© 1997 American Heart Association, Inc.
Articles |
Lifetime Smoking Exposure Affects the Association of C-Reactive Protein with Cardiovascular Disease Risk Factors and Subclinical Disease in Healthy Elderly Subjects
From the Departments of Pathology and Biochemistry (R.P.T.), Pathology (E.M., E.G.B., E.S.C.), Medicine and Pathology (M.C.), University of Vermont, Colchester, the Departments of Epidemiology and Health Services and Medicine (B.M.P.), University of Washington, Seattle, and the Departments of Epidemiology and Medicine (L.H.K.), University of Pittsburgh, Penn.
Correspondence and reprint requests to Russell P. Tracy, University of Vermont, Aquatec Bldg, T205, 55A S. Park Drive, Colchester, VT 05446. Email: rtracy{at}salus.uvm.edu
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Abstract Blood levels of C-reactive protein (CRP), a marker of inflammation, are related to cardiovascular disease risk. To determine cross-sectional correlates in the elderly, we measured CRP in 400 men and women older than 65 years and free of clinical cardiovascular disease at baseline as part of the Cardiovascular Health Study. Only 2% of the values were greater than 10 mg/L, the cut-point usually used to identify inflammation. CRP levels appeared tightly regulated, since there were strong bivariate correlations between CRP and the following: inflammation-sensitive proteins such as fibrinogen (r=.52); measures of fibrinolysis such as plasmin-antiplasmin complex (r=.23); pack-years of smoking (r=.30); and body mass index (r=.24; all P values
.001).
The association with pack-years was independent of the length of time
since cessation of smoking. CRP levels were also associated with
coagulation factors VIIc, IXc, and Xc; HDL cholesterol
(negative) and triglyceride; diabetes status;
diuretic use; ECG abnormalities; and level of exercise. Because
of effect modification, two multiple linear regression prediction
models were developed for CRP, one each for never smokers and ever
smokers. An a priori physiologic model was used to guide these
analyses, which disallowed the use of other
inflammation-sensitive variables such as fibrinogen. In never
smokers, the independent predictors were body mass index (+), diabetes
status (+), plasmin-antiplasmin complex (+), and the presence of ECG
abnormalities (+); this model predicted 15% of the CRP population
variance. In ever smokers, the predictors were body mass index (+),
plasmin-antiplasmin complex (+), pack-years of smoking (+), HDL
cholesterol (-), and ankle-arm blood pressure index (-);
this model predicted 42% of the population variance. We conclude that
levels of CRP in the healthy elderly are tightly regulated and reflect
lifetime exposure to smoking as well as level of obesity, ongoing level
of fibrinolysis, diabetes status, and level of
subclinical atherothrombotic disease. Moreover, exposure to smoking
affects the relation of CRP to these other factors.
Key Words: atherosclerosis • thrombosis • fibrinolysis • inflammation • acute-phase proteins
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Introduction |
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It is becoming apparent that inflammation is associated with atherosclerosis and the resulting thrombosis (atherothrombosis). This association with CVD is complex in nature. There are data to link inflammation with the formation of very early lesions, such as fatty streaks,1 the attachment of monocytes to damaged endothelium,2 3 and the active thrombotic process that accompanies plaque rupture.4 5 However, although it seems likely that some aspects of the inflammation may contribute to the atherothrombotic process, there is also evidence that some inflammatory responses may dampen it.6
The serum level of CRP is used clinically as an indicator of inflammation.7 When used in this way, relatively high values have the greatest diagnostic utility, since the combination of a relatively small within-subject variance and relatively large between-subjects variance limits the usefulness of healthy reference ranges in detecting early low-level inflammation,8 9 and the changes in CRP after significant acute inflammation are generally large, up to several hundredfold.7
Elevations in CRP have been shown to be positively associated with acute MI and sudden cardiac-related death in patients with unstable angina, linking inflammation and acute coronary events.10 11 12 Recently, we (L.K., R.T.) have extended these studies to show that in middle-aged men13 and elderly women14 free of prevalent CVD, higher CRP levels are associated with incident CVD events. In the study of middle-aged men, the association of CRP with CVD events, extending over 5 to 17 years of follow-up, was primarily seen in those men who were smokers; and in one previous study, smoking was associated with higher CRP levels.15 However, to date there have been no population-based studies examining the associations of CRP with other variables known to be related to CVD risk.
In the current study, we measured CRP in 400 subjects free of clinically recognized CVD, a subset of a well-defined, healthy elderly cohort in the CHS.16 We examined cross-sectional associations of CRP with other CVD risk factors and measures of prevalent subclinical disease such as carotid atherosclerosis defined by ultrasonography.
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Methods |
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Cardiovascular Health Study
The CHS has been described in detail.16 After the study was approved by all relevant institutional review boards, participants were recruited with informed consent, and examinations were performed from May 1989 to June 1990. The four CHS field centers were in Forsyth County, NC; Washington County, Md; Sacramento County, Calif; and, Pittsburgh, Penn. Participants were identified by random sampling from Medicare eligibility lists.17 For the present study, we obtained a sample of 400 CHS participants free of prevalent clinical CVD at baseline. A stratified random sample was selected, with 40 participants in each of 10 sex-age groups. Some analyses had slightly fewer than 400 data points, since data on every variable was not available on every participant.
The baseline examination consisted of an interview, a physical examination with several blood measurements, and an assessment of CVD status. Information was collected on blood pressure, anthropomorphic characteristics, and medical and lifestyle histories including a comprehensive assessment of medications. Blood samples were analyzed at the central laboratory, the Laboratory for Clinical Biochemistry Research at the University of Vermont, Burlington Vt. The general laboratory design and the quality assurance procedures and results have been published.18 Other measurements include AAI,19 carotid ultrasonography,20 echocardiography21 and resting 12-lead ECG.
Definitions
The definition of borderline hypertension was a random zero
seated systolic blood pressure (average of five measurements)
between 140 and 159 mm Hg or, if systolic was <140
mm Hg, an average diastolic between 90 and 94 mm Hg.
