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Chapter

9

Cardiovascular Diseases
and Physical Activity

Occupational and Leisure Time Physical Activity Studies
Physical Fitness Studies
Quantifying the Dose-Response Association
Physical Activity and Mortality in Women
Walking and Coronary Risk Reduction
Walking Versus Vigorous Activity and Cardiovascular Risk
Physical Activity and Stroke
Chronic Heart Failure and Exercise Training
Mechanisms for Improvement by Exercise Training
Exercise Training and Mortality in Heart Failure
Conclusions
Low Extremity Arterial Disease and Exercise
Exercise Therapy Findings
Exercise Mode
Intensity
Frequency, Duration, and Length of Training
Potential Mechanisms
Potential Mechanisms for the Physical Activity–Related Reduction in Cardiovascular Risk
Summary

230

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Chapter 9

Cardiovascular Diseases and Physical ActivityT

he association between physical activity and health, vitality, and longevity
has been recognized since antiquity.
Over 2,500 years ago, the Greek physician Hippocrates (460–377 bc) succinctly and accurately summed up the benefits of exercise andphysical activity as follows:
Speaking generally, all parts of the bodywhich have a function, if used in moderationand exercised in labors to which each is
accustomed, become thereby healthy andwell developed and age slowly; but if unused
and left idle, they become liable to disease,defective in growth, and age quickly.

The quest to define the role of physical activity in human health, disease, and mortality
began in the early 1950s. In their landmark
study, Morris and coworkers reported thatthose with physically demanding occupations(London mail carriers and double-decker bus
conductors) had approximately 50% lower
rates of CHD when compared to the more sedentary bus drivers and desk clerks.1 Despite
the fact that the investigators did not control
for confounding factors such as body weight,
blood pressure, and blood cholesterol, which
are likely to be more abnormal in the sedentary
cohort, these findings stimulated worldwide

231

interest in the relationship between physicalactivity and cardiovascular mortality.
Subsequent leisure time physical activity
studies and occupational studies from variety
of industries included postal, railroad, andfarm workers; employees of utility companies;
civil servants; longshoremen; police officers
and firefighters; all designed to examine thephysical activity–mortality relationship. Mostof these studies reported that the most active
individuals had one third to three fourths fewer
cardiovascular events and deaths when compared to the least active.2
A most influential review regarding physicalactivity and coronary heart disease was by
Powell and coworkers in 1987.3 To assess therelationship between physical activity andmortality, the authors identified 121 studies
and carefully evaluated the quality of each. Of
the 121 studies, 43 were found to be wellconducte­d and were included in the final analysis (meta-analysis). Their conclusion was thatphysical activity is inversely related to the riskof coronary heart disease (CHD). The association was independent of other confounding
factors and was as robust as that of establishedrisk factors such as smoking, hypercholesterolemia, and hypertension (Figure 9.1).

Figure 9.1

Relative risk for CAD. Note that physical inactivity carries a similar risk withthe established coronary factors.

Relative Risk

3

2

1.9

2.4

2.5

TC ≥ 268
mg/dl

Smoking≥ 1 pack

2.1

1

0

Physical
Inactivity

SBP > 150
mm Hg

Source: Modified from Powell, et al. Ann Review Public Health 1987;8:253–287.

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This chapter presents the most influential
studies examining the association between
physical activity, fitness and cardiovascular disease, and all-cause mortality. In addition, potential mechanisms of exercise-related protection
against cardiovascular disease are discussed.

