Published online before print August 8, 2005, doi: 10.1161/CIRCULATIONAHA.104.513085
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2005;112:976-983.)
© 2005 American Heart Association, Inc.
Epidemiology |
C-Reactive Protein, Interleukin-6, and Soluble Adhesion Molecules as Predictors of Progressive Peripheral Atherosclerosis in the General Population
Edinburgh Artery Study
From the Wolfson Unit for Prevention of Peripheral Vascular Diseases, Public Health Sciences, University of Edinburgh, Edinburgh (I.T., G.D.M., F.G.R.F.); Department of General Practice and Primary Care, University of Aberdeen, Foresterhill Health Centre, Aberdeen (A.J.L.); and Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, Glasgow (A.R., G.D.O.L.), Scotland.
Correspondence to Ioanna Tzoulaki, MSc, Wolfson Unit for Prevention of Peripheral Vascular Diseases, Public Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland. E-mail I.Tzoulaki{at}sms.ed.ac.uk
Received October 13, 2004; revision received May 4, 2005; accepted May 6, 2005.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— The relationship between levels of circulating inflammatory markers and risk of progressive atherosclerosis is relatively undetermined. We therefore studied inflammatory markers as predictors of peripheral atherosclerotic progression, measured by the ankle-brachial index (ABI) at 3 consecutive time points over 12 years.
Methods and Results— The Edinburgh Artery Study is a population cohort study of 1592 men and women aged 55 to 74 years. C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin were measured at baseline. Valid ABI measurements were obtained on 1582, 1081, and 813 participants at baseline and 5-year and 12-year follow-up examinations, respectively. At baseline, a significant trend was found between higher plasma levels of CRP (P
0.05) and increasing severity of peripheral arterial disease (PAD), after adjustment for baseline cardiovascular risk factors. IL-6 at baseline (P0.001) was associated with progressive atherosclerosis at 5 years (ABI change from baseline), and CRP (P0.01), IL-6 (P0.001), and ICAM-1 (P0.01) were associated with changes at 12 years, independently of baseline ABI, cardiovascular risk factors, and baseline cardiovascular disease. Only IL-6 independently predicted ABI change at 5 years (P0.01) and 12 years (P0.05) in analyses of all inflammatory markers simultaneously and adjusted for baseline ABI, cardiovascular risk factors, and cardiovascular disease at baseline.
Conclusions— These findings suggest that CRP, IL-6, and ICAM-1 are molecular markers associated with atherosclerosis and its progression. IL-6 showed more consistent results and stronger independent predictive value than other inflammatory markers.
Key Words: atherosclerosis • cell adhesion molecules • peripheral vascular disease • interleukins • C-reactive protein
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Inflammation may contribute to atherosclerosis by a variety of mechanisms depending on the stage of the disease.1 Circulating markers of systemic inflammation have been shown to predict future cardiovascular disease (CVD) such as myocardial infarction, stroke, and peripheral arterial disease (PAD).2 These markers of systemic inflammation include C-reactive protein (CRP), proinflammatory cytokines such as interleukin-6 (IL-6), and soluble adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin. CRP has received the most attention3–8 and, along with IL-6,9–11 appears to be a consistent predictor of future cardiovascular events in large prospective studies. Epidemiological data on adhesion molecules predicting risk of CVD are sparse.12,13 Moreover, the role of inflammatory markers in the preclinical stages of atherosclerosis is undetermined. A few studies14–17 have focused on their relationship with measures of atherosclerosis such as carotid intima-media thickness. Only the Rotterdam Study18 has examined the prospective association of CRP with asymptomatic atherosclerotic progression, and no studies have reported on possible similar associations for IL-6 or adhesion molecules. There is also a need for prospective analysis of the relative associations of all these inflammatory markers with lower-extremity atherosclerosis and its progression.
The ankle-brachial index (ABI) is an accurate and reliable marker of subclinical peripheral and generalized atherosclerosis in populations.19,20 In the Edinburgh Artery Study, a population-based cohort study, we compared for the first time the association between several inflammatory markers (CRP, IL-6, ICAM-1, VCAM-1, and E-selectin) and progression of peripheral atherosclerosis. This was evaluated by changes in the ABI at 3 time points over a 12-year follow-up period.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The Edinburgh Artery Study began in 1988 as a cross-sectional survey of 809 men and 783 women aged 55 to 74 years. This population, which was almost exclusively of white origin, was selected at random, in 5-year age bands, from 11 general practices serving a range of socioeconomic and geographic areas throughout the city. The response rate was 65%, and follow-up of a sample of nonresponders showed no substantial bias.21 Details of the study recruitment and examination process have been described.21 Ethics committee approval was given for this study, and informed consent was obtained from each subject.
Subjects completed a self-administered questionnaire at baseline that contained validated questions regarding personal characteristics, social class, intermittent claudication, and angina (World Health Organization [WHO] questionnaire),22 medical history, smoking, diet, alcohol consumption, exercise, and current medication for high blood pressure or diabetes. A similar modified questionnaire was repeated at each of the 5- and 12-year examinations.
Subjects were invited for a comprehensive clinical examination at baseline and at 5 and 12 years after the study commenced. Clinical measurements were conducted by trained research staff during each examination. A 12-lead ECG was taken and coded independently by 2 observers using the Minnesota code.23 Standing height (without shoes) was measured to the nearest 5 mm with the use of a free-standing metal ruler on a heavy base. Weight (without shoes and outer clothing) was measured to the nearest 100 g on digital scales (Soehnle). Body mass index (BMI) was calculated as the weight in kilograms divided by square of the height in meters. Systolic and diastolic (phase V) blood pressures were recorded in the right arm only, after 10 minutes of rest with the patient in the supine position, with a Hawksley random zero sphygmomanometer. The femoral, posterior tibial, and dorsalis pedis pulses were palpated in both legs. Ankle systolic pressures were measured first in the right leg and then in the left leg at the posterior tibial artery with the use of a Sonicaid Doppler ultrasound probe and a random zero sphygmomanometer with the cuff placed proximal to the malleoli. The pulse was located with the Doppler probe, and the cuff was inflated until the pulse was no longer audible. The cuff was then deflated, and the pressure was noted when the pulse reappeared. If the posterior tibial pulse was not detectable, the dorsalis pedis pulse was used wherever possible. ABI was calculated by dividing the ankle systolic pressure by the brachial systolic pressure. The lower of the 2 indices was used in the analysis as indicative of worse disease. Reproducibility of the ABI was tested before the commencement of the study on 36 subjects who had repeated measurements by 4 observers on 2 separate days.24 The 95% CIs for variability of the measurement were mean±16% for 1 measurement of the ABI. Quality control at baseline and at 5- and 12-year examination involved retraining of the observers of each examination, periodic checks for drift, and comparison of ABI measurements of the observers of each examination on the same patient. Three, 5, and 8 subjects at baseline, 5 years, and 12 years, respectively, had values of ABI >1.50 and were excluded because of probable arterial rigidity.