Hypertension was defined as an average systolic 
160
mm Hg or, if the systolic was <160 mm Hg, an average
diastolic 95 mm Hg, or the use of hypertension
medications. Abnormal glucose tolerance was defined as impaired
(fasting glucose <140 mg/dL and 2-hour post-glucose challenge
between 140 and 199 mg/dL) or diabetes (fasting glucose 140
mg/dL or 2-hour post-glucose challenge 200 mg/dL, or
self-reported diabetes, or if the participant was taking either insulin
or oral hypoglycemic medication). Smoking was defined as never, former,
or current; no restrictions were placed on the time since cessation of
smoking for the former smoker category. Responses to years since
cessation of smoking were based on the participants' recall. Obesity
was defined as BMI (in units of kg/m2) over 130% of
the ideal for sex and age. Exercise level, classified as none, low,
moderate and high, was based on questionnaire responses.16
Sitting systolic blood pressure was used to calculate the AAI,
with a value <0.9 considered abnormal.19 Abnormal ECG
results and the use of the ECG to define the left
ventricular mass have been described.22
Ultrasound methods and quality control are described in detail
elsewhere.20
Clinical coronary heart disease at entry to the study was defined by the following: (1) self-reported myocardial infarction, angina, or use of nitroglycerin; (2) definite myocardial infarction by resting ECG using the Minnesota code23 ; or (3) self-reported history of coronary angioplasty or coronary artery bypass graft. Cerebrovascular disease was defined as self-reported stroke, transient ischemic attack, or carotid endarterectomy. Peripheral vascular disease was defined as self-reported intermittent claudication or history of peripheral artery angioplasty or bypass surgery.
Blood Measurements
We (M.C., E.S.C., E.G.B., R.T.) have described blood collection
in detail.18 Briefly, blood was collected after fasting
with minimal tourniquet time. Along with serum and both citrated and
EDTA plasma, we collected blood in a special coagulation collection
tube (SCAT-1; Haematologic Technologies, Inc., Essex Junction, Vt) that
contained, at final concentration in blood, 4.5 mmol/L of
EDTA, 150 KIU/mL of aprotinin, and 20 mmol/L of
D-Phe-Pro-Arg chloromethyl ketone.24 CRP was
measured by in-house competitive immunoassay (antibodies and antigens
from Calbiochem, La Jolla, Calif) with an interassay CV (all subsequent
CVs are also interassay CVs) of 8.9%.25
1-Acid glycoprotein was also measured with
an in-house immunoassay with reagents from Calbiochem, using SCAT-1
plasma, with a CV of 7.9%. Lipid assays (under Centers for Disease
Control and Prevention certification) and general chemistries were
performed using EDTA plasma and serum respectively, as previously
reported.18 Lipoprotein(a) was measured in SCAT-1 plasma
with a specific immunoassay26 (reagents kindly donated by
Dr. Wai-Le Wong of Genentech), with a CV of 7.5%. Fibrinogen, factor
VII, and factor VIII were measured using citrate plasma as previously
described.18 27 Factor IX and factor X were measured in
citrate plasma using one-stage clot-rate assays and the
Diagnostica Stago ST4 instrument, according to the
manufacturer's recommendations,28 with CVs of 5.8 and
4.7%, respectively. Tissue-type plasminogen
activator, PAI-1, PAP, tissue-type plasminogen
activator/PAI-1 complex, and the fibrin fragment
D-dimer were measured by enzyme-linked immunoabsorbent
assays, with reagents kindly provided by Drs. D. Collen and P. Declerk,
Leuven, Belgium.29 30 31 32 33 34 The CVs for control samples in these
assays were, respectively: 5.2, 8.4, 3.0, 14.3, and 12.7%. With the
exception of PAI-1, which was measured in citrate
plasma,35 these assays were performed with SCAT-1 plasma.
Plasminogen36 and antithrombin III were
measured by rate chromogenic assays in citrate plasma, with
CVs of 3.6 and 5.0%, respectively. Protein C and protein S were
measured in SCAT-1 plasma using in-house immunoassays, with CVs of 2.0
and 9.9%, respectively.37 38 F1-2 was measured with an
enzyme-linked immunosorbent assay (Baxter-Dade, Miami, Fla) in SCAT-1
plasma with a CV of 9.3%. This assay has excellent correlation with
another F1-2 assay (Berhing Diagnostics, Inc., Westwood,
Mass), with a Pearson coefficient of 0.92 (P<.0001). FPA
was measured on fibrinogen-free SCAT-1 plasma by a double antibody
competition radioimmunoassay (Byk-Sangtec Diagnostica,
Dietzenbach, Germany). Fibrinogen was extracted with
bentonite.39 The postextraction CV was 8.4%; the total CV
for the assay, including extraction, was approximately
25%.39 Despite the relatively high CV, the FPA assay
remains the single best choice for estimating thrombin activity. Recent
studies indicate that FPA levels are useful in epidemiological
settings.40 Complete blood counts were performed at a
designated local laboratory near each field center site.
Statistical Analyses
SPSS for Windows41 was used for all
analyses. The data set used was distributed version 1.0, from
the CHS Coordinating Center. The distribution of CRP in our sample was
determined to be nonnormal. A natural log transformation achieved
normality, so ln-CRP values were used for statistical analyses.
Bivariate associations of ln-CRP with CVD risk factors and other
biochemical measurements were estimated using the Pearson correlation
coefficient or, for categorical variables, analysis of
variance. The significance level was set at P.01. Since
there were strong interactions between smoking status and a number of
other variables, all analyses were done on the full group
as well as on subgroups stratified on smoking status. Due to the small
number of current smokers (n=33), we combined current smokers and
former smokers (n=147) into a single group of ever smokers. We compared
known CVD risk factors between former smokers and current smokers; the
only variable that was significantly different was BMI: former
smokers, 26.3; current smokers, 23.5; P=.001. We also ran
our final multivariate model in both the ever smoker
and the former smoker groups. Formal testing for effect modification
was done using the SPSS MANOVA feature, which reports a significance
for the selected interaction terms.
