© 1998 American Heart Association, Inc.
Original Contributions |
Circulating Cell Adhesion Molecules Are Correlated With Ultrasound-Based Assessment of Carotid Atherosclerosis
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital (L.E.R., R.T.L., J.R., M.J., L.H.A., W.B., P.L., M.A.C., P.M.R.) and the Department of Laboratory Medicine, Children's Hospital (N.R.), Harvard Medical School, Boston, Mass.
Correspondence to Paul M. Ridker, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail pmridker{at}bics.bwh.harvard.edu
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Abstract |
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Abstract—Although cellular adhesion molecules (CAMs) are hypothesized to play an important role in atherogenesis, the relationship between CAMs and systemic atherosclerosis is uncertain. Among 92 outpatients (48 men; mean±SD age, 65±9 years), we evaluated the association of soluble vascular CAM-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) with carotid intimal-medial thickness (IMT), an index of early atherosclerosis. All subjects underwent a 2-dimensional ultrasound examination of both carotid arteries at the distal common carotid arteries and bifurcation. sVCAM-1 and sICAM-1 levels measured by enzyme-linked immunosorbent assay were significantly correlated with mean IMT of the common carotid artery (r=0.34 and r=0.30, respectively; P<0.01) and carotid bifurcation (r=0.31 and r=0.26, respectively; P<0.05), whereas sVCAM-1 was also positively associated with maximal carotid IMT (r=0.35, P<0.01). Adjustment for age attenuated the association between sVCAM-1 and common (r=0.16, P=0.13) and bifurcation (r=0.18, P=0.07) carotid IMT but had minimal effect on the associations between sICAM-1 and carotid measurements (r=0.32, P<0.01; r=0.23, P<0.05; for common and bifurcation IMT, respectively). Age-adjusted sICAM-1 levels increased in a stepwise fashion across common carotid IMT tertiles (253±27 versus 275±24 versus 384±26 pg/mL for the lowest, intermediate, and highest IMT tertiles, respectively; P<0.01). A similar trend was also found between sVCAM-1 levels and common carotid IMT tertiles (625±60 versus 650±53 versus 714±58 pg/mL; P<0.15). These associations were minimally affected in analyses adjusting for hypertension, diabetes, smoking, low and high density lipoprotein cholesterol, lipoprotein(a), and homocysteine, or in a subgroup analysis limited to those with no prior history of atherothrombotic disease. These data demonstrate a positive association between serum CAMs with carotid IMT and further support the hypothesis that systemic inflammation may have a role in atherosclerotic lesion development.
Key Words: adhesion molecules • atherosclerosis • ultrasound • inflammation
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Introduction |
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Cellular adhesion molecules (CAMs) mediate the adhesion and migration of leukocytes, steps that have been hypothesized to play a critical role in early atherogenesis.1 2 Focal expression of CAMs has been demonstrated in atherosclerotic lesions,3 4 5 precedes leukocyte infiltration,6 7 and appears to be mediated in part by modified lipoproteins or their constituents.8 However, data evaluating circulating CAMs and clinical atherosclerotic disease are limited. Two recent reports measured levels of soluble CAMs in patients with peripheral vascular disease and found contradictory results.9 10 In addition, Caterina et al11 recently demonstrated a significant association between soluble vascular cell adhesion molecule-1 (sVCAM-1) with carotid atherosclerosis in a small group of hypertensive patients. Conversely, Hwang et al12 failed to detect a significant association between sVCAM-1 and carotid and coronary disease in a case-control study.
Quantitative measures of mild vascular lesions and wall irregularities in the carotid system can be explored by ultrasound interrogation.13 Although it is not known why specific areas of thickening eventually progress to fully developed plaques and obstructive lesions, measurements of carotid intimal-medial thickness (IMT) are often used in epidemiological studies as a surrogate for early atherosclerosis.14 Carotid IMT increases with age,15 is correlated with traditional cardiovascular risk factors,16 17 and identifies subjects at increased risk of severe coronary artery disease17 18 19 and cerebrovascular morbidity.20
To further explore the relationship of inflammatory markers and atherosclerosis, we performed a cross-sectional survey of 92 outpatients and evaluated the association between circulating levels of sVCAM-1 and soluble intercellular adhesion molecule-1 (sICAM-1) with ultrasound-based carotid IMT.
