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Relationship Between Physical Activity and Inflammation Among Apparently Healthy Middle-aged and Older US Adults
Jerome L. Abramson, PhD;
Viola Vaccarino, MD, PhD
Arch Intern Med. 2002;162:1286-1292.
ABSTRACT
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Background Physical activity has been associated with a reduced risk of coronary
heart disease, but the mechanism underlying this association is unclear. Because
coronary heart disease is increasingly seen as an inflammatory process, it
might be reasonable to hypothesize that physical activity reduces risk of
coronary heart disease by reducing or preventing inflammation.
Methods The study examined the relationship between physical activity and elevated
inflammation as indicated by a high C-reactive protein level, white blood
cell count, or fibrinogen level. Study subjects were 3638 apparently healthy
US men and women 40 years and older who participated in the Third National
Health and Nutrition Examination Survey.
Results More frequent physical activity was independently associated with a
lower odds of having an elevated C-reactive protein level. Compared with those
engaging in physical activity 0 to 3 times per month, the odds of having an
elevated C-reactive protein level was reduced among those engaging in physical
activity 4 to 21 times per month (odds ratio, 0.77; 95% confidence interval,
0.58-1.02) and 22 or more times per month (odds ratio, 0.63; 95% confidence
interval, 0.43-0.93) (P for trend, .02). Similar
associations were seen for white blood cell count and fibrinogen levels.
Conclusions More frequent physical activity is independently associated with a lower
odds of having elevated inflammation levels among apparently healthy US adults
40 years and older, independent of several confounding factors. The results
suggest that the association between physical activity and reduced coronary
heart disease risk may be mediated by anti-inflammatory effects of regular
physical activity.
INTRODUCTION
A NUMBER OF STUDIES have shown that physical activity is associated
with a lower risk of coronary heart disease (CHD).1-7
The mechanisms underlying this association are not entirely clear. Recent
reports have indicated that markers of inflammation are predictive of increased
CHD incidence and mortality,3, 8-14
and the development of CHD is increasingly being viewed as an inflammatory
process.15 As such, it might be reasonable
to hypothesize that if physical activity lowers CHD risk, it may do so in
part by preventing or reducing inflammation.
A few previous reports using general population samples have indicated
that higher levels of physical activity are cross-sectionally associated with
lower levels of inflammation markers such as C-reactive protein (CRP),16 white blood cell (WBC) count,16
and fibrinogen.16-22
These reports, however, have been limited to some degree in certain respects.
First, although several studies examined the association of physical activity
with fibrinogen, they did not examine the relationship between physical activity
and other markers of systemic inflammation, such as CRP, that are more established
markers of CHD risk.17-22
Second, some of the studies failed to control for healthy lifestyle practices,
particularly diet,16-22
which could potentially confound the association between physical activity
and inflammation. Third, several studies included persons with prevalent diseases
(such as CHD, stroke, asthma, emphysema, or rheumatoid arthritis) that could
confound this association.16-22
Some studies have attempted to statistically adjust for the presence of certain
diseases such as CHD,16 but one might expect
that despite such adjustment, there may be residual confounding according
to disease severity. A better strategy is to exclude persons with diseases
that could affect both physical activity and inflammation levels.
Given the limitations of the studies noted above, the relationship between
physical activity and inflammation in the general population remains unclear.
Accordingly, the present study examined the association of physical activity
with 3 markers of inflammation—CRP, WBC count, and fibrinogen—in
a representative sample of apparently healthy US adults after control for
diet and other potential confounding factors.
SUBJECTS AND METHODS
STUDY DESIGN AND PARTICIPANTS
The present study was based on data from the Third National Health and
Nutrition Examination Survey (NHANES III), a cross-sectional study conducted
from 1988 to 1994 by the National Center for Health Statistics of the US Centers
for Disease Control and Prevention, Atlanta, Ga. Using a complex, stratified,
cluster-sampling procedure, investigators assembled a group of 33 994
participants who were representative of the noninstitutionalized civilian
US population. Data on each study participant were collected in 2 stages.