Step-wise multivariate linear regression models were
developed to predict ln-CRP as tests of the independence of
associations. P.05 was used to assess significance. We
started with general variables such as age and sex, then added
indices of disease and lipids, and then thrombosis and
fibrinolysis measures. Fibrinolysis and
thrombosis markers such as PAP levels and
fibrinopeptide A levels were considered for inclusion
into the models since we propose that thrombosis and subsequent
fibrinolysis are most likely in the causal pathway;
however, static levels of coagulation factors, eg, fibrinogen, and
certain other variables were not appropriate for the model since
they appear to be coregulated, at least to a certain extent, with CRP
through mediators of inflammation. Diabetes status was used in the
models instead of fasting or 2-hour glucose or insulin because
preliminary analyses showed stronger associations with CRP for
diabetes status. Pack-years was the variable used to
represent smoking in the regression models. Since approximately
half of the population has a value of 0 for pack-years (never smokers),
we ended up with two "final models": one for never smokers (without
pack-years as an independent variable) and one for ever
smokers.
Age and sex were not significant in either model when the models were developed as described. As a final step, we forced age and sex into the final models since many variables were significantly associated with age and sex in bivariate analyses.
We calculated the effect ratio for each variable that remained in the final models, as described previously.42 The effect ratio is the percentage of an SD change in ln-CRP "explained" by a 1-SD change in continuous predictor variables or a one-category change in categorical variables. In this way, the effect sizes of the variables may be more easily compared.
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Results |
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Distributions
The characteristics of this sample of the CHS cohort have been published.43 The average age of both the men and women was 77 years. Although free of clinical CVD at baseline, more than 25% of the men and more than 15% of the women had major ECG abnormalities. More than 35% of the men and more than 30% of the women had carotid stenosis greater than 24%. Approximately 14% of the women used hormone replacement therapy. Only about 10% of the men and 7% of the women were current smokers, but almost 50% of the men and a quarter of the women were former smokers.
The distributions of CRP for men and women (Fig 1
) are similar, skewed high and
characterized by relatively few individuals (four men, five women) with
values greater than 10 mg/L, the value commonly used to
represent clinically relevant inflammation.44 The
5 to 95 percentile range for men was 0.26 to 5.75 mg/L, and 0.21
to 7.26 mg/L for women. An association of CRP values with
smoking status has been suggested,15 and Fig 1 illustrates
the distributions when men and women are combined and the values
stratified on smoking status, ie, ever smokers and never smokers.
Again, the distributions are very similar, with 5 to 95 percentile
ranges of 0.26 to 7.54 mg/L and 0.19 to 6.70 mg/L for
ever smokers and never smokers, respectively.
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Associations with CVD Risk Factors
Table 1 illustrates correlations
between ln-CRP and other continuous variables, and Table 2 illustrates associations with
categorical variables. Men and women had similar values. Age also
was not associated with ln-CRP. Although smoking status per se was not
significantly associated with ln-CRP, there was a relatively strong
association of ln-CRP and pack-years among ever smokers. In a separate
analysis, there were no significant differences in ln-CRP
levels between never, former, and current smokers; however, the number
of current smokers was small.
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Pack-years and years since cessation were highly negatively correlated (R=-.49). In a multiple regression model, pack-years was significant whereas years since cessation was not. A formal test of interaction between pack-years and years since cessation was not significant (P=.17).
To further evaluate the relationship of ln-CRP to smoking, we
stratified our sample of former smokers based on tertiles of years
since cessation of smoking, then within each stratum, stratified on
tertiles of pack-years of smoking and calculated mean values for
ln-CRP. The results are shown in Fig 2.
Although the number of subjects in each cell is small, the relationship
of ln-CRP to number of pack-years within each stratum of years since
cessation appears consistent. Taken all together, our data
support the hypothesis that CRP is primarily related to lifetime
exposure of smoking (pack-years) and not to years since cessation of
smoking.
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To illustrate the interaction of smoking with other variables, mean
values for CRP (and for ln-CRP, data not shown) were actually greater
in women than in men among never smokers, whereas the opposite was true
among ever smokers (Fig 3, P=.04 for interaction term). A similar weak interaction
(P=.08) existed for the relationship of CRP to obesity
(Table 2
and Fig 3): The significantly
greater CRP values in obese subjects of the full group was primarily
due to greater values in the obese never smokers. However, the
bivariate correlation of ln-CRP to BMI was the same in ever smokers as
in never smokers (Table 1).
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The association of CRP to diabetes status (Fig 3 and Table 2) or serum
glucose (both fasting and after a 2-hour oral glucose tolerance test;
Table 1) was also strongly affected by smoking status, with significant
associations observed only in the never smokers (P=.006 for
interaction term for diabetes status). ln-CRP was not associated with
cholesterol (Table 1) or LDL cholesterol (data
not shown) but was associated with HDL cholesterol (-)
and, weakly, with fasting triglyceride (+).
Associations with Other Variables
ln-CRP showed several strong positive associations with
procoagulant factors (Table 1) including factor VIIc, factor VIIIc,
factor IXc, and factor Xc. With the exception of factor VIIc, these
associations were approximately the same in the never smokers and ever
smokers. Factor VIIc was more strongly associated with CRP in the never
smokers. Several measures of fibrinolysis were
positively correlated with ln-CRP. In particular, the associations with
t-PA, PAP (a measure of plasmin production), and the fibrin
fragment D-dimer (plasmin activity) were stronger in ever
smokers than in never smokers (P=.04 for interaction term
for PAP).
Although only nine of approximately 400 subjects (<3%) had CRP values
greater than the generally accepted cutoff for inflammation, ln-CRP
showed significant correlations to other known markers of inflammation,
including fibrinogen, 1-acid glycoprotein,
albumin (-), and white cell count. All of these associations
were stronger in the ever smoker subgroup than in the never smoker
group. ln-CRP was not associated with aspirin or nonsteroidal
antiinflammatory drug use, nor with postmenopausal estrogen use in
women. However, there was a significant association with
diuretic use (-).
Associations with Subclinical Disease Variables
ln-CRP was not significantly associated with left ventricle
ejection fraction, left ventricular mass, or carotid
atherosclerosis in this healthy population. However, in
ever smokers, ln-CRP was associated with AAI as a measure of
peripheral vascular disease (Table 1) and relatively weakly
associated with ECG abnormalities (minor) in never smokers.
Multivariate Models Predicting ln-CRP
We began the step-wise multivariate model for
never smokers with age and gender. After BMI and diabetes status
entered the model, neither age nor gender was significant. The presence
of minor ECG abnormalities was included, but not HDL or
triglycerides. PAP entered the model as a measure of
fibrinolysis. Other measures of
fibrinolysis, eg, the fibrin fragment
D-dimer, could be used in place of PAP but with less
statistical significance. Our final model for never smokers contained
BMI, diabetes, minor ECG abnormalities, and PAP (Table 3, Fig 4).
