(Circulation. 2001;103:491.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Soluble P-Selectin and the Risk of Future Cardiovascular Events
From the Center for Cardiovascular Disease Prevention (P.M.R., N.R.), the Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disease (P.M.R., N.R.); the Divisions of Preventive Medicine (P.M.R., J.E.B.) and Cardiology (P.M.R.), Brigham and Women’s Hospital; and the Department of Pathology, Children’s Hospital Medical Center (N.R.), Harvard Medical School, Boston, Mass.
Correspondence to Dr Paul M. Ridker, Brigham and Women’s Hospital, 900 Commonwealth Ave East, Boston, MA 02215. E-mail pridker{at}partners.org
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—P-selectin, a cell-surface adhesion molecule involved in leukocyte rolling and attachment, has been hypothesized to play a role in the initiation of atherosclerosis. However, little clinical data are available evaluating the role of soluble P-selectin in determining vascular risk.
Methods and Results—In a large-scale prospective study of apparently healthy women, we measured baseline plasma concentration of soluble P-selectin among 115 participants who subsequently developed cardiovascular events and among 230 age- and smoking-matched participants who remained free of disease during 3.5 years of follow-up. Overall, mean levels of soluble P-selectin were significantly higher at baseline among women who subsequently experienced cardiovascular events compared with those who did not (83.2 versus 69.3 ng/mL; P=0.003). The risk of future cardiovascular events increased with increasing quartiles of soluble P-selectin (P=0.02), such that women in the highest quartile at study entry had an age- and smoking-matched relative risk 2.2 times higher than those in the lowest quartile (95% confidence interval, 1.2 to 4.2; P=0.01). This effect was independent of traditional risk factors. For each quartile increase in soluble P-selectin, the risk of future cardiovascular events increased 28% (P=0.03) after additional adjustment for obesity, hypertension, hyperlipidemia, diabetes, and exercise frequency. The highest risks were observed among women with the very highest levels of P-selectin (>137.3 ng/mL, the 95th percentile cut point of the control distribution).
Conclusions—Soluble P-selectin levels are elevated among apparently healthy women at risk for future vascular events.
Key Words: inflammation • selectins • atherosclerosis • risk factors • cell adhesion molecules • myocardial infarction
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Introduction |
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Inflammation plays a major role in atherosclerosis,1 and plasma markers of inflammation such as high-sensitivity C-reactive protein may have clinical utility in the detection of atherothrombotic risk.2 3 Among the earliest inflammatory steps leading to atherogenesis is the slowing, tethering, and subsequent attachment of circulating leukocytes to the vascular endothelium, a process mediated partly by the selectin family of cell adhesion molecules.4 5 In particular, P-selectin is an adhesion receptor expressed on activated endothelial cells that mediates initial leukocyte "rolling."6 Evidence supporting a role for P-selectin in atherogenesis includes the observation that P-selectin is preferentially expressed in the endothelium overlying atherosclerotic plaques,7 that P-selectin–deficient mice develop reduced fatty streaks,8 9 10 and that anti–P-selectin antibodies inhibit monocyte rolling and attachment across carotid endothelium.11 In addition, atherogenic factors, including oxidized LDL,12 13 induce P-selectin expression.
Levels of soluble P-selectin can be measured in plasma and derive from both platelet and endothelial sources. However, clinical data relating soluble P-selectin to atherogenesis are sparse and limited to cross-sectional or retrospective studies describing elevated levels of soluble P-selectin among hypertensive,14 hyperlipidemic,15 and atherosclerotic patients.16 17 18 19 To date, no prospective data are available describing the role of soluble P-selectin among apparently healthy individuals being followed for incident myocardial infarction or stroke. Thus, whether plasma levels of soluble P-selectin are a marker for a high risk of future vascular events is uncertain.
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Methods |
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We evaluated the role of soluble P-selectin as a potential marker for cardiovascular risk among initially healthy participants in the Women’s Health Study, an ongoing trial of aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer.20 Details of the Women’s Health Study have been provided elsewhere; in brief, 28 263 women free of reported cardiovascular disease provided baseline plasma samples, which were collected in EDTA and stored in liquid nitrogen until the time of analysis. All study participants were then prospectively followed over an average period of 3.5 years for the occurrence of first-ever cardiovascular events (myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The end point of myocardial infarction was confirmed if symptoms of ischemia were present and if the event was associated with diagnostic changes in cardiac enzyme levels or if there were diagnostic electrocardiographic changes. Reports of coronary revascularization procedures were confirmed by record review. The diagnosis of stroke was confirmed if the patient had a new neurological deficit of >24-hour duration; computed tomography or magnetic resonance scanning was available for the majority of cases. Deaths from coronary heart disease were confirmed by record review, death certificates, autopsy reports, and information provided by family members.
