Published online before print January 28, 2008, doi: 10.1161/CIRCULATIONAHA.107.719369
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(Circulation. 2008;117:823-831.)
© 2008 American Heart Association, Inc.
Vascular Medicine |
Symptomatic Peripheral Arterial Disease in Women
Nontraditional Biomarkers of Elevated Risk
From the Center for Cardiovascular Disease Prevention (A.D.P., S.S., N.R.C., P.M.R.), Donald W. Reynolds Center for Cardiovascular Research (A.D.P., N.C., P.M.R.), Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (P.M.R.), and Division of Cardiovascular Medicine (M.A.C., P.M.R.), Brigham and Women’s Hospital and Harvard Medical School; Division of Cardiology, VA Boston Medical Center (A.D.P.); Department of Cardiology, Harvard Vanguard Medical Associates (S.S.); and Department of Pathology, Children’s Hospital Medical Center and Harvard Medical School (N.R.), Boston, Mass.
Correspondence to Aruna D. Pradhan, MD, MPH, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215–1204. E-mail apradhan{at}partners.org
Received June 13, 2007; accepted November 27, 2007.
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Abstract |
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Background— Most investigations of novel biomarkers for prediction of cardiovascular disease pertain to coronary artery disease. Few large-scale prospective studies have critically assessed plasma-based factors as predictors of peripheral arterial disease (PAD), and comparative data between individual biomarkers and lipid levels are sparse, especially among women.
Methods and Results— We evaluated the relationship between baseline levels of several novel biomarkers and confirmed incident symptomatic PAD (n=100) in a prospective cohort study (median follow-up, 12.3 years) involving 27 935 US female health professionals 
45 years of age without diagnosed vascular disease at baseline. Biomarkers assessed were high-sensitivity C-reactive protein, fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), homocysteine, lipoprotein(a), hemoglobin A1c, creatinine, and conventional lipid levels. In univariate analyses, levels of high-sensitivity C-reactive protein, fibrinogen, sICAM-1, homocysteine, lipoprotein(a), creatinine clearance, high-density lipoprotein cholesterol (HDL-C), non–HDL-C, and the ratio of total cholesterol to HDL-C (TC:HDL-C) were significantly related to PAD (all P<0.05). However, after multivariable adjustment, risk associations were significant only for high-sensitivity C-reactive protein (adjusted hazard ratio [HR] extreme tertiles, 2.1; 95% confidence interval, 1.2 to 3.7), sICAM-1 (adjusted HR, 4.0; 95% confidence interval, 1.9 to 8.6), HDL-C (adjusted HR, 0.4; 95% confidence interval, 0.3 to 0.8), and TC:HDL-C (adjusted HR, 2.2; 95% confidence interval, 1.2 to 3.9). In a model simultaneously controlling for traditional risk factors plus these significant biomarkers, sICAM-1 remained independently predictive of PAD (adjusted HR in each tertile, 1.0 [reference], 2.3, and 3.5).
Conclusions— Among a broad range of biomarkers of cardiovascular risk, only 4 factors, sICAM-1, high-sensitivity C-reactive protein, HDL-C, and TC:HDL-C, were significantly associated with incident symptomatic PAD in women. Findings pertaining to novel biomarkers provide clinical confirmation of a prominent role of endothelial activation and leukocyte recruitment in lower-extremity arterial disease.
Key Words: biomarkers • endothelium-derived factors • epidemiology • peripheral arterial disease • women • inflammation
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Introduction |
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Prospective data pertaining to both traditional and novel risk factors for lower-extremity peripheral arterial disease (PAD) have been less available than for coronary or cerebrovascular disease, particularly in women. Nonetheless, most traditional cardiovascular risk factors, including smoking, diabetes, dyslipidemia, and hypertension, are generally accepted clinical predictors of PAD. Existing data suggest that the relative impact of these exposures in the peripheral vasculature differs from the coronary circulation,1 thereby invoking potential site-specific atherogenic mechanisms. Furthermore, although biological processes such as subclinical inflammation, thrombosis, and endothelial dysfunction are linked to the incidence of myocardial infarction and stroke, relatively few prospective studies have evaluated the role of these emerging risk factors in the pathogenesis of PAD. We previously reported comparative data for a broad range of atherothrombotic biomarkers for clinical PAD in a large population of healthy men followed in the Physicians’ Health Study (PHS).2,3 However, similar prospective data pertaining to unique risk factor associations in women are sparse.