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Methods |
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Patients
From March 1997 to July 1997, outpatients aged 50 years or older who were referred to the Noninvasive Cardiac Laboratory of the Brigham and Women's Hospital for a transthoracic echocardiogram were invited to participate in the study. Patients with a clinical history consistent with active infection, systemic inflammatory disease, or heart transplant or those taking oral or parenteral corticosteroids were excluded. Overall, 92 eligible patients agreed to participate and constituted the study population. The protocol was reviewed and approved by the Human Research Committee of the Brigham and Women's Hospital, and informed, written consent was obtained for all patients. Individual data on atherosclerosis risk factors, prior cardiovascular history, comorbidities, and current medications were obtained before the imaging procedures.
Carotid Imaging
Each patient underwent a detailed ultrasound evaluation of the
carotid arteries. These examinations were performed by an experienced
ultrasonographer using commercially available equipment
(Hewlett-Packard Sonos 2500, Hewlett-Packard Medical Products) and
a 5.5/7.0-MHz linear transducer. The carotid image acquisition protocol
was adapted from the Atherosclerosis Risk in
Communities (ARIC) Study.16 In brief, images were
obtained with the patients in the supine position with the neck mildly
extended and the head rotated contralaterally to the side. The imaging
protocol involved obtaining longitudinal, lateral, and anterior oblique
views of the distal 10 mm of the right and left common carotid
arteries, the carotid bifurcation, and the internal carotid artery.
Because high-quality images in the internal carotid artery were
obtained in <50% of the subjects, internal carotid IMTs were not
analyzed in this study. The images were digitized and all
examinations were evaluated according to standard
recommendations16 by a single cardiologist
(L.E.R.). In brief, lines were drawn along the lumen-intima and
medial-adventitial interfaces in the far wall of the common carotid
artery and carotid bifurcation, and a mean IMT was computed in each
region. For the purpose of statistical analysis, right and left
measurements were averaged. Maximal thickness in any particular region
was also measured, irrespective of location. The maximal IMT index was
created to integrate data concerning the highest levels of thickening
or obstruction in any level of the carotid system. Patients were also
classified according to the presence of well-defined atherosclerotic
plaques. Plaques were defined by the presence of focal, severe wall
thickening (IMT >2 mm), wall irregularities, and calcification.
Intrareader reproducibility of the same carotid IMT measurements was
evaluated in a subset of patients (n=20). Correlation coefficients in
this blinded assessment exceeded 98%. Ultrasound technicians and
reader were unaware of serum analysis results.
Blood Measurements
EDTA-anticoagulated samples were obtained by nontraumatic
venipuncture by using a 19-gauge butterfly catheter. Blood
was then centrifuged for 20 minutes at 2500 rpm, and aliquots
were stored at -70°C. sVCAM-1 and sICAM-1 were measured in duplicate
by a sandwich ELISA based on purified proteins and polyclonal
antibodies (R&D Systems) according to the manufacturer's
recommendations. Reported sensitivity of the assays for sVCAM-1 and
sICAM-1 is<2 and 0.35 ng/mL, respectively. Methods used to measure LDL
and HDL cholesterol, lipoprotein(a), and total homocysteine
have been described elsewhere.21 22 23
Statistical Analysis
Unless otherwise noted, data are expressed as mean±SD. Spearman
correlation coefficients were calculated to evaluate evidence of the
association between carotid and serum measurements. In addition,
carotid measurements were categorized into 3 groups according to
tertiles of the distribution. The significance of any differences in
serum markers on the categorized carotid groups was computed by 1-way
ANOVA. To control for multiple comparisons, Tukey's test was used. To
evaluate the association between serum levels and carotid measurements
after controlling for other cardiovascular risk
factors, adjusted means of serum levels were estimated by using general
linear models. Adjusted associations were controlled for each risk
factor separately. In addition, multiple linear regression was
performed to assess the independent contribution of circulating CAMs. A
2-tailed P value <0.05 was considered statistically
significant.