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The model for ever smokers began with age, gender, pack-years of
smoking, and BMI, with BMI, pack-years, and age remaining in the model
at this stage. With pack-years in the model, years since cessation of
smoking was not significant. Diabetes did not enter the model, but AAI
did. ln-FPA entered the model but became nonsignificant, along with
age, as soon as PAP entered. (In a separate analysis, age and
PAP were significantly associated with a Pearson coefficient of .29;
P.0001.) HDL also entered this model, but
triglycerides, diuretic use, uric acid,
creatinine, and forced expiratory volume in 1 second,
FEV1 did not. Our final model contained BMI, pack-years,
AAI, PAP, and HDL (Table 3). In Fig 4, it can be seen that PAP is a
significantly stronger predictor in ever smokers compared with never
smokers, and that of the final predictors in ever smokers, PAP explains
the greatest proportion of the ln-CRP distribution. When run with
former smokers only, the model was essentially unchanged except for a
slight decrease in the coefficient and significance of AAI (new
P=.11).
None of the predictor variables became nonsignificant when age and sex were forced into the final models. In the model for never smokers, age was significantly associated with ln-CRP (-) when entered this way, and the overall R2 was increased slightly to .185. In the model for ever smokers, neither age nor sex was significant, and there was virtually no change in the overall R2.
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Discussion |
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In general, elevated levels of CRP are useful in detecting and monitoring infections, postoperative complications, and the effectiveness of treatment in the course of various diseases, when inflammation is in some way involved.7 44 45 46 The cell biology of CRP has been established, and IL-6 appears to play a major role in regulating the production of CRP.47 It has been reported that other proinflammatory cytokines may play important roles as well.48 Along with immunological activity, alternative pathways for IL-6-mediated CRP production may include fibrinolytic activity, since fibrin degradation products can stimulate monocyte production of IL-6.49 50
Recently, CRP levels have been used in population studies of CVD. The European Concerted Action on Thrombosis and Disability (ECAT) Angina Pectoris Study Group reported that in subjects with angina pectoris, baseline CRP correlated with several markers of coagulation and fibrinolysis activity as well as white cell count, suggesting an association of a low grade inflammation with atherothrombosis.12 On follow-up, the baseline CRP level was positively associated with MI and sudden cardiac-related death. Liuzzo et al measured CRP and serum amyloid A (another marker of inflammation) in subjects with chronic stable angina, unstable angina, and MI on presentation at the hospital.11 The CRP levels were highest in the subjects who went on to develop MI, followed by those who had only unstable angina. We have recently reported that CRP levels are predictive of incident CVD events in middle-aged men who are free of prevalent clinical CVD at baseline13 and in elderly women who have subclinical CVD.51 Therefore, it is important to understand the cross-sectional correlates of CRP.
Strengths of the current study include the removal of prevalent clinical CVD as a potential confounder; a carefully designed parent study with appropriate blood collection and storage procedures; a comprehensive battery of measurements related to lipids, coagulation, and fibrinolysis; and assessment of independence through multivariate analyses. The major weaknesses of this study are its cross-sectional nature and its limited generalizability due to selection criteria of the parent study and this substudy.
Distribution of CRP Levels
The distribution of CRP in this healthy population of elderly
subjects reflected the almost complete absence of clinical inflammation
in this group, with very few CRP values greater than 10 mg/L
(9/399 or 2% overall). We observed no significant association with
age. The strong associations with other inflammation-sensitive
proteins, eg, fibrinogen, provide evidence that CRP levels within the
healthy reference range are tightly regulated, most likely by IL-6
levels.47 We25 (E.M., R.P.T.) and
others52 have recently analyzed CRP biovariability
and found it to be characterized by relatively small within-person
variability and relatively large between-persons variability, in the
absence of clinically apparent inflammation.
Relation of CRP to Smoking
Despite the powerful effect modification of smoking status, there
was no significant association of CRP values with smoking status
itself, although CRP was strongly related to lifetime smoking exposure.
Although CRP was associated with years since cessation of smoking, this
association was not significant when the category pack-years was
included in a model. In addition, in our stratified analysis,
it appeared that even when the individuals had stopped smoking for 30
years or more, CRP was still associated with pack-years. These findings
suggest the hypothesis that if smoking is in the causal pathway for
CRP, some smoking effects may persist over long periods of time.
When looking at correlates, we examined smoking for effect modifications since we had seen a large interaction of smoking with incident events in middle-aged men.13 Smoking status had a significant effect on the associations of gender, obesity, and diabetes status with CRP, consistent with an hypothesis that smoking causes a chronic, increased inflammatory response, especially in the absence of other mitigating factors. In support of this, we have recently observed very high values for the inflammation-sensitive protein fibrinogen in normal and diabetic North American Indians, with the strongest correlate being albuminuria (R.T. et al, manuscript in review). Interestingly, smoking did not have a strong association with fibrinogen, and fibrinogen was not an independent risk factor for prevalent disease in these.53
The mechanism for the hypothesized long-lasting inflammatory effect of smoking is unknown but could be linked to the development of atherothrombotic plaque at sites of vessel wall damage. This suggestion is supported by the associations of CRP with several measures of subclinical CVD in the current study and the recent reports linking CVD with inflammation-associated cell adhesion molecules and selectins.54 55 56 57 58
We were able to develop a model in ever smokers that explained almost
three times as much of the population variance as in never smokers,
even though the distributions of CRP in these two groups were very
similar (Fig 1). The effect of including pack-years made up a large
share of this difference. In addition, the effect size of the
fibrinolysis variable was much larger in the ever
smokers compared with the never smokers. This is consistent
with our finding in bivariate analysis of stronger correlations
of both PAP and the fibrin fragment D-dimer with CRP in
ever smokers, and it suggests that damage associated with smoking may
have long-term consequences with respect to thrombotic activity and
concomitant plasmin generation.
