Exercise in Cardiovascular Disease
Physical Activity and Cardiovascular Health
Lessons Learned From Epidemiological Studies Across Age, Gender,
and Race/Ethnicity
Eric J. Shiroma, MSc; I-Min Lee, MBBS, ScD
I
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n 1953, Morris et al1,2 published the findings from a study
showing that bus conductors in London, who spent their
working hours walking the length of the buses as well as
climbing up and down the stairs of the English double-decker
buses to collect fares, experienced half the coronary heart
disease (CHD) mortality rates of their driver counterparts,
who spent their day sitting behind the wheel. Investigators
hypothesized that it was the physical activity of work that
protected the conductors from developing CHD, at the same
time realizing that other factors may also play a role because
the conductors were smaller in size, as evidenced by their
smaller uniform sizes. Thus was born the field of “physical
activity epidemiology”: formal epidemiological investigations into the associations of physical activity with many
health outcomes.4
Since the initial observations of Morris et al, many other
studies have been conducted, yielding similar results: Active
people have lower rates of CHD and cardiovascular disease
(CVD) than inactive ones.5–7 These findings have been
supported by plausible biological mechanisms, which are
detailed in other articles in this review series. The collective
body of evidence led the American Heart Association in 1992
to recognize physical inactivity as a risk factor for CHD and
CVD8 and led the Surgeon General in 1996 to conclude that
“regular physical activity or cardiorespiratory fitness decreases the risk of CVD … and CHD.”9 The basis for these
conclusions was derived primarily from studies in men and in
white populations; for example, in a 1990 meta-analysis of
physical activity in the prevention of CHD10 that included 33
studies, women were subjects in 5 studies, and racial/ethnic
minorities were the focus of 2 studies.
In 2008, the federal government issued its first-ever physical activity guidelines for Americans11 based on a comprehensive and systematic review of studies published since the
1996 Surgeon General’s report on physical activity and
health.9 Many of these studies now included women, and
several also included substantial numbers of racial/ethnic
minorities as subjects. The purpose of this review is to
summarize the current state of knowledge about physical
activity and cardiovascular health on the basis of epidemio-
logical studies included in the systematic evidence review5 of
the 2008 Physical Activity Guidelines for Americans (hereafter referred to as the 2008 Guidelines) and supplemented by
recent studies published after the review. In particular, 3 specific
questions are addressed, with reference to age, gender, and
racial/ethnic subgroups where applicable:
1. What is the magnitude of the association between
physical activity and CHD/CVD?
2. Is there a dose-response relation between physical
activity and CHD/CVD? If so, what is the shape of the
dose-response curve?
3. Can physical activity ameliorate the increased risk of
CHD/CVD associated with adiposity?
Magnitude of the Association
There is substantial evidence, all from observational epidemiological studies, to support an inverse relationship between
physical activity and CHD/CVD risk.5–7 For the purpose of
this review, we will focus on the findings from prospective
cohort studies because this study design represents the strongest observational study design, minimizing the potential for
bias from recall of physical activity. In these studies, investigators typically have defined CHD as including myocardial
infarction, revascularization procedures, and angina and have
defined CVD as including CHD, cerebrovascular disease, and
cardiovascular death.
The systematic evidence review behind the 2008 Guidelines
summarized 30 prospective cohort studies published between
1995 and 2007, all using self-reported data on physical activity,
to examine the association with CHD risk (Table).5 These
studies were conducted in a several countries including the
United States (14 studies),12–25 the United Kingdom (5),26 –30
Finland (4),31–34 Sweden (3),35–37 Canada (2),38,39 Israel (1),40
and Norway (1).41 In total, these studies included ⬎141 000
men and ⬎263 000 women in gender-specific analyses and
⬎50 000 subjects in analyses of both genders combined.
However, few of the reviewed studies focused on older (ⱖ65
years) or minority subjects. Only 2 studies were conducted in
which the median age of participants was ⱖ65 years,18,23 and
From the Department of Epidemiology, Harvard School of Public Health (E.J.S., I.L.), and Division of Preventive Medicine, Brigham and Women’s
Hospital, Harvard Medical School (I.L.), Boston, Mass.
Correspondence to I-Min Lee, MD, ScD, Brigham and Women’s Hospital and Harvard Medical School, 900 Commonwealth Ave E, Boston, MA
02215. E-mail [email protected]
(Circulation. 2010;122:743-752.)
© 2010 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.109.914721
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Prospective Cohort Studies of Physical Activity and Risk of CHD or CVD
No. of Studies
(No. of Subjects)
No. of Studies With Mean or Median
Age ⱖ65 y (No. of Subjects)
No. of Studies With
⬎10% Minorities* (No. of Subjects)
CHD
17 (141 074)
2 (14 644)
2 (6873)
CVD
10 (68 438)
0 (0)
0 (0)
CHD
13 (263 274)
0 (0)
1 (7833)
CVD
13 (347 827)
1 (9518)
3 (150 404)
Studies of men only
Studies of women only
Studies including both
men and women
CHD
5 (50 177)
0 (0)
0 (0)
CVD
5 (88 245)
1 (1845)
2 (15 921)
*Includes studies of nonwhite subjects outside of the United States.
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another 2 studies included ⬎10% nonwhite subjects in their
investigations.12,14
In the systematic evidence review supporting the 2008
Guidelines, the expert panel concluded that compared with the
least active subjects, the most active men and women had
median risk reductions of ⬇30% to 35% for developing CHD.5
The amount of physical activity currently recommended,11 at
least 150 min/wk of moderate-intensity aerobic physical
activity or 75 min/wk of vigorous-intensity aerobic physical
activity, is clearly associated with reduced risk. Furthermore,
the available data also suggest that this does not represent a
minimum threshold level for risk reduction. In fact, some data
suggest that especially among those with very low levels of
physical activity or who are unfit, even smaller amounts of
physical activity may be associated with CHD/CVD risk,
supporting a “some is good; more is better” message (see
additional discussion under “Dose-Response Relation”
below).