Clinical Perspective p 831
To address these issues, we evaluated several novel biomarkers and conventional lipids as predictors of symptomatic PAD in a large-scale study of initially healthy middle-aged and older American women. Biomarkers were chosen on the basis of prior reports of risk assessment for coronary and cerebrovascular disease and available data for PAD and included high-sensitivity C-reactive protein (hsCRP), fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), homocysteine, lipoprotein(a) [Lp(a)], hemoglobin A1c (HbA1c), creatinine, and standard lipid parameters.
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Methods |
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Study Population
The Women’s Health Study (WHS)4 is a recently completed randomized trial of low-dose aspirin and vitamin E in primary prevention of cardiovascular disease and cancer. Between November 1992 and July 1995, a total of 39 876 US female health professionals
45 years of age without prior cancer or cardiovascular disease (including myocardial infarction, stroke, coronary, and peripheral arterial revascularization) were enrolled and randomized into the study. Subjects alive and willing to be contacted were invited to participate in the ongoing observational component of the WHS. Participants provided baseline information on behavioral, lifestyle, and demographic factors and are followed prospectively by annual questionnaire. Morbidity and mortality data are available on 99% and 100% of participants, respectively. Before randomization, 28 345 participants provided blood specimens, which were stored in liquid nitrogen (–150°C to –180°C) until analysis. Of the samples received, 27 939 were usable for determination of the analytes of interest. Subjects with confirmed prerandomization PAD (n=4) were excluded from analysis. The final study population (n=27 935) was followed up for a median of 12.3 years. Fewer than 3% of data were missing for major vascular risk factors, including age, hypertension, diabetes, smoking, body mass index (BMI), and menopausal hormone therapy (HT).
Outcome Ascertainment
WHS participants are surveyed annually for several health outcomes, including PAD events, defined as intermittent claudication and/or peripheral arterial surgery. As of January 5, 2007, 407 such events were reported. Case confirmation occurred by telephone interview during which the presence of vascular claudication was established with the Edinburgh Claudication Questionnaire. This instrument is a modified version of the World Health Organization/Rose Claudication Questionnaire, which has previously been validated in a community outpatient setting with 92% sensitivity and 99% specificity for physician-diagnosed intermittent claudication.5 In addition, medical records were obtained to assess the concordance of reported symptoms with diagnostic testing when available. Reports of peripheral arterial surgery were confirmed after review of operative notes or procedural reports in the case of peripheral angioplasty or stenting. Of 407 self-reported PAD events, 100 were confirmed with these methods. Among disconfirmed events, venous disease, lower-extremity arthritis, lumbar disk disease, and peripheral neuropathy were the main causes of nonischemic leg pain. There were 73 unrefuted events in women who were unreachable for telephone interview, deceased, or unwilling to participate. These were included in sensitivity analyses only.
Laboratory Analysis
Analytes were measured in a core laboratory certified by the National Heart, Lung, and Blood Institute/Centers for Disease Control and Prevention Lipid Standardization Program. Plasma hsCRP was measured with a validated high-sensitivity immunoturbidimetric method (Denka Seiken, Niigata, Japan). Fibrinogen was determined with an immunoturbidimetric assay (Kamiya Biomedical Co, Seattle, Wash). Homocysteine was measured with an enzymatic assay (Catch Inc, Seattle, Wash). Lp(a) was determined by a latex-enhanced turbidimetric method independently of apolipoprotein(a) isoform size and kringle IV type 2 repeats with reagents and calibrators from Denka Seiken. HbA1c was estimated with the Tina-Quant turbidimetric inhibition immunoassay (Roche Diagnostics, Indianapolis, Ind) on packed red blood cells. Plasma creatinine was quantified by a rate-blanked method that is based on the Jaffé reaction (Roche Diagnostics). Creatinine clearance was estimated by use of the Cockcroft-Gault formula for women6 and standardized to body surface area. Total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) were measured enzymatically, and low-density lipoprotein cholesterol (LDL-C) was determined by a homogenous direct method (Genzyme, Cambridge, Mass). Non–HDL-C was calculated by subtracting HDL-C from TC. The above-mentioned analytes were measured on the Hitachi 917 analyzer from Roche Diagnostics. The interassay coefficients of variation using 2 levels of control materials ranged from 1.07% to 5.20%. sICAM-1 was measured by quantitative sandwich ELISA (R&D Systems, Minneapolis, Minn) with a reproducibility of 8.89% and 6.39% at concentrations of 171.8 and 289.1 ng/mL, respectively.