The relatively strong association of BMI and CRP (Tables 1 and 3) was
unexpected and is unexplained at this time. However, we found CRP
associated with BMI in another study,59 and in the
Women's Healthy Lifestyle Project, we observed that weight loss
was associated with a decrease in CRP (E. Meilahn, personal
communication, 1996). Recently, we observed that moderate weight loss,
independent of diet changes, also was associated with a decrease in
PAI-1, another acute-phase protein.60 The mechanism is
unclear but may be related to diet- and/or exercise-mediated changes in
triglyceride levels since in this study CRP was correlated
to triglycerides, and we have observed similar correlations
for fibrinogen43 and PAI-1 (M.C., manuscript in
preparation) in CHS.
CRP was strongly associated with a variety of measures of procoagulant activity and fibrinolysis in both bivariate and multivariate models. We believe that these associations fall into two categories: (1) associations that are the result of the inflammation caused by underlying subclinical atherothrombotic disease, including those with ambient levels of acute-phase factors such as fibrinogen, factor VIIIc, and PAI-1; (2) associations between CRP and factors that reflect an ongoing process such as thrombin generation (prothrombin fragment 1-2) or plasmin generation (PAP). We hypothesize that these processes contribute to the inflammation of CVD, possibly through monocyte IL-6 production in the presence of fibrin degradation products, which are the inevitable result of coagulation and fibrinolysis.50 In fact, CRP itself may be procoagulant, through its ability to stimulate monocyte tissue factor expression.61
In conclusion, levels of CRP in the healthy elderly indicate little clinical inflammation. However, these levels appear to be tightly regulated, with relatively strong associations with other inflammation-sensitive proteins, eg, fibrinogen, as well as BMI, fibrinolytic activity, glucose tolerance status, and some measures of subclinical CVD. Lifetime exposure to smoking, even in those who have stopped smoking, is strongly associated with CRP and affects the association of CRP with other variables. Our data suggest that some effects of smoking may persist for many years after cessation.
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Acknowledgments |
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This work was supported by grant RO1 HL-46696 (R.P.T.) from the National Heart, Lung, and Blood Institute (NHLBI) and by NHLBI contracts NO1-HC-85079 through -85086. Dr. Cushman was supported by US Public Health Service training grant T3207594. We thank Drs. Collen and DeClerck of Leuven, Belgium, for their kind gift of reagents for the fibrinolysis immunoassays, and Dr. Wai-Le Wong of Genentech (South San Francisco, Calif) for reagents to assay lipoprotein(a). We also thank the investigators and staff of the Cardiovascular Health Study: Forsyth County, NC-Bowman Gray School of Medicine of Wake Forest University: Gregory L. Burke, Alan Elster, Walter H. Ettinger, Curt D. Furberg, Edward Haponik, Gerardo Heiss, Dalane Kitzman, H. Sidney Klopfenstein, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Maurice B. Mittelmark, Cathy Nunn, Ward Riley, Grethe S. Tell, James F. Toole, and Beverly Tucker; Bowman Gray School of Medicine EKG Reading Center: Kris Calhoun, Harry Calhoun, Farida Rautaharju, Pentti Rautaharju, and Loralee Robertson; Sacramento County, Calif—University of California, Davis: William Bommer, Charles Bernick, Andrew Duxbury, Mary Haan, Calvin Hirsch, Paul Kellerman, Lawrence Laslett, Marshall Lee, Virginia Poirier, John Robbins, Marc Schenker, and Nemat Borhani; Washington County, Md—The Johns Hopkins University: M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, and Melvyn Tockman; Washington County, Md—The Johns Hopkins University MRI Reading Center: R. Nick Bryan, Carolyn C. Meltzer, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Michael Kraut, Grace Lee, Larry Schertz, Earl P. Steinberg, Scott Wells, Linda Wilkins, and Nancy C. Yue; Allegheny County, Penn—University of Pittsburgh: Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Lewis H. Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, and Sidney K. Wolfson; University of California, Irvine, Echocardiography Reading Center (Baseline): Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, and Nathan Wong; Washington, DC—Georgetown Medical Center Echocardiography Reading Center (Follow-Up): John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, and Retha Webb; Geisinger Medical Center Ultrasound Reading Center: Daniel H. O'Leary, Joseph F. Polak, and Laurie Funk; University of Arizona, Tucson, Respiratory Sciences: Paul Enright; University of Washington, Seattle, Coordinating Center: Alice Arnold, Annette L. Fitzpatrick, Bonnie K. Lind, Richard A. Kronmal, Bruce M. Psaty, David S. Siscovick, Lynn Shemanski, Lloyd Fisher, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, and Maryann McBurnie; National Heart, Lung, and Blood Institute Project Office, Bethesda, Md: Diane E. Bild, Teri A. Manolio, Peter J. Savage, Patricia Smith, and Rachel Solomon.
Received August 23, 1996; accepted March 5, 1997.