At baseline, a fasting 20-mL sample of venous blood was taken for estimation of biochemical, inflammatory, and hemostatic factors. Tests for serum total cholesterol, HDL cholesterol, and blood glucose were performed on a Cobas Bio analyzer (Roche Products) with standard kits. The total/HDL cholesterol ratio was calculated by dividing the total by the HDL cholesterol value. Diabetic status of the subject was assessed in a number of ways. At baseline examination, a blood sample was taken for measurement of blood glucose, and then each subject not known to be diabetic consumed 75 g of glucose in the form of 335 mL Solripe Gluctoza Health Drink (Strathmore Mineral Water Company). A second blood glucose specimen was taken 2 hours after the oral glucose load. In addition, at baseline, 5-, and 12-year examinations, self-reported diabetic status and use of insulin injections and tablets for diabetes were recorded. High-sensitivity CRP was measured immunologically with a BN ProSpec nephelometer (Dade Behring). Plasma levels of IL-6, ICAM-1, VCAM-1, and E-selectin were measured with high-sensitivity ELISA kits (R&D Systems. Intra-assay and interassay variability coefficients were as follows, respectively: for CRP, 4.7% and 8.3%; for IL-6, 7.4% and 8.8%; for ICAM-1, 4.8% and 7.4%; for VCAM-1, 4.3% and 8.5%; and for E-selectin, 4.8% and 5.7%. Quality control practices included repeating values outside 95% of the normal range and use of internal quality control plasma with each assay for each marker.
Throughout the 12 years of follow-up, fatal and nonfatal cardiovascular events were recorded and defined with criteria adapted from the American Heart Association.23,25 The process of follow-up has been described in detail previously.26 To identify all deaths occurring in the cohort, each participant’s record was flagged at the UK National Health Service Central Registry so that death certificates would be automatically forwarded to the investigators. If a postmortem examination was not performed, causes of death were verified by consulting hospital or general practitioner records. Intermittent claudication was recorded if either of the following was true: (1) evidence of intermittent claudication by WHO criteria at baseline or at any time during follow-up or (2) verified clinical diagnosis of intermittent claudication by a general practitioner or in the hospital.
Data Analysis
Data were analyzed with the use of the SPSS version 12.0 software package. Pack-years of smoking were calculated as years of cigarette smoking multiplied by the average number of packs smoked per day with the value zero entered for lifelong nonsmokers. The distribution of pack years was skewed, and a square-root transformation was used in all analyses. Distributions of CRP, IL-6, ICAM-1, VCAM-1, and E-selectin were also positively skewed and were logarithmically transformed to approach normality for all analyses. For presentation purposes, means and 95% CIs of transformed variables have been back transformed to geometric means. Ninety-eight subjects with CRP levels >10 mg/L and 11 subjects with IL-6 levels >100 pg/mL were excluded from all analyses because these levels indicate presence of acute inflammatory disease. Physical activity was used as a 4-group categorical variable (no activity, light activity, moderate activity, and strenuous activity) as previously described.27 Presence of diabetes was defined by either physician recall, treatment for diabetes, or glucose concentration of the 2-hour blood sample 
11.1 mmol/L. Subjects with CVD at baseline were those who had reported experiencing a myocardial infarction or stroke event.
Associations between logarithmically transformed inflammatory markers were calculated with the Pearson correlation coefficient. Mean levels of inflammatory markers according to PAD status were compared by ANOVA and ANCOVA adjusted for baseline risk factors: age, sex, pack-years of smoking, presence of diabetes, total/HDL cholesterol ratio, BMI, and physical activity. Homogeneity of variance assumption was tested. Symptomatic individuals were defined as those positive in the WHO intermittent claudication questionnaire at baseline, whereas asymptomatic subjects were defined as those without claudication but with ABI 0.9 at baseline. We also performed separate linear regression for ABI at baseline with each inflammatory marker as a predictor variable. Analysis was adjusted for age and further adjusted for the aforementioned risk factors and CVD status at baseline.
Change in ABI was calculated as ABI at 5 years or ABI at 12 years minus ABI at baseline. Linear regression was used to test associations between each inflammatory marker and ABI change at 5 and 12 years separately. Analyses were initially adjusted for baseline ABI and age and further adjusted for sex, pack-years of smoking, presence of diabetes, total/HDL cholesterol ratio, BMI, physical activity, and baseline CVD. We then entered all inflammatory markers and baseline risk factors predicting ABI change at 5 and 12 years, respectively, into the model. Tests were made for collinearity, and residual plots were examined to check assumptions of regression analysis. We also tested for effect modification between age and sex and inflammatory markers, but the interaction terms were not statistically significant. Finally, we performed separate linear regression on the subgroup (n=1080) that was free of baseline PAD (no symptoms of intermittent claudication or ABI >0.9). Throughout all analyses, a 2-sided probability value 0.05 was taken to denote statistical significance.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
A total of 1592 subjects were recruited at baseline; 1156 of them participated in the 5-year follow-up examination (131 additional subjects completed the questionnaire only), and 831 participated in the 12-year follow-up (88 others completed the questionnaire only). During the 5 years of follow-up, there were 203 deaths (12.8%) recorded, of which 89 (43.8%) were cardiovascular. Up to the 12-year examination, the total number of deaths was 485 (30.5%), of which 207 (42.7%) were cardiovascular. At baseline, 4.9% of the population was suffering from intermittent claudication and 23% from asymptomatic PAD. In addition, 179 new cases of intermittent claudication had been identified by 12 years of follow-up. Of these 179 new cases, 15 (8.4%) had undergone vascular surgery or amputation over the follow-up period. Characteristics of the baseline population are presented in Table 1.