For this analysis, baseline plasma samples were obtained from 115 study participants who subsequently developed a confirmed cardiovascular end point during follow-up (cases). For each of these women, baseline plasma samples were also obtained from 2 control women, who were selected from the pool of remaining study participants who did not develop cardiovascular events during follow-up. Two controls were matched to each case on the basis of age (±1 year) and smoking status (former, current, never). Thus, a total of 345 women (115 cases and 230 controls) were included in this prospective, nested, case-control analysis.
Baseline plasma samples from each case and control participant were thawed and assayed for soluble P-selectin by enzyme-linked immunoassay (R&D Systems). Matched plasma specimens were analyzed in blinded triplets, with the position of the case specimen varied at random to reduce systematic bias and minimize interassay variability. In pilot data performed for this study, intra-assay and interassay coefficients of variation were <8% across expected ranges of soluble P-selectin. Lipid profiles and other markers of inflammation were measured in these women using techniques described elsewhere.3 21 22
Means and proportions for baseline risk factors were
computed for case and control participants and compared using the
Student’s t test or
2 analysis. Tests for trend were used to
evaluate evidence of association between increasing levels of soluble
P-selectin and subsequent vascular risk after dividing the study
population into quartiles on the basis of the distribution of control
values. Adjusted risk estimates were obtained with the use of logistic
regression models that, in addition to accounting for the matching
variables of age and smoking status, also adjusted for potential
confounding variables. Finally, to evaluate threshold effects, we
repeated these analyses using a prespecified series of cut points for
soluble P-selectin based on the 50th, 75th, 90th, and 95th percentile
cut points of the control distribution. All probability values are
2-tailed, and confidence intervals were computed at the 95%
level.
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Results |
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Table 1
shows the baseline clinical characteristics of the
study participants. As expected, initially healthy women who
subsequently developed cardiovascular events (cases) were more likely
at baseline to have a history of hypertension, obesity, diabetes, or
hyperlipidemia when compared with women who remained free of reported
disease (controls). Because of matching, age and smoking status were
similar in the 2 study groups.
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The distribution of soluble P-selectin levels observed in
our study is consistent with that expected in studies of unselected
healthy individuals (R&D Systems;
Figure 1). However, as shown in
Table 1
and
Figure 2, both mean (83.2 versus 69.3 ng/mL;
P=0.003) and median (68.6
versus 62.7 ng/mL; P=0.02)
levels of soluble P-selectin were significantly higher at baseline
among study participants who subsequently developed a first-ever
cardiovascular event (cases) than in those who did not
(controls).
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In these data, increasing levels of soluble P-selectin at
baseline were associated with increased risks of future cardiovascular
events over the 3.5-year follow-up period. As shown in
Table 2, the age- and smoking-matched relative risk of
future cardiovascular events increased 27% (95% confidence interval,
4% to 56%) for each quartile increase in baseline level of soluble
P-selectin (P=0.02). These
effects persisted after controlling for other baseline clinical
characteristics, such that the adjusted relative risks of future
cardiovascular events for women with the lowest (referent) to highest
baseline quartiles of soluble P-selectin were 1.0, 1.3, 1.3, and 2.2
(P-trend=0.03) after additional
control for body mass index (kg/m2),
hypertension, hyperlipidemia, family history of coronary disease,
diabetes, and exercise frequency
(Table 2).
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Cigarette consumption was associated with elevated levels of
soluble P-selectin, such that nonsmokers had significantly lower levels
of P-selectin (67.9 ng/mL) than did former (76.8 ng/mL) or current
smokers (80.6 ng/mL; P=0.01;
Figure 3). However, because our study design matched cases
and controls on smoking status, the potential for confounding on this
basis is minimal. To assess for effect modification, analyses limited
to nonsmokers were performed; they had almost identical overall
results.
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To evaluate potential threshold effects, we repeated these
analyses using a series of prespecified cut points for soluble
P-selectin. As shown in
Table 3, the relative risks associated with baseline
soluble P-selectin concentrations exceeding the 50th, 75th, 90th, and
95th percentiles of the control distribution were 1.4
(P=0.1), 1.9
(P=0.01), 2.0
(P=0.03), and 2.3
(P=0.04), respectively. Thus,
much of the excess risk associated with baseline soluble P-selectin was
due to an excess of high values among the case subjects. Similar
effects were observed in analyses stratified by the presence or absence
of hypertension, obesity, diabetes, and hyperlipidemia.
