American Journal of Epidemiology

Copyright 2001 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
242
Vol. 153, No. 3
Printed in U.S.A.
Association of Physical Activity with Inflammation Markers Geffken et al.
Association between Physical Activity and Markers of Inflammation in a
Healthy Elderly Population
Dominic F. Geffken,
1
Mary Cushman,
1,2
Gregory L. Burke,
3
Joseph F. Polak,
4
Pamela A. Sakkinen,
1
and
Russell P. Tracy
1,5
Higher levels of physical activity are associated with lower risk of cardiovascular disease. There is growing
evidence that the development of the atherosclerotic plaque is associated with inflammation. In this study, the
authors investigated the cross-sectional association between physical activity and markers of inflammation in a
healthy elderly population. Data obtained in 19891990 and 19921993 from the Cardiovascular Health Study,
a cohort of 5,888 men and women aged 65 years, were analyzed. Concentrations of the inflammation
markersC-reactive protein, fibrinogen, Factor VIII activity, white blood cells, and albuminwere compared
cross-sectionally by quartile of self-reported physical activity. Compared with persons in the lowest quartile,
those in the highest quartile of physical activity had 19%, 6%, 4%, and 3% lower concentrations of C-reactive
protein, white blood cells, fibrinogen, and Factor VIII activity, respectively, after adjustment for gender, the
presence of cardiovascular disease, age, race, smoking, body mass index, diabetes, and hypertension.
Multivariate regression models suggested that the association of higher levels of physical activity with lower
levels of inflammation markers may be mediated by body mass index and glucose. There was no association
between physical activity and albumin. Higher levels of physical activity were associated with lower
concentrations of four out of five inflammation markers in this elderly cohort. These data suggest that increased
exercise is associated with reduced inflammation. Prospective studies will be required for verification of these
findings. Am J Epidemiol 2001;153:24250.
atherosclerosis; cardiovascular diseases; C-reactive protein; exercise; Factor VIII; fibrinogen; inflammation;
leukocyte count
Received for publication April 9, 1999, and accepted for publica-
tion April 14, 2000.
Abbreviations: CHS, Cardiovascular Health Study; CV, coefficient
of variation.
1
Department of Pathology, College of Medicine, University of
Vermont, Burlington, VT.
2
Department of Medicine, College of Medicine, University of
Vermont, Burlington, VT.
3
Department of Public Health Sciences, Bowman Gray School of
Medicine, Wake Forest University, Winston-Salem, NC.
4
Department of Radiology, Harvard Medical School, Boston, MA.
5
Department of Biochemistry, College of Medicine, University of
Vermont, Burlington, VT.
Reprint requests to Dr. Russell P. Tracy, Colchester Research
Facility, University of Vermont College of Medicine, 55A South Park
Drive, Colchester, VT 05446 (e-mail: rtracy@salus.uvm.edu).
There is increasing evidence that the development of the
atherosclerotic plaque is associated with an inflammatory
process (14), and that measurement of this inflammation
has predictive value in determining risk for future throm-
botic events. Arecent meta-analysis revealed that there were
moderate but statistically significant associations between
four markers of inflammationC-reactive protein, fibrino-
gen, albumin, and white blood cellsand coronary heart
disease (5). High levels of Factor VIII activity have also
been shown to be associated with atherothrombotic events
in comparison with control levels (6, 7), and Factor VIII is
a known acute-phase reactant (8). Ridker et al. (9) found
that aspirin use decreased risk of myocardial infarction and
ischemic stroke in apparently healthy men, primarily in
those with the highest levels of C-reactive protein. This sug-
gests that even a moderate reduction in inflammation may
be protective.
There is evidence that physical activity may modify the
inflammatory process. Cross-sectional studies of physical
activity and physical fitness have shown inverse associations
with levels of fibrinogen (1014). Intervention studies have
demonstrated reductions in fibrinogen (1517) and C-reactive
protein (18) when exercise groups are compared with con-
trols, although the numbers of subjects in these latter studies
have been small and few elderly subjects have been studied.
The mechanism through which physical activity may be
associated with lower levels of inflammation markers is
unknown. Higher levels of C-reactive protein have also been
associated with obesity (19) and insulin resistance (20).
Physical activity is associated with lesser degrees of central
obesity (21, 22) and insulin resistance (2325). Taking these
findings together, one could speculate that physical activity
may be associated with lower levels of inflammation
through its inverse association with central obesity and
increasing insulin resistance.
In this study, we measured the association of self-reported
physical activity with several markers of inflammation in a