|
Moreover, CRP and IL-6 as well as ICAM-1 and VCAM-1 were moderately and significantly correlated (r=0.51 and r=0.38, respectively; P<0.001). E-selectin was significantly and positively associated with both ICAM-1 and VCAM-1 (r=0.36 and r=0.16, respectively; P<0.001). Adhesion molecules were all positively and significantly associated with CRP and IL-6, with similar correlation coefficients ranging between 0.10 and 0.30 (P<0.001). Geometric mean values of inflammatory markers according to baseline PAD status are presented in Table 2. A significant trend was found between higher plasma levels of CRP (P0.001), IL-6 (P=0.002), ICAM-1 (P=0.01), and VCAM-1 (P=0.03) and individuals classified as having worsening PAD (from normal, asymptomatic to symptomatic). This trend remained statistically significant only for CRP (P=0.02) and was borderline significant (P=0.07) for IL-6 after adjustment for baseline risk factors: age, sex, pack-years of smoking, diabetes, total/HDL cholesterol ratio, BMI, and physical activity. Levels of E-selectin did not show any significant trends (Table 2). On linear regression analyses (after age adjustment) of inflammatory markers as predictor variables for baseline ABI, significant inverse associations were found between CRP (P0.001), IL-6 (P0.001), and ICAM-1 (P0.001) and ABI (data not shown). After adjustment for baseline risk factors (age, sex, pack-years of smoking, diabetes, total/HDL cholesterol ratio, BMI, physical activity) and CVD status, these associations were attenuated, and only IL-6 remained independently associated with baseline ABI, albeit weakly (P=0.05). Significant associations were not present for VCAM-1 and E-selectin in both age-adjusted and risk factor–adjusted analyses.
|
Table 3 shows the mean (SD) and mean (SD) changes of ABI at the 3 time points (baseline, 5 years, and 12 years). Valid ABI measurements were available for 1582 subjects (99% of participants) at baseline, for 1081 subjects (93.1%) at the 5-year follow-up, and for 813 subjects (97.8%) at the 12-year follow-up. Moreover, 747 subjects had valid ABI measurements at all 3 clinical examinations. As shown in Table 3, mean ABI declined over time to a similar degree in all subjects measured at each time point and in the subgroup of subjects who had an ABI measured at all 3 time points.
|
The mean ABI change (unadjusted) from baseline to 5 and 12 years of follow-up by tertiles of inflammatory marker levels is demonstrated graphically in the Figure. Subjects with CRP, IL-6, ICAM-1, and VCAM-1 in the top tertile had a greater ABI decline by 5 years than subjects in the bottom tertile. This difference became more prominent after 12 years of follow-up. In fact, the bottom tertiles of CRP and IL-6 did not show any significant change in mean ABI between 5 and 12 years, whereas the middle and top tertiles of CRP and IL-6 showed further decline in mean ABI (mean [SD] ABI change, –0.02 [0.19] and –0.04 [0.20] for top tertiles of CRP and IL-6, respectively). Substantial differences were also observed for ICAM-1. After 12 years, the mean change (SD) in ABI from baseline for subjects in the bottom ICAM-1 tertile was –0.04 (0.18), whereas for those in the top tertile it was –0.11 (0.21). There was no significant relationship of ABI change across E-selectin tertiles.
|
), middle tertile (
), and top tertile (•) are shown. Cutoff points for tertiles were 1.11 and 2.88 mg/L for CRP, 1.65 and 2.96 pg/mL for IL-6, 197 and 242 ng/mL for ICAM-1, 341 and 410 ng/mL for VCAM-1, and 34 and 48 ng/mL for E-selectin.
We then performed separate linear regression analysis for ABI change from baseline to 5 years and from baseline to 12 years with each inflammatory marker as a predictor variable (Table 4). CRP and IL-6 were significant predictors of ABI change at 5 years (CRP, P=0.03; IL-6, P0.001) and at 12 years of follow-up (CRP, P=0.002; IL-6, P0.001) in analysis adjusted for both age and baseline ABI. Little change in these associations was found after adjustment for baseline ABI and risk factors of age, sex, pack-years of smoking, diabetes, total/HDL cholesterol ratio, BMI, physical activity, and CVD status in the 12-year analysis. However, CRP had only nonsignificant (P=0.08) associations with ABI change at 5 years in risk factor–adjusted analysis. ICAM-1 was significantly inversely associated with ABI change at 5 years (P=0.02) and at 12 years of follow-up (P0.001) in analysis adjusted for age and baseline ABI. On further adjustments for baseline risk factors, ICAM-1 remained an independent predictor of ABI change at 12 years (P=0.01) only.
|
Table 4 presents the results of the aforementioned linear regression analyses. To compare the effects of each marker on ABI change, we standardized the regression coefficients to represent mean (95% CI) differences in ABI decline between the top and bottom tertiles of each marker. The magnitude of this difference up to 5 years of follow-up was greatest for IL-6. However, at 12 years, increased levels of CRP, IL-6, and ICAM-1 had effects of similar strength on ABI change. Finally, we examined the simultaneous effect of all inflammatory markers on ABI change at 5 and 12 years using linear regression with all inflammatory markers and baseline risk factors simultaneously entered into the model. In this final analysis, IL-6 was the only significant inflammatory marker that independently predicted ABI change at 5 years (P=0.002) and 12 years (P=0.02), and the difference (95% CI) in ABI decline between subjects in the top and bottom tertiles of IL-6 was –0.017 (–0.120, –0.008) and –0.016 (–0.030, –0.002) at 5 and 12 years, respectively. The aforementioned results were confirmed by repeated-measures analysis of ABI. In this analysis, IL-6, for example, had a significant interaction term with time (baseline, 5 years, or 12 years) in both age-adjusted (P=0.014) and risk factor–adjusted analyses (P=0.024).
