP-1 levels in the highest quartile.
Conclusions: Short treatment with atorvastatin reduced sICAM-1 and sMCP-1 plasma levels showing anti-inflammatory effects in subjects at high cardiovascular risk.

Endothelial dysfunction occurs during the early stages of atherogenesis and is characterized by increased permeability of endothelial cells and enhanced adhesion due to increased endothelial expression of several adhesion molecules.[1,2] Intercellular adhesion molecule 1 (ICAM-1) is thought to be a key factor when circulating monocytes adhere to the endothelium and subsequently transmigrate into the intima. Similarly, monocyte chemoattractant protein 1 (MCP-1) is the main chemokine responsible for the recruitment of monocytes to sites of active inflammation including the developing atheromatous plaque.[3] Furthermore, MCP-1 activates monocytes to release superoxide anions and tissue factor, and in this manner, contributes to plaque instability.[4] The role of ICAM-1 and MCP-1 in the pathogenesis of atherosclerosis has been confirmed by the fact that mice undergoing targeted deletion of either ICAM-1 or MCP-1 genes have less monocyte accumulation and reduced number of atherosclerotic plaques compared to controls.[5,6]

Searching biomarkers that can reflect intermediary phenotypes between healthy subjects and patients at high cardiovascular risk is currently one of the hottest topics in the cardiovascular field. Biomarkers can be used as indicators of disease trait (risk factor), disease state (preclinical or clinical), or disease rate (progression).[7] In this respect, concentrations of inflammatory biomarkers could reflect the inflammatory status of subjects and contribute to determine the risk of developing a cardiovascular event. Both ICAM-1 and MCP-1 can be secreted by cells present in the arterial wall and detected in human plasma. Different studies have focused on soluble ICAM-1 (sICAM-1) and soluble MCP-1 (sMCP-1) plasma levels as biomarkers with potential clinical use. Results from large prospective studies have demonstrated an association between sICAM-1 and sMCP-1 concentrations and risk for future coronary events.[8,9,10] Furthermore, both proteins have also been associated with several traditional cardiovascular risk factors such as age, hypercholesterolemia, diabetes, and hypertension.[11,12]

Hypercholesterolemia has been associated with endothelial dysfunction, resulting in increased endothelial expression of adhesion molecules that results in enhanced binding of mononuclear cells. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) are effective lipid-lowering drugs used extensively in medical practice. The Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study was designed to determine whether using atorvastatin at starting doses appropriate for the degree of low-density-lipoprotein (LDL-C) reduction required would achieve LDL-C targets quickly with either no titration or just one titration step. This study included patients with coronary heart disease (CHD), CHD equivalent (defined as diabetes, peripheral vascular disease, or cerebrovascular disease), or a 10-year CHD risk >20%. In the Atorvastatin on Inflammatory Markers (AIM) substudy of ACTFAST, we evaluated whether atorvastatin treatment changed the levels of sICAM-1 and sMCP-1 in subjects at high cardiovascular risk who were statin-free at baseline. Furthermore, we studied the effect of atorvastatin treatment in prespecified subgroups defined by the presence of diabetes or the metabolic syndrome.


The ACTFAST study was a 12-week, prospective, multicenter, open-label trial which enrolled subjects (either statin-free or statin-treated at baseline) with CHD, a CHD equivalent (defined as diabetes, peripheral vascular disease, or cerebrovascular disease), or a 10-year CHD risk >20%.[13] In addition, subjects had to present with an LDL-C of >2.6 and ≤5.7 mmol/L, as well as triglycerides ≤6.8 mmol/L and had to be willing to follow the National Cholesterol Education Program (NCEP) III multifaceted lifestyle approach (or local equivalent). The substudy only included patients who were statin-free at baseline (either never previously prescribed a statin or who have been statin-free for a minimum of 2 months before recruitment).

