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From the Divisions of Preventive Medicine (P.M.R, C.H.H.), Cardiovascular
Disease (P.M.R.), and Channing Laboratory (M.J.S.), Department of Medicine,
Brigham and Women's Hospital, and the Department of Ambulatory Care and
Prevention (C.H.H.), Harvard Medical School, Boston, Mass; the Departments of
Epidemiology (M.J.S., C.H.H.) and Nutrition (M.J.S.), Harvard School of Public
Health, Boston, Mass; and the Laboratory for Clinical Biochemistry Research,
University of Vermont (M.C., R.P.T.), Burlington.
Correspondence to Dr Paul M Ridker, Brigham and Women's Hospital, 900 Commonwealth Ave E, Boston, MA 02115-1204. E-mail pmridker{at}bics.bwh.harvard.edu
Methods and Results—Using a prospective, nested, case-control
design, we measured baseline levels of CRP in 144 apparently healthy
men participating in the Physicians' Health Study who subsequently
developed symptomatic PAD (intermittent claudication or
need for revascularization) and in an equal number
of control subjects matched on the basis of age and smoking habit who
remained free of vascular disease during a follow-up period of 60
months. Median CRP levels at baseline were significantly higher among
those who subsequently developed PAD (1.34 versus 0.99 mg/L;
P=.04). Furthermore, the risks of developing PAD
increased significantly with each increasing quartile of baseline CRP
concentration such that relative risks of PAD from lowest (referent) to
highest quartile of CRP were 1.0, 1.3, 2.0, and 2.1
(Ptrend=.02). Compared with those with no
clinical evidence of disease, the subgroup of case patients who
required revascularization had the highest baseline
CRP levels (median=1.75 mg/L; P=.04); relative risks
from lowest to highest quartile of CRP for this end point were 1.0,
1.8, 3.8, and 4.1 (Ptrend=.02). Risk
estimates were similar after additional control for body mass index,
hypercholesterolemia, hypertension, diabetes,
and a family history of premature atherosclerosis.
Conclusions—These prospective data indicate that among apparently
healthy men, baseline levels of CRP predict future risk of developing
symptomatic PAD and thus provide further support for the
hypothesis that chronic inflammation is important in the pathogenesis
of atherothrombosis.
Recent studies3 suggest that low-grade
inflammation is present among patients at risk for future
atherothrombotic disease, at least in the coronary and cerebral
circulations. Specifically, elevated levels of C-reactive protein
(CRP), a marker for systemic inflammation, have been found among
individuals with stable and unstable angina who are at risk for future
myocardial infarction or sudden death,4 5 6
elderly patients at risk for symptomatic coronary
heart disease,7 those at high risk for
coronary death,8 and apparently healthy
men at risk for first-ever myocardial infarction or
stroke.3 As such, it has been hypothesized that
CRP may provide a molecular marker of the underlying severity of
preclinical atherosclerosis.
Currently, few data are available relating CRP to future risk of
developing symptomatic PAD. We therefore sought to
determine whether increased levels of CRP among apparently healthy men
are also associated with increased risk of developing
symptomatic claudication or need for peripheral
arterial revascularization.
Questionnaires are sent to all PHS participants annually to elicit
information on risk factors and incident health events, including
self-reports of the development of intermittent claudication and
hospitalizations for peripheral arterial
revascularization procedures. For this
analysis, case subjects were defined as those apparently
healthy PHS participants who provided an adequate baseline plasma
sample and who subsequently reported either intermittent claudication
or peripheral arterial
revascularization during a mean follow-up period of
60 months. Control subjects were apparently healthy PHS participants
who provided baseline plasma samples and who remained free of reported
cardiovascular disease at the time the matched case
patient reported his event. Control subjects were selected randomly
from among study participants who met the matching criteria of age,
smoking habit, and length of follow-up. Using these methods, we
evaluated 144 patients and an equal number of control subjects in a
prospective, nested, case-control study. None of the case subjects
reported a history of intermittent claudication at study entry.
For each case and control subject, plasma collected and stored at
baseline was thawed and assayed for CRP as previously
described.3 10 Blood specimens were
analyzed in blinded pairs with the position of the patient's
specimen varied at random to reduce the possibility of systematic bias
and decrease interassay variability. The mean coefficient of variation
was <.05.