Finally, we performed subgroup analysis of the 1080 subjects without baseline PAD (no symptoms of intermittent claudication or ABI >0.9). After 5 and 12 years, in analyses adjusted for baseline ABI, IL-6 (P=0.02) and ICAM-1 (P0.03) were significant predictors of ABI change. However, in analyses adjusted for baseline risk factors, IL-6 was the only independent predictor of ABI change at either the 5-year (P=0.01) or 12-year (P=0.03) examination.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this prospective study, we have shown that CRP, IL-6, and ICAM-1 were significant predictors of lower-extremity atherosclerotic progression measured by ABI over 12 years of follow-up independently of cardiovascular risk factors. Moreover, IL-6 was a significant and independent predictor of ABI change after 5 years of follow-up. Of all the markers studied, IL-6 was the only one to predict ABI changes at both 5 and 12 years of follow-up independently of other inflammatory markers and of cardiovascular risk factors. All inflammatory markers were moderately and significantly correlated, as previously reported.17
The epidemiological data on adhesion molecules and PAD are very limited, and most reported studies have been either small or cross-sectional.28–32 To our knowledge, this is the first large cohort study to examine, on a community basis, the predictive power of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) for ABI change across 3 time points. Adhesion molecules are thought to contribute to atherosclerotic lesion formation and to plaque rupture. E-selectin mediates the first step in leukocyte adhesion at sites of inflammation, whereas ICAM-1 and VCAM-1 facilitate the firm attachment of leukocytes and their emigration into the arterial wall.33 We did not show any significant association between E-selectin and PAD at baseline and between E-selectin and ABI changes. This is in accordance with previous studies, which did not find any association between E-selectin levels and PAD severity or PAD location.29,31,34–36 We also found no significant associations between VCAM-1 and ABI change. In contrast, ICAM-1 was an independent predictor of ABI change after 12 years of follow-up. A weak trend was found for both markers with PAD severity at baseline, but it was attenuated after adjustment for baseline risk factors. Additionally, ICAM-1 was a significant predictor of ABI change at 5 and 12 years of follow-up in subjects without PAD at baseline (baseline ABI– and age-adjusted analyses). The present study supports previous evidence for a different role between ICAM-1 and VCAM-1 according to the stage of the disease: studies have shown that VCAM-1 is associated with PAD progression in subjects with preexisting disease, but ICAM-1 predicts disease development in healthy populations.28,29,31,32,37,38
IL-6 is one of the most studied cytokines with proinflammatory and proatherogenic activity. It is the main stimulant for hepatic production of CRP and other reactant proteins but also has other important roles leading to increased endothelial cell adhesiveness by upregulating E-selectin, ICAM-1, and VCAM-1 and releasing inflammatory mediators, including IL-6 itself.39 Evidence of an association of CRP and IL-6 with peripheral atheroma is limited. CRP and IL-6 were found to be significantly elevated in some, but not all, case-control studies in selected populations.40–47 Ridker et al48 showed that CRP, along with total/HDL cholesterol ratio, was the strongest predictor of PAD among several biomarkers assessed in healthy individuals in a prospective study. Moreover, in the Rotterdam Study,18 CRP significantly predicted PAD after 6.5 years of follow-up in the general population. In contrast, McDermott et al16 failed to show any significant association between CRP and ABI in subjects without a history of CVD. In another study,49 IL-6, but not CRP, was elevated significantly in patients with subclinical CVD compared with healthy controls.
This is the first study to examine the predictive value of IL-6 in relation to PAD prospectively. We found a significant trend between PAD severity at baseline and levels of IL-6 and CRP. However, the trend remained significant only for CRP after adjustment for cardiovascular risk factors. Furthermore, we showed an independent association between IL-6 with ABI at baseline, ABI change at 5 years, and ABI change at 12 years of follow-up in analyses adjusted for conventional risk factors. These results were also confirmed by longitudinal analysis with the use of ABI as a repeated measurement over 3 time points. IL-6 showed a greater effect on ABI change at 5-year follow-up compared with CRP, whereas CRP was an independent predictor of ABI change after 12 years only. On the other hand, IL-6 was also an independent predictor of ABI change at 5 years and at 12 years, when both risk factors and inflammatory markers (CRP, ICAM-1, VCAM-1, and E-selectin) were simultaneously entered as covariates into the model. Finally, IL-6 was the only inflammatory marker that predicted ABI decline after 5 and 12 years of follow-up independently of baseline risk factors in subjects without PAD at baseline.
This independent predictive power of IL-6 over and above other inflammatory markers in relation to peripheral atherosclerotic progression may reflect its vital role both in inflammation and in hemostasis. In addition to upregulating CRP and adhesion molecule production, IL-6 upregulates several hemostatic variables, including fibrinogen, tissue factor, von Willebrand factor, and factor VII.50 Although our findings suggest a key role for IL-6 in detection of progressive atherosclerosis, CRP merits consideration as a predictive inflammatory marker from a practical viewpoint.30
The present study has some limitations. First, the inflammatory markers were measured only once, and intraindividual variation therefore could not be taken into account. Nevertheless, this would tend to result in an underestimation of the true effect. Second, participants of the 5- and 12-year follow-up examinations were probably healthier at baseline than those who died during the follow-up period. This explains the higher baseline ABI (1.07) of those 747 subjects who attended all 3 clinical examinations. However, the trend in ABI decline during the 12 years between the individual examination attenders and the group who had attended all 3 clinical examinations was similar and suggest that our findings and conclusions are likely to be valid. We did not adjust our analysis for aspirin or statin use at baseline; however, at the time of baseline examination (1987/1988), very few of the Edinburgh population took such drugs for the prevention of CVD. Furthermore, the generalization of our results to other ethnic populations and age groups is unknown.