Statistical Analysis
Continuous data are summarized as either mean±SD or median and interquartile range based on normality of distributions. Categorical data are expressed as percentages. Between-group differences were assessed by the unpaired 2-tailed Student t test and the Wilcoxon rank-sum test as appropriate. Categorical data were analyzed with the 
2 test. Women were classified on the basis of thirds (tertiles) of baseline biomarker values. Cox proportional-hazards models were then constructed, estimating the hazard ratio (HR) and 95% confidence interval (CI) according to biomarker tertiles with the lowest tertile as referent. Tests of linear trend across tertiles were computed using median values within each tertile. With a linear effect over tertiles assumed, these analyses are estimated to have 
83% power to detect a linear trend and an HR of 2.1 in the highest versus lowest tertile.
Multivariable estimates were derived from models adjusting for age, smoking (never, past, current), baseline history of diabetes (no/yes), baseline history of hypertension (no/yes self-report 140/90 mm Hg), BMI (linear continuous), and menopausal HT. Linearity assumptions for continuous variables were assessed by quadratic and natural log transformations and through the use of regression splines. Age was modeled using a natural log transformation, and BMI was entered as a linear term. Model fit was compared by the likelihood ratio 2 statistic, with a higher value indicating superior fit. To assess for effects independent of other biomarkers, significant markers identified during the initial analysis were entered together in a single model.
Secondary analyses adjusted for race/ethnicity, parental history of myocardial infarction, exercise frequency, and randomized treatment assignment. Sensitivity analyses included cases of unrefuted PAD events. Kaplan-Meier survival curves were plotted, and differences in event-free survival according to biomarker tertile were assessed with the log-rank test for multiple-group comparison. To evaluate joint effects of biomarker combinations, women were divided into 4 groups based on median cut points of each predictive biomarker and multivariable HRs computed from Cox regression models. All 95% CIs are 2-tailed and calculated at the 0.05 level. Analyses in data tables and figures were conducted with SAS statistical software version 9.1 (SAS Institute, Cary, NC).
The institutional review board approved the study, and all subjects provided informed consent. The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Overall, the incidence of symptomatic PAD was low (0.03 annualized percentage). As expected, women developing peripheral arterial events were older and were more likely to smoke and have baseline diagnosed diabetes, hypertension, and dyslipidemia (Table 1). As shown in Table 2, plasma levels of hsCRP, fibrinogen, sICAM-1, homocysteine, Lp(a), non–HDL-C, and ratio of TC to HDL-C (TC:HDL-C) were all higher in subjects with incident PAD. Levels of HDL-C and estimated creatinine clearance were lower, and no statistically significant difference was noted in HbA1c, creatinine, TC, or LDL-C.
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Table 3 shows results of age-adjusted and multivariable-adjusted analyses after women were classified according to baseline biomarker tertiles. In both age-adjusted and multivariable-adjusted models, sICAM-1 was the strongest predictor, with a 4-fold increase in risk in the highest versus lowest tertile (adjusted HR, 4.0; 95% CI, 1.9 to 8.6; P for trend <0.001). There was a 2-fold increase in risk associated with elevated hsCRP (adjusted HR, 2.1; 95% CI, 1.2 to 3.7; P for trend=0.03) and TC:HDL-C (adjusted HR, 2.2; 95% CI, 1.2 to 3.9; P for trend=0.02]. The latter finding appeared to be driven largely by elevated HDL-C levels because this factor but not TC was significantly associated with risk; women in the highest tertile of HDL-C had a 60% lower risk (adjusted HR extreme tertiles, 0.4; 95% CI, 0.3 to 0.8; P for trend=0.004). A modest and borderline nonsignificant result was noted for Lp(a) (adjusted HR extreme tertiles, 1.6; 95% CI, 1.0 to 2.6; P=0.07; P for trend=0.050). In contrast, in multivariable analyses, no significant effects were observed for homocysteine, HbA1c, creatinine, creatinine clearance, TC, LDL-C, and non–HDL-C. Comparison of the model likelihood ratio 2 statistic, a global measure of model fit with larger values indicating superior fit, showed that the model with sICAM-1 had the highest value (147.5; df=9), followed by HDL-C (137.9; df=9), TC:HDL-C (136.8; df=9), hsCRP (135.1; df=9), and Lp(a) (134.1; df=9).