Occupational and
Leisure Time Physical
Activity Studies
Occupational and leisure time activity studies
utilized questionnaires to assess the physicalactivity habits of the participants. Despite thesubjective nature of such surveys, the overallfindings of these studies support a graded
reduction in mortality risk with increased levelof physical activity. This association is similar
for men and women regardless of age. Severalof these studies are discussed in some detailbecause of their unique aspects.
The study by Paffenbarger and Hale4 followed 6,351 longshoremen for 22 years. The
unique feature of this study is that the level ofenergy output for each participant was estimated based on the energy requirements of 49
longshoring jobs. Accordingly, workers who
loaded and unloaded ships were classified asheavy activity, clerks as light activity, and thosein between as moderate activity workers. The
age-adjusted coronary death rate was 70%
higher in the moderate activity and 80% higher
in the light activity work group. Because there
was little difference in the death rates between
moderate and heavy activity workers, theinvestigators suggested the existence of a protective threshold of physical activity or caloric
expenditure.4
Fatal and non-fatal coronary events wereassessed in 5,288 men and 5,229 women who
lived in 58 Israeli settlements called kibbutzim.5
Participants were classified as physically active

or sedentary based on data collected by a physical activity questionnaire. One unique aspect of
this study is that these kibbutzim provided communal dining facilities and similar medical care
for a relatively homogeneous group. Thus,
many of the confounding factors present in epidemiologic studies were eliminated. In addition, risk factors were similar in between
physically active and sedentary groups. The
other unique aspect is that the study provided
information on a large number of women.
The investigators reported that the 15-year
relative risk value for fatal and non-fatal coronary events was 2.5 times higher in men engaged
in sedentary occupations compared to the men
who performed with more physically demanding jobs. For women, the risk was 3.1 times
greater for the corresponding occupations.5
Not all studies came to similar conclusions.
In a Finnish study, the rate of coronary heartdisease mortality was greater among lumberjacks compared to less active farmers of thesame region.6 However, this finding must be
interpreted with caution for two reasons.
Although farmers were less active than lumberjacks, they were not sedentary. Thus, thestudy compared highly active (lumberjacks) tosomewhat less active (farmers) individuals.
This along with the higher fat consumption andsmoking rates among lumberjacks is likely tohave attenuated the positive effects of physicalactivity in the lumberjacks and showed morefavorable outcomes for the farmers.
The landmark epidemiologic work byPaffenbarger and associates provided persuasive evidence on the association between physical activity and mortality. In 1978, the sameinvestigators assessed the association between
leisure time physical activity and heart attacks
in 16,963 Harvard alumni who entered Harvard
between 1916 and 1950 and responded to aquestionnaire.7 The cohorts were categorizedbased on weekly caloric expenditure based on
leisure time activities, ranging from < 500 to© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity

more than 4,000 kcal/week. The data revealed
that the risk of first heart attack was related
inversely to the level of energy expenditureduring leisure time. A sharp reduction in fatal
and non-fatal heart attacks rates with increase
in weekly energy expenditure was noted at theenergy expenditure of 2,000 kcal per week.
Those who expended less than 2,000 kcal per
week had a 64% higher risk for a heart attack.
Another important finding of this study wasthat the reduction in risk was only evident if
physical activity was maintained throughout
the study participant’s life. Those who played
varsity sports but did not maintain a physically
active lifestyle had a higher mortality rate compared to those who maintained a physically
active lifestyle in adulthood. Conversely, those
who avoided athletics in college but subsequently took up a more active lifestyle also had
similarly low rates of mortality.7
In the next two reports that followed on thesame cohort,8,9 the investigators reported aconsisten­t, inverse, and graded trend towards
a lower all-cause mortality rate; as physicalactivity-related caloric expenditure increased
form 500 to 2,000 kcal per week, the mortality
rate decreased. More specifically, the mortality risk for men whose weekly energy expenditure from leisure time activities total 2,000 kcal
or more had about 25% to 33% lower mortality
rate compared to those with a caloric expenditure of less than 2,000 kcal per week. Paffenbarger et al. speculated that physical activity
accounted for approximately 1 to 2 years ofadditional life. An interesting observation of
the study was that the mortality risk tended toincrease slightly in those expending more than
3,500 kcal per week.8 This is equivalent to about
30 to 35 miles of jogging per week.
In the more recent study, Paffenbarger et al.9
examined the relative risk of death based on
different types of physical activity that included
walking (miles/week), stair-climbing (floors),
and playing sports in 10,269 Harvard alumni