Finally, in this analysis we studied the predictive power of inflammatory factors on ABI changes. ABI has shown very small changes between tertiles of inflammatory markers, and the clinical importance of our results needs further investigation. On the other hand, the present analysis is suggestive of a relationship between inflammation and progressive atherosclerosis. Despite the prospective design of our study, an observational study cannot establish causal relations, and residual confounding cannot be ruled out. Therefore, the precise pathway through which inflammation influences atherosclerotic progression and the directionality of the reported associations remain unknown. Similarly, nonsignificant associations such as the ones shown by CRP in risk factor–adjusted analysis could result if inflammatory markers exert their effect on ABI via cardiovascular risk factors like diabetes or BMI. If this is true, these variables should not be used as covariates in the model because they are not confounders but intermediary factors.
In summary, we have shown strong independent associations between baseline levels of CRP, IL-6, and ICAM-1 with ABI change measured 12 years after baseline in analyses adjusted for cardiovascular risk factors. IL-6 also predicted ABI change from baseline to 5 years of follow-up independently of conventional risk factors. The 3 markers had comparable effects on ABI change at 12 years, whereas IL-6 had a greater effect than CRP on ABI change at 5 years. Finally, IL-6 predicted the ABI decline after 5 and 12 years of follow-up independently of CRP, ICAM-1, VCAM-1, and E-selectin and of baseline risk factors. Further studies are required to validate these results, to further assess the relative importance of each inflammatory marker on the progression of peripheral atherosclerosis, and to establish whether these associations are of causal significance.
|
Acknowledgments |
|---|
We thank the British Heart Foundation for financial support and all participants, staff, and general practitioners involved in the Edinburgh Artery Study. Ioanna Tzoulaki is funded by the Scottish Executive (Chief Scientist Office).
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
2. Lind L. Circulating markers of inflammation and atherosclerosis. Atherosclerosis. 2003; 169: 203–214.[CrossRef][Medline] [Order article via Infotrieve]
3. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998; 97: 425–428.
4. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.
5. Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999; 99: 237–242.
6. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J. 2002; 144: 233–238.[CrossRef][Medline] [Order article via Infotrieve]
7. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study: Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996; 144: 537–547.
8. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004; 350: 1387–1397.
9. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101: 1767–1772.
10. Lowe GD, Rumley A, McMahon AD, Ford I, O’Reilly DS, Packard CJ. Interleukin-6, fibrin D-dimer, and coagulation factors VII and XIIa in prediction of coronary heart disease. Arterioscler Thromb Vasc Biol. 2004; 24: 1529–1534.
11. de Lemos JA, Hennekens CH, Ridker PM. Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk. J Am Coll Cardiol. 2000; 36: 423–426.
12. Malik I, Danesh J, Whincup P, Bhatia V, Papacosta O, Walker M, Lennon L, Thomson A, Haskard D. Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis. Lancet. 2001; 358: 971–976.[CrossRef][Medline] [Order article via Infotrieve]
13. Shyu KG, Chang H, Lin CC, Kuan P. Circulating intercellular adhesion molecule-1 and E-selectin in patients with acute coronary syndrome. Chest. 1996; 109: 1627–1630.[CrossRef][Medline] [Order article via Infotrieve]
14. Wang TJ, Nam BH, Wilson PW, Wolf PA, Levy D, Polak JF, D’Agostino RB, O’Donnell CJ. Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2002; 22: 1662–1667.
15. Folsom AR, Pankow JS, Tracy RP, Arnett DK, Peacock JM, Hong Y, Djousse L, Eckfeldt JH. Association of C-reactive protein with markers of prevalent atherosclerotic disease. Am J Cardiol. 2001; 88: 112–117.[CrossRef][Medline] [Order article via Infotrieve]
16. McDermott MM, Green D, Greenland P, Liu K, Criqui MH, Chan CL, Guralnik JM, Pearce WH, Ridker PM, Taylor L, Rifai N, Schneider JR. Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index. Am J Cardiol. 2003; 92: 194–199.[Medline] [Order article via Infotrieve]
17. Van DM, I, De Maat MP, Bots ML, Breteler MM, Meijer J, Kiliaan AJ, Hofman A, Witteman JC. Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study. Arterioscler Thromb Vasc Biol. 2002; 22: 838–842.
18. Van DM, I, De Maat MP, Hak AE, Kiliaan AJ, Del Sol AI, Van Der Kuip DA, Nijhuis RL, Hofman A, Witteman JC. C-reactive protein predicts progression of atherosclerosis measured at various sites in the arterial tree: the Rotterdam Study. Stroke. 2002; 33: 2750–2755.
19. Bird CE, Criqui MH, Fronek A, Denenberg JO, Klauber MR, Langer RD. Quantitative and qualitative progression of peripheral arterial disease by non-invasive testing. Vasc Med. 1999; 4: 15–21.
20. Fisher CM, Burnett A, Makeham V, Kidd J, Glasson M, Harris JP. Variation in measurement of ankle-brachial pressure index in routine clinical practice. J Vasc Surg. 1996; 24: 871–875.[CrossRef][Medline] [Order article via Infotrieve]
21. Fowkes FG, Housley E, Cawood EH, Macintyre CC, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1991; 20: 384–392.
22. Rose GA. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bull World Health Organ. 1962; 27: 645–658.[Medline] [Order article via Infotrieve]
23. Prineas RJ, Crow RS, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings: Standards and Procedures for Measurement and Classification. London, UK: John Wright; 1982.
24. Fowkes FG, Housley E, Macintyre CC, Prescott RJ, Ruckley CV. Variability of ankle and brachial systolic pressures in the measurement of atherosclerotic peripheral arterial disease. J Epidemiol Community Health. 1988; 42: 128–133.
25. Gillum RF, Fortmann SP, Prineas RJ, Kottke TE. International diagnostic criteria for acute myocardial infarction and acute stroke. Am Heart J. 1984; 108: 150–158.[CrossRef][Medline] [Order article via Infotrieve]
26. Leng GC, Lee AJ, Fowkes FG, Whiteman M, Dunbar J, Housley E, Ruckley CV. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1996; 25: 1172–1181.
27. Housley E, Leng GC, Donnan PT, Fowkes FG. Physical activity and risk of peripheral arterial disease in the general population: Edinburgh Artery Study. J Epidemiol Community Health. 1993; 47: 475–480.