Exclusion criteria included acute liver disease or hepatic dysfunction (asparate amino transferase or alanine transaminase ≥2 times the upper limit of normal), elevated serum creatinine (≥181 µmol/L), creatinine phosphokinase >3 times the upper limit of normal, uncontrolled diabetes (HbA1c >10%), evidence of gastrointestinal disease that could reduce absorption, uncontrolled hypertension (sitting blood pressure >160/100 mm Hg), uncontrolled primary hypothyroidism (thyroid stimulating hormone ≥1.5 times the upper limit of normal), known intolerance or hypersensitivity to hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors. In addition, patients using prohibited medication were also excluded. These drugs included strong CYP3A4 inhibitors (eg, erythromycin or systemic azole antifungals) and other lipid-regulating drugs such as niacin, probucol, fibrates and derivatives, bile acid-sequestering resins, ezetimibe, fish oils, and other HMG-CoA reductase inhibitors. Anti-inflammatory drugs in the previous year, with the exception of low doses of acetylsalicylic acid (<325 mg/d), or immunosuppressive drugs were also excluded in the per-protocol analysis of inflammatory markers. Subjects were ineligible for the study if they had any severe disease or had undergone a surgical procedure within 3 months before screening, or women who were pregnant or lactating or of childbearing potential not using an acceptable method of contraception.

The institutional review board of all participating centers approved the ACTFAST study protocol and all participants provided written informed consent. This study was conducted in compliance with the ethical principles of the Declaration of Helsinki.[14]

For comparison, age- and sex-matched blood donors (n = 130) were used as controls. Control subjects did not present hypertension, hypercholesterolemia, diabetes, the metabolic syndrome, and history of cardiovascular diseases at the time of blood extraction.

Subjects were assigned to a starting dose of atorvastatin (10-80 mg/d) based on LDL-C at screening (patients with LDL-C of 100-149, 150-159, 160-169, and 170-220 mg/dL were assigned to doses of 10, 20, 40, and 80 mg/d, respectively). After 6 weeks, if not already at maximum dose, subjects not reaching LDL-C target (<100 mg/dL) had their dose doubled. Subjects initially allocated to 80 mg/d atorvastatin who did not reach LDL-C targets were continued on that dose, and a more intense therapeutic lifestyle intervention (NECP step II diet or equivalent) was recommended.

As part of the main protocol, fasting venous blood samples were collected into tubes with EDTA anticoagulant at baseline and at 12 weeks. Plasma was isolated by low-speed centrifugation and shipped to a core laboratory for storage at -70°C. The paired baseline and 12-week samples were then shipped to the laboratory (Madrid, Spain) and measured in batches. Both sICAM-1 and sMCP-1 were measured with commercially available enzyme-linked immunosorbent assay kits (R&D System, Europe, Abingdon, UK). The minimum detectable concentrations of sICAM-1 and sMCP-1 were 0.35 ng/mL and 5.1 pg/mL, respectively. The reproducibility of the assays over the study was excellent. Intraassay and interassay coefficients of variation were 4.8% to 7.2% (sICAM-1) and 4.9% to 5.8% (sMCP-1), respectively. For high-sensitivity C-reactive protein (hsCRP) measurement, whole venous blood was collected in tubes without anticoagulant and centrifuged at room temperature. Serum CRP was assessed with a high-sensitivity, latex microparticle-enhanced immunoturbidimetric assay (Tina-Quant; Roche Diagnostics GmbH, Mannheim, Germany). The minimum detectable concentration of hsCRP was 0.03 mg/L. Intraassay and interassay variation coefficients of hsCRP assay were 1.34% and 5.70%, respectively.

This report focuses on the 1078 subjects in the AIM substudy with baseline and 12-week samples available for measurement of inflammatory markers. As expected, the distributions of the inflammatory markers were skewed. To meet the distributional assumptions, the markers were log-transformed for the statistical models and antilog-transformed for descriptive purposes, yielding geometric means and 95% confidence intervals (CI) for baseline, week 12 concentrations, and the change in concentrations over the study period. The prespecified primary end point was the effect of 10, 20, 40, and 80 mg atorvastatin on decreasing sICAM-1 and sMCP-1 over the 12-week study period. The primary end point was assessed by analysis of covariance, adjusted for the initial level of the marker. Secondary end points included the effect of atorvastatin on the changes in sICAM-1 or sMCP-1 levels over 12 weeks, according to the presence of diabetes or metabolic syndrome [defined by NCEP-III as when 3 or more of the following criteria are met: waist circumference >102 cm in men or >88 cm in women; triglycerides ≥150 mg/dL (1.7 mmol/L); high-density-lipoprotein cholesterol (HDL-C) <40 mg/dL (1.0 mmol/L) in men, <50 mg/dL (1.3 mmol/L) in women; blood pressure ≥130/≥85 mm Hg or on antihypertensive therapy; FPG ≥110 mg/dL (6.1 mmol/L)]. Posthoc analyses were designed to analyze the differences between sICAM-1 and sMCP-1 concentrations in subjects at high cardiovascular risk and healthy subjects matched for age and sex. In addition, changes in sICAM-1 and sMCP-1 over 12 weeks, based on the presence of hypertension, were analyzed. The association between sICAM-1 and sMCP-1 (both log-transformed) vs continuous variables were explored with Pearson correlation coefficients, without adjustment for doses used. Statistical significance was defined as a value of P < .05.