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G.D.O. Lowe, P.M. Sweetnam, J.W.G. Yarnell, A. Rumley, C. Rumley, D. Bainton, and Y. Ben-Shlomo C-Reactive Protein, Fibrin D-Dimer, and Risk of Ischemic Heart Disease: The Caerphilly and Speedwell Studies Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1957 - 1962. [Abstract] [Full Text] [PDF]
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 Y. Agmon, B. K. Khandheria, I. Meissner, T. M. Petterson, W. M. O'Fallon, D. O. Wiebers, T. J. H. Christianson, J. P. McConnell, J. P. Whisnant, J. B. Seward, et al. C-Reactive Protein and Atherosclerosis of the Thoracic Aorta: A Population-Based Transesophageal Echocardiographic Study Arch Intern Med, September 13, 2004; 164(16): 1781 - 1787. [Abstract] [Full Text] [PDF]
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C. M. L. Chapman, J. P. Beilby, B. M. McQuillan, P. L. Thompson, and J. Hung Monocyte Count, But Not C-Reactive Protein or Interleukin-6, Is an Independent Risk Marker for Subclinical Carotid Atherosclerosis Stroke, July 1, 2004; 35(7): 1619 - 1624. [Abstract] [Full Text] [PDF]
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D. J Baer, J. T Judd, B. A Clevidence, and R. P Tracy Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study Am. J. Clinical Nutrition, June 1, 2004; 79(6): 969 - 973. [Abstract] [Full Text] [PDF]
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M. Zureik, S. Kony, C. Neukirch, D. Courbon, B. Leynaert, D. Vervloet, P. Ducimetiere, and F. Neukirch Bronchial Hyperresponsiveness to Methacholine Is Associated With Increased Common Carotid Intima-Media Thickness in Men Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1098 - 1103. [Abstract] [Full Text]
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 J. A. Ambrose and R. S. Barua The pathophysiology of cigarette smoking and cardiovascular disease: An update J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1731 - 1737. [Abstract] [Full Text] [PDF]
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 S. Taponen, H. Martikainen, M.-R. Jarvelin, U. Sovio, J. Laitinen, A. Pouta, A.-L. Hartikainen, M. I. McCarthy, S. Franks, M. Paldanius, et al. Metabolic Cardiovascular Disease Risk Factors in Women with Self-Reported Symptoms of Oligomenorrhea and/or Hirsutism: Northern Finland Birth Cohort 1966 Study J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2114 - 2118. [Abstract] [Full Text] [PDF]
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M. Cesari, B. W. J. H. Penninx, M. Pahor, F. Lauretani, A. M. Corsi, G. R. Williams, J. M. Guralnik, and L. Ferrucci Inflammatory Markers and Physical Performance in Older Persons: The InCHIANTI Study J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2004; 59(3): M242 - M248. [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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T. P. Erlinger, E. A. Platz, N. Rifai, and K. J. Helzlsouer C-Reactive Protein and the Risk of Incident Colorectal Cancer JAMA, February 4, 2004; 291(5): 585 - 590. [Abstract] [Full Text] [PDF]
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A. Festa, A. J.G. Hanley, R. P. Tracy, R. D'Agostino Jr, and S. M. Haffner Inflammation in the Prediabetic State Is Related to Increased Insulin Resistance Rather Than Decreased Insulin Secretion Circulation, October 14, 2003; 108(15): 1822 - 1830. [Abstract] [Full Text] [PDF]
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M. P. Reilly, M. L. Wolfe, A. R. Localio, and D. J. Rader C-Reactive Protein and Coronary Artery Calcification: The Study of Inherited Risk of Coronary Atherosclerosis (SIRCA) Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1851 - 1856. [Abstract] [Full Text] [PDF]
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 R. P. Tracy Thrombin, Inflammation, and Cardiovascular Disease: An Epidemiologic Perspective Chest, September 1, 2003; 124 (2009): 49S - 57S. [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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J. J. Cao, C. Thach, T. A. Manolio, B. M. Psaty, L. H. Kuller, P. H.M. Chaves, J. F. Polak, K. Sutton-Tyrrell, D. M. Herrington, T. R. Price, et al. C-Reactive Protein, Carotid Intima-Media Thickness, and Incidence of Ischemic Stroke in the Elderly: The Cardiovascular Health Study Circulation, July 15, 2003; 108(2): 166 - 170. [Abstract] [Full Text] [PDF]
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M. Frohlich, M. Sund, H. Lowel, A. Imhof, A. Hoffmeister, and W. Koenig Independent association of various smoking characteristics with markers of systemic inflammation in men: Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95) Eur. Heart J., July 2, 2003; 24(14): 1365 - 1372. [Abstract] [Full Text] [PDF]
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 N. Aziz, J. L. Fahey, R. Detels, and A. W. Butch Analytical Performance of a Highly Sensitive C-Reactive Protein-Based Immunoassay and the Effects of Laboratory Variables on Levels of Protein in Blood Clin. Vaccine Immunol., July 1, 2003; 10(4): 652 - 657. [Abstract] [Full Text] [PDF]
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M. T. Schram, N. Chaturvedi, C. Schalkwijk, F. Giorgino, P. Ebeling, J. H. Fuller, and C. D. Stehouwer Vascular Risk Factors and Markers of Endothelial Function as Determinants of Inflammatory Markers in Type 1 Diabetes: The EURODIAB Prospective Complications Study Diabetes Care, July 1, 2003; 26(7): 2165 - 2173. [Abstract] [Full Text] [PDF]
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 L. A. Bazzano, J. He, P. Muntner, S. Vupputuri, and P. K. Whelton Relationship between Cigarette Smoking and Novel Risk Factors for Cardiovascular Disease in the United States Ann Intern Med, June 3, 2003; 138(11): 891 - 897. [Abstract] [Full Text] [PDF]
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G. D. Slade, E. M. Ghezzi, G. Heiss, J. D. Beck, E. Riche, and S. Offenbacher Relationship Between Periodontal Disease and C-Reactive Protein Among Adults in the Atherosclerosis Risk in Communities Study Arch Intern Med, May 26, 2003; 163(10): 1172 - 1179. [Abstract] [Full Text] [PDF]
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D. E. King, A. G. Mainous III, T. A. Buchanan, and W. S. Pearson C-Reactive Protein and Glycemic Control in Adults With Diabetes Diabetes Care, May 1, 2003; 26(5): 1535 - 1539. [Abstract] [Full Text] [PDF]
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P. Risley, P. Jerrard-Dunne, M. Sitzer, A. Buehler, S. von Kegler, and H. S. Markus Promoter Polymorphism in the Endotoxin Receptor (CD14) Is Associated With Increased Carotid Atherosclerosis Only in Smokers: The Carotid Atherosclerosis Progression Study (CAPS) Stroke, March 1, 2003; 34(3): 600 - 604. [Abstract] [Full Text] [PDF]