With regard to CVD, a similar picture was observed in data
from prospective cohort studies (Table). The systematic
evidence review supporting the 2008 Guidelines summarized
the findings from 20 prospective cohort studies on this topic
that were published between 1995 and 2007.5 The magnitude
of the inverse association with CVD was generally similar to
that observed for CHD. These studies of CVD were conducted in the United States (7 studies),19,42– 47 Finland
(3),34,48,49 the United Kingdom (3),30,50,51 Germany (2),52,53
Sweden (2),54,55 Norway (1),41 Canada (1),38 and China (1).56
These studies included ⬎68 000 men and ⬎347 000 women
in gender-specific analyses and ⬎88 000 men and women in
analyses that combined both genders. As with the CHD
studies, only 2 studies were conducted in which the median
age of participants was ⱖ65 years,42,46 and 5 studies included
populations with ⬎10% nonwhite subjects.42,45– 47,56
Since the systematic evidence review behind the 2008
Guidelines was published, 4 additional prospective cohort
studies have been published.57– 60 These recent studies report
results that are in agreement with the aforementioned findings. The median risk reduction observed in the 4 studies for
CHD/CVD, comparing most active with least active subjects,
was ⬇40% (range, 25% to 50%).
Because the inverse association of physical activity and
CHD/CVD risk is observed from data derived only from
observational studies and not from randomized controlled
trials, these data cannot prove a causal relation. However, the
available evidence strongly supports a causal relationship
between increased activity and decreased risk of disease.
Most importantly, plausible biological mechanisms, demonstrated in randomized clinical trials, exist, which are discussed in other articles in this review. Second, the findings
from these studies, published in many countries throughout
the world, overall showed consistent inverse associations
between physical activity and CHD/CVD risk. Third, bias
due to decreased physical activity from ill health (ie, a
spurious inverse relation, with ill health causing decreased
physical activity rather than physical activity causing lower
mortality rates) is unlikely because many studies excluded
subjects with CVD and cancer, major causes of ill-health, at
baseline. Additionally, many of the studies had long
follow-up periods, thus diluting the bias from ill health
decreasing physical activity because with longer years of
follow-up, more of the ill subjects die.
Fourth, although misclassification of physical activity
likely existed because all of the studies used self-reported
physical activity, because of the prospective nature of the
study design, this misclassification is most likely random and
thus would tend to attenuate observed findings toward the
null. The prospective cohort study design also prevents
recall bias (ie, participants could not be influenced by the
presence of disease because they reported their physical
activity before the onset of disease). Finally, the vast
majority of the observational studies attempted to account
for the clustering of physical activity with other healthy
lifestyle habits by statistically adjusting for several potential confounders, including age, gender, race, education,
smoking, alcohol, diet, personal and family medical history, and reproductive variables in women. In fact, several
of the studies may indeed have “overcontrolled” their
analyses, accounting for potential intermediate, beneficial
effects of physical activity, such as body mass index,
hypertension, dyslipidemia, and diabetes mellitus. Thus,
by controlling for the beneficial effects of physical activity
on CVD risk factors, the reported risk reductions between
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Figure 1. Relative risks of CHD/CVD, comparing most active with least active men.
physical activity and the development of CHD/CVD likely
are underestimated.
Differences by Age?
Most of the studies of physical activity and CHD/CVD risk
included in the systematic evidence review behind the 2008
Guidelines were conducted in middle-aged adults, with the
median or mean ages of subjects primarily in the range of 45
to 60 years. The median or mean ages of subjects at baseline
exceeded 60 years in only 8 studies,14,17,18,23,32,43,45,61 and in
most of these studies, the average age was in the range of 60
to 69 years. These data suggest that physical activity is also
inversely related to CHD/CVD risk among subjects older
than 60 years.
For example, in the Harvard Alumni Study,18 in which the
mean age of men at the start of the study was 66 years, those
expending ⱖ16 800 kJ/wk (4000 kcal/wk) in physical activity
experienced a multivariate relative risk of 0.62 (0.41 to 0.96)
for CHD (ie, risk reduction of 38% [4% to 59%]) compared
with those expending ⬍4200 kJ/wk (1000 kcal/wk). Among
women in the Women’s Health Initiative,45 the age-adjusted
relative risks of CVD, comparing the most active with the
least active quintile in 3 age groups of 50 to 59, 60 to 69, and
70 to 79 years, were 0.45, 0.50, and 0.64, respectively.
Among older community-dwelling men and women in Washington state,61 where the average age was 70 to 74 years,
walking ⬎4 h/wk was associated with a 31% (10% to 52%)
reduction in risk of hospitalization from CVD in both men
and women.
A recent publication from the Rancho Bernardo study,
published after the 2008 Guidelines review, included 50- to
90-year-old individuals (56% of subjects were aged ⬎70
years) and investigated the association of walking and
leisure-time physical activity with CHD.58 Self-reported exercise occurring at least 3 times a week was associated with
a multivariate hazard ratio of 0.49 (0.31 to 0.77) for CHD
mortality compared with a lesser frequency of exercise. Thus,
these data support an inverse relation between physical
activity and CHD/CVD risk among older men and women
(with data primarily available on those in their 60s and 70s)
of a magnitude at least similar to that seen for younger
individuals.
Differences by Gender?
Many of the studies in the systematic evidence review
supporting the 2008 Guidelines included samples of women
only (13 studies) or samples of both men and women (5
studies). In addition, all of the 4 recently published studies
included women, with 2 being studies of women only.57,60
The inverse association between physical activity and risk of
developing CHD/CVD is present in both men and women
and, as shown in Figures 1 and 2, is similar, if not more
pronounced, in women compared with men. The median risk
reduction in women was 40%* when most active women
were compared with least active women, whereas that in men
was 30%.†
*References 12, 15–17, 20, 24, 25, 31, 32, 34, 35, 38, 41.
†References 12–15, 17–19, 22, 23, 26, 28, 30 –34, 36.
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Figure 2. Relative risks of CHD/CVD, comparing most active with least active women.