28. Blann AD, McCollum CN. Circulating endothelial cell/leukocyte adhesion molecules in atherosclerosis. Thromb Haemost. 1994; 72: 151–154.[Medline] [Order article via Infotrieve]
29. De Caterina R, Basta G, Lazzerini G, Dell’Omo G, Petrucci R, Morale M, Carmassi F, Pedrinelli R. Soluble vascular cell adhesion molecule-1 as a biohumoral correlate of atherosclerosis. Arterioscler Thromb Vasc Biol. 1997; 17: 2646–2654.
30. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003; 107: 499–511.
31. Peter K, Nawroth P, Conradt C, Nordt T, Weiss T, Boehme M, Wunsch A, Allenberg J, Kubler W, Bode C. Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. Arterioscler Thromb Vasc Biol. 1997; 17: 505–512.
32. Tsakiris DA, Tschopl M, Jager K, Haefeli WE, Wolf F, Marbet GA. Circulating cell adhesion molecules and endothelial markers before and after transluminal angioplasty in peripheral arterial occlusive disease. Atherosclerosis. 1999; 142: 193–200.[CrossRef][Medline] [Order article via Infotrieve]
33. Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis. 2003; 170: 191–203.[CrossRef][Medline] [Order article via Infotrieve]
34. Hulthe J, Wikstrand J, Mattsson-Hulten L, Fagerberg B. Circulating ICAM-1 (intercellular cell-adhesion molecule 1) is associated with early stages of atherosclerosis development and with inflammatory cytokines in healthy 58-year-old men: the Atherosclerosis and Insulin Resistance (AIR) study. Clin Sci (Lond). 2002; 103: 123–129.[Medline] [Order article via Infotrieve]
35. Blann AD, Seigneur M, Steiner M, Boisseau MR, McCollum CN. Circulating endothelial cell markers in peripheral vascular disease: relationship to the location and extent of atherosclerotic disease. Eur J Clin Invest. 1997; 27: 916–921.[CrossRef][Medline] [Order article via Infotrieve]
36. Blann AD, Farrell A, Picton A, McCollum CN. Relationship between endothelial cell markers and arterial stenosis in peripheral and carotid artery disease. Thromb Res. 2000; 97: 209–216.[CrossRef][Medline] [Order article via Infotrieve]
37. Blann AD, Seigneur M, Steiner M, Miller JP, McCollum CN. Circulating ICAM-1 and VCAM-1 in peripheral artery disease and hypercholesterolaemia: relationship to the location of atherosclerotic disease, smoking, and in the prediction of adverse events. Thromb Haemost. 1998; 79: 1080–1085.[Medline] [Order article via Infotrieve]
38. Pradhan AD, Rifai N, Ridker PM. Soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and the development of symptomatic peripheral arterial disease in men. Circulation. 2002; 106: 820–825.
39. von der Thusen, Kuiper J, van Berkel TJC, Biessen EAL. Interleukins in atherosclerosis: molecular pathways and therapeutic potential. Pharmacol Rev. 2003; 55: 133–166.
40. Brevetti G, Piscione F, Silvestro A, Galasso G, Di Donato A, Oliva G, Scopacasa F, Chiariello M. Increased inflammatory status and higher prevalence of three-vessel coronary artery disease in patients with concomitant coronary and peripheral atherosclerosis. Thromb Haemost. 2003; 89: 1058–1063.[Medline] [Order article via Infotrieve]
41. DePalma RG, Hayes VW, Cafferata HT, Mohammadpour HA, Chow BK, Zacharski LR, Hall MR. Cytokine signatures in atherosclerotic claudicants. J Surg Res. 2003; 111: 215–221.[CrossRef][Medline] [Order article via Infotrieve]
42. Grau AJ, Buggle F, Becher H, Werle E, Hacke W. The association of leukocyte count, fibrinogen and C-reactive protein with vascular risk factors and ischemic vascular diseases. Thromb Res. 1996; 82: 245–255.[CrossRef][Medline] [Order article via Infotrieve]
43. Schillinger M, Exner M, Amighi J, Mlekusch W, Sabeti S, Rumpold H, Wagner O, Minar E. Joint effects of C-reactive protein and glycated hemoglobin in predicting future cardiovascular events of patients with advanced atherosclerosis. Circulation. 2003; 108: 2323–2328.
44. Signorelli SS, Mazzarino MC, Di Pino L, Malaponte G, Porto C, Pennisi G, Marchese G, Costa MP, Digrandi D, Celotta G, Virgilio V. High circulating levels of cytokines (IL-6 and TNFalpha), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test. Vasc Med. 2003; 8: 15–19.
45. Yu HI, Sheu WHH, Song YM, Liu HC, Lee WJ, Chen YT. C-reactive protein and risk factors for peripheral vascular disease in subjects with type 2 diabetes mellitus. Diabet Med. 2004; 21: 336–341.[CrossRef][Medline] [Order article via Infotrieve]
46. Aso Y, Okumura K, Inoue T, Matsutomo R, Yoshida N, Wakabayashi S, Takebayashi K, Inukai T. Results of blood inflammatory markers are associated more strongly with toe-brachial index than with ankle-brachial index in patients with type 2 diabetes. Diabetes Care. 2004; 27: 1381–1386.
47. Fiotti N, Giansante C, Ponte E, Delbello C, Calabrese S, Zacchi T, Dobrina A, Guarnieri G. Atherosclerosis and inflammation: patterns of cytokine regulation in patients with peripheral arterial disease. Atherosclerosis. 1999; 145: 51–60.[CrossRef][Medline] [Order article via Infotrieve]
48. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001; 285: 2481–2485.
49. Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Tracy RP, Rubin SM, Harris TB, Pahor M. Inflammatory markers and cardiovascular disease (the Health, Aging and Body Composition [Health ABC] Study). Am J Cardiol. 2003; 92: 522–528.[CrossRef][Medline] [Order article via Infotrieve]
50. Kerr R, Stirling D, Ludlam CA. Interleukin 6 and haemostasis. Br J Haematol. 2001; 115: 3–12.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  F. J Khawaja and I. J Kullo Novel markers of peripheral arterial disease Vascular Medicine, November 1, 2009; 14(4): 381 - 392. [Abstract] [PDF]
|
|
|
|
 |
|
 M. M. McDermott and D. M. Lloyd-Jones The role of biomarkers and genetics in peripheral arterial disease. J. Am. Coll. Cardiol., September 29, 2009; 54(14): 1228 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Ali, P. Sarcia, T. H Mosley, V. Kondragunta, and I. J Kullo Association of serum myeloperoxidase with the ankle-brachial index and peripheral arterial disease Vascular Medicine, August 1, 2009; 14(3): 215 - 220. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Barbui, A. Carobbio, A. Rambaldi, and G. Finazzi Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood, July 23, 2009; 114(4): 759 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. I. Paraskevas, N. Bessias, T. T. Papas, V. Andrikopoulos, and D. P. Mikhailidis Is High-sensitivity C-reactive Protein Associated With Subclinical Peripheral Atherosclerosis? Angiology, February 1, 2009; 60(1): 8 - 11. [PDF]
|
|
|
|
 |
|
 Y. Wang, X. Zhao, H. Jin, H. Wei, W. Li, D. Bu, X. Tang, Y. Ren, C. Tang, and J. Du Role of Hydrogen Sulfide in the Development of Atherosclerotic Lesions in Apolipoprotein E Knockout Mice Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 173 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Forman, H. Choi, and G. C. Curhan Uric Acid and Insulin Sensitivity and Risk of Incident Hypertension Arch Intern Med, January 26, 2009; 169(2): 155 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.C. Bennett, S. Silverman, P.S. Gill, and G.Y.H. Lip Ethnicity and peripheral artery disease QJM, January 1, 2009; 102(1): 3 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Addabbo, B. Ratliff, H.-C. Park, M.-C. Kuo, Z. Ungvari, A. Ciszar, B. Krasnikof, K. Sodhi, F. Zhang, A. Nasjletti, et al. The Krebs Cycle and Mitochondrial Mass Are Early Victims of Endothelial Dysfunction: Proteomic Approach Am. J. Pathol., January 1, 2009; 174(1): 34 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Khaleghi, Z. Ali, T. H. Mosley Jr., S. T. Turner, and I. J. Kullo Association of Soluble Cell Adhesion Molecules with Ankle-Brachial Index in a Biethnic Cohort of Predominantly Hypertensive Individuals Clin. Chem., November 1, 2008; 54(11): 1788 - 1795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T Fung, A. M Wilson, F. Zhang, N. Harris, K. A Edwards, J. W Olin, and J. P Cooke A biomarker panel for peripheral arterial disease Vascular Medicine, August 1, 2008; 13(3): 217 - 224. [Abstract] [PDF]
|
|
|
|
 |
|
 A. L. Hogh, J. Joensen, J. S. Lindholt, M. R. Jacobsen, and L. Ostergaard C-Reactive Protein Predicts Future Arterial and Cardiovascular Events in Patients With Symptomatic Peripheral Arterial Disease Vascular and Endovascular Surgery, August 1, 2008; 42(4): 341 - 347. [Abstract] [PDF]
|
|
|
|
 |
|
 E. I. Boesen, J. M. Sasser, M. A. Saleh, W. A. Potter, M. Woods, T. D. Warner, J. S. Pollock, and D. M. Pollock Interleukin-1{beta}, but not interleukin-6, enhances renal and systemic endothelin production in vivo Am J Physiol Renal Physiol, August 1, 2008; 295(2): F446 - F453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Arenillas, J. Alvarez-Sabin, C. A. Molina, P. Chacon, I. Fernandez-Cadenas, M. Ribo, P. Delgado, M. Rubiera, A. Penalba, A. Rovira, et al. Progression of Symptomatic Intracranial Large Artery Atherosclerosis Is Associated With a Proinflammatory State and Impaired Fibrinolysis Stroke, May 1, 2008; 39(5): 1456 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Schmeck, W. Beermann, P. D. N'Guessan, A. C. Hocke, B. Opitz, J. Eitel, Q. T. Dinh, M. Witzenrath, M. Krull, N. Suttorp, et al. Simvastatin Reduces Chlamydophila pneumoniae-Mediated Histone Modifications and Gene Expression in Cultured Human Endothelial Cells Circ. Res., April 25, 2008; 102(8): 888 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Tzoulaki, M.-R. Jarvelin, A.-L. Hartikainen, M. Leinonen, A. Pouta, M. Paldanius, A. Ruokonen, D. Canoy, U. Sovio, P. Saikku, et al. Size at birth, weight gain over the life course, and low-grade inflammation in young adulthood: northern Finland 1966 birth cohort study Eur. Heart J., April 9, 2008; (2008) ehn105v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. West, P. J. Nestel, A. C. Kirby, R. Schnabel, D. Sullivan, R. J. Simes, C. Pollicino, E. Lubos, T. F. Munzel, H. D. White, et al. The value of N-terminal fragment of brain natriuretic peptide and tissue inhibitor of metalloproteinase-1 levels as predictors of cardiovascular outcome in the LIPID study Eur. Heart J., April 1, 2008; 29(7): 923 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ramaraj Gender Differences Between High-Sensitivity C-Reactive Protein and Intima Media Thickness Progression Stroke, April 1, 2008; 39(4): e73 - e73. [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Pradhan, S. Shrivastava, N. R. Cook, N. Rifai, M. A. Creager, and P. M Ridker Symptomatic Peripheral Arterial Disease in Women: Nontraditional Biomarkers of Elevated Risk Circulation, February 12, 2008; 117(6): 823 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dayhoff-Brannigan, L. Ferrucci, K. Sun, L. P. Fried, J. Walston, R. Varadhan, J. M. Guralnik, and R. D. Semba Oxidative Protein Damage Is Associated With Elevated Serum Interleukin-6 Levels Among Older Moderately to Severely Disabled Women Living in the Community J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2008; 63(2): 179 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ichiki, M. Jougasaki, M. Setoguchi, J. Imamura, H. Nakashima, T. Matsuoka, M. Sonoda, K. Nakamura, S. Minagoe, and C. Tei Cardiotrophin-1 