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R. A. Hegele, M. E. Kraw, M. R. Ban, B. A. Miskie, M. W. Huff, and H. Cao Elevated Serum C-Reactive Protein and Free Fatty Acids Among Nondiabetic Carriers of Missense Mutations in the Gene Encoding Lamin A/C (LMNA) With Partial Lipodystrophy Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 111 - 116. [Abstract] [Full Text] [PDF]
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References Circulation, December 17, 2002; 106(25): 3373 - 3421. [Full Text]
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M. Naruszewicz, M.-L. Johansson, D. Zapolska-Downar, and H. Bukowska Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers Am. J. Clinical Nutrition, December 1, 2002; 76(6): 1249 - 1255. [Abstract] [Full Text] [PDF]
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N. S. Jenny, R. P. Tracy, M. S. Ogg, L. A. Luong, L. H. Kuller, A. M. Arnold, A. R. Sharrett, and S. E. Humphries In the Elderly, Interleukin-6 Plasma Levels and the -174G>C Polymorphism Are Associated With the Development of Cardiovascular Disease Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2066 - 2071. [Abstract] [Full Text] [PDF]
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R. P. Tracy Inflammation in Cardiovascular Disease: Cart, Horse or Both-Revisited Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1514 - 1515. [Full Text] [PDF]
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T. J. Wang, B.-H. Nam, P. W.F. Wilson, P. A. Wolf, D. Levy, J. F. Polak, R. B. D'Agostino, and C. J. O'Donnell Association of C-Reactive Protein With Carotid Atherosclerosis in Men and Women: The Framingham Heart Study Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1662 - 1667. [Abstract] [Full Text] [PDF]
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E. A. Bermudez, N. Rifai, J. Buring, J. E. Manson, and P. M. Ridker Interrelationships Among Circulating Interleukin-6, C-Reactive Protein, and Traditional Cardiovascular Risk Factors in Women Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1668 - 1673. [Abstract] [Full Text] [PDF]
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S. Kiechl, P. Werner, G. Egger, F. Oberhollenzer, M. Mayr, Q. Xu, W. Poewe, and J. Willeit Active and Passive Smoking, Chronic Infections, and the Risk of Carotid Atherosclerosis: Prospective Results From the Bruneck Study Stroke, September 1, 2002; 33(9): 2170 - 2176. [Abstract] [Full Text] [PDF]
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M. J. Jarvisalo, A. Harmoinen, M. Hakanen, U. Paakkunainen, J. Viikari, J. Hartiala, T. Lehtimaki, O. Simell, and O. T. Raitakari Elevated Serum C-Reactive Protein Levels and Early Arterial Changes in Healthy Children Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1323 - 1328. [Abstract] [Full Text] [PDF]
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D. E. King, A. G. Mainous III, and W. S. Pearson C-Reactive Protein, Diabetes, and Attendance at Religious Services Diabetes Care, July 1, 2002; 25(7): 1172 - 1176. [Abstract] [Full Text] [PDF]
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M. Visser, M. Pahor, D. R. Taaffe, B. H. Goodpaster, E. M. Simonsick, A. B. Newman, M. Nevitt, and T. B. Harris Relationship of Interleukin-6 and Tumor Necrosis Factor-{alpha} With Muscle Mass and Muscle Strength in Elderly Men and Women: The Health ABC Study J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2002; 57(5): M326 - 332. [Abstract] [Full Text]
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A. Tchernof, A. Nolan, C. K. Sites, P. A. Ades, and E. T. Poehlman Weight Loss Reduces C-Reactive Protein Levels in Obese Postmenopausal Women Circulation, February 5, 2002; 105(5): 564 - 569. [Abstract] [Full Text] [PDF]
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 E. S. Ford Leukocyte Count, Erythrocyte Sedimentation Rate, and Diabetes Incidence in a National Sample of US Adults Am. J. Epidemiol., January 1, 2002; 155(1): 57 - 64. [Abstract] [Full Text] [PDF]
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T. Wu, J. P. Dorn, R. P. Donahue, C. T. Sempos, and M. Trevisan Associations of Serum C-reactive Protein with Fasting Insulin, Glucose, and Glycosylated Hemoglobin : The Third National Health and Nutrition Examination Survey, 1988-1994 Am. J. Epidemiol., January 1, 2002; 155(1): 65 - 71. [Abstract] [Full Text] [PDF]
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R. Blackburn, P. Giral, E. Bruckert, J.-M. Andre, S. Gonbert, M. Bernard, M. J. Chapman, and G. Turpin Elevated C-Reactive Protein Constitutes an Independent Predictor of Advanced Carotid Plaques in Dyslipidemic Subjects Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1962 - 1968. [Abstract] [Full Text] [PDF]
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S. Zevin, S. Saunders, S. G. Gourlay, P. Jacob III, and N. L. Benowitz Cardiovascular effects of carbon monoxide and cigarette smoking J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1633 - 1638. [Abstract] [Full Text] [PDF]
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N. S. Rost, P. A. Wolf, C. S. Kase, M. Kelly-Hayes, H. Silbershatz, J. M. Massaro, R. B. D'Agostino, C. Franzblau, and P. W.F. Wilson Plasma Concentration of C-Reactive Protein and Risk of Ischemic Stroke and Transient Ischemic Attack: The Framingham Study Stroke, November 1, 2001; 32(11): 2575 - 2579. [Abstract] [Full Text] [PDF]
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 J. I. Barzilay, L. Abraham, S. R. Heckbert, M. Cushman, L. H. Kuller, H. E. Resnick, and R. P. Tracy The Relation of Markers of Inflammation to the Development of Glucose Disorders in the Elderly: The Cardiovascular Health Study Diabetes, October 1, 2001; 50(10): 2384 - 2389. [Abstract] [Full Text]
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M. D. P. Luyer, S. Khosla, W. G. Owen, and V. M. Miller Prospective Randomized Study of Effects of Unopposed Estrogen Replacement Therapy on Markers of Coagulation and Inflammation in Postmenopausal Women J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3629 - 3634. [Abstract] [Full Text] [PDF]
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H. Hashimoto, K. Kitagawa, H. Hougaku, Y. Shimizu, M. Sakaguchi, Y. Nagai, S. Iyama, H. Yamanishi, M. Matsumoto, and M. Hori C-Reactive Protein Is an Independent Predictor of the Rate of Increase in Early Carotid Atherosclerosis Circulation, July 3, 2001; 104(1): 63 - 67. [Abstract] [Full Text] [PDF]
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S. Yamada, T. Gotoh, Y. Nakashima, K. Kayaba, S. Ishikawa, N. Nago, Y. Nakamura, Y. Itoh, and E. Kajii Distribution of Serum C-Reactive Protein and Its Association with Atherosclerotic Risk Factors in a Japanese Population : Jichi Medical School Cohort Study Am. J. Epidemiol., June 15, 2001; 153(12): 1183 - 1190. [Abstract] [Full Text] [PDF]