233

over a 9-year period. The inverse and gradedassociation between mortality risk and volumeof physical activity was again evident and inaccord with their previous findings. In addition,and particularly noteworthy, was the 30% to
40% reduction in mortality risk, evident in thoseindividuals engaging in moderate-to-vigorous
activity levels (≥ 4.5 METs; see Chapter 2) with
only minimal additional benefits achieved byengaging in activities of greater intensity. The
reduction was similar when physical activity
was expressed as kilocalories per week (thesum of walking, stair climbing, and sports participation), suggesting that a 40% reduction in
mortality occurs by engaging in modest levelsof activity (1,000 to 2,000 kcal/week, equivalent
to three to five 1-hour sessions of activity).
Collectively, the findings of these studies4,7,9
provided evidence in support of an exercise
intensity threshold of about 5 to 6 METs and an
exercise volume threshold somewhere between
1,000 and 2,000 kcal per week for a significant
reduction in mortality risk. Furthermore, thefindings suggest that most of the benefits occur
at moderate exercise volumes and moderateintensities.
Similar results have been reported fromlarge studies that have followed cohorts forcoronary heart disease (CHD) morbidity andmortality in the range of 10 to 20 years among
British civil servants, U.S. railroad workers,
San Francisco longshoremen, nurses, physicians, other healthcare workers, and othercohorts. The findings of these studies are summarized in two comprehensive reviews.10,11
Clearly, the accumulated epidemiologicalevidence provided strong support for the existence of a strong inverse relationship between
physical exercise and risk of CHD. As stated byPaffenbarger and Hyde, “. . . the questions to beaddressed are not whether exercise is a real element for cardiovascular health, but what kindof exercise is needed, and how much, i.e., withwhat frequency, intensity, timing, and duratio­n.

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Cardiovascular Disease Epidemiology and Physical Activity

An understanding of the ways and means bywhich exercise alters coronary heart diseaserisk is only beginning to emerge, but there is
wide acceptance that its benefits are vitallyneeded in the sedentary Western world.”12
According to a recent review that included
44 observational studies from 1966 to 2000,13
the collective findings support the following:First, there is strong evidence of an inverse linear dose-response relationship between volumeof physical activity and all-cause mortality.
Secon­d, an exercise volume threshold can be
defined beyond which a significant reduction in
mortality risk occurs. This threshold appears to
be at a caloric expenditure of approximately
1,000 kcal per week for an average reduction of
20% to 30% in mortality risk. Further reductions
in risk are observed with higher volumes ofenergy expenditure. Third, the independent
contribution of the exercise components ofintensity, duration, and frequency to the reduction of mortality risk was not clear. The authorsemphasized the need for more research to better understand the contribution of each component.13 Indeed, efforts to define the intensity,
duration, frequency, volume, and type of exercise necessary for cardiovascular health andlongevity continue. Although progress has been
made, much more work is needed.
The influence of genetic factors in the reduction of the mortality risk cannot be dismissed.
Furthermore, the argument can be made that it
is not the physical activity that provides protection but the genetic composition of these
individuals.
In this regard, the independent association ofphysical activity and mortality and the influenceof genetic and other familial factors wereassessed in a cohort of same-sex twins born in
Finland before 1958 and with both alive in
1967.14 In 1975, healthy men (n = 7,925) andhealthy women (n = 7,977) responded to a questionnaire on physical activity, occupation,smokin­g habits, body weight, alcohol use, andphysician-diagnosed diseases. Individuals whoreported engaging in brisk walk for a mean duration of 30 minutes, at least six times per month
were classified as physically active. Those whoreported no leisure time activity were classified
as sedentary. The remaining individuals wereclassified as occasional exercisers. When compared to the sedentary twins, the adjusted riskof mortality was 33% lower among the twins
who exercised occasionally and 44% lower
among the physically active twins. The investigators concluded that physical activity is associated with lower mortality independent of genetic
and other confounding factors.
Epidemiological evidence supports a strong inverse relationship between physical exercise andcoronary heart disease risk.