The first stage involved an initial in-home interview in which participants
were questioned about demographic factors, health status, health behaviors,
and a variety of other variables. The second stage, which was conducted within
4 weeks after the initial in-home interview, involved the administration of
additional questionnaires as well as a medical examination by a board-eligible
physician. Further details about the design of NHANES III have been published
elsewhere.23
Of the 33 994 persons who participated in NHANES III, we excluded
22 546 persons who were younger than 40 years. Excluding persons younger
than 40 years was necessary because fibrinogen, one of the markers of inflammation
included in our analysis, was measured only in subjects 40 years or older.
We additionally excluded 6332 persons with a history of diseases that could
affect inflammation levels as well as one's ability to engage in physical
activity. These diseases included rheumatoid arthritis, asthma, bronchitis,
emphysema, cancer, stroke, diabetes, heart failure, and CHD. The history of
each of the aforementioned diseases was based on self-report, except for history
of CHD, which was based on self-reported CHD history (myocardial infarction
or angina) or an electrocardiogram reading during the medical examination
that was indicative of a previous myocardial infarction. We further excluded
1478 persons with missing data on physical activity, markers of inflammation,
or other covariates used in our analyses. After all exclusions, the present
study arrived at a sample of 3638 apparently healthy adults 40 years or older.
STUDY MEASURES
Physical Activity
During the household interview, participants were asked about the frequency
with which they had participated in the following 9 activities during the
preceding month: walking a mile without stopping, jogging or running, swimming,
regular dancing, aerobic exercise or aerobic dancing, riding a regular bicycle
or exercise bicycle, calisthenics, garden or yard work, and weight lifting.
They were also asked to list the frequency with which they participated in
up to 4 physical activities not included in the list noted above. From this
information, the total number of times that a participant engaged in any physical
activity in the month before the household interview was determined. Only
frequency of activity was recorded; no information on duration of each activity
was collected.
Markers of Inflammation
During the medical examination, phlebotomists obtained blood samples
from participants by venipuncture. These samples were stored in vials in refrigerated
(4°C to 8°C) or frozen (-20°C) conditions, and then sent
to analytical laboratories for testing. We chose to focus on 3 markers of
inflammation that were obtained from these samples: serum CRP level, WBC count,
and plasma fibrinogen level. These markers were chosen because each has been
associated with CHD risk.9-10,14
The CRP level was measured by means of latex-enhanced nephelometry. This method
of measuring CRP was unable to detect CRP levels less than 0.22 mg/dL. Thus,
persons with CRP levels below this limit were simply grouped together as having
CRP levels that were in the "undetectable" range of less than 0.22 mg/dL.
White blood cell count was measured using a quantitative automated hematology
analyzer (Coulter Counter Model S-Plus JR; Coulter Electronics, Hialeah, Fla).
Fibrinogen levels were determined by a quantitative assay that compared the
clotting time of a blood sample with the clotting time of a standardized fibrinogen
preparation. Quality control procedures relating to the measurement of CRP,
WBC, and fibrinogen in NHANES III have been described previously.24
Other Study Measures
To see whether physical activity was associated with inflammatory markers
independent of other factors that may predict inflammation, we included a
number of other factors in our analyses as control variables. Demographic
factors included age, sex, 3 categories of race (white, black, and other),
and 3 categories of educational attainment (<12 years, 12 years, and >12
years). Total and high-density lipoprotein cholesterol levels, as well as
serum glucose levels, were also included in analyses. Anthropometric measurements
allowed us to include 2 measures of obesity—body mass index (weight
in kilograms divided by the square of height in meters) and waist-to-hip ratio—in
our analyses. Smoking status was accounted for on the basis of self-reported
smoking of cigarettes, cigars, or pipes, and participants were categorized
as current smokers, past smokers, or never smokers. Frequency of alcohol consumption
during the preceding month was categorized as 0 times, 1 to 30 times, and
more than 30 times. Current use of antihypertensive medications, based on
self-report, was also included as a variable in our analyses. Finally, we
also controlled for dietary factors that we thought might be indicative of
an overall healthy diet. These dietary factors included total fat intake as
well as total intake of vitamins C and E as determined from a 24-hour food
recall completed during the household interview.