stimulates intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in human aortic endothelial cells Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H750 - H763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Brevetti, V. Schiano, E. Laurenzano, G. Giugliano, M. Petretta, F. Scopacasa, and M. Chiariello Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease Eur. Heart J., January 2, 2008; 29(2): 224 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Addabbo, F. Mallamaci, D. Leonardis, R. Tripepi, G. Tripepi, M. S. Goligorsky, and C. Zoccali Searching for biomarker patterns characterizing carotid atherosclerotic burden in patients with reduced renal function Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3521 - 3526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.R.S. Girn, N.M. Orsi, and S. Homer-Vanniasinkam An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease Vascular Medicine, November 1, 2007; 12(4): 299 - 309. [Abstract] [PDF]
|
|
|
|
 |
|
 S. M. Nelson, N. Sattar, D. J. Freeman, J. D. Walker, and R. S. Lindsay Inflammation and Endothelial Activation Is Evident at Birth in Offspring of Mothers With Type 1 Diabetes Diabetes, November 1, 2007; 56(11): 2697 - 2704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, J. W. Huffman, A. Csiszar, Z. Ungvari, K. Mackie, S. Chatterjee, et al. CB2-receptor stimulation attenuates TNF-{alpha}-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2210 - H2218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Wilson, E. Kimura, R. K. Harada, N. Nair, B. Narasimhan, X.-Y. Meng, F. Zhang, K. R. Beck, J. W. Olin, E. T. Fung, et al. {beta}2-Microglobulin as a Biomarker in Peripheral Arterial Disease: Proteomic Profiling and Clinical Studies Circulation, September 18, 2007; 116(12): 1396 - 1403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Hardev Ramandeep Singh Girn, S. Ahilathirunayagam, A. I. D. Mavor, and S. Homer-Vanniasinkam Reperfusion Syndrome: Cellular Mechanisms of Microvascular Dysfunction and Potential Therapeutic Strategies Vascular and Endovascular Surgery, September 1, 2007; 41(4): 277 - 293. [Abstract] [PDF]
|
|
|
|
|
|
Q. Li, Y. Laumonnier, T. Syrovets, and T. Simmet Plasmin Triggers Cytokine Induction in Human Monocyte-Derived Macrophages Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1383 - 1389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J. Khawaja, K. R. Bailey, S. T. Turner, S. L. Kardia, T. H. Mosley Jr, and I. J. Kullo Association of Novel Risk Factors With the Ankle Brachial Index in African American and Non-Hispanic White Populations Mayo Clin. Proc., June 1, 2007; 82(6): 709 - 716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Tzoulaki, G. D. Murray, A. J. Lee, A. Rumley, G. D.O. Lowe, and F. G. R. Fowkes Relative Value of Inflammatory, Hemostatic, and Rheological Factors for Incident Myocardial Infarction and Stroke: The Edinburgh Artery Study Circulation, April 24, 2007; 115(16): 2119 - 2127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Jimenez, R. M. Estepa, R. M. Camacho, R. C. Estrada, F. G. Luna, and F. B. Guitarte Endothelial dysfunction is related to insulin resistance and inflammatory biomarker levels in obese prepubertal children Eur. J. Endocrinol., April 1, 2007; 156(4): 497 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Wannamethee, A. G. Shaper, G. D.O. Lowe, L. Lennon, A. Rumley, and P. H. Whincup Renal function and cardiovascular mortality in elderly men: the role of inflammatory, procoagulant, and endothelial biomarkers Eur. Heart J., December 2, 2006; 27(24): 2975 - 2981. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Howard-Alpe, J. W. Sear, and P. Foex Methods of detecting atherosclerosis in non-cardiac surgical patients; the role of biochemical markers Br. J. Anaesth., December 1, 2006; 97(6): 758 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zoccali, G. Tripepi, and F. Mallamaci Dissecting Inflammation in ESRD: Do Cytokines and C-Reactive Protein Have a Complementary Prognostic Value for Mortality in Dialysis Patients? J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S169 - S173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Vlachopoulos, K. Aznaouridis, N. Ioakeimidis, K. Rokkas, C. Vasiliadou, N. Alexopoulos, E. Stefanadi, A. Askitis, and C. Stefanadis Unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease Eur. Heart J., November 2, 2006; 27(22): 2640 - 2648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Csiszar, K. Smith, N. Labinskyy, Z. Orosz, A. Rivera, and Z. Ungvari Resveratrol attenuates TNF-{alpha}-induced activation of coronary arterial endothelial cells: role of NF-{kappa}B inhibition. Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1694 - H1699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Aboyans, M. H. Criqui, J. O. Denenberg, J. D. Knoke, P. M Ridker, and A. Fronek Risk Factors for Progression of Peripheral Arterial Disease in Large and Small Vessels Circulation, June 6, 2006; 113(22): 2623 - 2629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Mazziotti, G. Amato, F. Sorvillo, M. Piscopo, M. R. Rizzo, E. Lalli, L. Iride, M. Cioffi, A. M. Molinari, G. Paolisso, et al. Increased serum osteoprotegerin values in long-lived subjects: different effects of inflammation and bone metabolism. Eur. J. Endocrinol., March 1, 2006; 154(3): 373 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Tzoulaki, G. D. Murray, J. F. Price, F. B. Smith, A. J. Lee, A. Rumley, G. D. O. Lowe, and F. G. R. Fowkes Hemostatic Factors, Inflammatory Markers, and Progressive Peripheral Atherosclerosis: The Edinburgh Artery Study Am. J. Epidemiol., February 15, 2006; 163(4): 334 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D.O. Lowe The association between elevated levels of inflammation biomarkers and coronary artery disease and death. Can. Med. Assoc. J., February 14, 2006; 174(4): 479 - 480. [Full Text] [PDF]
|
|
|
|
|
|
G. Brevetti, V. Schiano, and M. Chiariello Cellular adhesion molecules and peripheral arterial disease Vascular Medicine, February 1, 2006; 11(1): 39 - 47. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||