Physical Fitness Studies
Physical activity questionnaires provide valuable information and are useful in assessing
physical activity levels. However, by nature,they are not objective. A shift from assessing
physical activity by questionnaires to a moreobjective assessment was provided by Steve
Blair and his co-investigators in their landmark
study.15 The investigators assessed physical fitness of 10,224 men and 3,120 women by a maximal exercise test at the Institute of Aerobic
Research. The cohort was grouped into five fitness categories based on the MET level achieved
and were followed for a period of over 8 years.
After adjusting for age, blood pressure, smoking habits, fasting blood glucose levels, andfamily history of coronary heart disease, there
was an inverse, strong, and graded association
between physical fitness and cardiovascularand all-cause mortality for both men andwomen. The most striking finding of the study
was that the major reduction in mortality risk
occurred when moving from the least fit (< 7© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity

Figure 9.2

235

Age-adjusted all-cause mortality in men according to exercise capacity.

Deaths per 10,000
Person-Years

150

100

50

0

<7

7

8
9
10
Peak METs achieved

11

12+

Source: From Blair, et al. JAMA 1989;262:2395–2401.

both examinations had the highest mortality
rate. Those who increased their physical activity and moved from the unfit to fit category
within the first and subsequent examinations
had a 44% reduction in adjusted mortality risk
when compared to men who remained unfit atboth examinations (Figure 9.3). In addition, theFigure 9.3

Survival curves for fit and unfit
men. A 44% reduction in adjusted mortality
risk was noted in the unfit who became fit
compared to the unfit men who stayed unfit.
1.00
Unfit Fit
Survival Probability

METs) to the next fit category of 7 METs. The
risk continued to decline with higher fitnesslevels and appears to plateau at approximately
9 to 10 METs for women and men, respectively(Figure 9.2). The investigators emphasized that
the MET levels of 7 to 10 achieved for optimal
health benefits are attainable by a brisk walk of
30 to 60 minutes each day.
Despite the objectivity of the maximal exercise test and its greater accuracy in the classification of fitness categories, it still represents asingle baseline assessment of fitness. With asingle exposure assessment at baseline, it isdifficult to discount the influence of genetic
factors, underlying diseases, and other confounding variables on the association between
fitness and mortality. For example, the low
exercise capacity at baseline and the cause ofdeath within the follow-up period of the study
may be due to underlying disease and not the
low fitness level. In this case, the mortality risk
for the low fitness categories will be overinflated and the association spurious.
To address this issue, Blair and coworkers
controlled for some of these confounding variables by assessing the fitness of the cohort
with two maximal exercise tests. The investigators reported that men who were unfit at

0.90

Unfit Unfit
0.80

0.70
0

2

4

6

8

10 12 14 16 18

Follow-up (years)

Source: From Blair, et al. JAMA 1995;273:1093–1097.