Although the magnitude of association appears stronger in
women than in men, comparisons across gender are limited
by the fact that the different studies used varied questionnaires for assessing physical activity and different categorizations (eg, by amount of energy expended, intensity of
activities, duration, or frequency) of physical activity for
analyses. Because women are less active than men62,63 and
because comparisons typically are performed relative to the
least active group studied, the categories of physical activity
used in analyses (eg, total energy expended) may represent
different amounts and intensities of physical activity in
women than in men.
Differences by Race/Ethnic Group?
Relatively few studies have examined the relationship of
physical activity and CHD/CVD risk in nonwhite populations. Seven of the studies in this review included ⬎10%
racial/ethnic minorities among subjects12,42,45– 47 or were conducted among Japanese Americans14 and Chinese women in
Shanghai.56
The data from these studies indicate that the inverse
association between physical activity and CHD/CVD risk
holds in white and nonwhite populations. Only 3 studies
formally examined interactions among racial/ethnic groups.
In the Women’s Health Initiative45 and among subjects drawn
from the National Health Interview Survey (which includes a
representative sample of the US population),47 no statistically
significant interactions among race were observed. However,
the Atherosclerosis Risk in Communities study12 reported a
significant interaction of race, such that the inverse associa-
tion between physical activity and CHD risk was observed
only among nonblack men and women but not among black
subjects. The investigators suggested that possible reasons for
the lack of association in the latter group included small
sample size, lack of range of physical activity among black
subjects, and a physical activity questionnaire that had not
been specifically validated for the black population.
Dose-Response Relation
The expert panel conducting the systematic evidence review
behind the 2008 Guidelines concluded the following:
“Greater amounts of activity appear to provide greater benefit
but the shapes of any dose-response relations have not been
well defined.” The concept of “dose” in physical activity
studies has been applied variously to the total volume of
energy expended or the intensity, duration, or frequency of
physical activity, with most data available on the total
volume.
As discussed above, the difficulty in combining data across
studies in trying to define a dose-response relation arises from
different questionnaires used across the various studies to assess
physical activity in 1 or more of these domains of activity
(leisure-time, household, occupation, and commuting activity),
with most assessing primarily leisure-time physical activity. In
analyses, the studies classified subjects by different classification
schemes, such as by energy expended or intensity, duration, and
frequency of activity.
Nonetheless, the panel attempted to define 3 groups of
different doses of physical activity and concluded that compared with men and women having low amounts or intensity
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Low
Moderate
High
Physical Acvity Level
Figure 3. Median relative risks of CHD/CVD by dose of physical activity.
of physical activity, on average, those with moderate amounts
or intensity of physical activity had ⬇20% to 25% reduced
risk of CHD and those with high amounts or intensity had
⬇30% to 35% risk reductions (Figure 3).5 Although the
available data do not allow for a specific and clear definition
of what constitutes a “moderate” or “high” amount of
physical activity, these data are consistent with the 2008
federal physical activity guidelines, which recommend at
least 150 min/wk of moderate- or 75 min/wk of vigorousintensity aerobic physical activity for “substantial health
benefits” and 300 min/wk of moderate- or 150 min/wk of
vigorous-intensity aerobic physical activity for “additional
and more extensive health benefits.”11
In the 4 new studies published since the 2008 Guidelines
review, similar inverse dose-response associations were observed. The median risk reductions in these 4 studies for
CHD/CVD when moderate and low amounts of physical activity
were compared were ⬇20% (range, 17% to 33% reduction), and
they were 40% (range, 25% to 50% reduction) when high and
low amounts of activity were compared.57– 60
To provide a more detailed picture of the doses of physical
activity, we provide data from 2 exemplar studies, 1 in men
and 1 in women. In the Harvard Alumni Study, which
followed ⬎7000 men for 6 years, physical activity was
estimated from self-reported walking, climbing stairs, and
participation in sports or recreational activities.18 On the basis
of these activities, investigators estimated the total energy
expenditure per week and classified men into those expending ⬍1000, 1000 to 1999, 2000 to 2999, 3000 to 3999, and
ⱖ4000 kcal/wk. After adjustment for age, smoking, parental
history of premature mortality, alcohol, diet, and the intensity
and duration of activities, the hazard ratios for CHD across
these categories were 1.00, 0.80, 0.80, 0.74, and 0.62,
respectively, with P for trend ⬍0.05 (Figure 4). The shape of
this curve in men appears curvilinear (ie, although additional
amounts of activity are associated with additional risk reductions, these additional risk reductions are of smaller magnitudes), which is similar to the curvilinear, inverse doseresponse curve for physical activity and all-cause mortality
concluded by the 2008 Guidelines expert panel, when 5 levels
of physical activity were used (based on data from 11
studies).5
Among ⬎20 000 women in the Women’s Health Study,57
followed for ⬎10 years, physical activity was assessed in a
fashion similar to that of the Harvard Alumni Health Study.
Women were then categorized into ⬍200, 200 to 599, 600 to
1499, and ⱖ1500 kcal/wk of energy expended. As expected,
the energy expended by women here, assessed with a questionnaire similar to that used in men in the previous study,
was less than that in men from the Harvard Alumni Health
Study. After adjustment for age, smoking, parental history of
myocardial infarction, alcohol, diet, menopausal status, and
use of postmenopausal hormones, the hazard ratios for CHD
across these categories were 1.00, 0.84, 0.76, and 0.62,
respectively, with P for trend⫽0.001 (Figure 5). The shape of
this curve in women appears more linear than the curvilinear
shape seen in men; this is likely due to the lower levels of
physical activity in women, so that the portion of the
dose-response curve seen in these women represents the more
linear shape of the dose-response curve at the lower end of the
physical activity spectrum.
Physical Inactivity Versus Overweight/Obesity
There is current interest in whether higher levels of physical
activity (or fitness) can ameliorate the increased risk for
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2000-2999
1000-1999
3000-3999
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Physical Acvity (kcal/wk)
Points represent relave risks; lines indicate 95% confidence intervals.