STATISTICAL ANALYSIS
The main goal of the analysis was to determine whether the frequency
of physical activity was associated with markers of inflammation after controlling
for other factors. We accomplished this goal by running multivariable adjusted
logistic regression models that used physical activity as the predictor variable
and dichotomous indicators of elevated levels of CRP, WBC, or fibrinogen as
the outcome variables. The other study measures were included as control variables
in these models. In the logistic regression models, the frequency of physical
activity in the previous month was divided into 3 levels: low (0-3 times),
medium (4-21 times), and high (22 or more times). The highest 2 activity levels
were entered into the models as dummy variables, and the lowest activity level
was treated as the referent level. These 3 levels of activity were chosen
because they represented approximate tertiles of the weighted distribution
of the frequency of physical activity in our sample. Elevated levels of CRP,
WBC, and fibrinogen were defined as greater than or equal to 0.70 mg/dL, greater
than or equal to 9550/µL, and greater than or equal to 373 mg/dL, respectively
(top 10% of the weighted distribution of each marker). We decided to analyze
these inflammation markers as dichotomous outcomes in a logistic regression
model because the distributions of the markers (especially CRP) were quite
skewed, which would have made analyzing these markers as continuous variables
in a linear regression model potentially inappropriate. The top 10% cutoff
points ensured that the odds ratios (ORs) generated by the logistic regression
models would be roughly interpretable as relative risks.25
Other study measures were entered into the models as continuous independent
variables (age, systolic and diastolic blood pressure, body mass index and
waist-to-hip ratio, glucose, total fat intake, and total intake of vitamins
C and E) or categorical variables according to the categories described above
(sex, race, smoking, alcohol consumption, and antihypertensive medication
use). To test whether a linear trend existed between increasing levels of
physical activity and the odds of having an elevated inflammation level, we
ran models that contained an ordinal physical activity variable. This ordinal
variable was created by assigning values of 1, 2, and 3 to persons reporting
an activity frequency of 0 to 3, 4 to 21, and 22 or more times per month,
respectively.
Because NHANES III was a complex, stratified cluster sample, standard
statistical techniques that assume a simple random sample are inappropriate.
Consequently, all of our analyses were conducted in SUDAAN (Research Triangle
Institute, Research Triangle Park, NC), a statistical program that accounts
for the complex design of the NHANES III sample. In particular, SUDAAN allowed
us to incorporate sampling weights that corrected for unequal probabilities
of selection and differential nonresponse rates, thereby ensuring that the
results of our analyses would be generalizable to the population from which
the NHANES III sample was drawn (ie, the noninstitutionalized civilian population
of the United States). All of the means, percentages, and ORs presented in
this study are weighted. In addition, the weighting, stratification, and clustering
inherent in the NHANES III sample can affect SEs, and SUDAAN uses techniques
to adjust the SEs accordingly. This ensured that the SEs and P values reported in our study were valid given the complex nature
of the sample.
RESULTS
Of the 3638 persons included in our analyses, the mean age was 52.9
years. Slightly less than half (49.4%) of the participants were female. Whites
made up 87.8% of the sample, while 8.1% of the participants were black and
4.1% were members of other racial or ethnic groups. Approximately 34.8%, 31.5%,
and 33.7% of the participants reported engaging in physical activity 0 to
3 times, 4 to 21 times, and 22 or more times in the preceding month, respectively.
The means ± SEs of CRP, WBC, and fibrinogen values for the study population
were 0.37 ± 0.01 mg/dL, 6990 ± 70/µL, and 290.37 ±
2.96 mg/dL, respectively. However, approximately 78% of the participants had
CRP levels in the "undetectable" range of less than 0.22 mg/dL and were simply
recorded as having a CRP level of 0.21 mg/dL; thus, the mean value reported
above for CRP is not entirely accurate. The percentages of participants with
elevated levels of CRP, WBC, and fibrinogen were 10.5%, 10.1%, and 10.1%,
respectively.