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Results |
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Patient Characteristics
Table 1
shows the baseline
characteristics of the 92 outpatients studied (mean±SD age, 65±9
years; 48% female). Approximately half had a history of hypertension
or hypercholesterolemia, <10% were current
smokers, and 56% were former smokers. Previous myocardial infarction
had occurred in 18 (20%) patients, and 7 (8%) had a history of
previous neurological events (5 were transient ischemic
episodes). Reasons for ordering the echocardiogram included left
ventricular functional evaluation (34%), valvular
assessment (31%), coronary artery disease (14%),
arrhythmia (5%), preoperative evaluation (5%), or others
(11%).
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Mean levels of sVCAM-1 and sICAM-1 were 664±315 and 305±142
ng/mL, respectively (medians were 572 and 270 ng/mL). The lipid profile
and other serum measurements are also described in Table 1
. Mean IMT in
the carotid bifurcation was greater than in the common carotid artery
(1.2±0.3 versus 0.9±0.2 mm, P<0.05). Well-defined
plaques were observed in 29 patients (31%) (all with wall thickening
>2 mm), although no severe obstruction was identified. Common
carotid IMT tertiles were defined as follows: lowest (IMT
0.7
mm), intermediate (0.7<IMT0.9 mm), and highest (IMT>0.9
mm). Carotid bifurcation IMT tertiles were also defined as lowest
(IMT0.95 mm), intermediate (0.95<IMT1.25 mm), and
highest (IMT>1.25 mm), as were maximal IMT tertiles: lowest
(IMT1.0 mm), intermediate (1.0<IMT1.6 mm), and highest
(IMT>1.6 mm).
Unadjusted Association Between Carotid Parameters and
Serum Measurements
The correlation coefficients between sVCAM-1 and sICAM-1 and
carotid parameters are presented in Table 2. sVCAM-1 and sICAM-1 levels were
correlated significantly with mean IMT of the common carotid artery
(r=0.34 and r=0.30, respectively;
P<0.01) and carotid bifurcation (r=0.31 and
r=0.26, respectively; P<0.01). sVCAM-1 was also
positively associated with maximal carotid IMT (r=0.35,
P<0.001). Subgroup analysis of patients without
prior manifestations of atherothrombotic vascular disease (no history
of angina, myocardial infarction,
revascularization, or previous neurological events)
also demonstrated a statistically significant association between CAMs
and most of the carotid variables evaluated (Table 2). No other
serum marker was significantly associated with IMT measurements, except
for a trend for a negative association between HDL levels and common
carotid, bifurcation, and maximal IMT.
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sVCAM-1 levels were significantly increased in the highest tertiles
when compared with the lowest tertiles of carotid thickness (773±419
versus 564±191 ng/mL for common carotid mean IMT, P<0.05;
826±444 versus 560±175 ng/mL for carotid bifurcation mean IMT,
P<0.05; and 787±429 versus 535±158 ng/mL for maximal mean
IMT, P<0.05). The same differences were observed between
sICAM-1 levels and common carotid IMT tertiles (376±171 versus
263±112 ng/mL, P<0.05). Age-adjusted sVCAM-1 and sICAM-1
levels according to tertile distribution of carotid IMT are shown in
the Figure.
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P<0.15 highest versus lowest tertile.Carotid vascular disease was also classified according to the presence of well-defined plaques at any level of the carotid system. Patients with carotid plaques had higher levels of sVCAM-1 than did patients without lesions, irrespective of IMT measurements (820±436 versus 592±208 ng/mL, P=0.01). These differences were not observed for sICAM-1.