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

Association of Physical Activity with Inflammation Markers 243
Am J Epidemiol Vol. 153, No. 3, 2001
population-based elderly cohort, using data from the
Cardiovascular Health Study (CHS). Previous cross-
sectional analysis of a subgroup of CHS participants with
subclinical cardiovascular disease found inverse associa-
tions between exercise and fibrinogen levels in males and
females and between exercise and Factor VIII activity in
males (26). The markers of inflammation studied in this
analysis were C-reactive protein, fibrinogen, Factor VIII
activity, white blood cell count, and albumin.
MATERIALS AND METHODS
Study sample
A description of the population-based design of the CHS
and recruitment has been previously published (27). The
original cohort was recruited in 19891990 from four US
communities using a defined sample of Medicare beneficia-
ries aged 65 years. It consisted of 5,201 participants (2,962
females and 2,239 males). An additional group made up pre-
dominantly of African Americans was added to the cohort in
19921993 (431 females and 256 males) (28).
Eligible participants included all persons living in the
household of someone sampled from Health Care Financing
Administration eligibility lists who 1) were aged 65 years or
older; 2) were not institutionalized; 3) expected to remain in
the area for 3 years; and 4) were able to give informed con-
sent and did not require a proxy respondent. Participants
were eligible for the CHS regardless of whether they had a
history of cardiovascular disease. Excluded persons
included those who were wheelchair-bound and those who
were receiving hospice care or treatment for cancer.
In this study, we used the full cohort for analysis (n
5,888). Participants were classified from the baseline data as
having either clinical cardiovascular disease (n 2,051) or
no cardiovascular disease (n 3,837). Clinical disease was
defined as previously described (29), with the addition of
participants diagnosed with atrial fibrillation or myocardial
infarction by electrocardiogram.
Baseline examination
All data were obtained from the baseline examination,
which consisted of a home interview and a clinic examina-
tion. The baseline period for the original cohort was June
1989June 1990; for the new cohort, it was June 1992June
1993. During the home interview, information was collected
on medical history, medication use, and physical activity.
Information was also obtained on impairment of physical
functioning. The clinic examination included a fasting blood
sample, seated blood pressure and resting heart rate mea-
surements, anthropometric measurements, assessment of
ankle-brachial systolic blood pressure index, and a resting
electrocardiogram. Details on the baseline examination pro-
cedures have been provided elsewhere (27).
Measurement of variables
Assessment of leisure time physical activity in the CHS
has been described previously (26). During the baseline
examination, participants were asked whether they had
engaged in any of 15 leisure time activities in the prior 2
weeks. Participants were asked about their participation
in the following activities: swimming, hiking, aerobics,
tennis, jogging, racquetball, walking, gardening, mowing,
raking, golfing, bicycling, dancing, calisthenics, and rid-
ing an exercise cycle. The intensity of each activity has
been established and validated by the Minnesota Heart
Survey (30). Participant responses regarding type of
activity, frequency, and duration were used to calculate
leisure time physical activity, expressed in kilocalories
per week.
Blood collection occurred in the morning after an
overnight fast, as previously described (27, 31). Samples
were collected in ethylenediaminetetraacetic acid tubes and
were sent to laboratories located close to the field centers for
complete blood counts (not including differential white cell
count) (32). Separation of plasma and serum occurred
within 40 minutes after venipuncture; aliquots were frozen
on-site at 70C and then shipped on dry ice to the Central
Blood Analysis Laboratory at the University of Vermont.
Details on quality control methods and results have been
published elsewhere (31). Briefly, serum chemical analyses
were performed on the Kodak Ektachem 700 Analyzer
(Eastman Kodak Corporation, Rochester, New York),
including analyses of albumin (coefficient of variation
(CV) 3.25 percent) and glucose (CV 1.86 percent).
Plasma lipid analyses (standardized according to the
Centers for Disease Control and Prevention) were per-
formed on an Olympus Demand system (Olympus
Corporation, Lake Success, New York) and included mea-
surement of total cholesterol, triglycerides, and high den-
sity lipoprotein cholesterol (CV 3.56 percent). Insulin
was measured in a competitive radioimmunoassay
(Diagnostic Products Corporation, Malvern, Pennsylvania)
(CV 19.01 percent). Plasma fibrinogen was measured by
a modification of the method of Clauss (33), using a BBL
Fibrometer (Becton Dickinson, Cockeysville, Maryland;
CV 2.95 percent). The Factor VIII activity assay was
performed with the Coag-A-Mate X2 instrument (Organon-
Teknika, Durham, North Carolina) using factor immunode-
ficient plasma (Organon-Teknika) and partial thrombo-
plastin (Organon-Teknika). Factor VIII activity was stan-
dardized against reference material from the World Health
Organization (CV 9.74 percent). C-reactive protein was
measured using an enzyme-linked immunosorbent assay
technique (34), calibrated with the World Health Organi-
zation reference material (CV 8.9 percent).
Levels of albumin, fibrinogen, white blood cells, glucose,
and high density lipoprotein cholesterol were measured dur-
ing two separate time periods concurrent with enrollment of
the two cohorts. To adjust for possible analytical error due
to this time difference, we applied a correction factor to the
new cohort values, such that values for the new cohort (pre-
dominantly African Americans) were adjusted to mean val-
ues obtained for African Americans enrolled in the original
cohort. C-reactive protein was measured at the same time
for both cohorts. Factor VIII activity was not measured in
the new cohort.