Figure 1 shows the crude percentage
of participants with elevated CRP, WBC, and fibrinogen levels according to
physical activity level. Persons who engaged in physical activity more frequently
were less likely to have elevated CRP levels. Among those engaging in low,
medium, and high physical activity levels, the percentages of persons with
elevated CRP levels were 15.1%, 9.7%, and 6.5%, respectively (P<.001 according to  2 test). Similarly, the percentage
of persons with elevated WBC or fibrinogen levels decreased with increasing
levels of physical activity (2, P<.001
and .01, respectively). In addition to showing crude associations with CRP,
WBC, and fibrinogen levels, however, physical activity showed crude associations
with many of the other study variables (Table 1). For example, higher levels of physical activity were less
likely to be seen among women and among those taking antihypertensive medication,
whereas they were more likely to be seen among those with higher education
levels and those with frequent alcohol consumption. In addition, increasing
levels of physical activity tended to be associated with lower mean values
of age, systolic and diastolic blood pressures, total cholesterol level, body
mass index, and waist-to-hip ratio. In contrast, higher physical activity
levels were associated with higher mean values of high-density lipoprotein
cholesterol and vitamin C intake. Physical activity did not show a clear relationship
with race, although there did seem to be evidence that the middle category
of physical activity was less common among black and members of other racial
or ethnic groups. With regard to smoking status, there was some indication
that higher levels of activity were more likely to be seen among former smokers
and less likely to be seen among current smokers.
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Unadjusted percentages of persons with elevated C-reactive protein
(CRP) levels, white blood cell (WBC) count, and fibrinogen levels, according
to frequency of physical activity. See "Study Measures" subsection of the
"Subjects and Methods" section for definitions. P values by 2 for the unadjusted associations of physical activity with CRP, WBC,
and fibrinogen were P<.001, P<.001, and P = .01, respectively.
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Table 1. Unadjusted Association of Other Study Variables With Physical
Activity Level*
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To see whether the unadjusted associations between physical activity
and markers of elevated inflammation would withstand adjustment for other
study variables, we ran multivariable-adjusted logistic regression models
(Table 2). Model 1 showed that,
as physical activity levels increased, the odds of having an elevated CRP
level significantly decreased, independent of other factors. For those engaging
in physical activity 4 to 21 times and 22 or more times in the previous month,
the ORs of having an elevated CRP level were 0.77 (95% confidence interval
[CI], 0.58-1.02) and 0.63 (95% CI, 0.43-0.93), respectively (P for trend, .02), compared with those engaging in physical activity
0 to 3 times.
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Table 2. Multivariable-Adjusted Logistic Regression Models Assessing
the Association Between Physical Activity and Markers of Inflammation*
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Similarly, model 2 showed a significant trend between increasing physical
activity levels and lower odds of having an elevated WBC count after adjustment
for other factors. For those with medium and high levels of physical activity
in the preceding month, the ORs of having an elevated WBC count were 0.81
(95% CI, 0.55-1.19), and 0.59 (95% CI, 0.41-0.84), respectively (P for trend, .006), compared with those with a low level of physical
activity.
Model 3 showed an association between increasing physical activity and
a decreasing odds of having an elevated fibrinogen level. However, the association
in model 3 did not achieve statistical significance. For those engaging in
physical activity 4 to 21 times and 22 or more times in the previous month,
the ORs of having an elevated fibrinogen level were 0.77 (95% CI, 0.52-1.16),
and 0.77 (95% CI, 0.56-1.06), respectively (P for
trend, .10), compared with those with the lowest physical activity level.