Risk Factor–Adjusted sVCAM-1 and sICAM-1 Levels
Tables 3 and 4 present estimated sVCAM-1 and
sICAM-1 levels according to carotid tertiles after individual
adjustment for age, hypertension, diabetes, current smoking, lipids,
and homocysteine. Estimated sVCAM-1 levels were significantly
correlated with carotid parameters after adjustment for
these risk factors, except for age-adjusted level in common carotid
artery IMT tertiles. Estimated sICAM-1 values also remained positively
associated with common carotid IMT after adjustment. As noted, most of
the risk factors evaluated had minimal impact on the association
between sVCAM-1 or sICAM-1 and carotid IMT.
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We further evaluated the impact of other risk factors on CAM levels. sVCAM-1 was significantly associated with age only (r=0.41, P<0.001), whereas sICAM-1 levels were negatively associated with HDL levels (r=-0.27, P<0.01). In multivariate analysis after adjustment for age, history of hypertension, hypercholesterolemia, diabetes, family history of ischemic heart disease, lipids, and homocysteine levels, sVCAM-1 (P<0.01) was the only variable that remained significantly associated with maximal IMT, whereas sICAM-1 (P<0.05) and age (P<0.01) were the only independent correlates for both common carotid and bifurcation IMTs.
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Discussion |
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These data demonstrate a direct association between plasma concentrations of CAMs (sVCAM-1 and sICAM-1) and ultrasound-based assessment of carotid IMT. Furthermore, this association appears to be minimally influenced by a large number of lipid-related and non–lipid-related risk factors. These findings are in agreement with previous reports on the role of CAMs in atherogenesis and add potentially important information on the early pathophysiological events that lead to development of atherosclerotic plaques.
Several studies suggest a role for CAMs in atherogenesis. Focal expression of VCAM-1 has been demonstrated in human atherosclerotic plaques.3 4 This expression occurs particularly in the neovascular endothelium and smooth muscle cells and importantly, is correlated with the macrophage content in human coronary lesions.3 After an atherogenic diet, VCAM-1 expression in endothelial cells rapidly increases and appears to precede leukocyte accumulation.5 6 Studies with endothelial cells in culture8 24 25 26 27 show that constituents of modified lipoproteins and other lipid-derived products can regulate expression of VCAM-1. Recently, 2 reports28 29 demonstrated in mice that a deficiency of several CAMs (ICAM-1, P-selectin, and CD18) reduces the development of atherosclerotic fatty streaks after a high-fat, high-cholesterol diet. Finally, prospective data from a large cohort of apparently healthy men indicate that elevated baseline levels of sICAM-1 are associated with increased future myocardial infarction.30
Circulating levels of VCAM-1 have been associated with the extent of clinical atherosclerosis as measured angiographically in patients with known peripheral arterial disease.10 Our data agree with this report, as circulating sVCAM-1 was significantly higher in patients with atherosclerotic carotid plaques. Enders et al31 also demonstrated expression of VCAM-1 in advanced atherosclerotic plaques by immunohistochemistry, whereas ICAM-1 expression was identified in normal carotid arteries. Interestingly, Blann and McCollum10 failed to demonstrate increased levels of sVCAM-1 in patients with clinically defined atherosclerosis when compared with apparently healthy control subjects. These apparently conflicting results may be explained in part by the presence of asymptomatic disease in the controls, by differences in sample size, by variability in the assays used, and by residual confounding. Our data also reinforce and extend the findings of Caterina et al.11 In their study, a striking association between sVCAM-1 levels and carotid IMT was demonstrated in a small population of hypertensive patients. Our results were similar in a more heterogeneous population, even after excluding patients with previous atherothrombotic disease and after adjustment for clinical and serum (lipid and nonlipid) risk factors for atherosclerosis. A recent substudy from the Atherosclerosis Risk in Communities (ARIC) study12 failed to demonstrate differences in sVCAM-1 levels among patients with carotid atherosclerosis, incident coronary heart disease and control subjects. The reasons for these discrepancies are unclear but can be partially explained by differences in population characteristics. Mean sVCAM-1 levels in our patients were higher than in all 3 groups of patients evaluated in the ARIC substudy (664±315 ng/mL in our sample versus 458±150 ng/mL in their carotid atherosclerosis group, for example). Soluble fractions of different CAMs may not be operative in populations in which the atherosclerotic burden is less accentuated.