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In a model that included hsCRP, sICAM-1, and HDL-C, as well as traditional risk factors, sICAM-1 remained significantly associated with incident PAD with a slightly attenuated effect (adjusted HR for increasing tertiles, 1.0 [reference], 2.3, and 3.5; P for trend <0.001). However, hsCRP was no longer significant (P for trend=0.3). HDL-C also remained predictive (adjusted HR for increasing tertiles, 1.0, 0.7, and 0.5; P for trend=0.03). Additional adjustment for race/ethnicity, physical activity, parental history of premature coronary disease, and randomized treatment assignment did not alter these risk associations; in this expanded model, the HR for highest versus lowest tertile of sICAM-1 was 4.0 (95% CI, 1.9 to 8.7; P for trend <0.001). Our main findings persisted in analyses that also included unrefuted PAD events (data not shown). PAD cumulative incidence curves are shown in Figure 1. Although modest overlap is evident when women are classified by either hsCRP or HDL-C (log-rank P=0.007 and <0.001, respectively), there is better separation of curves according to TC:HDL-C (P<0.001) and sICAM-1 (P<0.001), with clear delineation of risk in the highest sICAM-1 tertile.
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To evaluate the potential joint role of lipid and inflammation parameters in PAD risk, HRs were estimated after classification based on median values of HDL-C, TC:HDL-C, and each inflammatory marker (Figure 2). As shown, at lipid levels either below or above the population median, the presence of elevated inflammatory markers was associated with a higher risk for PAD. Overall, risk estimates were consistently higher for women with high levels of sICAM-1.
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Discussion |
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In this prospective evaluation of biomarkers for PAD development in women, we found the proinflammatory cellular adhesion molecule sICAM-1 to be the strongest predictor of confirmed clinical events. hsCRP, HDL-C, and TC:HDL-C also were significant, although of lower magnitude, with borderline nonsignificant results for Lp(a). In this otherwise healthy population, after adjustment for concomitant cardiovascular risk factors and HT use, we did not find significant associations for fibrinogen, homocysteine, HbA1c, creatinine, estimated creatinine clearance, TC, LDL-C, or non–HDL-C. To the best of our knowledge, this study is the first prospective analysis of PAD in women to provide comparative data for the most commonly evaluated novel biomarkers, including indicators of dysglycemia and renal dysfunction, against each other and conventional lipid levels.
Findings from most7–12 but not all13,14 previously published prospective reports suggest that the impact of traditional risk factors on PAD development may differ from that for incident coronary and cerebrovascular disease. This observation may relate to the acuity of events under consideration, thereby implicating factors differentiating plaque rupture from systemic atherosclerosis progression. In most large-scale epidemiological studies, PAD is determined as the first occurrence of intermittent claudication, revascularization, or decline in ankle-brachial index, which in most instances is subacute in nature. In contrast, studies of incident coronary and cerebrovascular disease commonly evaluate "hard" end points such as myocardial infarction, stroke, or cardiovascular death that are generally characterized by sudden, obliterative vascular occlusion. Although atheromatous disease is a common underlying feature, factors predisposing to abrupt plaque rupture differ from those causing more gradual luminal obstruction. In this regard, we believe our findings of a prominent effect of sICAM-1 may offer additional mechanistic insight.