Because CRP values are skewed toward higher values, median plasma
concentrations were computed, and the significance of any differences
in median values between case and control subjects was assessed by use
of Wilcoxon rank sum test. Tests for trend were used to assess
any relation of increasing CRP values with the risk of developing PAD
after the study sample was divided into quartiles defined by the
distribution of the control values. Adjusted estimates of risk were
obtained by use of conditional logistic-regression models that
accounted for the matching variables and also controlled for
randomized treatment assignment, body mass index, diabetes, history of
hypercholesterolemia, history of hypertension,
and a family history of coronary artery disease. All
probability values are two-tailed, and CIs are computed at the 95%
level.
Overall, median levels of CRP were significantly higher at baseline
among those study participants who subsequently developed
symptomatic PAD than among those who did not (1.34 versus
0.99 mg/mL; P=.04).
Table 2
As shown in the Figure
In a prior report from the PHS,11 aspirin
assignment was found to reduce the risk of peripheral
arterial revascularization by 46%. In
the current data, no statistically significant evidence of interaction
was noted between randomized aspirin assignment and CRP among study
participants who required peripheral
revascularization.
Several hypotheses have been suggested as mechanisms by which CRP may
increase atherosclerotic risk. For example, in addition to being a
hepatically derived marker for systemic inflammation, it has been
hypothesized that CRP may have procoagulant effects related to its
ability to enhance expression of tissue factor.12
Experimental work also suggests that CRP can be found within
endothelial vessel walls,13 that
CRP avidly binds to human neutrophils,14 and that
CRP can induce complement activation.15
Furthermore, recent data suggest that CRP and CRP peptides may be
involved in processes related to shedding of some cellular adhesion
molecules,16 an intriguing finding because these
molecules play an important role in the adhesion and transmigration of
leukocytes across the endothelial wall, an important
step in the initiation of atherosclerosis. It has also
been hypothesized that low-grade inflammation detected by CRP reflects
evidence of chronic infection. In this regard, some cross-sectional and
case-control studies have reported elevated antibody titers directed
against Chlamydia pneumoniae, Helicobacter
pylori, and cytomegalovirus among those with prevalent heart
disease.17 Finally, it is possible that the
association of CRP with vascular risk is the result of
cytokines such as interleukin-6 that promote leukocyte adhesion
and stimulate CRP production.18
In contrast to findings from this cohort for myocardial
infarction,3 we found no evidence in these data
of a statistically significant interaction between inflammation,
aspirin, and risks of PAD. However, because data from the PHS suggest
that aspirin reduces the need for peripheral
arterial surgery but not intermittent
claudication,11 this analysis was limited
to those 31 case subjects who required
revascularization. Thus, the power to detect a
statistically significant interaction in these data is insufficient to
exclude a true positive effect.
In summary, these prospective data indicate that baseline level of CRP
predicts risk of future PAD. Moreover, the highest levels of CRP were
found among those study participants who required surgical
revascularization in addition to developing
intermittent claudication. Thus, these data further support the
hypothesis that CRP may serve as a molecular marker for underlying
atherosclerosis and that higher levels correlate with
greater extent of disease.3
Received October 29, 1997;
revision received December 1, 1997;
accepted December 11, 1997.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Plasma Concentration of C-Reactive Protein and Risk of Developing Peripheral Vascular Disease
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Among apparently healthy
men, elevated levels of C-reactive protein (CRP), a marker for systemic
inflammation, predict risk of myocardial infarction and thromboembolic
stroke. Whether increased levels of CRP are also associated with the
development of symptomatic peripheral
arterial disease (PAD) is unknown.