The baseline characteristics of the studied population are summarized in . Posthoc analyses of circulating sICAM-1 and sMCP-1 concentrations showed that sICAM-1 was higher in subjects at high cardiovascular risk compared to healthy subjects [geometric mean (95% CI); 283.8 (278.1-289.6) vs 131.9 (127.3-136.64) ng/mL; P < .0001]. In addition, sMCP-1 was also higher in subjects at high cardiovascular risk [164.1 (159.9-168.3) vs 131.2 (123.1-139.6) pg/mL, P < .0001]. When sICAM-1 and sMCP-1 were considered as continuous variables, weak, but statistically significant, associations were observed between sICAM-1, sMCP-1, triglycerides, and HDL-C concentrations ( ). Furthermore, ICAM-1 concentrations were associated with CRP concentrations (r = 0.25; P < .0001).

  Baseline Characteristics of the 1078 Subjects Included in the AIM Substudy

Variable mean (SD) or n (%) Atorvastatin, 10 mg (n = 560) Atorvastatin, 20 mg (n = 149) Atorvastatin, 40 mg (n = 131) Atorvastatin, 80 mg (n = 238) Overall (N = 1078)
Age, y 64.2 (10.6) 64 (11.3) 62.1 (10.8) 62 (11) 63.4 (10.8)
Weight, kg 82.8 (17.6) 79.7 (15.5) 81.9 (15.6) 81.1 (16.5) 81.9 (16.9)
Body mass index? 29.4 (5.5) 28.5 (4.9) 29.2 (5.3) 29.2 (5.2) 29.2 (5.3)
Men 384 (68.6) 93 (62.4) 81 (61.8) 141 (59.2) 699 (64.8)
White 518 (92.5) 140 (94) 124 (94.7) 229 (96.2) 1011 (93.8)
Smoking status          
Current smoker 86 (15.4) 33 (22.1) 35 (26.7) 73 (30.7) 227 (21.1)
Past or nonsmoker 474 (84.6) 116 (77.9) 96 (73.3) 165 (69.3) 851 (78.9)
Alcohol consumption 261 (46.6) 72 (48.3) 70 (53.4) 122 (51.3) 525 (48.7)
History of hypertension 383 (68.4) 105 (70.5) 94 (71.8) 166 (69.8) 748 (69.4)
History of diabetes mellitus 271 (48.4) 64 (43) 63 (48.1) 96 (40.3) 494 (45.8)
Metabolic syndrome 274 (48.9) 61 (40.9) 73 (55.7) 113 (47.5) 521 (48.3)
History of CVD 49 (8.8) 19 (12.8) 10 (7.6) 23 (9.7) 101 (9.4)
History of PVD 52 (9.3) 8 (5.4) 12 (9.2) 16 (6.7) 88 (8.2)
History of CHD 308 (55) 70 (47) 54 (41.2) 112 (47.1) 544 (50.5)

CVD, Cerebrovascular disease; PVD, peripheral vascular disease.
?Calculated as weight in kilograms divided by the square of the height in meters.

  Baseline Correlation Between Continuous Variables, sICAM-1 and sMCP-1

  sICAM-1 correlation coefficient P value sMCP-1 correlation coefficient P value
Total cholesterol .02 -.02
.53 .47
LDL-C .04 -.02
.25 .43
HDL-C -.07 -.06
.03 .04
Triglycerides .08 .08
.007 .009
No HDL .05 .002
.12 .94

Correlations and P values from Pearson correlation coefficient.

When we analyzed prespecified subgroups in subjects at high cardiovascular risk according to the following categories defined by diabetes or the metabolic syndrome, univariate analysis demonstrated that circulating sICAM-1 are increased in patients with the metabolic syndrome compared to patients without this pathology ( ).