We then conducted 2 sets of secondary analyses. First, because of recent
interest in possible sex differences in chronic disease risk factors and outcomes,
we attempted to see whether there was an interaction between sex and physical
activity on inflammation outcomes. In logistic regression models, however,
we found that terms representing the interaction between sex and physical
activity were not significant predictors of any of the 3 inflammatory outcomes
(data not shown). Second, because our categorization of physical activity
into tertiles led to fairly broad categories, we sought to examine how a more
refined categorization of physical activity would be related to the inflammation
outcomes. Thus, we divided physical activity into quartiles (0-1 time, 2-9
times, 10-29 times, and  30 times in the previous month). The results from
using quartiles in adjusted logistic regression models were fairly similar
to those that were obtained when tertiles were used, although the linearity
of the association was not as clear. For example, we found that increasing
quartiles of activity tended to be associated with a reduced odds of having
an elevated CRP level. For those in the second through fourth quartiles, the
ORs of having an elevated CRP level compared with those in the first quartile
were 0.77, 0.81, and 0.55, respectively (P for trend,
.001). For the WBC outcome, the results for the second through fourth quartiles
were 0.66, 0.55, and 0.51, respectively (P for trend,
.005), compared with the lowest quartile of physical activity. For the fibrinogen
outcome, the ORs for the second through fourth quartiles were 0.81, 0.82,
and 0.77, respectively (P for trend, .17), compared
with the first quartile.
COMMENT
The present study investigated the cross-sectional relationship between
physical activity and markers of systemic inflammation among a representative
sample of apparently healthy middle-aged and older US adults. The findings
of the study indicated that a higher frequency of physical activity was associated
with a significantly lower odds of having elevated CRP and WBC levels after
adjustment for a number of potential confounding factors. The study also found
that more frequent physical activity was associated with a lower odds of having
an elevated fibrinogen level after controlling for confounders, although this
association was not statistically significant. Overall, these results suggest
that more frequent physical activity may be associated with lower levels of
systemic inflammation among healthy US adults who are 40 years or older.
Previous cross-sectional studies had reported that higher activity levels
were associated with lower levels of inflammation markers such as CRP,16 WBC,16 and fibrinogen.16-22
As noted earlier however, these previous studies were limited in a number
of respects. First, some studies examined the association of physical activity
with fibrinogen level but failed to look at the relationship between physical
activity and other markers of systemic inflammation, such as CRP level, that
are more established predictors of CHD.17-22
Second, other studies failed to control for important potential confounders
such as diet.16-22
Third, some of the previous studies were based on cross-sectional analyses
of samples that included persons with existing diseases that could affect
both inflammation and physical activity such as CHD, emphysema, and rheumatoid
arthritis. This third limitation is highly problematic because it could cause
one to find an inverse association between activity and inflammation, simply
because the diseases with high inflammation levels are precluding persons
from being active. The present study overcomes the limitations of these previous
studies to a certain extent, and therefore provides stronger evidence that
a higher frequency of physical activity may help reduce levels of systemic
inflammation in the general population.
Although the findings of the present study indicate that physical activity
may help reduce inflammation, one must consider that this study had a number
of limitations that may have affected its findings. First, our measurement
of physical activity was fairly crude in that it was based on self-report
and assessed only frequency of activity without considering duration of activity.
In addition, although quality control measures were used to help ensure that
the measurements of the inflammation markers were as accurate as possible,
it is likely that there was some mismeasurement of these markers. Thus, both
physical activity and inflammation were probably misclassified to a certain
extent in this study. However, it is likely that such misclassification was
random and would have biased our results toward the null. As such, misclassification
of this type would not explain away our results, but instead would suggest
that we may have underestimated the inverse association between physical activity
and inflammation.
Second, our study was based on observational data. Therefore, our findings
may have been due to residual confounding from some of our control variables.
In addition, there may have been some unknown confounders that we did not
control for, and these unknown confounders may have affected our results.