Key Words: C-reactive protein • inflammation • claudication • arteries • atherosclerosis • risk factors
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Claudication due to
peripheral arterial vascular disease is a
common condition, affecting 2% to 5% of the United States population
older than 50 years of age.1 Among patients with
severe claudication, chronic lower extremity ischemia can lead
to recurrent infection, need for surgical
revascularization, and limb loss. In general, risk
factors for peripheral arterial disease (PAD)
are similar to those for coronary heart
disease.2 However, as with coronary
disease, many patients develop symptomatic claudication
without such factors.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The study population consisted of apparently healthy men
participating in the Physicians' Health Study (PHS), a randomized,
double-blind, placebo-controlled trial of aspirin and ß-carotene in
the primary prevention of heart disease and cancer conducted among
22 071 US male physicians aged 40 to 84 years.9
Participants had no prior history of cardiovascular
disease or cancer and were randomly assigned to one of four treatments:
325 mg of aspirin on alternate days, 50 mg of ß-carotene on alternate
days, both, or neither. Before randomization, participants were asked
to provide baseline blood samples; the procedures used to collect,
process, and store these EDTA-anticoagulated baseline blood samples are
described elsewhere.3 Overall, 14 916 (68%) of
the cohort provided baseline plasma samples.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Table 1
displays baseline clinical
characteristics of the 144 initially healthy study subjects who
subsequently developed claudication or underwent peripheral
arterial revascularization during
follow-up (case subjects) and of the 144 matched study participants who
remained free of vascular disease (control subjects). Because case and
control subjects were matched for age and smoking status, these
variables are identical between groups. As expected, the prevalence
of diabetes was higher among case subjects than control subjects. The
median time to first report of PAD was 30 months after the collection
of baseline blood samples.
View this table:
[in a new window]
Table 1. Baseline Characteristics of Study Participants displays the distribution of
study subjects after the sample was divided into quartiles based on the
distribution of CRP among control subjects. The relative risks of
developing symptomatic PAD increased significantly with
each increasing quartile of baseline concentration of CRP such that men
in the highest quartile had a twofold increase in risk compared with
men in the lowest quartile (relative risk, 2.1; 95% CI, 1.1 to 4.1;
P=.03). Specifically, the relative risks of developing
future PAD from lowest (referent) to highest quartile of CRP at
baseline were 1.0, 1.3, 2.0, and 2.1
(Ptrend=.02). Analyses that further
adjusted for body mass index, hypercholesteremia, diabetes, and a
family history of premature atherosclerosis had minimal
impact on these relationships; after adjustment for these potential
confounding factors, men in the highest quartile of CRP at baseline
were found to have a risk of future PAD 2.2 times that of men in the
lowest quartile (95% CI, 1.1 to 4.8; P=.04) (Table 2).
View this table:
[in a new window]
Table 2. Relative Risks of Developing Future
Peripheral Arterial Disease According to
Baseline Level of C-Reactive Protein , median levels of
baseline CRP were highest in the subgroup of 31 case subjects who
required peripheral arterial
revascularization in addition to developing
intermittent claudication. Relative risks for this end point increased
significantly from lowest to highest quartile of baseline CRP (relative
risks, 1.0, 1.8, 3.8, and 4.1; Ptrend=.02).
After adjustment for body mass index,
hypercholesterolemia, diabetes, and a family
history of atherosclerosis, relative risks of
revascularization from lowest to highest quartiles
of baseline CRP were 1.0, 2.8, 8.6, and 7.1
(Ptrend=.01).
View larger version (16K):
[in a new window]
Figure 1. Median levels of CRP at baseline among study participants who
subsequently developed intermittent claudication or who required
peripheral arterial
revascularization (case subjects) and for those who
remained free of vascular disease during follow- up (control
subjects).
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
These prospective data indicate that among apparently healthy men,
elevated baseline levels of CRP predict future risk of developing
symptomatic PAD. In previous data from this cohort,
elevated baseline levels of CRP were found to predict risk of future
myocardial infarction and thromboembolic stroke.3
Thus, these data extend the role of CRP as a marker of vascular risk
among otherwise healthy individuals and provide evidence that this
effect is not limited to the coronary and cerebral
circulations. Taken together, these observations and those from prior
studies3 4 5 6 7 8 support the hypothesis that CRP may
serve as a molecular marker for underlying systemic
atherosclerosis.
Acknowledgments
Supported by grants from the National Heart, Lung, and Blood
Institute as well as an established investigator award from the
American Heart Association, Dallas, Tex (Dr. Ridker).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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