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

244 Geffken et al.
Am J Epidemiol Vol. 153, No. 3, 2001
Statistical analysis
The Statistical Package for the Social Sciences (version
7.5) was used for analysis (SPSS, Inc., Chicago, Illinois).
Non-normally distributed continuous variables, including C-
reactive protein, white blood cell count, glucose, and high
density lipoprotein cholesterol, were natural log-transformed
so that parametric statistical tests could be applied. For ease
of interpretation, results of non-normally distributed variables
are reported as nontransformed values of the geometric
means. For some analyses, the physical activity variable
was divided into quartiles with the following boundaries:
1) <367.5 kcal/week (n 1,461), 2) 367.5<1,050 kcal/
week (n 1,461), 3) 1,050<2,270 kcal/week (n 1,478),
and 4) 2,270 kcal/week (n 1,468).
Initial analyses of physical activity and inflammation
markers according to cardiovascular disease risk factors
were performed with simple analysis of variance proce-
dures, Pearson correlations, and
2
tests for categorical vari-
ables.
Multivariate analysis of variance and linear regression
were used to analyze these associations in more detail. Risk
factors that were significantly related to physical activity
and the markers of inflammation were considered as covari-
ates in multivariate analyses and were used in multivariate
modeling if they remained significant. The standardized
effect size was calculated as the change in the inflammation
markers associated with a 1-standard-deviation change in
physical activity. We also used linear regression to explore
possible mediating variables with respect to the relation
between physical activity and C-reactive protein. An initial
model was constructed with the natural log of C-reactive
protein as the dependent variable and the natural log of
physical activity as the independent variable. The following
variables were then tested individually: gender, cardiovas-
cular disease status, age, smoking history, body mass index
(weight (kg)/height (m)
2
), fasting glucose, fasting insulin,
race, and hypertension status. Variables which caused a
decrease of 10 percent in the R
2
of physical activity were
entered into a model simultaneously. Any variables that
were then nonsignificant were removed from the final
model.
RESULTS
Results from bivariate analyses of the relations between
physical activity and cardiovascular disease risk factors are
shown in tables 1 and 2. Higher physical activity was asso-
ciated with younger age, male gender, Caucasian race, fewer
pack-years of cigarettes smoked, alcohol consumption,
lower body mass index, and lower levels of fasting glucose
and insulin. After stratification by gender, high density
lipoprotein cholesterol (positively) and fasting insulin (neg-
atively) were associated with physical activity in females
but not in males (results not shown). These results are simi-
lar to those from a previous study of exercise in CHS par-
ticipants with subclinical disease (26). Fewer participants
had clinical cardiovascular disease, hypertension, and dia-
betes at higher exercise levels.
Bivariate associations between the markers of inflamma-
tion and cardiovascular disease risk factors are shown in
tables 3 and 4. Age was positively correlated with fibrino-
gen, Factor VIII activity, and white blood cell count.
Females and African Americans had higher mean values for
TABLE 1. Mean values for cardiovascular disease risk factors, by quartile of physical activity: Cardiovascular Health Study,
19891990 and 19921993
Demographic characteristics
Age (years)
Lifestyle characteristics
Pack-years of smoking
Alcohol consumption (drinks/week)
Physical characteristics
Body mass index
Waist:hip ratio
Lipids, glucose, and insulin
High density lipoprotein cholesterol
(mg/ml)
Glucose (mg/dl)
Insulin (U/ml)
74.1
36.3
2.1
27.5
0.94
54.2
116.5
18.7
6.2
30.2
6.4
5.5
0.09
16.3
43.5
25.8
73.1
35.4
2.4
26.8
0.93
54.2
111.5
19.0
5.7
28.4
6.5
4.7
0.09
15.8
37.0
35.8
72.4
34.1
2.3
26.3
0.92
54.4
109.2
15.3
5.3
28.5
5.6
4.3
0.08
15.2
37.3
18.8
71.7
32.3
3.0
26.2
0.92
54.5
108.0
16.4
5.0
27.7
6.8
4.2
0.09
15.8
29.9
25.1
<0.001
0.041
<0.001
<0.001
<0.001
0.938
<0.001
<0.001
Variable
Physical activity quartile (kcal/week)
p
value*
<367.5
(n = 1,461)
367.51,049.9
(n = 1,461)
1,0502,269.9
(n = 1,478)
2,270
(n = 1,468)
Mean SD Mean SD Mean SD Mean SD
* Calculated using analysis of variance.
SD, standard deviation.
Calculated for former and current smokers only.
Weight (kg)/height (m)
2
.

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

Association of Physical Activity with Inflammation Markers 245
Am J Epidemiol Vol. 153, No. 3, 2001
C-reactive protein, fibrinogen, and Factor VIII activity in
comparison with males and Caucasians, respectively.
Higher mean values of C-reactive protein, fibrinogen, and
white blood cell count were seen in current smokers com-
pared with former and never smokers. These associations
between smoking, C-reactive protein, fibrinogen, and white
blood cell count are consistent with previous CHS analyses
(10, 19, 32). Mean Factor VIII activity was lower in current
smokers than in never and former smokers, as has been pre-
viously demonstrated (10). High density lipoprotein choles-
terol was negatively correlated with all of the markers
except albumin. Compared with those without disease, par-
ticipants with clinical cardiovascular disease and diabetes
showed higher mean values for all markers except albumin.
Alcohol consumption was inconsistently and weakly associ-
ated with inflammation markers (data not shown).
Results from analysis of variance are shown in figures
15. The adjusted mean values obtained for the inflamma-
tion markers are shown graphically by physical activity cat-
egory. Each marker of inflammation was adjusted for gen-
der, cardiovascular disease status, age, race, smoking status,
diabetes status, body mass index, and hypertension. Mean
values of the inflammation markers for the lowest and high-
est quartiles of physical activity, respectively, were as fol-
lows: C-reactive protein (mg/liter), 2.24 and 1.82 ( p trend <
0.001); white blood cell count (1,000 cells/l), 6.37 and
5.96 ( p trend < 0.001); fibrinogen (mg/dl), 329 and 317
( p trend < 0.001); Factor VIII activity (percent activity), 126
TABLE 2. Prevalence (%) of cardiovascular disease risk factors, by quartile of physical activity:
Cardiovascular Health Study, 19891990 and 19921993
Demographic characteristics
Female gender
African-American race
Lifestyle characteristics
Never smoked
Pharmacologic factors
Aspirin use
Disease status
Clinical cardiovascular disease
Diabetes mellitus
Hypertension
65.0
25.5
47.7
44.1
40.5
15.8
43.0
59.8
17.2
48.2
47.0
34.7
10.5
40.8
55.7
12.4
47.4
47.0
33.5
9.7
35.8
50.3
7.8
43.1
49.1
30.4
7.5
33.8
<0.001
<0.001
0.020
0.058
<0.001
<0.001
<0.001
Variable
Physical activity quartile (kcal/week)
<367.5
(n = 1,461)
367.51,049.9
(n = 1,461)
1,0502,269.9
(n = 1,478)
2,270
(n = 1,468)
p
value*
* Calculated using
2
analysis.
TABLE 3. Pearson correlations between markers of inflammation and cardiovascular disease risk
factors: Cardiovascular Health Study, 19891990 and 19921993
Demographic characteristics
Age (years)
Lifestyle characteristics
Pack-years of smoking
Physical characteristics
Body mass index
Waist:hip ratio
Lipids and glucose
High density lipoprotein
cholesterol (mg/dl)
Glucose (mg/dl)
0.024
0.134**
0.291**
0.149**
0.164**
0.182**
0.067**
0.095**
0.130**
0.059**
0.143**
0.081**
0.129**
0.003
0.095**
0.028*
0.049**
0.196**
0.042**
0.156**
0.081**
0.155**
0.162**
0.152**
0.097**
0.002
0.042**
0.017
0.000
0.063**
C-reactive
protein
(mg/liter)
Fibrinogen
(mg/dl)
Factor VIII
activity
(% activity)
White blood
cell count
(1,000/cells/l)
Albumin
(g/dl)
* p < 0.05; ** p 0.001 (obtained from linear regression analysis).
Former and current smokers only.
Weight (kg)/height (m)
2
.