  Soluble ICAM-1 and sMCP-1 Markers According to the Presence Diabetes or the Metabolic Syndrome at Baseline

Marker Diabetes (n = 444), mean (95% CI) No diabetes (n = 534), mean (95% CI) P
sICAM-1 (ng/mL) 283.5 (275.2-291.9) 284 (276.2-277.6) .84
sMCP-1 (pg/mL) 162.5 (156.6-168.7) 165.3 (159.7-171.1) .57
Marker Metabolic syndrome (n = 469), mean (95% CI) No metabolic syndrome (n = 506), mean (95% CI) P
sICAM-1 (ng/mL) 295.5 (285.2-302.1) 275 (267.2-283) .0009
sMCP-1 (pg/mL) 165.1 (159.8-170.5) 163.1 (157-169.5) .63

Mean, Geometric mean. P values from t test.

At baseline, 52%, 14%, 12%, and 22% of subjects were assigned to doses of 10, 20, 40, and 80 mg, respectively. At this time, atorvastatin treatment significantly reduced total cholesterol [mean (95% CI); 223 (220.9-224.7) to 150 (146.4-154.7) mg/dL; P < .0001], LDL-C [147 (146.1-149.1) to 80 (79-81.2) mg/dL; P < .0001], triglycerides [151 (146.4-154.7) to 114 (111.2-117.3) mg/dL; P < .0001], and ApoB [1.11 (1.1-1.12) to 0.66 (0.65-0.67) g/L; P < .0001], and increased HDL-C [48 (47.6-48.9) to 49 (48.2-49.6) mg/dL; P = .001] from baseline. Percentages of patients who attained LDL-C <100 mg/dL were 87%, 84%, 91%, and 78% for atorvastatin 10, 20, 40, and 80 mg/d, respectively. In the whole population, 85% of subjects reached LDL-C target. The effect of atorvastatin on sICAM-1 and sMCP-1 concentrations is shown in . In the whole group, atorvastatin lowered circulating sICAM-1 and sMCP-1 in subjects at high cardiovascular risk. Interestingly, in subjects with sICAM-1 or sMCP-1 concentrations at baseline in the highest quartile, all doses of atorvastatin diminished both inflammatory markers (Figure 1).

  Changes in sICAM-1 and sMCP-1 Values From Baseline in all Atorvastatin Doses Studied

Atorvastatin dose sICAM-1 change (95% CI) P sMCP-1 change (95% CI) P
10 mg -3% (-5% to -0.9%) .005 -3.6% (-6.4% to 0.6%) .018
20 mg -2.8% (-6.9% to 1.5%) .21 -7% (-12.1% to -1.5%) .013
40 mg 1.4% (-4% to 7.2%) .45 -6% (-11% to -0.7%) .03
80 mg -2% (-5.3% to 1.4%) .54 -2.1% (-6.7% to 2.7%) .37
Overall -2.2% (-3.8% to -0.6%) .007 -4% (-6.1% to -2%) <.001

P values from paired t test.

Effect of all doses of atorvastatin on sICAM-1 and sMCP-1 in the highest quartile. P values from t test: *P < .001; †P < .01.

Furthermore, posthoc analyses were designed to assess whether the observed atorvastatin-induced changes in sICAM-1 and sMCP-1 were related to atorvastatin-induced changes in lipid parameters. We found no evidence of association between percentage change observed in total cholesterol, LDL-C or HDL-C, and percentage change in sICAM-1 (r = 0.01, P = .81; r = -0.02, P = .51; and r = -0.01, P = .77; respectively) or sMCP-1 (r = 0.02, P = .47; r = -0.03, P = .29; and r = -0.04; P = 0.15). Interestingly, we found evidence of association between the percentage change observed in triglycerides and the percentage change in sICAM-1 (r = 0.09, P = .007) or sMCP-1 (r = 0.15, P < .0001). Furthermore, the diminution noted in sICAM-1 and sMCP-1 with atorvastatin was only significant in subjects with baseline triglycerides exceeding the median value [147.5 mg/dL, -2.8 (-5.1 to -0.5), P = .016; and -5.6 (-8.4 to -2.8), P < .0001; respectively]. We found no evidence of association with the other lipid parameters analyzed.

As expected, all doses of atorvastatin diminished CRP concentrations [-23.4 (-29.1 to -17.2), P < .0001; -27.4 (-36.4 to -17.1), P < .0001; -21.7 (-32.1 to -9.7), P = .0009; -38.3 (-45.3 to -30.4), P < .0001; for 10, 20, 40, and 80 mg/d, respectively). Furthermore, we found evidence of association between the percentage change observed in CRP and the percentage change in sICAM-1 (r = 0.1, P = .002).