Cellular adhesion molecules are principal mediators of leukocyte–endothelial cell interactions. Leukocyte recruitment is an initial event during atherogenesis during which ICAM-1 facilitates high-affinity adhesion and transmigration of inflammatory cells into the subendothelial space. This process, when unabated, is implicated in endothelial dysfunction, tissue injury, and ensuing atherosclerosis. Although ICAM-1 is constitutively expressed on many cell types, de novo synthesis undergoes dynamic transcription-dependent regulation in endothelial cells with marked heterogeneity between different vascular beds. Importantly, ICAM-1 is preferentially expressed in endothelium overlying human atheroma,15 and the circulating level of sICAM-1 shed from the endothelial surface is a proposed index of endothelial activation.16
Although CRP elevation before the onset of vascular disease may be expected on the basis of known inflammatory triggers, biomechanical activation may be a unique proinflammatory stimulus for ICAM-1 because transcriptional upregulation by both laminar17 and oscillatory18 shear stress has been previously described. Moreover, biomechanical forces are particularly relevant at arterial bifurcations where local geometry is a major determinant of wall stress. Interestingly, these branch points in the peripheral vasculature are also atheroma prone. Furthermore, during progressive luminal stenosis, monocyte adhesion to shear stress–activated endothelium via ICAM-1–dependent interactions precedes neovascularization and collateral vessel formation.19
The present results and our previous analysis in healthy men3 concur with these experimental observations. Our findings provide confirmation that sICAM-1 is a potent predictor of clinical PAD and suggest that this effect appears stronger than for coronary or cerebrovascular events. Indeed, a meta-analysis of 5 prospective studies of sICAM-1 and incident coronary heart disease (myocardial infarction or death) suggested a modest effect, if any, after multivariable adjustment.20 In the WHS, sICAM-1 was not predictive of the combined end point of incident myocardial infarction, coronary revascularization, or stroke.21 However, when events were analyzed separately, levels were predictive of coronary atherosclerosis progression (HR extreme quintiles, 1.6; P for trend=0.008) but not myocardial infarction or stroke.22
In contrast to our findings for sICAM-1, hsCRP, HDL-C, TC:HDL-C, and to a lesser degree Lp(a), we found no evidence of association for other commonly assessed novel biomarkers. Prior data in this regard have been limited and heavily reliant on cross-sectional or retrospective reports of individuals with prevalent disease. However, a recent prospective analysis of symptomatic PAD (intermittent claudication, critical limb ischemia, or surgical intervention) in the Edinburgh Artery Study23 found significant associations for CRP, Lp(a), and fibrinogen but not sICAM-1 among a broad range of inflammatory, hemostatic, and rheological factors assessed. Importantly, subjects with baseline coronary disease (14%) were included in the analysis, and because this characteristic alone was the strongest predictor of subsequent PAD, this inclusion may have influenced the observed relationships. A related analysis of PAD progression in the Edinburgh population demonstrated that sICAM-1 levels were strongly associated with declining ankle-brachial index.24 Data for fibrinogen are conflicting, with no significant association in a French population-based study of men and women.25 However, in our prior report from the PHS,2 we found a 2-fold increase in risk among men in the highest versus lowest fibrinogen quartile (adjusted relative risk [RR] for extreme quartiles, 2.2; P for trend=0.02). No association was found for homocysteine. To the best of our knowledge, prospective data are otherwise unavailable.
Our findings pertaining to Lp(a) require further discussion. Prior reports have been mixed, with most studies demonstrating a modest effect of a magnitude similar to that in the present analysis. In the Framingham Heart Study, the presence of sinking pre-beta lipoprotein, a putative surrogate marker for Lp(a), was an independent predictor (adjusted RR, 1.94; 95% CI, 1.1 to 3.5) of intermittent claudication in women.26 Similarly, in the Edinburgh Artery Study,27 after exclusion of subjects with baseline cardiovascular disease, the adjusted RR for intermittent claudication was 1.20 (95% CI, 0.99 to 1.45) overall with a slightly higher RR for women (adjusted RR, 1.40; 95% CI, 1.03 to 1.92). We found no significant association among men in the PHS.2 Although the lack of statistical significance in the present analysis may relate to the low event rate, the magnitude of effect is consistent with prior findings in women and modest compared with our results for sICAM-1 and hsCRP. Additionally, a strength of our Lp(a) analysis is the use of an assay unaffected by apolipoprotein(a) isoform size and kringle type 2 repeats.
Although diabetes is a major risk factor for PAD and among diabetic patients both glycemic control28 and diabetes duration29 are strongly associated with PAD risk, prospective data with regard to HbA1c as a marker of dysglycemia in the general population are sparse. In this cohort of initially healthy women with a low baseline prevalence of diabetes, we found no association between HbA1c and future PAD. We also found no association with markers of renal dysfunction as has been previously documented.30,31 It is important to note, however, that few women met clinical criteria for renal insufficiency at baseline (creatinine 1.4 mg/dL, n=91 [0.3%]; creatinine clearance <60 mL · min–1 · 1.73 m–2, n=936 [3.5%]). In addition, we did not use other potentially more sensitive measures of incipient diabetes or kidney disease such as fasting or postload glucose and cystatin C, which have previously been shown to discriminate PAD risk.32,33
Of conventional lipids, HDL-C and TC:HDL-C were the only significant predictors, suggesting that the lipid profile encountered in women at risk for PAD more typically resembles the dyslipidemia of insulin resistance. In contrast to prior data in men2,9,10 and older individuals,14 we did not discern an independent effect of TC or LDL-C. In the Framingham11 and Edinburgh23 studies, TC (20% increased odds per 40 mg/dL) and the TC:HDL-C ratio (41% increase per 1.9 U) were independent predictors in populations of middle-aged and older men and women. Estimates were not provided separately for women. Prospective data in women otherwise derive from the Heart and Estrogen/Progestin Replacement Study,34 in which HDL-C but not LDL-C was predictive among women allocated to placebo. In sum, our results allude to gender-related differences in disease susceptibility and suggest that, as for cardiovascular disease,35 the atheroprotective effect of HDL-C or insulin sensitivity in women may be more important than other lipid abnormalities.