Figure 4. Relative risks of CHD by dose of physical activity in men, Harvard Alumni Health Study.
premature mortality or CHD/CVD associated with being
overweight or obese.64 In part, this has arisen because the
prevalence of overweight and obesity in the United States has
increased dramatically over the past 2 decades.65 In addition,
whereas effective strategies exist for weight loss, the vast
majority of people who lose weight do not maintain their
weight loss over time.66,67
Although some studies indicate that being physically fit
can mitigate the excess risk for premature or CVD mortality
associated with being overweight or obese,68,69 other studies
indicate a more nuanced relation,25,70 with each risk factor
(inactivity or overweight/obesity) independently being associated with increased risk, of about equal magnitude but not
canceling the increased risk of the other. Thus, physical
activity was significantly and inversely related to risk, independent of body mass index, in these other studies. In
addition, body mass index was significantly and directly
related to risk, independent of physical activity. Higher levels
of physical activity did not remove the increased risk associated with obesity. The highest risks were observed among
subjects who were both inactive and overweight/obese.
An example of a study supporting the former viewpoint is
the Aerobics Center Longitudinal Study.71 In multivariate
analyses, compared with fit and normal-weight subjects, fit
but obese (body mass index 30 to 34.9 kg/m2) subjects did not
have an increased risk (relative risk⫽1.12 [0.76 to 1.12]) for
premature mortality, but unfit subjects of normal weight did
(relative risk⫽3.63 [2.47 to 5.32). In contrast, findings
supporting the latter viewpoint come from the Nurses’ Health
Study.25 Compared with active and normal-weight women,
active but obese women had an elevated risk for CHD
(relative risk⫽2.48 [1.84 to 3.34]), as did inactive women
with normal weight (relative risk⫽1.48 [1.24 to 1.77].
Women who were both inactive and obese experienced the
highest risk (relative risk⫽3.44 [2.81 to 4.21]).
A recent review64 concluded that more research is needed;
however, on the basis of the available limited data, higher
levels of physical fitness appear to be able to offset the
increased risk of CVD associated with being overweight or
obese. However, higher levels of physical activity do not (for
more discussion on physical fitness versus physical activity,
see below), with studies of physical activity indicating that
inactivity and overweight/obesity represent independent risk
factors, of about equal magnitude, which do not cancel each
other. However, for type 2 diabetes mellitus, a major risk
factor for CVD, the data are more consistent in showing that
being overweight or obese is associated with far greater
increases in risk of developing type 2 diabetes mellitus than
being unfit or being inactive and that higher levels of physical
fitness or activity do not ameliorate the increase in risk of
type 2 diabetes mellitus. With regard to whether there are
differences by age, gender, or race/ethnicity, the data are too
limited to be able to make any definitive statements.
Additional Issues
Studies of Physical Fitness
Physical activity and physical fitness represent distinct,
though related, characteristics. Physical activity is any bodily
movement produced by skeletal muscle that results in energy
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Physical Acvity (kcal/wk)
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Figure 5. Relative risks of CHD by dose of physical activity in women, Women’s Health Study.
expenditure.72 Physical fitness is a set of attributes that one
possesses (based on genetic profile) or achieves from regular
physical activity, including muscular endurance (or cardiorespiratory fitness), muscular strength, body composition, and
flexibility.72 In many individuals and particularly in those
who have low levels of physical activity, increases in physical
fitness can be achieved by increasing one’s physical activity.5
However, physical fitness also has a genetic component, and
improvement in physical fitness is highly variable across
individuals who undergo an exercise program.73,74 Additionally, physically fit individuals find it easier to be physically
active.
Studies of physical fitness and CHD/CVD risk in men and
women observe findings that are congruent with those from
studies of physical activity.75 In fact, the magnitude of
association appears larger than that observed for physical
activity.76 In part, this may reflect the greater precision with
which physical fitness is measured, as contrasted with selfreported physical activity in observational epidemiological
studies. Additionally, physical fitness and physical activity
measure different, though related, characteristics. A recent
study of cardiorespiratory fitness and all-cause mortality, in
which most deaths were likely due to CVD, showed similar
associations in white and black men.77
The intent of this review is to focus on studies of physical
activity rather than physical fitness because studies of physical fitness, although a marker of recent physical activity,
cannot provide the direct information needed to make public
health recommendations with regard to the kinds of activity
and their intensity, duration, and frequency that is needed for
health. Nonetheless, studies of physical fitness can provide
useful data to inform public health recommendations. In the
Aerobics Center Longitudinal Study, physical activity was
obtained by self-reported questionnaires and then compared
with cardiorespiratory fitness as measured by maximal treadmill exercise testing.78 Men with low and moderate levels of
cardiorespiratory fitness reported an average of 112 and 130
min/wk of walking, respectively. In women, the corresponding walking times were 128 and 148 min/wk, respectively.
These data indicate that cardiorespiratory fitness of a moderate level can be achieved by following current physical
activity guidelines5 recommending at least 150 min/wk of
moderate-intensity physical activity, of which brisk walking
is an example. In addition, data from the Aerobics Center
Longitudinal Study show that cardiorespiratory fitness of at
least a moderate level is associated with lower rates of
premature mortality and CVD risk.71,79
Sedentary Behavior
There has been recent interest in “inactivity” physiology as
separate and distinct from “activity” physiology.80 In part,
this stems from the realization that if one follows current
recommendations and walks briskly for, say, 30 min/d in at
least 10-minute bouts, for the remaining 15.5 hours of the day
(assuming 8 h/d of sleep), one can sit most of the time or
make many brief, spontaneous movements (eg, fidgeting,
standing up, and sitting down) that would not “count” toward
physical activity recommendations. A person who exercises
for 30 min/d but sits most of the rest of the day may actually
expend less total energy than someone who does not exercise
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but is constantly “puttering” around. Animal studies show
that experimentally decreasing spontaneous standing and
ambulatory time in rats had a far greater magnitude of
deleterious effect on lipoprotein lipase regulation compared
with the magnitude of the beneficial effect of adding exercise
to rats’ normal activity.80
Several studies have shown that sedentary behavior, such
as the amount of time watching television, using a computer,
or playing video games, is associated with obesity,81,82
metabolic syndrome,83 and type 2 diabetes mellitus,84 all of
which increase the risk of developing CHD/CVD. Additionally, a recent study that followed ⬎1700 men and women in
the Canadian Fitness Study for 12 years reported that increased sitting time (self-reported as “almost none of the
time,” “1/4 of the time,” “1/2 of the time,” “3/4 of the time,”
or “almost all of the time”) was directly related, in a graded
fashion, to all-cause and CVD mortality.85 Of special interest
was the observation that even among people active enough to
meet physical activity recommendations, those spending
more time sitting were at increased risk of all-cause and CVD
mortality compared with those sitting less. If these findings
are confirmed by additional studies, targeting and decreasing
sedentary behavior may prove to be an effective and independent mechanism for decreasing cardiovascular risk in
addition to increasing physical activity.