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R. P. Tracy Is Visceral Adiposity the "Enemy Within"? Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 881 - 883. [Full Text] [PDF]
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I. Lemieux, A. Pascot, D. Prud'homme, N. Almeras, P. Bogaty, A. Nadeau, J. Bergeron, and J.-P. Despres Elevated C-Reactive Protein : Another Component of the Atherothrombotic Profile of Abdominal Obesity Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 961 - 967. [Abstract] [Full Text] [PDF]
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E. Barinas-Mitchell, M. Cushman, E. N. Meilahn, R. P. Tracy, and L. H. Kuller Serum Levels of C-reactive Protein Are Associated with Obesity, Weight Gain, and Hormone Replacement Therapy in Healthy Postmenopausal Women Am. J. Epidemiol., June 1, 2001; 153(11): 1094 - 1101. [Abstract] [Full Text] [PDF]
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M. Langlois, D. Duprez, J. Delanghe, M. De Buyzere, and D. L. Clement Serum Vitamin C Concentration Is Low in Peripheral Arterial Disease and Is Associated With Inflammation and Severity of Atherosclerosis Circulation, April 10, 2001; 103(14): 1863 - 1868. [Abstract] [Full Text] [PDF]
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G. D. O. Lowe, J. W. G. Yarnell, A. Rumley, D. Bainton, and P. M. Sweetnam C-Reactive Protein, Fibrin D-Dimer, and Incident Ischemic Heart Disease in the Speedwell Study : Are Inflammation and Fibrin Turnover Linked in Pathogenesis? Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 603 - 610. [Abstract] [Full Text] [PDF]
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I. S. Ockene, C. E. Matthews, N. Rifai, P. M. Ridker, G. Reed, and E. Stanek Variability and Classification Accuracy of Serial High-Sensitivity C-Reactive Protein Measurements in Healthy Adults Clin. Chem., March 1, 2001; 47(3): 444 - 450. [Abstract] [Full Text] [PDF]
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S. Volpato, J. M. Guralnik, L. Ferrucci, J. Balfour, P. Chaves, L. P. Fried, and T. B. Harris Cardiovascular Disease, Interleukin-6, and Risk of Mortality in Older Women : The Women's Health and Aging Study Circulation, February 20, 2001; 103(7): 947 - 953. [Abstract] [Full Text] [PDF]
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M. Cushman, J. P. Costantino, R. P. Tracy, K. Song, L. Buckley, J. D. Roberts, and D. N. Krag Tamoxifen and Cardiac Risk Factors in Healthy Women : Suggestion of an Anti-inflammatory Effect Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 255 - 261. [Abstract] [Full Text] [PDF]
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D. F. Geffken, M. Cushman, G. L. Burke, J. F. Polak, P. A. Sakkinen, and R. P. Tracy Association between Physical Activity and Markers of Inflammation in a Healthy Elderly Population Am. J. Epidemiol., February 1, 2001; 153(3): 242 - 250. [Abstract] [Full Text] [PDF]
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 M. Visser, L. M. Bouter, G. M. McQuillan, M. H. Wener, and T. B. Harris Low-Grade Systemic Inflammation in Overweight Children Pediatrics, January 1, 2001; 107(1): 13e - 13. [Abstract] [Full Text]
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D. R. Taaffe, T. B. Harris, L. Ferrucci, J. Rowe, and T. E. Seeman Cross-sectional and Prospective Relationships of Interleukin-6 and C-Reactive Protein With Physical Performance in Elderly Persons: MacArthur Studies of Successful Aging J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2000; 55(12): 709M - 715. [Abstract] [Full Text]
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R. P. Tracy An Author Responds to Meigs' Invited Commentary Am. J. Epidemiol., November 15, 2000; 152(10): 912 - 912. [Full Text] [PDF]
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C. F. Pieper, K. M. K. Rao, M. S. Currie, T. B. Harris, and H. J. Cohen Age, Functional Status, and Racial Differences in Plasma D-Dimer Levels in Community-Dwelling Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2000; 55(11): 649M - 657. [Abstract] [Full Text]
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A. Festa, R. D'Agostino Jr, G. Howard, L. Mykkanen, R. P. Tracy, and S. M. Haffner Chronic Subclinical Inflammation as Part of the Insulin Resistance Syndrome : The Insulin Resistance Atherosclerosis Study (IRAS) Circulation, July 4, 2000; 102(1): 42 - 47. [Abstract] [Full Text] [PDF]
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R. F. Redberg, N. Rifai, L. Gee, and P. M. Ridker Lack of association of C-reactive protein and coronary calcium by electron beam computed tomography in postmenopausal women: implications for coronary artery disease screening J. Am. Coll. Cardiol., July 1, 2000; 36(1): 39 - 43. [Abstract] [Full Text] [PDF]
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E.S. Kilpatrick, B.G. Keevil, C. Jagger, R.J. Spooner, and M. Small Determinants of raised C-reactive protein concentration in type 1 diabetes QJM, April 1, 2000; 93(4): 231 - 236. [Abstract] [Full Text] [PDF]
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J. Gussekloo, M. C. L. Schaap, M. Frolich, G. J. Blauw, and R. G. J. Westendorp C-Reactive Protein Is a Strong but Nonspecific Risk Factor of Fatal Stroke in Elderly Persons Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1047 - 1051. [Abstract] [Full Text] [PDF]
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J. Willeit, S. Kiechl, F. Oberhollenzer, G. Rungger, G. Egger, E. Bonora, M. Mitterer, and M. Muggeo Distinct Risk Profiles of Early and Advanced Atherosclerosis : Prospective Results From the Bruneck Study Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 529 - 537. [Abstract] [Full Text] [PDF]
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G.D. Slade, S. Offenbacher, J.D. Beck, G. Heiss, and J.S. Pankow Acute-phase Inflammatory Response to Periodontal Disease in the US Population Journal of Dental Research, January 1, 2000; 79(1): 49 - 57. [Abstract] [PDF]
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C. J. Wiedermann, S. Kiechl, S. Dunzendorfer, P. Schratzberger, G. Egger, F. Oberhollenzer, and J. Willeit Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: Prospective results from the bruneck study J. Am. Coll. Cardiol., December 1, 1999; 34(7): 1975 - 1981. [Abstract] [Full Text] [PDF]
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A. Jager, V. W. M. van Hinsbergh, P. J. Kostense, J. J. Emeis, J. S. Yudkin, G. Nijpels, J. M. Dekker, R. J. Heine, L. M. Bouter, and C. D. A. Stehouwer von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects : The Hoorn Study Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 3071 - 3078. [Abstract] [Full Text] [PDF]
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