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Part III

Cardiovascular Disease Epidemiology and Physical Activity

investigators estimate a 7.9% reduction in mortality risk for every minute increase in the peaktreadmill exercise time between examinations.16 This finding also provides evidence tosupport that the association between fitness
and mortality is independent and beyond
genetic factors.
The inverse association between physicalactivity and mortality remains robust after statistical adjustments of potential confounders.
However, the impact of physical activity withingroups in the presence of known risk factors
such as hypertension, diabetes, or smoking has
not been assessed. In this regard, Blair andcoworkers17 assessed the impact of fitness
within groups who possess specific risk factors. The cohort consisted of 25,241 men and
7,080 women with baseline evaluations that
included a maximal exercise test. Low, moderate, and high-fit categories were establishedbased on the peak exercise time.
The findings of this study lead to three principal conclusions. First, an inverse and gradedassociation between fitness and mortality wasevident and consistent within the various subgroups examined. For men who smoked, had
high blood cholesterol and elevated systolicblood pressure, or were unhealthy, the adjusted
all-cause mortality rates were 17% to 39% lower
if they were moderately fit compared to low fit.
For the fit men, the risk was 32% to 50% lower.
Second, moderate and high fitness levels
appear to provide protection against the cumulative detrimental effect of multiple risk factors. For example, the death rates in high-fit
individuals with two or three risk factors(smoking, high blood cholesterol, or elevatedsystolic blood pressure) were significantly
lower (15%) when compared to low-fit individuals with no risk factors.
Third, the relative risk for all-cause and cardiovascular mortality due to physical inactivity
was similar to those of cigarette smoking andelevated cholesterol levels.

Although the physical activity–mortality
relationship was well established by now,
informatio­n on the intensity, duration, and typeof physical activity was still speculative. To
address these questions, Lakka and coworkers18 directly assessed the maximal oxygen
uptake by a standardized exercise test. In addition, they collected information by questionnaires on the leisure time physical activity
habits of 1,453 healthy men. The cohort was
followed for an average of 4.9 years and myocardial infarctions were recorded.
The association between the risk of myocardial infarction and both leisure time physicalactivity and oxygen uptake was inverse andgraded. After adjusting for a number of coronary risk factors, men with an oxygen uptakeof more that 34 ml/kg/min (the highest one
third of the cohort) had a 55% lower risk of
myocardial infarction compared to the risk of
the least fit man (the lowest one third). Similarly, men engaging in leisure time activity
for more than 2 hours per week had a 60%
lower risk than the least fit men. The investigators also reported that a mean intensity of
about 6 METs may be the threshold for a reduction in risk.
The unique aspect of this study is that bothoxygen uptake and leisure time activity wereassessed. Because oxygen uptake was directly
measured and not estimated, fitness level ismore accurately assessed. Collectively, theoxygen consumption of 34 ml/kg/min, the hoursof physical activity per week, and the very similar decrease in risk (55% and 60%) support thecontention that physical activity of moderateintensity (about 6 METs as stated by the investigators) is required for risk reduction.
Similar findings were reported in a study of
1,960 middle-aged, Norwegian men whose
physical fitness was assessed at baseline by an
exercise tolerance test using a bicycle ergometer. During a 16-year follow-up period, the relative risk for cardiovascular mortality was© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity

inversely related to physical fitness. Onceagain, the major reduction in mortality risk
(41%) occurred when moving from the least fit(quintile 1) to the next fit category (quintile 2).
The risk continued to decline with higher fitness levels reaching 55% and 59% for quintiles
3 and 4, respectively.19
The independent effects of exercise type andintensity on the risk for coronary heart disease
were assessed in a large cohort of 44,452 menenrolled in the Health Professionals’ Follow-up
Study.20 The MET level for each activity performed was calculated and the cohort was categorized into fitness quintiles based on the
MET-hours per week of total physical activity.
The findings of this study support an inverseand graded association between the risk ofcoronary heart disease and the weekly volume
of exercise or physical activity. In this regard,
the findings of the study are in accord with previous findings and strengthen the contention
that physical activity is protective against premature heart disease. In addition, the study
provided information on the type, volume, andintensity of several physical activities and theirrespective efficacy on coronary heart diseaserisk reduction. It is also important to mention
that this was the first study that provided evidence on the efficacy of weight training or
resistance training on coronary heart diseaserisk reduction. The risk reduction achieved by237