Third, as was the case with previous large-scale epidemiologic studies
investigating the association between physical activity and markers of inflammation,
our study was based on cross-sectional data. Consequently, the temporal ordering
of the association we observed between physical activity and reduced levels
of inflammation is unclear. The association could indicate that activity reduces
inflammation or protects against the onset of inflammation, but it could also
indicate that diseases associated with elevated inflammation levels prevent
one from being active. As already noted, we minimized the possibility of the
latter scenario by excluding persons with diseases that could be related to
inflammation and the ability to be active. However, it is certainly possible
that persons with subclinical diseases were included in our study. Thus, we
cannot rule out that our results are due to the fact that diseases with high
inflammation levels precluded persons from being active in our study. However,
2 studies based on very small samples have shown that physical activity can
prospectively reduce CRP levels.26-27
Because of small sample sizes, the generalizability of these 2 studies is
limited. Nevertheless, they suggest that the findings of the present study
may reasonably be interpreted to indicate that physical activity leads to
the prevention or reduction of systemic inflammation.
Assuming physical activity does indeed help prevent or reduce inflammation,
what is the mechanism by which it would accomplish this effect? Strenuous
physical activity can lead to muscle damage and thereby increase inflammation.28 In contrast, however, there are plausible mechanisms
by which physical activity could also reduce inflammation. For example, obesity
is a factor that is strongly related to higher levels of inflammation,29 and it has been suggested that physical activity
may reduce inflammation by reducing obesity levels.16
However, in the present study, we observed that physical activity was associated
with lower levels of inflammation even after adjustment for measures of general
obesity (body mass index) and central obesity (waist-to-hip ratio). Thus,
it seems unlikely that the association between activity and inflammation is
mediated entirely by reductions in obesity. Other mechanisms linking exercise
to lower inflammation levels may involve antioxidant effects of exercise.
Although exercise increases oxidative metabolism and thereby induces oxidative
stress, there is also evidence from studies involving animals and humans that
adapting to long-term exercise or physical training can significantly elevate
antioxidant defenses.30-34
The ability of long-term exercise to induce an antioxidant effect may explain
why such exercise has been reported to reduce the susceptibility of low-density
lipoprotein to oxidation35 and prevent age-related
impairment in nitric oxide availability.36
Preventing low-density lipoprotein oxidation and impairments in nitric oxide
availability would, in turn, help prevent endothelial injury or dysfunction
and the inflammation that could result from such dysfunction. Indeed, some
investigators have reported that exercise does improve coronary endothelial
dysfunction in persons with existing CHD.37
Still other evidence indicates that physical training decreases the expression
of adhesion molecules on leukocytes,38 a phenomenon
that would presumably inhibit the inflammatory process. The effects of physical
training on antioxidant defenses, oxidation of low-density lipoprotein, availability
of nitric oxide, and adhesion molecule expression are far from clear, however,
and explaining the association we found in terms of such effects is necessarily
speculative.
In summary, the present study has demonstrated that increasing levels
of physical activity are associated with lower levels of CRP and other markers
of inflammation in a representative sample of apparently healthy middle-aged
and older US adults. Since elevated levels of CRP and other markers of inflammation
have been shown to be important predictors of increased CHD risk, the current
study implies, although it does not prove, that physical activity may lower
CHD risk by reducing inflammation. Studies that examine physical activity
as a prospective predictor of inflammation in general population samples are
needed to definitively establish whether physical activity truly prevents
or reduces inflammation, and whether this reduction accounts for the association
between increased physical activity and lower CHD risk. In addition, if physical
activity is proved to reduce inflammation, further research would need to
clarify the duration and intensity of activity that is required to best achieve
reductions in inflammation.
AUTHOR INFORMATION
Accepted for publication October 15, 2001.
Corresponding author and reprints: Jerome L. Abramson, PhD, Department
of Medicine (Cardiology), Emory University School of Medicine, 1256 Briarcliff
Rd NE, Suite 1 North, Atlanta, GA 30306 (e-mail: jabram3{at}emory.edu).
From the Division of Cardiology, Department of Medicine, Emory University
School of Medicine, Atlanta, Ga.
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