The association of sVCAM-1 and sICAM-1 with carotid IMT emphasizes the role of these proteins in early phases of atherogenesis. Ultrasound-based IMT evaluation of carotid arteries is a reliable, reproducible, and safe noninvasive method to study vascular disease.13 32 Carotid IMT measurements have been used in epidemiological studies as a surrogate for preclinical atherosclerosis, and several reports have shown a significant association with traditional cardiovascular risk factors.15 16 17 Recently, cytomegalovirus titers33 and plasma homocysteine levels34 have also been associated with ultrasonography-based carotid measurements. Our data support the concept that circulating CAMs could potentially be used as serum markers for preclinical atherosclerosis10 and further strengthen the link between inflammation and arterial pathology in humans. The independence of the associations between sVCAM-1 or sICAM-1 and carotid IMT of a large number of lipid-related and non–lipid-related risk factors reinforces this hypothesis.
CAMs are known to be present in a variety of cell types, including endothelium, macrophages, lymphocytes, and certain tumor cell lines. The mechanism for generation of soluble forms of adhesion molecules is uncertain but could involve proteolytic cleavage from the cell surface. The plasma concentration of circulating CAMs observed in our study may reflect total body atherosclerotic load, as such molecules can be expressed nonspecifically throughout the vascular system. As such, the current data support the hypothesis that the plasma concentration of soluble CAMs may provide a molecular marker for total atherosclerosis.30
Limitations of our study design merit consideration. Carotid thickening measured by 2-dimensional ultrasound is not a perfect surrogate for preclinical atherosclerosis.16 However, the natural history of atherosclerotic structural changes is well documented and known to progress through the stage of diffuse, intimal thickening.35 Furthermore, as outlined above, carotid thickening has been effectively used in several epidemiological studies. The patients' use of drugs could have modified lipid measurements and CAM levels. Nevertheless, there were no differences in sVCAM-1 and sICAM-1 levels when patients using lipid-lowering drugs were compared with those who were not (data not shown). The positive associations observed in this study should be considered in the context of the study population characteristics. Because our study evaluated patients referred to a noninvasive cardiac laboratory, the generalizability of our data may be limited. Mean common carotid and bifurcation IMT values in our sample, for example, were higher than carotid IMT levels previously described for younger and healthier subjects.19
In conclusion, sVCAM-1 and sICAM-1 are associated with carotid IMT, an index of early atherosclerosis. This association appears to be unaffected by other known cardiovascular risk factors. Our findings concur with evidence suggesting that inflammation plays a critical role in several atherosclerotic syndromes.10 30 36 Further large-scale prospective studies are thus needed to determine the prognostic value of these inexpensive and easily assessable markers.
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Acknowledgments |
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L.E.R. is supported by a scholarship from Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil. P.M.R. is supported by an Established Investigator Award from the American Heart Association. This work was also supported by grants from the National Institutes of Health, Bethesda, Md (HL 54759 to R.T.L.).
Received January 16, 1998; accepted May 4, 1998.