Conclusions
There is substantial evidence to indicate that physically active
individuals have lower rates of CHD and CVD. This review
summarizes the data supporting the assertion and is based
primarily on the systematic evidence review behind the 2008
Guidelines and supplemented by 4 recent studies published
after the review. Although all of the data discussed in this
review have come from observational epidemiological studies that cannot prove cause and effect, many plausible
biological mechanisms demonstrated in randomized clinical
trials (discussed in other articles in this review) strongly
support a causal relation. The most active individuals, compared with the least active, have an ⬇30% to 40% risk
reduction.
Of specific interest in this review is whether the inverse
relation is present across age, gender, and racial/ethnic
groups. The available data indicate that the relation holds for
younger and older individuals, but limited data are available
for individuals aged ⱖ80 years. As for gender, there is
substantial evidence to indicate that the same inverse association exists in women as well as men, and there are suggestive data that the magnitude of association may be even more
pronounced in women. With respect to racial/ethnic groups,
there are few data on nonwhite populations, but the available
data indicate that the inverse association is also present across
different racial/ethnic groups.
This review also examined dose-response relations between physical activity and risk of CHD/CVD. It is clear that
increasing amounts of physical activity are associated with
additional risk reductions in both men and women, although
the shape of the dose-response curve is not well defined.
Because of the heterogeneity of data collected and analyzed
in physical activity studies, less clear is what specifically
constitutes “moderate” or “high” amounts of physical activity. The available data, however, are consistent with the 2008
federal physical activity guidelines that require at least 150
min/wk of moderate- or 75 min/wk of vigorous-intensity
aerobic physical activity and that state that additional benefits
occur with 300 min/wk of moderate- or 150 min/wk of
vigorous-intensity aerobic physical activity.
This review is limited by interstudy variation in data
collected on physical activity, as well as its classification. The
expert panel concluded in the 2008 Guidelines that “uniform
data collection is needed with respect to the type of physical
activity (eg, leisure-time, occupational) and physical activity
characteristics (intensity, duration, amount).” Recently, technological advances have increased rapidly, allowing for
greater accuracy and precision of the assessment of physical
activity in free-living populations, especially through the use
of motion sensors and physiological monitoring. These improvements, along with uniform and detailed data collection,
will lead to a better understanding of the health benefits and
dose response of physical activity.
In conclusion, although there is a large body of evidence
clearly supporting reduced risks of CHD/CVD with physical
activity, details of the relationship are less clear. Further
research on older populations, particularly those older than 80
years, as well as in racial/ethnic minorities is needed. Additionally, future studies that can provide more detail on the
dose-response relation are important to inform future physical
activity recommendations. The available data on dose response have come primarily from observational studies with
self-reported physical activity. Although these data are useful
and can be valid, self-reports have limitations with regard to
their imprecision, limited ability to identify light-intensity
physical activity (for example, it is harder to accurately report
household chores, which tend to be light intensity, but easier
to accurately report a regular exercise regimen such as
running for 1 hour, 3 d/wk), and limited ability to assess
sedentary behavior comprehensively. The costs of devices
using technological advances that allow for greater accuracy
and precision of the assessment of physical activity and
sedentary behavior in free-living populations, such as motion
sensors (eg, accelerometers) and physiological monitors (eg,
heart rate monitors) have decreased over time, making their
use increasingly feasible in large-scale cohort studies. Using
these devices in free-living populations to study associations
with clinical end points, such as CVD end points, will lead to
a better understanding of the health benefits of physical
activity and dose-response relationships.
Disclosures
Dr Lee serves as a consultant for Virgin HealthMiles and serves on
its Scientific Advisory Board. E.J. Shiroma reports no conflicts.
References
1. Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. Coronary
heart-disease and physical activity of work. Lancet. 1953;265:
1053–1057; contd.
2. Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. Coronary
heart-disease and physical activity of work. Lancet. 1953;265:
1111–1120; concl.
3. Heady JA, Morris JN, Raffle PA. Physique of London busmen: epidemiology of uniforms. Lancet. 1956;271:569 –570.
Shiroma and Lee
Epidemiological Studies of Physical Activity and CHD
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
4. Lee I-M, ed. Epidemiologic Methods in Physical Activity Studies. New
York, NY: Oxford University Press; 2009.
5. Physical Activity Guidelines Committee. Physical Activity Guidelines
Advisory Committee Report. Washington, DC: Dept of Health and Human
Services; 2008.
6. Nocon M, Hiemann T, Müller-Riemenschneider F, Thalau F, Roll S,
Willich SN. Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur
J Cardiovasc Prev Rehabil. 2008;15:239 –246.
7. Sofi F, Capalbo A, Cesari F, Abbate R, Gensini GF. Physical activity
during leisure time and primary prevention of coronary heart disease: an
updated meta-analysis of cohort studies. Eur J Cardiovasc Prev Rehabil.
2008;15:247–257.
8. Fletcher GF, Blair SN, Blumenthal J, Caspersen C, Chaitman B, Epstein
S, Falls H, Froelicher ES, Froelicher VF, Pina IL. Statement on exercise:
benefits and recommendations for physical activity programs for all
Americans: a statement for health professionals by the Committee on
Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart Association. Circulation. 1992;86:340 –344.