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

246 Geffken et al.
Am J Epidemiol Vol. 153, No. 3, 2001
FIGURE 1. Adjusted mean values for C-reactive protein (CRP), by
quartile of physical activity: Cardiovascular Health Study, 19891990
and 19921993. Data were adjusted for gender, cardiovascular dis-
ease status, age, race, smoking status, diabetes status, body mass
index, and hypertension (p for trend 0.001). Note that the y axis is
truncated. Numbers in bars, number of subjects in quartile.
FIGURE 2. Adjusted mean values for white blood cell count (WBC),
by quartile of physical activity: Cardiovascular Health Study,
19891990 and 19921993. Data were adjusted for gender, cardio-
vascular disease status, age, race, smoking status, diabetes status,
body mass index, and hypertension (p for trend 0.001). Note that the
y axis is truncated. Numbers in bars, number of subjects in quartile.
and 122 ( p trend 0.016); and albumin (g/dl), 4.008 and
4.005 ( p trend 0.840). From adjusted linear regression,
the corresponding standardized effect sizes for a 1-standard-
deviation change in physical activity were 0.45 mg/liter for
C-reactive protein, 6.13 mg/dl for fibrinogen, 0.14
1,000 cells/l for white blood cell count, 2.70 percent
TABLE 4. Mean values for markers of inflammation, according to levels of cardiovascular disease risk factors: Cardiovascular
Health Study, 19891990 and 19921993
Demographic characteristics
Gender
Female (n = 3,393)
Male (n = 2,495)
Race
Caucasian (n = 4,927)
African-American (n = 916)
Lifestyle characteristics
Smoking
Never smoked (n = 2,738)
Former smoker (n = 2,444)
Current smoker (n = 700)
Pharmacologic factors
Aspirin use
No (n = 3,105)
Yes (n = 2,727)
Disease status
Clinical cardiovascular disease
Yes (n = 2,051)
No (n = 3,837)
Diabetes mellitus
Yes (n = 636)
No (n = 5,214)
Hypertension
Yes (n = 3,595)
No (n = 2,234)
2.05*
1.88
1.88**
2.60
1.85**
1.99
2.52
1.93
2.02
2.31**
1.82
2.76**
1.90
2.43**
1.73
2.80
2.83
2.77
2.90
2.77
2.84
2.85
2.85
2.79
2.85
2.78
2.90
2.79
2.74
2.81
324*
320
320**
335
321**
319
339
322
322
329**
319
337**
321
330**
317
66
69
65
74
65
68
70
68
66
71
65
74
66
70
64
125**
119
121**
138
124*
121
118
123
121
127**
120
138**
120
126**
120
38
36
37
45
39
37
35
38
37
39
37
40
37
39
37
6.03**
6.18
6.14**
5.88
5.88**
6.10
7.05
6.05*
6.14
6.32**
5.98
6.62**
6.03
6.26**
5.99
1.32
1.31
1.31
1.34
1.30
1.31
1.33
1.00
1.01
1.32
1.31
1.32
1.31
1.31
1.32
3.986**
4.026
4.007*
3.978
3.992*
4.017
3.993
4.006
4.001
4.003
4.003
4.002
4.003
4.015*
3.995
C-reactive
protein
(mg/liter)
Fibrinogen
(mg/dl)
Factor VIII
activity
(% activity)
White blood
cell count
(1,000/cells/l)
Mean SD Mean SD Mean SD
Albumin
(g/dl)
* p < 0.05; ** p 0.001 (obtained from analysis of variance).
SD, standard deviation.
Mean SD Mean SD
0.286
0.294
0.291
0.284
0.287
0.293
0.290
0.291
0.288
0.294
0.288
0.297
0.289
0.291
0.290