When we examined the effect of atorvastatin treatment in prespecified subgroups, we observed that atorvastatin treatment decreased sMCP-1 in subjects with [-3.2 (-6 to -0.3); P = .03] or without the metabolic syndrome [-4.7 (-7.6 to -1.7); P = .002]. However, sICAM-1 levels were decreased by atorvastatin in subjects with the metabolic syndrome [-3.2 (-5.8 to -1.3); P = .004], but not in those without the metabolic syndrome [-1.1 (-3.3 to 1); P = .29].


Our results demonstrate that sICAM-1 and sMCP-1 plasma levels are increased in subjects at high cardiovascular risk. Interestingly, sICAM-1 concentrations were higher in subjects with the metabolic syndrome compared to those without the syndrome. However, we have not noted any difference between subjects with or without diabetes on sICAM-1 levels. Furthermore, sMCP-1 concentrations were similar in subjects with or without the metabolic syndrome or diabetes. The data may be clinically important because increased levels of sICAM-1 have been shown to be associated with an increased risk of future myocardial infarction in apparently healthy men and postmenopausal women, and sMCP-1 concentrations have been related to risk for future cardiovascular events.[8,10,15] We have observed that both biomarkers are inversely associated with HDL-C and directly associated with triglyceride concentrations in subjects at high cardiovascular risk.

We have also analyzed the effect of atorvastatin on sICAM-1 and sMCP-1 in subjects at high cardiovascular risk in a large population study. We have observed that treatment with atorvastatin diminished both inflammatory markers in the whole population. Other studies have tested the effect of intensive (80 mg/d) vs low (10 mg/d) or moderate (20-40 mg/d) treatment on inflammatory markers.[16,17,18] However, our report is the first study to compare the effect of all available doses of atorvastatin on sICAM-1 and sMCP-1. At the dose of 10 mg/d, atorvastatin significantly reduced sICAM-1 concentrations. However, atorvastatin at 20, 40, and 80 mg/d were less effective in the reduction of this inflammatory marker. Although the changes in sICAM-1 induced by atorvastatin were only significant with 10 mg, it is important to note that no statistically significant differences was noted between the various doses used. Furthermore, the sample size for the 10-mg dose of atorvastatin was higher than that of 20-, 40-, or 80-mg dose groups, augmenting the statistical power of this group. Therefore, we can not rule out that the small sample size of 20, 40, or 80 mg groups could influence the observed results. In addition, when we analyzed the effect of atorvastatin on sICAM-1 in subjects at the highest quartile, all doses of atorvastatin decreased sICAM-1 at a similar range. These results could indicate that the effect of atorvastatin on sICAM-1 is independent of the dose used. Furthermore, atorvastatin (10-40 mg/d) also significantly decreased sMCP-1 plasma levels. The lack of effect with 80 mg atorvastatin on both inflammatory markers was also noted when we analyzed other biomarkers such as Fas.[19] Although this information could be relevant, more studies comparing all doses of statins need to be conducted to confirm this result.

Contradictory results have been published about the effect of statins on sICAM-1 plasma concentrations. In a number of small population studies, different authors have noted that treatment with statins diminished sICAM-1 concentrations in subjects with hypercholesterolemia or CHD.[20,21,22,23,24] However, Wiklund et al[25] observed a small and inconsistent effect of simvastatin and atorvastatin treatment in hypercholesterolemic patients. Furthermore, Jilma et al[26] demonstrated that atorvastatin, simvastatin, or pravastatin did not modify sICAM-1 concentrations after 3 months of treatment in subjects with moderate hypercholesterolemia. Although atorvastatin had a weak effect on sICAM-1 concentrations in the whole population, in the highest quartile all doses of atorvastatin diminished sICAM-1 plasma levels by more than 10% in subjects at high cardiovascular risk, indicating that atorvastatin has a greater effect in subjects with higher systemic inflammation. In this sense, we have observed that atorvastatin was more effective in the reduction of ICAM-1 concentrations in subjects with the metabolic syndrome, who are characterized by a higher inflammatory status than those without the metabolic syndrome. In addition, some studies have analyzed the effect of statins on sMCP-1 concentrations. However, no more than 30 patients have been included in these studies.[27,28] Now, in a large population study we have demonstrated that atorvastatin treatment reduced sMCP-1 in subjects at high cardiovascular risk. Furthermore, in the highest quartile, all doses of atorvastatin reduced sMCP-1 concentrations by more than 15%, indicating that short-term treatment with atorvastatin efficiently lowers sMCP-1 plasma levels.