9. US Department of Health and Human Services. Physical Activity and
Health: A Report of the Surgeon General. Atlanta, Ga: US Dept of Health
and Human Services, Centers for Disease Control and Prevention,
National Center for Disease Control and Prevention and Health Promotion; 1996.
10. Berlin JA, Colditz GA. A meta-analysis of physical activity in the prevention of coronary heart disease. Am J Epidemiol. 1990;132:612– 628.
11. 2008 Physical Activity Guidelines for Americans. US Department of
Health and Human Services. http://www.health.gov/paguidelines/.
Accessed January 16, 2010.
12. Folsom AR, Arnett DK, Hutchinson RG, Liao F, Clegg LX, Cooper LS.
Physical activity and incidence of coronary heart disease in middle-aged
women and men. Med Sci Sports Exerc. 1997;29:901–909.
13. Leon AS, Myers MJ, Connett J. Leisure time physical activity and the
16-year risks of mortality from coronary heart disease and all-causes in
the Multiple Risk Factor Intervention Trial (MRFIT). Int J Sports Med.
1997;18(suppl 3):S208 –S215.
14. Hakim AA, Petrovitch H, Burchfiel CM, Ross GW, Rodriguez BL, White
LR, Yano K, Curb JD, Abbott RD. Effects of walking on mortality among
nonsmoking retired men. N Engl J Med. 1998;338:94 –99.
15. Dorn JP, Cerny FJ, Epstein LH, Naughton J, Vena JE, Winkelstein W Jr,
Schisterman E, Trevisan M. Work and leisure time physical activity and
mortality in men and women from a general population sample. Ann
Epidemiol. 1999;9:366 –373.
16. Manson JE, Hu FB, Rich-Edwards JW, Colditz GA, Stampfer MJ, Willett
WC, Speizer FE, Hennekens CH. A prospective study of walking as
compared with vigorous exercise in the prevention of coronary heart
disease in women. N Engl J Med. 1999;341:650 – 658.
17. Sherman SE, D’Agostino RB, Silbershatz H, Kannel WB. Comparison of
past versus recent physical activity in the prevention of premature death
and coronary artery disease. Am Heart J. 1999;138:900 –907.
18. Lee IM, Sesso HD, Paffenbarger RS Jr. Physical activity and coronary
heart disease risk in men: does the duration of exercise episodes predict
risk? Circulation. 2000;102:981–986.
19. Sesso HD, Paffenbarger RS Jr, Lee IM. Physical activity and coronary
heart disease in men: the Harvard Alumni Health Study. Circulation.
2000;102:975–980.
20. Lee IM, Rexrode KM, Cook NR, Manson JE, Buring JE. Physical activity
and coronary heart disease in women: is “no pain, no gain” passe? JAMA.
2001;285:1447–1454.
21. Talbot LA, Morrell CH, Metter EJ, Fleg JL. Comparison of cardiorespiratory fitness versus leisure time physical activity as predictors of
coronary events in men aged ⬍ or ⫽65 years and ⬎65 years. Am J
Cardiol. 2002;89:1187–1192.
22. Tanasescu M, Leitzmann MF, Rimm EB, Willett WC, Stampfer MJ, Hu
FB. Exercise type and intensity in relation to coronary heart disease in
men. JAMA. 2002;288:1994 –2000.
23. Lee IM, Sesso HD, Oguma Y, Paffenbarger RS Jr. Relative intensity of
physical activity and risk of coronary heart disease. Circulation. 2003;
107:1110 –1116.
24. Conroy MB, Cook NR, Manson JE, Buring JE, Lee IM. Past physical
activity, current physical activity, and risk of coronary heart disease. Med
Sci Sports Exerc. 2005;37:1251–1256.
25. Li TY, Rana JS, Manson JE, Willett WC, Stampfer MJ, Colditz GA,
Rexrode KM, Hu FB. Obesity as compared with physical activity in
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
751
predicting risk of coronary heart disease in women. Circulation. 2006;
113:499 –506.
Davey Smith G, Shipley MJ, Batty GD, Morris JN, Marmot M. Physical
activity and cause-specific mortality in the Whitehall study. Public
Health. 2000;114:308 –315.
Wagner A, Simon C, Evans A, Ferrieres J, Montaye M, Ducimetiere P,
Arveiler D. Physical activity and coronary event incidence in Northern
Ireland and France: the Prospective Epidemiological Study of Myocardial
Infarction (PRIME). Circulation. 2002;105:2247–2252.
Batty GD, Shipley MJ, Marmot MG, Smith GD. Leisure time physical
activity and disease-specific mortality among men with chronic bronchitis: evidence from the Whitehall study. Am J Public Health. 2003;93:
817– 821.
Hillsdon M, Thorogood M, Murphy M, Jones L. Can a simple measure of
vigorous physical activity predict future mortality? Results from the
OXCHECK study. Public Health Nutr. 2004;7:557–562.
Yu S, Yarnell JW, Sweetnam PM, Murray L. What level of physical
activity protects against premature cardiovascular death? The Caerphilly
Study. Heart. 2003;89:502–506.
Haapanen N, Miilunpalo S, Vuori I, Oja P, Pasanen M. Association of
leisure time physical activity with the risk of coronary heart disease,
hypertension and diabetes in middle-aged men and women. Int J
Epidemiol. 1997;26:739 –747.
Haapanen-Niemi N, Miilunpalo S, Pasanen M, Vuori I, Oja P, Malmberg
J. Body mass index, physical inactivity and low level of physical fitness
as determinants of all-cause and cardiovascular disease mortality: 16 y
follow-up of middle-aged and elderly men and women. Int J Obes Relat
Metab Disord. 2000;24:1465–1474.
Kaprio J, Kujala UM, Koskenvuo M, Sarna S. Physical activity and other
risk factors in male twin-pairs discordant for coronary heart disease.
Atherosclerosis. 2000;150:193–200.