weight training was simila­r to that observed bybrisk walking and rowing, and approximately
half of that observed by running. These findings are summarized in Table 9.1.
Because walking was the most frequent
form of exercise (58% of men reported walking
at least 1 hour per week), the investigators
examined the independent effects of intensityand duration of walking on the risk for coronary heart disease. They found that walking
pace (intensity) was inversely related to therisk of coronary heart disease independent ofwalking volume (Figure 9.4). A 4% reduction incoronary risk was observed for every 1-MET
increase in exercise intensity. The duration ofwalking was also inversely related to the risk.
However, the much stronger association
between intensity and risk suggests that walking intensity has a stronger effect on risk reduction than duration.
Evidence supports that both exercise intensityand duration are associated with a reduction in
mortality risk. However, the stronger association
between intensity and risk suggests that additional health benefits may be possible with relatively higher exercise intensities. There is also
limited evidence that weight training may be aseffective in lowering mortality risk as aerobic
exercis­e.

Table 9.1 Activity Performed and Coronary Heart Disease
Relative Risk Reduction in Men
Activity Performed per Week

Relative Risk Reduction

Running ≥ 1 hour
Rowing ≥ 1 hour
Brisk walk ≥ 30 minutes
Weight training ≥ 30 minutes

42%
18%
18%
23%

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Cardiovascular Disease Epidemiology and Physical Activity

Part III

Figure 9.4

Adjusted risk for coronary heart disease according to walking pace.

Relative Risk

1

1
p < 0.001

0.8

0.72
0.61

0.6

0.51
0.4

< 2 mph2–3 mph3–4 mph> 4 mph

Source: Modified from Tanasescu M, et al. JAMA 2002;288:1994–2000.

Quantifying the
Dose-Response Association
Recently, several more studies have reported
a more precise quantification of the dose(amount of exercise or degree of fitness) and
response (mortality risk-reduction) relationship by expressing exercise capacity in thecontext of survival benefit per MET (Table 9.2).
These studies present the change in mortality
risk for each 1-MET increase in exercise capacity assessed by a maximal exercise test. The
reduction in mortality risk per 1-MET increasein exercise capacity ranges between 10% and25%.16,21–27 This is evident in both men andwomen. There is also evidence to suggest thatthe strength of exercise capacity in predicting
risk of mortality may even be greater among
women than men.22,28
Information on the association between
physical activity, exercise capacity, and mortality among African Americans is lacking. It is
well-documented that the age-adjusted allcause mortality rates in African Americans are
as much as 60% higher when compared toAmerican Caucasians. To address this issue,
Kokkinos et al.27 assessed the association

between exercise capacity and mortality risk
in 6,749 African-American and 8,911 Caucasianmen. The investigators found exercise capacity to be a more powerful predictor of risk for
all-cause mortality than established risk factors (smoking, dyslipidemia, diabetes, andhypertension) among both African Americans
and Caucasians after adjusting for cardiac
medications. The risk for mortality was 13%
lower for every 1-MET increase in exercise
capacity for the entire cohort, with similar
reductions observed for those with and without CVD.
In addition, when fitness groups wereconsidere­d, the relative risk for all-cause mortality was approximately 20% lower in thosewith an exercise capacity of 5 to 7 METs (moderate fit category) when compared to thoseachieving < 5 METs. The mortality risk was 50%
lower for those with an exercise capacity of 7.1
to 10 METs and 70% lower for those with an
exercise capacity of more than 10 METs. This
gradient for a reduction in mortality withincreasing fitness was similar in African Americans and Caucasians in the entire cohort (Figure9.5) and in individuals with and without CVD(Figures 9.6 and 9.7). These findings are very© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity

239

Table 9.2 Survival Benefit per 1-MET Increase in Studies Using Maximal Exercise
Testing as a Measure of Fitness

Study

CohortBlair et al.16
Dorn et al.22
Goraya et al.23

Men
Cardiac rehabilitation- Younger- Elderly
Middle-aged men with and withoutcoronary heart disease test
Healthy women
Women in the Lipid Research Clinics Trial
Framingham Offspring Study:- Men- WomenFor every 1,000 kcal/week adulthood
activity
Middle-aged men with and withoutcoronary heart disease referred for an
exercise treadmill test