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

Association of Physical Activity with Inflammation Markers 247
Am J Epidemiol Vol. 153, No. 3, 2001
FIGURE 3. Adjusted mean values for fibrinogen, by quartile of
physical activity: Cardiovascular Health Study, 19891990 and
19921993. Data were adjusted for gender, cardiovascular disease
status, age, race, smoking status, diabetes status, body mass index,
and hypertension (p for trend 0.001). Note that the y axis is trun-
cated. Numbers in bars, number of subjects in quartile.
FIGURE 4. Adjusted mean values for Factor VIII activity (Factor
VIII:C), by quartile of physical activity: Cardiovascular Health Study,
19891990 and 19921993. Data were adjusted for gender, cardio-
vascular disease status, age, race, smoking status, diabetes status,
body mass index, and hypertension (p for trend = 0.016). Note that the
y axis is truncated. Numbers in bars, number of subjects in quartile.
FIGURE 5. Adjusted mean values for albumin, by quartile of phys-
ical activity: Cardiovascular Health Study, 19891990 and
19921993. Data were adjusted for gender, cardiovascular disease
status, age, race, smoking status, diabetes status, body mass index,
and hypertension (p for trend = 0.840). Note that the y axis is trun-
cated. Numbers in bars, number of subjects in quartile.
activity for Factor VIII activity, and 0.01 g/dl for albumin.
Participants aged 72 years showed associations similar to
those of participants aged <72 years (data not shown). For
the prediction of inflammation variables, no significant
interactions were observed between physical activity and
either cardiovascular disease status, gender, or smoking.
Using C-reactive protein as a representative inflammation
marker, we employed linear regression to explore possible
mediating variables. Table 5 shows that for C-reactive pro-
tein and physical activity, the greatest decrease in effect size
and partial R
2
was observed when body mass index was
included in the model. In the final multivariate model, phys-
ical activity retained its significance, as did body mass
index, glucose, and hypertension, while race did not.
DISCUSSION
The major findings of this study were: 1) physical activ-
ity as measured in the CHS was associated with signifi-
cantly lower levels of markers of inflammation, including
C-reactive protein, fibrinogen, Factor VIII activity, and
white blood cell count; 2) these findings were independent
of known cardiovascular disease risk factors; and 3) no sig-
TABLE 5. Results from multivariate linear regression
analysis of the natural log of C-reactive protein according to
the natural log of physical activity: Cardiovascular Health
Study, 19891990 and 19921993
C-reactive protein and
physical activity
With body mass index
With fasting glucose
With race
With hypertension status
Final model
0.333
0.254
0.294
0.289
0.301
0.208
0.014
0.009
0.011
0.010
0.011
0.006
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
Regression
model*
Standardized
effect size
(mg/liter)
p value
for physical
activity
Partial R
2
for physical
activity
* Top row represents C-reactive protein by physical activity
alone. Middle rows represent C-reactive protein by physical activity,
plus the variable listed. Bottom row represents the final model of C-
reactive protein by physical activity with body mass index, fasting
glucose, and hypertension status included.
Change in C-reactive protein for a 1-standard-deviation
change in physical activity.