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In prior work from this cohort, the inflammatory markers soluble intercellular adhesion molecule 1 (sICAM-1), high-sensitivity C-reactive protein, and interluekin-6 were also predictive of future cardiovascular events.3 In these data, modest but statistically significant correlations were observed between soluble P-selectin and sICAM-1 (r=0.23, P=0.001) and high-sensitivity C-reactive protein (r=0.11, P=0.04). No relationship was observed between soluble P-selectin and interleukin-6 (r=0.06, P=0.6). After adjustment for sICAM-1 and high-sensitivity C-reactive protein, the relationship between soluble P-selectin and vascular disease was minimally attenuated, such that the relative risk of future cardiovascular events increased 25% for each quartile increase in baseline level of soluble P-selectin (P=0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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P-selectin is an adhesion molecule stored within the
-granules of platelets and the Weibel-Palade bodies of endothelial
cells.23 Basic laboratory
work has demonstrated that, after stimulation, P-selectin quickly
redistributes to the surface of endothelial cells and mediates several
early processes in inflammatory cell adhesion, particularly those
associated with leukocyte rolling along endothelial
surfaces.4 5 6 7
On the basis of these data and on experimental results obtained from
P-selectin–deficient
mice,8 9 10 11 24
it has been hypothesized that P-selectin may play an important role in
the initiation of atherosclerosis. In this prospective epidemiological evaluation of apparently healthy women, elevated baseline levels of soluble P-selectin were associated with increasing risks of future myocardial infarction, stroke, coronary revascularization, and cardiovascular death. This association was independent of age and smoking status and persisted after additional control for several lipid and nonlipid cardiovascular risk factors. In these data, the strongest correlates of P-selectin were smoking status and sICAM-1. However, the effects of P-selectin on risk were only minimally attenuated in analyses further controlling for these factors and for other traditional markers of cardiovascular risk. These data thus provide strong clinical confirmation of an important role for P-selectin in the processes leading to atherosclerotic vascular occlusion.
Prior clinical data relating soluble P-selectin to coronary artery disease are limited and have been derived primarily from small cross-sectional or retrospective studies of patients with acute coronary syndromes.17 18 19 Because soluble P-selectin levels may increase with acute ischemia, it has thus been impossible from these prior studies to discern whether elevations of soluble P-selectin are a cause or a result of vascular occlusion. By contrast, in our study, plasma samples were obtained several years before the onset of first-ever vascular events, eliminating the possibility that acute ischemia was the underlying cause of soluble P-selectin release.
In these data, cigarette consumption was directly associated with increased levels of soluble P-selectin. These data are thus in accord with prior work demonstrating potential adverse effects of smoking on endothelial function and on the expression of other adhesion molecules, including ICAM-1 and vascular cell adhesion molecle-1. However, because we matched case and control subjects on smoking status, it is highly unlikely that this effect explains our result. Further, we observed almost identical findings in a post hoc subgroup analysis limited to nonsmokers.
Potential limitations of our study include the fact that we
relied on a single, frozen baseline plasma sample and that we evaluated
only postmenopausal women. However, observed soluble P-selectin levels
in our study are very similar to those expected in fresh plasma
(Figure 1); these data suggest that our collection and
storage procedures, which include freezing at -170°C are sufficient
to preserve the integrity of our samples. However, sex-specific
findings for soluble P-selectin are possible; thus, care must be taken
when generalizing these data to men. Finally, because soluble
P-selectin derives from both platelets and endothelial cells, the
present measurements cannot distinguish between these 2 potential
sources of circulating soluble P-selectin. Furthermore, the plasma
levels of soluble P-selectin could increase due to increased expression
on the platelet or endothelial surface or be due to excessive shedding
by as-yet poorly understood mechanisms.
In summary, the current report, together with prior data for other adhesion molecules,3 22 25 provides strong epidemiological support for the hypothesis that the very early inflammatory processes of leukocyte rolling, tethering, attachment, and transmigration across the vascular endothelium are critical initiating events in atherothrombosis.1 4 5 These data also provide a human extension of basic work demonstrating that P-selectin–deficient mice have delayed fatty streak formation8 9 10 and that anti–P-selectin antibodies inhibit cell adhesion in early atherogenesis, at least in apoE-deficient mice.11 Thus, accumulating data support the potential for adhesion molecules to serve as novel targets for the treatment and prevention of cardiovascular disorders.
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Acknowledgments |
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Supported by grants HL-58755 and HL-63293 from the National Heart, Lung, and Blood Institute. Dr Ridker is additionally supported by an Established Investigator Award from the American Heart Association and by a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation. The authors thank Dr Peter Libby for reviewing this manuscript.