On the other hand, when we analyzed subjects with diabetes in comparison with those without diabetes with a similar cardiovascular risk, we did not find any differences in sMCP-1 and sICAM-1 concentrations. It is important to note that patients without diabetes were included in our study by the presence of CHD, CHD-equivalent, or 10-year CHD-risk > 20%, which should affect the inflammatory marker concentrations. In this context, our results are in agreement with the reported of Bláha et al,[29] in which sMCP-1 was not increased in subjects with type 2 diabetes mellitus compared to those without diabetes but with a history of cardiovascular disease. Furthermore, in the cohort of patients with type 2 diabetes mellitus, correlation between sMCP-1 and HbA1c was not observed. In this respect, we have not found any differences in sICAM-1 or sMCP-1 concentrations in diabetic subjects with HbA1c < 7 or HbA1c ≥ 7 (not shown), which indicates the possibility that at least in the 2 proteins tested, diabetic status is not related with their plasma concentrations.

Changes in sICAM-1 and sMCP-1 concentrations were related to the observed change in triglyceride concentration. Furthermore, the effect of atorvastatin was superior in subjects whose triglycerides exceeded the median value, suggesting that the potential benefit could be related to the lipid-lowering effects of statins. However, we can not rule out that the observed effect of atorvastatin could also be related to the nonlipid-lowering properties of statins.[30,31] In this sense, different mechanisms by which atorvastatin can reduce ICAM-1 and MCP-1 expression have been proposed, among them the inhibition of transcription factor activation, mainly nuclear factor kappaB (NF-?B).[32] This transcription factor is the main nuclear factor implicated in the activation of the transcription of several proinflammatory proteins including ICAM-1 and MCP-1.[33] The diminution of NF-?B activation has been associated with the reduction of macrophage infiltration in human atherosclerotic plaques observed after atorvastatin treatment.[34] This effect could be attributed to the down-regulation of adhesion molecule and chemokine expression in atherosclerotic plaques, indicating that atorvastatin treatment could be reducing atherosclerotic plaque inflammation. In this sense, it has been reported that CRP can modulate ICAM-1 expression through NF-?B activation,[35] and we have shown that CRP concentrations are related with ICAM-1 concentrations before and after treatment. The diminution observed in CRP concentrations was higher than that observed for ICAM-1 and MCP-1. It is important to note that statin treatment diminished CRP concentration in only 1 month.[36] However, other inflammatory biomarkers may need a more prolonged treatment to normalize their plasma concentrations. In this sense, we have previously reported that soluble FasL concentrations was only normalized by atorvastatin treatment after 1 year.[37] In this context, it is plausible that a considerably prolonged treatment could reduce MCP-1 and ICAM-1 levels in subjects at high cardiovascular risk in the range of CRP diminution.

It is important to emphasize that although atorvastatin lowered sICAM-1 and sMCP-1 concentrations, they did not reach "normal" levels. Long-term treatment could have additional beneficial effect on both inflammatory biomarkers and potentially diminish the degree of systemic inflammation.

Another interesting hypothesis to explain the anti-inflammatory effects of atorvastatin treatment is interference with the prenylation of small G proteins.[31,38] Inhibition of HMG-CoA reductase by statins inhibits the generation of isoprenoids (geranylgeranyl pyrophosphate and farnesyl pyrophosphate) in vascular cells. The binding of isoprenoids to a number of signaling small G proteins (such as Rho and Ras) enable them to function in inflammatory signaling pathways.[39] In this sense, the inhibition of RhoA activation induced by statins has been related to the reduction of ICAM-1 expression in endothelial cells.[40]

In summary, the possibility that statins may interfere with inflammatory activity seems very attractive in the primary prevention of CHD. This large population study provides, for the first time, evidence that atorvastatin diminishes sICAM-1 and sMCP-1 concentrations. In addition, all available doses of atorvastatin were found to lower the concentrations of both markers in subjects presenting with the highest baseline levels. The present study indicates that short-term treatment with atorvastatin exhibits anti-inflammatory effects in subjects at high cardiovascular risk.


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