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

248 Geffken et al.
Am J Epidemiol Vol. 153, No. 3, 2001
nificant association was observed between physical activity
and albumin.
The differences seen with higher levels of physical activ-
ity were independent of known cardiovascular disease risk
factors, as well as the presence or absence of clinical cardio-
vascular disease. This indicates that the observed differences
were not entirely due to these participants having fewer risk
factors or having had cardiovascular disease events. Lower
values of C-reactive protein, fibrinogen, Factor VIII activity,
and white blood cell count were associated with higher lev-
els of physical activity, but these associations were not of the
same magnitude: Comparing the highest quartile of physical
activity with the lowest, 19 percent, 6 percent, 4 percent, and
3 percent lower values were seen for C-reactive protein,
white blood cell count, fibrinogen, and Factor VIII activity,
respectively. C-reactive protein demonstrated strikingly
lower values when the three upper exercise quartiles were
compared with the lowest exercise quartile. Albumin was not
associated with physical activity at all. The reason for these
differences among markers is unknown. These markers are
known to respond differently to proinflammatory cytokines
as part of the acute-phase reaction (35); those differences
may be reflected in the associations we observed. From a
molecular genetic standpoint, differences in response to
exercise would not be unexpected, since the genetic regula-
tory elements for these markers are not identical.
Albumin was the only negative acute-phase protein inves-
tigated in this analysis (a negative acute-phase reactant
exhibits lower levels in the presence of inflammation), and
lower levels of albumin have been associated with increased
cardiovascular disease risk (36). Therefore, an association
with exercise would have been demonstrated by the pres-
ence of higher albumin levels with higher levels of physical
activity. However, no significant association was seen
between physical activity and albumin. No differences were
seen in albumin concentrations between participants with
and without clinical cardiovascular disease at baseline,
which calls into question the utility of albumin as a marker
of the atherosclerotic process in older people (table 4). This
is in contrast to the other markers of inflammation studied,
which were elevated in participants with clinical cardiovas-
cular disease compared with those without it. Because low
albumin concentrations have been associated with increased
risk of myocardial infarction and coronary heart disease
death in studies of middle-aged people (5, 36), the relation
between albumin and risk of cardiovascular disease
deserves further study in the older, population-based CHS
cohort.
Physical activity most likely confers cardioprotective
effects through multiple mechanisms. These could include
direct effects on the cardiovascular system through an
increase in stroke volume (37, 38) and an increase in max-
imal oxygen uptake (39). Exercise also increased the
dimensions of coronary arteries in an animal model (40).
Long term exercise regimens seem to predispose the coag-
ulation system toward fibrinolytic activity rather than
thrombotic activity, with higher levels of tissue plasmino-
gen activator activity and lower levels of plasminogen acti-
vator inhibitor-1 (17).
The association of physical activity with lower levels of
inflammation may provide another cardioprotective mecha-
nism, although this topic has received little prior investiga-
tion. Of the markers of inflammation we studied, the associ-
ation of fibrinogen with physical activity has been
investigated most often (1113, 41). In comparison with our
observations, these previous studies demonstrated similar
associations between physical activity and fibrinogen levels,
but they focused on the procoagulant activity of fibrinogen
rather than its role in inflammation.
One current concept regarding the pathophysiologic
mechanisms of the inflammation associated with atheroscle-
rosis concerns the production of proinflammatory cytokines
in response to stimuli from oxidized low density lipoproteins
and macrophages associated with the atherosclerotic plaque
(42, 43). The proinflammatory cytokines produced during
this process include interleukin-1 , interleukin-6, and
tumor necrosis factor-. In vitro studies have shown that
various combinations of these cytokines stimulate the pro-
duction of the inflammation-sensitive proteins C-reactive
protein (44), fibrinogen (45), and Factor VIII (8), as well as
leukocytosis (46). Prospective studies are needed to deter-
mine whether increased activity status in older people is
associated with cytokine lowering as well as changes in
acute-phase protein levels.
While no causation can be inferred from a cross-sectional
study, our results suggest that the association of physical activ-
ity with lower levels of inflammation may be mediated by the
association of exercise with lesser degrees of central obesity
and lower glucose levels. Inflammation as measured by C-
reactive protein is independently correlated with obesity (19).
Recent studies have shown that omental adipocytes from cen-
trally obese individuals produce higher levels of interleukin-6
and tumor necrosis factor- than do adipocytes from controls
(47, 48). In our analysis, physical activity was significantly
associated with decreasing body mass index and waist:hip
ratio; such associations have been reported in other studies
(22, 49, 50). Waist:hip ratio is considered a measurement of
central obesity (21). Taken together, these studies suggest that
central obesity is associated with an increased inflammatory
state, and that lesser degrees of central obesity associated with
exercise could also be associated with less inflammation.
Our findings of a negative correlation between physical
activity and levels of glucose are consistent with results of
other studies (24, 25). Insulin resistance is associated with
inflammation as measured by higher levels of C-reactive
protein and interleukin-6 and lower values for albumin
(5154). Physical activity has been shown to decrease insulin
resistance (24, 25), which suggests a hypothesis that
improved insulin sensitivity associated with physical activity
would also be associated with lower levels of inflammation.
In summary, we have identified an association between
self-reported physical activity and several markers of inflam-
mation in a cross-sectional study of the elderly. Lesser degrees
of central obesity and glucose levels associated with physical
activity may also be associated with these observed lower lev-
els of inflammation. These data suggest that reduced inflam-
mation is associated with increased exercise. Prospective
studies will be required for verification of these findings.