Myers et al.26
Gulati et al.28
Mora et al.24
Balady et al.21

Myers et al.25
Kokkinos et al.27

Figure 9.5

N

Mortality Risk
Reduction/MET
Increase

9,777
651
2,593
514
6,213

~16%
8%–14%
14%
18%
12%

5,721
2,994

17%
20%
13%

1,431
1,612
6,213

20%

15,66013%

Adjusted risk for all-cause mortality in African Americans and Caucasians.
1.2< 5 METs

5–7 METs

7.1–10 METs

> 10 METs

Relative Risk

1.0
0.8
0.6

0.81

0.8
0.51

0.4

0.79
0.52

0.5
0.31

0.34

0.26

0.2
0

All

African-American

Source: Adapted from Kokkinos, et al. Circulation 2008;117:614–622.

Caucasian© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

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Cardiovascular Disease Epidemiology and Physical Activity

Part III

Figure 9.6

Adjusted risk for all-cause mortality in African Americans and Caucasians

with CVD.
1.2< 5 METs

5–7 METs

Relative Risk

1.0
0.8

7.1–10 METs
0.86

0.81

0.6

0.5

0.4

0.78
0.53

0.46

0.42

> 10 METs

0.46

0.34

0.2
0

All

African-American

Caucasian

Source: Adapted from Kokkinos, et al. Circulation 2008;117:614–622.

similar to the mortality rate reduction reported
by Myers et al.26 in men with and without CVD.
Because the cohort of the two studies26,27 consisted of veterans with very similar health care(the Veterans Affairs Health Care System
ensures equal access to care independent of apatient’s financia­l status), the findings
strengthen the evidence that higher exercise
capacity is associated with lower cardiovascular and all-cause mortality regardless of factors
related to socioeconomic strata.

Figure 9.7

A more precise quantification of the dose (amountof exercise or degree of fitness) and response(mortality risk-reduction) relationship revealed a
10% to 25% reduction in mortality risk for each
1-MET increase in exercise capacity.

These findings have significant public health
implications. Mortality risk can be cut in half
by just engaging in brisk walk for 2 to 3 hours
per week or 30 minutes per session 4 to 5 days

Adjusted risk for all-cause mortality in African Americans and Caucasians

with no CVD.
1.2

< 5 METs

5–7 METs

7.1–10 METs

> 10 METs

Relative Risk

1.0
0.8
0.6

0.79

0.79
0.52

0.51

0.4

0.78

0.27

0.5
0.3

0.23

0.2
0

All

African-American

Source: Adapted from Kokkinos, et al. Circulation 2008;117:614–622.

Caucasian© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity

per week. This was shown for both African
Americans and Caucasians with and without
heart disease (see Figures 9.5 to 9.7). Collectively, the findings of the aforementioned studies support the concept that exercise capacity
should be given as much attention by clinicians
as other major risk factors.

Physical Activity andMortality in Women
Most of the information on the association
between physical activity, fitness, and mortality risk has been derived from studies on men.
Extrapolating from the findings of the studies
on men and the few studies that included
women, the health benefits of exercise arelikely to be similar for women. These assumptions were substantiated by a number of relatively large studies published since the late
1990s.
In a study of 10,224 men and 3,120 women,
Blair et al.15 reported similarly lower all-cause
and cardiovascular disease mortality rates withincreased fitness in men and women. Thesefindings were strengthened by their more
recent study that included a substantially larger
cohort of women (n = 7,080).17 In addition to
the inverse and graded association between
physical fitness and mortality, these data
revealed differences between men and women,suggesting that the influence of physical activity or fitness on mortality rates may be different in women and men.
First, physical fitness seems to offer agreater degree of protection in women withhigh blood pressure than men. The reduced
risk of mortality in hypertensive but high-fit
women was 81% lower when compared to lowfit women. In men, the risk reduction for thecomparable groups was only 32%. For the samegroup comparisons, the risk reduction for elevated blood cholesterol was 50% in men and
23% in women.