Received July 18, 2000; revision received September 14, 2000; accepted September 19, 2000.
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 P. Bogaty, J. M. Brophy, M. Noel, L. Boyer, S. Simard, F. Bertrand, and G. R. Dagenais Impact of Prolonged Cyclooxygenase-2 Inhibition on Inflammatory Markers and Endothelial Function in Patients With Ischemic Heart Disease and Raised C-Reactive Protein: A Randomized Placebo-Controlled Study Circulation, August 24, 2004; 110(8): 934 - 939. [Abstract] [Full Text] [PDF]
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P. M Ridker, N. J. Brown, D. E. Vaughan, D. G. Harrison, and J. L. Mehta Established and Emerging Plasma Biomarkers in the Prediction of First Atherothrombotic Events Circulation, June 29, 2004; 109(25_suppl_1): IV-6 - IV-19. [Full Text] [PDF]
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H. S. Lim, A. D. Blann, and G. Y.H. Lip Soluble CD40 Ligand, Soluble P-Selectin, Interleukin-6, and Tissue Factor in Diabetes Mellitus: Relationships to Cardiovascular Disease and Risk Factor Intervention Circulation, June 1, 2004; 109(21): 2524 - 2528. [Abstract] [Full Text] [PDF]
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J. T. Willerson and P. M. Ridker Inflammation as a Cardiovascular Risk Factor Circulation, June 1, 2004; 109(21_suppl_1): II-2 - II-10. [Abstract] [Full Text] [PDF]
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U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
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P. Lind, G. Engstrom, L. Stavenow, L. Janzon, F. Lindgarde, and B. Hedblad Risk of Myocardial Infarction and Stroke in Smokers Is Related to Plasma Levels of Inflammation-Sensitive Proteins Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 577 - 582. [Abstract] [Full Text] [PDF]
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B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]
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J. D. Smout, D. P. Mikhailidis, B. K. Shenton, and G. Stansby Combination Antiplatelet Therapy in Patients with Peripheral Vascular Bypass Grafts Clinical and Applied Thrombosis/Hemostasis, January 1, 2004; 10(1): 9 - 18. [Abstract] [PDF]
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A. D. Blann, S. K. Nadar, and G. Y.H. Lip The adhesion molecule P-selectin and cardiovascular disease Eur. Heart J., December 2, 2003; 24(24): 2166 - 2179. [Abstract] [Full Text] [PDF]
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D. D. Wagner and P. C. Burger Platelets in Inflammation and Thrombosis Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2131 - 2137. [Abstract] [Full Text] [PDF]
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E. Lutgens, R.-J. van Suylen, B. C. Faber, M. J. Gijbels, P. M. Eurlings, A.-P. Bijnens, K. B. Cleutjens, S. Heeneman, and M. J.A.P. Daemen Atherosclerotic Plaque Rupture: Local or Systemic Process? Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2123 - 2130. [Abstract] [Full Text] [PDF]
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 A. P. Miller, Y.-F. Chen, D. Xing, W. Feng, and S. Oparil Hormone Replacement Therapy and Inflammation: Interactions in Cardiovascular Disease Hypertension, October 1, 2003; 42(4): 657 - 663. [Abstract] [Full Text] [PDF]
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A. Ponthieux, B. Herbeth, S. Droesch, D. Lambert, and S. Visvikis Age- and Sex-related Reference Values for Serum Adhesion Molecule Concentrations in Healthy Individuals: Intercellular Adhesion Molecule-1 and E-, P-, and L-Selectin Clin. Chem., September 1, 2003; 49(9): 1544 - 1546. [Full Text] [PDF]
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 P. Cherian, G. J. Hankey, J. W. Eikelboom, J. Thom, R. I. Baker, A. McQuillan, J. Staton, and Q. Yi Endothelial and Platelet Activation in Acute Ischemic Stroke and Its Etiological Subtypes Stroke, September 1, 2003; 34(9): 2132 - 2137. [Abstract] [Full Text] [PDF]
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T. B. Ledue and N. Rifai Preanalytic and Analytic Sources of Variations in C-reactive Protein Measurement: Implications for Cardiovascular Disease Risk Assessment Clin. Chem., August 1, 2003; 49(8): 1258 - 1271. [Abstract] [Full Text] [PDF]
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S. Tsiara, M. Elisaf, I. A. Jagroop, and D. P. Mikhailidis Platelets as Predictors of Vascular Risk: Is There a Practical Index of Platelet Activity? Clinical and Applied Thrombosis/Hemostasis, July 1, 2003; 9(3): 177 - 190. [Abstract] [PDF]