Potential limitations of our study merit consideration. First, WHS participants do not undergo a health examination. Therefore, the use of symptomatic PAD as our primary a priori end point by definition excludes subclinical disease, which may have otherwise been detected by physical examination through abnormal pulse examination or ankle-brachial index. However, we believe our data to be not only relevant from a mechanistic perspective as discussed above but also of clinical importance for the following reasons. First, claudication and limb ischemia requiring revascularization are the principal clinical manifestations of PAD. Second, self-reported events were confirmed by a validated claudication questionnaire and medical record review. In addition, women enrolled in the WHS are female health professionals and are therefore less likely to encounter barriers to medical care, which may otherwise have led to underdiagnosis. Furthermore, although potential misclassification resulting from atypical or occult disease may have occurred, this, if anything, would have biased our results toward the null by inclusion of potentially misclassified cases in the event-free group. Thus, we believe our use of self-reported symptomatic PAD confirmed by the Edinburgh Claudication Questionnaire and medical record review not only is valid but also represents an important clinical end point.
Another potential limitation is the low event rate in this cohort of healthy women. However, we did achieve 80% power for detecting a linear trend across biomarker tertiles, and although low, our event rate is similar to the Women’s Health Initiative36,37 in which the annualized percentage ranged from 0.03 to 0.08. Furthermore, our rigorous approach to case validation allowed elimination of spurious reports of nonischemic leg pain, which would likely have altered the observable risk associations. It also should be noted that treatment allocation to low-dose aspirin and/or vitamin E is unlikely to have altered our findings because the cardiovascular risk reduction with either agent in the WHS is small.4,22,38 Furthermore, baseline blood specimens were obtained during the run-in phase before randomization; thus, baseline biomarker levels are unaffected by treatment assignment. Lastly, gender-specific associations are possible and furthermore are supported by our data; thus, caution must be used when our findings are applied to men.
Although there is now clear appreciation of factors such as subclinical inflammation in the development of myocardial infarction and stroke,39 relatively few prospective data have been presented to evaluate novel risk factors for PAD, especially in women. Although we found that hsCRP and HDL-C are predictive, these data suggest an even greater role for sICAM-1, thus providing human extension of basic work implicating the early process of leukocyte adherence and transmigration as a critical initiating event in atherogenesis. However, the clinical utility of this marker for both risk assessment and potentially therapeutic applications requires corroboration of these results in other large cohorts of healthy individuals and the development of inexpensive, standardized commercial assays. Given the strength of these data and related prior reports on atherosclerosis progression, we believe that assessment of endothelial activation as measured by sICAM-1 levels warrants further investigations in these areas.
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Acknowledgments |
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Sources of Funding
This work was supported by grants from the National Heart, Lung, and Blood Institute (HL-58755, HL-43851, and HL-082740), the National Cancer Institute (CA47988), and the Donald W. Reynolds Foundation.
Disclosures
Dr Pradhan currently receives investigator-initiated research support from Sanofi-Aventis. Dr Rifai has received research support from Merck and has been a consultant for Sanofi-Aventis. Dr Creager receives research support from Sanofi-Aventis and is a consultant for ActivBiotics, Biomarin, Genzyme, KOS, Sanofi-Aventis, and Sigma Tau. Dr Ridker has received research funding support from multiple not-for-profit entities and investigator-initiated research support from multiple for-profit entities, including AstraZeneca, Bayer, Bristol-Myers Squibb, Dade-Behring, Novartis, Pharmacia, Roche, Sanofi-Aventis, and Variagenics. Dr Ridker is listed as a coinventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and has served as a consultant to Schering-Plough, Sanofi-Aventis, AstraZeneca, Isis Pharmaceutical, and Dade-Behring. The other authors report no conflicts.
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Guest Editor for this article was Alan T. Hirsch, MD.
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Circulation 2008 117: 711-713.
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