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

Association of Physical Activity with Inflammation Markers 249
Am J Epidemiol Vol. 153, No. 3, 2001
ACKNOWLEDGMENTS
This work was supported by Cardiovascular Health Study
contracts NO1-HC-85079-85086, KO8-HL-03618 (M. C.),
T32-HL-07594 (P. A. S.), and RO1-HL-46696 (R. P. T.) and
by grants from the Office of the Dean and the Department of
Pathology at the University of Vermont College of Medicine
(D. F. G.).
The authors thank the investigators and staff of the
Cardiovascular Health Study, especially Maureen Badger,
Elaine Cornell, Florence Keating, Elizabeth Macy, Sarah
Nightingale, Dr. Raymond Losito, and Adam Smiles of the
Central Blood Analysis Laboratory.
Cardiovascular Health Study investigators and staff:
Forsyth County, North CarolinaBowman Gray School of
Medicine, 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; EKG
Reading Center, Bowman Gray School of Medicine: Kris
Calhoun, Harry Calhoun, Farida Rautaharju, Pentti
Rautaharju, and Loralee Robertson; Sacramento County,
CaliforniaUniversity 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, MarylandJohns
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; MRI Reading Center,
Johns Hopkins University: 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, PennsylvaniaUniversity 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;
Orange County, CaliforniaEchocardiography Reading
Center (baseline), University of California, Irvine: Hoda
Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom
Kurosaki, and Nathan Wong; Washington, DCEcho-
cardiography Reading Center (follow-up), Georgetown
Medical Center: John Gottdiener, Eva Hausner, Stephen
Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, and
Retha Webb; Danville, PennsylvaniaUltrasound Reading
Center, Geisinger Medical Center: Daniel H. OLeary,
Joseph F. Polak, and Laurie Funk; Colchester, Vermont
Central Blood Analysis Laboratory, University of Vermont:
Edwin Bovill, Elaine Cornell, Mary Cushman, and Russell
P. Tracy; Tucson, ArizonaRespiratory Sciences,
University of Arizona, Tucson: Paul Enright; Seattle,
WashingtonCoordinating Center, University of
Washington, Seattle: 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; Bethesda, MarylandNational
Heart, Lung, and Blood Institute Project Office: Diane E.
Bild, Teri A. Manolio, Peter J. Savage, Patricia Smith, and
Rachel Solomon.
REFERENCES
1. Tracy R. Atherosclerosis, thrombosis and inflammation: a
problem of linkage. Fibrinolysis 1997;11:15.
2. Alexander RW. Inflammation and coronary artery disease.
(Editorial). N Engl J Med 1994;331:4689.
3. Ross R. The pathogenesis of atherosclerosis: a perspective for
the 1990s. Nature 1993;362:8019.
4. Munro J, Cotran R. The pathogenesis of atherosclerosis:
atherogenesis and inflammation. Lab Invest 1988;58:24961.
5. Danesh J, Collins R, Appleby P, et al. Association of fibrino-
gen, C-reactive protein, albumin, or leukocyte count with coro-
nary heart disease: meta-analyses of prospective studies.
JAMA 1998;279:147782.
6. Folsom A, Wu K, Rosamond W, et al. Prospective study of
hemostatic factors and incidence of coronary heart disease:
The Atherosclerosis Risk in Communities (ARIC) Study.
Circulation 1997;96:11028.
7. Cortellaro M, Boschetti C, Cofrancesco E, et al. The PLAT
Study: hemostatic function in relation to atherothrombotic
ischemic events in vascular disease patients. Principal results.
Progetto Lombardo Atero-Trombosi (PLAT) Study Group.
Arterioscler Thromb 1992;12:106370.
8. Stirling D, Hannant W, Ludlam C. Transcriptional activation
of the factor VIII gene in liver cell lines by interleukin-6.
Thromb Haemost 1998;79:748.
9. Ridker P, Cushman M, Stampfer M, et al. Inflammation,
aspirin, and the risk of cardiovascular disease in apparently
healthy men. N Engl J Med 1997;336:9739.
10. Cushman M, Yanez D, Psaty BM, et al. Association of fibrino-
gen and coagulation factors VII and VIII with cardiovascular
risk factors in the elderly: The Cardiovascular Health Study.
Cardiovascular Health Study Investigators. Am J Epidemiol
1996;143:66576.
11. Elwood P, Yarnell J, Pickering J, et al. Exercise, fibrinogen,
and other risk factors for ischaemic heart disease. Caerphilly
Prospective Heart Disease Study. Br Heart J 1993;69:1837.
12. Lakka TA, Salonen JT. Moderate to high intensity conditioning
leisure time physical activity and high cardiorespiratory fitness
are associated with reduced plasma fibrinogen in eastern
Finnish men. J Clin Epidemiol 1993;46:111927.
13. Connelly J, Cooper J, Meade T. Strenuous exercise, plasma
fibrinogen, and factor VII activity. Br Heart J 1992;67:3514.
14. Folsom A, Conlan M, Davis C, et al. Relations between hemo-
stasis variables and cardiovascular risk factors in middle-aged
adults. Atherosclerosis Risk in Communities (ARIC) Study
Investigators. Ann Epidemiol 1992;2:48194.
15. DeSouza C, Jones P, Seals D. Physical activity status and
adverse age-related differences in coagulation and fibrinolytic
factors in women. Arterioscler Thromb Vasc Biol 1998;18:
3628.
16. Zanettini R, Bettega D, Agostoni O, et al. Exercise training in
mild hypertension: effects on blood pressure, left ventricular
mass and coagulation factor VII and fibrinogen. Cardiology
1997;88:46873.
17. Stratton J, Chandler W, Schwartz R, et al. Effects of physical
conditioning on fibrinolytic variables and fibrinogen in young
and old healthy adults. Circulation 1991;83:16927.
18. Tisi P, Hulse M, Chulakadabba A, et al. Exercise training for
intermittent claudication: does it adversely affect biochemical
markers of the exercise-induced inflammatory response? Eur J
Vasc Endovasc Surg 1997;14:34450.