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P. C. Burger and D. D. Wagner Platelet P-selectin facilitates atherosclerotic lesion development Blood, April 1, 2003; 101(7): 2661 - 2666. [Abstract] [Full Text] [PDF]
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N.T. Mulvihill, B. Foley, P. Crean, and M. Walsh Prediction of cardiovascular risk using soluble cell adhesion molecules Eur. Heart J., October 2, 2002; 23(20): 1569 - 1574. [Full Text] [PDF]
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A. D. Blann, P. M. Ridker, and G. Y.H. Lip Inflammation, Cell Adhesion Molecules, and Stroke: Tools in Pathophysiology and Epidemiology? Stroke, September 1, 2002; 33(9): 2141 - 2143. [Full Text] [PDF]
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D. Tanne, M. Haim, V. Boyko, U. Goldbourt, T. Reshef, S. Matetzky, Y. Adler, Y. A. Mekori, and S. Behar Soluble Intercellular Adhesion Molecule-1 and Risk of Future Ischemic Stroke: A Nested Case-Control Study From the Bezafibrate Infarction Prevention (BIP) Study Cohort Stroke, September 1, 2002; 33(9): 2182 - 2186. [Abstract] [Full Text] [PDF]
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S. Blankenberg, L. Tiret, C. Bickel, D. Peetz, F. Cambien, J. Meyer, H. J. Rupprecht, and for the AtheroGene Investigators Interleukin-18 Is a Strong Predictor of Cardiovascular Death in Stable and Unstable Angina Circulation, July 2, 2002; 106(1): 24 - 30. [Abstract] [Full Text] [PDF]
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C. G.C. Spencer, D. Gurney, A. D. Blann, D. G. Beevers, and G. Y.H. Lip Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension: A Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Hypertension, July 1, 2002; 40(1): 61 - 66. [Abstract] [Full Text] [PDF]
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M. Haim, D. Tanne, V. Boyko, T. Reshef, U. Goldbourt, J. Leor, Y. A. Mekori, and S. Behar Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease: Data from the Bezafibrate Infarction Prevention (BIP) Study J. Am. Coll. Cardiol., April 3, 2002; 39(7): 1133 - 1138. [Abstract] [Full Text] [PDF]
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
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 C. Stollberger and J. Finsterer Role of Infectious and Immune Factors in Coronary and Cerebrovascular Arteriosclerosis Clin. Vaccine Immunol., March 1, 2002; 9(2): 207 - 215. [Full Text] [PDF]
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G.J. Blake and P.M. Ridker Tumour necrosis factor-{alpha}, inflammatory biomarkers, and atherogenesis Eur. Heart J., March 1, 2002; 23(5): 345 - 347. [Full Text] [PDF]
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G. J. Blake, N. Dada, J. C. Fox, J. E. Manson, and P. M. Ridker A prospective evaluation of lipoprotein-associated phospholipase A2 levels and the risk of future cardiovascular events in women J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1302 - 1306. [Abstract] [Full Text] [PDF]
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 G. Targher, R. C. Bonadonna, M. Alberiche, M. B. Zenere, M. Muggeo, and E. Bonora Relation Between Soluble Adhesion Molecules and Insulin Sensitivity in Type 2 Diabetic Individuals: Role of adipose tissue Diabetes Care, November 1, 2001; 24(11): 1961 - 1966. [Abstract] [Full Text] [PDF]
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G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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S. C. Barbaux, S. Blankenberg, H. J. Rupprecht, C. Francomme, C. Bickel, G. Hafner, V. Nicaud, J. Meyer, F. Cambien, and L. Tiret Association Between P-Selectin Gene Polymorphisms and Soluble P-Selectin Levels and Their Relation to Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., October 1, 2001; 21(10): 1668 - 1673. [Abstract] [Full Text] [PDF]
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 A D Blann, R Adams, R Ashleigh, S Naser, U Kirkpatrick, and C N McCollum Changes in endothelial, leucocyte and platelet markers following contrast medium injection during angiography in patients with peripheral artery disease Br. J. Radiol., September 1, 2001; 74(885): 811 - 817. [Abstract] [Full Text] [PDF]
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P. Ziccardi, F. Nappo, G. Giugliano, K. Esposito, R. Marfella, M. Cioffi, F. D'Andrea, A. M. Molinari, and D. Giugliano Reduction of Inflammatory Cytokine Concentrations and Improvement of Endothelial Functions in Obese Women After Weight Loss Over One Year Circulation, February 19, 2002; 105(7): 804 - 809. [Abstract] [Full Text] [PDF]
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