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K. K. Koh, S. H. Han, and M. J. Quon Inflammatory Markers and the Metabolic Syndrome: Insights From Therapeutic Interventions J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1978 - 1985. [Abstract] [Full Text] [PDF]
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W. Marz, H. Scharnagl, M. M. Hoffmann, B. O. Boehm, and B. R. Winkelmann The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study) Eur. Heart J., December 1, 2004; 25(23): 2109 - 2119. [Abstract] [Full Text] [PDF]
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J. F. Keaney Jr, J. M. Massaro, M. G. Larson, R. S. Vasan, P. W. F. Wilson, I. Lipinska, D. Corey, P. Sutherland, J. A. Vita, and E. J. Benjamin Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study J. Am. Coll. Cardiol., July 7, 2004; 44(1): 168 - 173. [Abstract] [Full Text] [PDF]
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A. Papagianni, E. Kokolina, M. Kalovoulos, A. Vainas, C. Dimitriadis, and D. Memmos Carotid atherosclerosis is associated with inflammation, malnutrition and intercellular adhesion molecule-1 in patients on continuous ambulatory peritoneal dialysis Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1258 - 1263. [Abstract] [Full Text] [PDF]
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M. K.C. Ng, P. Y. Liu, A. J. Williams, S. Nakhla, L. P. Ly, D. J. Handelsman, and D. S. Celermajer Prospective Study of Effect of Androgens on Serum Inflammatory Markers in Men Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1136 - 1141. [Abstract] [Full Text] [PDF]
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K. Kohara, Y. Tabara, Y. Yamamoto, M. Igase, and T. Miki Chlamydia pneumoniae Seropositivity Is Associated With Increased Plasma Levels of Soluble Cellular Adhesion Molecules in Community-Dwelling Subjects: The Shimanami Health Promoting Program (J-SHIPP) Study Stroke, June 1, 2002; 33(6): 1474 - 1479. [Abstract] [Full Text] [PDF]
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S. Devaraj, A. V. C. Chan Jr., and I. Jialal {alpha}-Tocopherol Supplementation Decreases Plasminogen Activator Inhibitor-1 and P-Selectin Levels in Type 2 Diabetic Patients Diabetes Care, March 1, 2002; 25(3): 524 - 529. [Abstract] [Full Text] [PDF]
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D. Baldassarre, M. Amato, L. Pustina, E. Tremoli, C. R. Sirtori, L. Calabresi, and G. Franceschini Increased Carotid Artery Intima-Media Thickness in Subjects With Primary Hypoalphalipoproteinemia Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 317 - 322. [Abstract] [Full Text] [PDF]
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T. A. Elhadd, T. A. Abdu, J. Oxtoby, G. Kennedy, M. McLaren, R. Neary, J. J. F. Belch, and R. N. Clayton Biochemical and Biophysical Markers of Endothelial Dysfunction in Adults with Hypopituitarism and Severe GH Deficiency J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4223 - 4232. [Abstract] [Full Text] [PDF]
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M. Otsuki, H. Saito, X. Xu, S. Sumitani, H. Kouhara, T. Kishimoto, and S. Kasayama Progesterone, but Not Medroxyprogesterone, Inhibits Vascular Cell Adhesion Molecule-1 Expression in Human Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 243 - 248. [Abstract] [Full Text] [PDF]
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L. B. Goldstein, R. Adams, K. Becker, C. D. Furberg, P. B. Gorelick, G. Hademenos, M. Hill, G. Howard, V. J. Howard, B. Jacobs, et al. Primary Prevention of Ischemic Stroke : A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association Stroke, January 1, 2001; 32(1): 280 - 299. [Full Text] [PDF]
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D. Zanger, B. K. Yang, J. Ardans, M. A. Waclawiw, G. Csako, L. M. Wahl, and R. O. Cannon III Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1797 - 1802. [Abstract] [Full Text] [PDF]
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J. A. de Lemos, C. H. Hennekens, and P. M. Ridker Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk J. Am. Coll. Cardiol., August 1, 2000; 36(2): 423 - 426. [Abstract] [Full Text] [PDF]
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N. Rifai, R. Joubran, H. Yu, M. Asmi, and M. Jouma Inflammatory Markers in Men with Angiographically Documented Coronary Heart Disease Clin. Chem., November 1, 1999; 45(11): 1967 - 1973. [Abstract] [Full Text] [PDF]
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