Barengo NC, Hu G, Lakka TA, Pekkarinen H, Nissinen A, Tuomilehto J.
Low physical activity as a predictor for total and cardiovascular disease
mortality in middle-aged men and women in Finland. Eur Heart J.
2004;25:2204 –2211.
Lissner L, Bengtsson C, Bjorkelund C, Wedel H. Physical activity levels
and changes in relation to longevity: a prospective study of Swedish
women. Am J Epidemiol. 1996;143:54 – 62.
Rosengren A, Wilhelmsen L. Physical activity protects against coronary
death and deaths from all causes in middle-aged men: evidence from a
20-year follow-up of the primary prevention study in Goteborg. Ann
Epidemiol. 1997;7:69 –75.
Sundquist K, Qvist J, Johansson SE, Sundquist J. The long-term effect of
physical activity on incidence of coronary heart disease: a 12-year
follow-up study. Prev Med. 2005;41:219 –225.
Weller I, Corey P. The impact of excluding non-leisure energy expenditure on the relation between physical activity and mortality in women.
Epidemiology. 1998;9:632– 635.
Chen J, Millar WJ. Health effects of physical activity. Health Rep.
1999;11:21–30(Eng); 21–31(Fre).
Eaton CB, Medalie JH, Flocke SA, Zyzanski SJ, Yaari S, Goldbourt U.
Self-reported physical activity predicts long-term coronary heart disease
and all-cause mortalities: twenty-one-year follow-up of the Israeli Ischemic Heart Disease Study. Arch Fam Med. 1995;4:323–329.
Wisloff U, Nilsen TI, Droyvold WB, Morkved S, Slordahl SA, Vatten
LJ. A single weekly bout of exercise may reduce cardiovascular
mortality: how little pain for cardiac gain? The HUNT study, Norway.
Eur J Cardiovasc Prev Rehabil. 2006;13:798 – 804.
Kaplan GA, Strawbridge WJ, Cohen RD, Hungerford LR. Natural history
of leisure-time physical activity and its correlates: associations with
mortality from all causes and cardiovascular disease over 28 years. Am J
Epidemiol. 1996;144:793–797.
Kushi LH, Fee RM, Folsom AR, Mink PJ, Anderson KE, Sellers TA.
Physical activity and mortality in postmenopausal women. JAMA. 1997;
277:1287–1292.
Rockhill B, Willett WC, Manson JE, Leitzmann MF, Stampfer MJ,
Hunter DJ, Colditz GA. Physical activity and mortality: a prospective
study among women. Am J Public Health. 2001;91:578 –583.
Manson JE, Greenland P, LaCroix AZ, Stefanick ML, Mouton CP,
Oberman A, Perri MG, Sheps DS, Pettinger MB, Siscovick DS. Walking
compared with vigorous exercise for the prevention of cardiovascular
events in women. N Engl J Med. 2002;347:716 –725.
Fang J, Wylie-Rosett J, Cohen HW, Kaplan RC, Alderman MH. Exercise,
body mass index, caloric intake, and cardiovascular mortality. Am J Prev
Med. 2003;25:283–289.
752
Circulation
August 17, 2010
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
47. Gregg EW, Gerzoff RB, Caspersen CJ, Williamson DF, Narayan KM.
Relationship of walking to mortality among US adults with diabetes. Arch
Intern Med. 2003;163:1440 –1447.
48. Haapanen N, Miilunpalo S, Vuori I, Oja P, Pasanen M. Characteristics of
leisure time physical activity associated with decreased risk of premature
all-cause and cardiovascular disease mortality in middle-aged men. Am J
Epidemiol. 1996;143:870 – 880.
49. Hu G, Tuomilehto J, Silventoinen K, Barengo N, Jousilahti P. Joint
effects of physical activity, body mass index, waist circumference and
waist-to-hip ratio with the risk of cardiovascular disease among
middle-aged Finnish men and women. Eur Heart J. 2004;25:2212–2219.
50. Wannamethee SG, Shaper AG, Walker M. Changes in physical activity,
mortality, and incidence of coronary heart disease in older men. Lancet.
1998;351:1603–1608.
51. Khaw KT, Jakes R, Bingham S, Welch A, Luben R, Day N, Wareham N.
Work and leisure time physical activity assessed using a simple,
pragmatic, validated questionnaire and incident cardiovascular disease
and all-cause mortality in men and women: the European Prospective
Investigation into Cancer in Norfolk prospective population study. Int J
Epidemiol. 2006;35:1034 –1043.
52. Mensink GB, Deketh M, Mul MD, Schuit AJ, Hoffmeister H. Physical
activity and its association with cardiovascular risk factors and mortality.
Epidemiology. 1996;7:391–397.
53. Raum E, Rothenbacher D, Ziegler H, Brenner H. Heavy physical activity:
risk or protective factor for cardiovascular disease? A life course perspective. Ann Epidemiol. 2007;17:417– 424.
54. Engstrom G, Hedblad B, Janzon L. Hypertensive men who exercise
regularly have lower rate of cardiovascular mortality. J Hypertens. 1999;
17:737–742.
55. Calling S, Hedblad B, Engstrom G, Berglund G, Janzon L. Effects of
body fatness and physical activity on cardiovascular risk: risk prediction
using the bioelectrical impedance method. Scand J Public Health. 2006;
34:568 –575.
56. Matthews CE, Jurj AL, Shu XO, Li HL, Yang G, Li Q, Gao YT, Zheng
W. Influence of exercise, walking, cycling, and overall nonexercise
physical activity on mortality in Chinese women. Am J Epidemiol. 2007;
165:1343–1350.
57. Mora S, Cook N, Buring JE, Ridker PM, Lee IM. Physical activity and
reduced risk of cardiovascular events: potential mediating mechanisms.
Circulation. 2007;116:2110 –2118.
58. Smith TC, Wingard DL, Smith B, Kritz-Silverstein D, Barrett-Connor E.
Walking decreased risk of cardiovascular disease mortality in older adults
with diabetes. J Clin Epidemiol. 2007;60:309 –317.