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m

250 Geffken et al.
Am J Epidemiol Vol. 153, No. 3, 2001
19. Tracy R, Psaty B, Macy E, et al. Lifetime smoking exposure
affects the association of C-reactive protein with cardiovascular
disease risk factors and subclinical disease in healthy elderly
subjects. Arterioscler Thromb Vasc Biol 1997;17:216776.
20. Juhan-Vague I, Thompson S, Jespersen J. Involvement of the
hemostatic system in the insulin resistance syndrome: a study
of 1500 patients with angina pectoris. The ECAT Angina
Pectoris Study Group. Arterioscler Thromb 1993;13:186573.
21. Samaras K, Campbell L. The non-genetic determinants of cen-
tral adiposity. Int J Obes Relat Metab Disord 1997;21:83945.
22. Kriska A, LaPorte R, Pettitt D, et al. The association of physi-
cal activity with obesity, fat distribution and glucose intoler-
ance in Pima Indians. Diabetologia 1993;36:8639.
23. Bloomgarden Z. Insulin resistance: current concepts. Clin Ther
1998;20:21631.
24. Mayer-Davis E, DAgostino RJ, Karter A, et al. Intensity and
amount of physical activity in relation to insulin sensitivity:
The Insulin Resistance Atherosclerosis Study. JAMA 1998;
279:66974.
25. Holloszy JO, Schultz J, Kusnierkiewicz J, et al. Effects of
exercise on glucose tolerance and insulin resistance: brief
review and some preliminary results. Acta Med Scand Suppl
1986;711:5565.
26. Siscovick DS, Fried L, Mittelmark M, et al. Exercise intensity
and subclinical cardiovascular disease in the elderly: The
Cardiovascular Health Study. Am J Epidemiol 1997;145:
97786.
27. Fried L, Borhani N, Enright P, et al. The Cardiovascular Health
Study: design and rationale. Ann Epidemiol 1991;1:26376.
28. Kuller L, Fisher L, McClelland R, et al. Differences in preva-
lence of and risk factors for subclinical vascular disease among
black and white participants in the Cardiovascular Health
Study. Arterioscler Thromb Vasc Biol 1998;18:28393.
29. Kuller L, Shemanski L, Psaty B, et al. Subclinical disease as an
independent risk factor for cardiovascular disease. Circulation
1995;92:7206.
30. Taylor H, Jacobs DJ, Schucker B, et al. Aquestionnaire for the
assessment of leisure time physical activities. J Chronic Dis
1978;31:74155.
31. Cushman M, Cornell E, Howard P, et al. Laboratory methods
and quality assurance in the Cardiovascular Health Study. Clin
Chem 1995;41:26470.
32. Bovill EG, Bild DE, Heiss G, et al. White blood cell counts in
persons aged 65 years or more from the Cardiovascular Health
Study: correlations with baseline clinical and demographic
characteristics. Am J Epidemiol 1996;143:110715.
33. Clauss A. Gerinnungsphysiologische Schnellmethode zur
Bestimmung des Fibrinogens. Acta Haematol 1957;17:23746.
34. Macy E, Hayes T, Tracy R. Variability in the measurement of
C-reactive protein in healthy subjects: implications for refer-
ence intervals and epidemiological applications. Clin Chem
1997;43:528.
35. Richards C, Gauldie J. Role of cytokines in acute-phase
response. In: Aggarwal BB, Puri RK, eds. Human cytokines:
their role in disease and therapy. Ann Arbor, MI: Blackwell
Scientific Publications, 1995:25370.
36. Kuller LH, Eichner JE, Orchard TJ, et al. The relation between
serum albumin levels and risk of coronary heart disease in the
Multiple Risk Factor Intervention Trial. Am J Epidemiol 1991;
134:126677.
37. Wolfe L, Martin R, Watson D, et al. Chronic exercise and left
ventricular structure and function in healthy human subjects. J
Appl Physiol 1985;58:40915.
38. Saltin B. Physiological effects of physical conditioning. Med
Sci Sports 1969;1:506.
39. Morris C, Froelicher V. Cardiovascular benefits of improved
exercise capacity. Sports Med 1993;16:22536.
40. Kramsch D, Aspen A, Abramowitz B, et al. Reduction of coro-
nary atherosclerosis by moderate conditioning exercise in mon-
keys on an atherogenic diet. N Engl J Med 1981;305:14839.
41. MacAuley D, McCrum EE, Stott G, et al. Physical activity,
physical fitness, blood pressure, and fibrinogen in the Northern
Ireland health and activity survey. J Epidemiol Community
Health 1996;50:25863.
42. Berliner JA, Navan M, Fogelman AM, et al. Atherosclerosis:
basic mechanisms. Oxidation, inflammation, and genetics.
Circulation 1995;91:248896.
43. Wick G, Romen M, Amberger A, et al. Atherosclerosis,
autoimmunity, and vascular-associated lymphoid tissue.
FASEB J 1997;11:1199207.
44. Smith J, McDonald T. Production of serum amyloid A and C-
reactive protein by HepG2 cells stimulated with combinations
of cytokines or monocyte conditioned media: the effects of
prednisolone. Clin Exp Immunol 1992;90:2939.
45. Baumann H, Isseroff H, Latimer J, et al. Phorbol ester modu-
lates interleukin 6- and interleukin 1-regulated expression of
acute-phase plasma proteins in hepatoma cells. J Biol Chem
1988;263:173906.
46. Mizel SB. The interleukins. FASEB J 1989;3:237988.
47. Fried S, Bunkin D, Greenberg A. Omental and subcutaneous
adipose tissues of obese subjects release interleukin-6: depot
difference and regulation by glucocorticoid. J Clin Endocrinol
Metab 1998;83:84750.
48. Spiegelman B, Flier J. Adipogenesis and obesity: rounding out
the big picture. Cell 1996;87:37789.
49. Williams P. Coronary heart disease risk factors of vigorously
active sexagenarians and septuagenarians. J Am Geriatr Soc
1998;46:13442.
50. Williams P. Relationships of heart disease risk factors to exer-
cise quantity and intensity. Arch Intern Med 1998;158:23745.
51. Howard G, Tracy R, Wagenknecht L, et al. Predictors of
inflammatory status in a middle-aged population. (Abstract).
Circulation 1999;99:1108.
52. Festa A, DAgostino R Jr, Mykkanen L, et al. Relative contri-
bution of insulin and its precursors to fibrinogen and PAI-1 in
a large population with different states of glucose tolerance:
The Insulin Resistance Atherosclerosis Study (IRAS).
Arterioscler Thromb Vasc Biol 1999;19:5628.
53. Pickup J, Mattock M, Chusney G, et al. NIDDM as a disease of
the innate immune system: association of acute-phase reactants
and interleukin-6 with metabolic syndrome X. Diabetologia
1997;40:128692.
54. McMillan D. Increased levels of acute-phase serum proteins in
diabetes. Metabolism 1989;38:10426.

b
y

g
u
e
s
t

o
n

M
a
r
c
h

2
9
,

2
0
1
1
a
j
e
.
o
x
f
o
r
d
j
o
u
r
n
a
l
s
.
o
r
g
D
o
w
n
l
o
a
d
e
d

f
r
o
m