59. Stamatakis E, Hamer M, Lawlor DA. Physical activity, mortality, and
cardiovascular disease: is domestic physical activity beneficial? The
Scottish Health Survey—1995, 1998, and 2003. Am J Epidemiol. 2009;
169:1191–1200.
60. van Dam RM, Li T, Spiegelman D, Franco OH, Hu FB. Combined impact
of lifestyle factors on mortality: prospective cohort study in US women.
BMJ. 2008;337:a1440.
61. LaCroix AZ, Leveille SG, Hecht JA, Grothaus LC, Wagner EH. Does
walking decrease the risk of cardiovascular disease hospitalizations and
death in older adults? J Am Geriatr Soc. 1996;44:113–120.
62. Prevalence of regular physical activity among adults—United States,
2001 and 2005. MMWR Morb Mortal Wkly Rep. 2007;56:1209 –1212.
63. Troiano RP, Berrigan D, Dodd KW, Masse LC, Tilert T, McDowell M.
Physical activity in the United States measured by accelerometer. Med Sci
Sports Exerc. 2008;40:181–188.
64. Fogelholm M. Physical activity, fitness and fatness: relations to mortality,
morbidity and disease risk factors: a systematic review. Obes Rev. 2010;
11:202–221.
65. Wang Y, Beydoun MA. The obesity epidemic in the United States—
gender, age, socioeconomic, racial/ethnic, and geographic characteristics:
a systematic review and meta-regression analysis. Epidemiol Rev. 2007;
29:6 –28.
66. Jeffery RW, Drewnowski A, Epstein LH, Stunkard AJ, Wilson GT, Wing
RR, Hill DR. Long-term maintenance of weight loss: current status.
Health Psychol. 2000;19:5–16.
67. Katan MB. Weight-loss diets for the prevention and treatment of obesity.
N Engl J Med. 2009;360:923–925.
68. Gill JM, Malkova D. Physical activity, fitness and cardiovascular disease
risk in adults: interactions with insulin resistance and obesity. Clin Sci
(Lond). 2006;110:409 – 425.
69. Lee DC, Sui X, Blair SN. Does physical activity ameliorate the health
hazards of obesity? Br J Sports Med. 2009;43:49 –51.
70. Lee IM, Paffenbarger RS Jr. Associations of light, moderate, and
vigorous intensity physical activity with longevity: the Harvard Alumni
Health Study. Am J Epidemiol. 2000;151:293–299.
71. Sui X, LaMonte MJ, Laditka JN, Hardin JW, Chase N, Hooker SP, Blair
SN. Cardiorespiratory fitness and adiposity as mortality predictors in
older adults. JAMA. 2007;298:2507–2516.
72. Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise,
and physical fitness: definitions and distinctions for health-related
research. Public Health Rep. 1985;100:126 –131.
73. Bouchard C, Rankinen T. Individual differences in response to regular
physical activity. Med Sci Sports Exerc. 2001;33:S446 –S451; discussion
S452–S443.
74. Church TS, Earnest CP, Skinner JS, Blair SN. Effects of different doses
of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a
randomized controlled trial. JAMA. 2007;297:2081–2091.
75. Blair SN, Cheng Y, Holder JS. Is physical activity or physical fitness
more important in defining health benefits? Med Sci Sports Exerc. 2001;
33:S379 –S399; discussion S419 –S320.
76. Williams PT. Physical fitness and activity as separate heart disease risk
factors: a meta-analysis. Med Sci Sports Exerc. 2001;33:754 –761.
77. Kokkinos P, Myers J, Kokkinos JP, Pittaras A, Narayan P, Manolis A,
Karasik P, Greenberg M, Papademetriou V, Singh S. Exercise capacity
and mortality in black and white men. Circulation. 2008;117:614 – 622.
78. Stofan JR, DiPietro L, Davis D, Kohl HW III, Blair SN. Physical activity
patterns associated with cardiorespiratory fitness and reduced mortality:
the Aerobics Center Longitudinal Study. Am J Public Health. 1998;88:
1807–1813.
79. Blair SN, Kampert JB, Kohl HW, III, Barlow CE, Macera CA, Paffenbarger RS Jr, Gibbons LW. Influences of cardiorespiratory fitness and
other precursors on cardiovascular disease and all-cause mortality in men
and women. JAMA. 1996;276:205–210.
80. Hamilton MT, Hamilton DG, Zderic TW. Role of low energy expenditure
and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes. 2007;56:2655–2667.
81. Hu FB, Li TY, Colditz GA, Willett WC, Manson JE. Television watching
and other sedentary behaviors in relation to risk of obesity and type 2
diabetes mellitus in women. JAMA. 2003;289:1785–1791.
82. Jakes RW, Day NE, Khaw KT, Luben R, Oakes S, Welch A, Bingham S,
Wareham NJ. Television viewing and low participation in vigorous recreation are independently associated with obesity and markers of cardiovascular disease risk: EPIC-Norfolk population-based study. Eur J Clin
Nutr. 2003;57:1089 –1096.
83. Ford ES, Kohl HW III, Mokdad AH, Ajani UA. Sedentary behavior,
physical activity, and the metabolic syndrome among U.S. adults. Obes
Res. 2005;13:608 – 614.
84. Hu FB, Leitzmann MF, Stampfer MJ, Colditz GA, Willett WC, Rimm
EB. Physical activity and television watching in relation to risk for type
2 diabetes mellitus in men. Arch Intern Med. 2001;161:1542–1548.
85. Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time and
mortality from all causes, cardiovascular disease, and cancer. Med Sci
Sports Exerc. 2009;41:998 –1005.
KEY WORDS: cardiovascular diseases
䡲 exercise 䡲 women
䡲
coronary disease
䡲
epidemiology
Physical Activity and Cardiovascular Health: Lessons Learned From Epidemiological
Studies Across Age, Gender, and Race/Ethnicity
Eric J. Shiroma and I-Min Lee
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Circulation. 2010;122:743-752
doi: 10.1161/CIRCULATIONAHA.109.914721
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