241

Second, the protection against the cumulative detrimental effect of multiple risk factors
appears greater for women than men. For example, the death rates in high-fit individuals with
two or three risk factors (smoking, high blood
cholesterol, or elevated systolic blood pressure)
were 15% men and 50% in women when compared to low-fit individuals with no risk factors.
In one of the earlier and largest studies on
postmenopausal women (The Iowa Women’s
Health Study), 40,417 women responded to asurvey that included questions related to healthhabits such as smoking, diet, alcohol consumption, anthropometry, medical history, and leisure time physical activity.29 Women wereclassified in three categories (low, moderate
and high-fit) based on the frequency and intensity of activity. Physical activities were classified as moderate (those requiring ≤ 6 METs) orvigorous (> 6 METs). Women who participatedin moderate activities more than four times per
week and those who participated in vigorous
activities two or more times per week comprised the high-fit category (n = 9,919). Those
who reported vigorous activity once a week ormoderate activity one to four times a week
comprised the moderate-fit category (n =10,987). The remaining women comprised lowfit category (n = 19,940). The follow-up period
was approximately 7 years.
After adjusting for confounding factors, theinvestigators reported that high levels of physical activity were associated with decreased
risk of mortality.29 The adjusted risk of mortality was 34% and 48% lower in the moderate- andhigh-fit women, respectively. Because women
who are ill tend to be less active and are likely
to die at a higher rate, the mortality rate in the
low-fit category may be inflated. To control forthis factor, the investigators excluded from theanalysis all women who died of cancer or heartdisease within the first 3 years of follow-up.
When the analysis was repeated, the results did
not change substantially.

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Another important finding of this study isthat the risk appears to be significantly reduced
even in those who participated in moderate
physical activity once per week to a few permonth. This is similar to the findings reported
in the Finnish Twin Study.14 It also supports
previous findings of a threshold requirement of
about 6 METs for a significant reduction in
mortality risk.18 However, it is in contrast toother studies that reported more vigorous andgreater volume of physical activity required forsignificant risk reduction.7
Two reports from the Nurses’ HealthStudy30,31 provided valuable information on theassociation between intensity, duration, frequency, and volume of physical activity necessary to reduce the risk of cardiovascular eventsin women.
The Nurses’ Health Study, initiated in 1976,
was designed to examine the association
between total physical activity (walking andvigorous exercise) and the incidence of cardiovascular events in women. The first study31

assessed the association between physicalactivity and the risk of coronary heart disease.
The cohort consisted of 72,488 middle-aged
women nurses, 40 to 65 years of age, free ofcancer and cardiovascular disease at the timeof entry into the study who completed a detailed
questionnaire about their physical activity habits. Each physical activity (walking, biking, jogging, aerobics, etc.) was expressed in METs andthen the total activity level was expressed as
MET-hours per week. Five physical activity categories were established as presented in Table
9.3. The follow-up period was 8 years.
The large size of the cohort and the longterm follow-up allowed the investigators toaddress several important questions including
the exercise intensity, duration, and volume on
the risk for coronary events. By excluding
the women who died within the first 2 years offollow-up, the possible overestimation of themortality rate within the low-fit categories as aresult of illness and not low fitness was
minimized.

Table 9.3 Relative Risk of Coronary Events According to Weekly Physical Activity(MET-hr/week)
Fitness Category

1

2

3

4

5

(MET-hr/wk)
Age-adjusted
relative risk
Multivariate

0–2.0
1.0

Multivariate
Excluding first
2 years

1.0

2.1–4.6
0.77(0.62–0.96)
0.83(0.71–0.95)
0.89(0.75–1.04)

4.7–10.4
0.65(0.51–0.95)
0.72(0.62–0.84)
0.81(0.68–0.97)

10.5–21.7
0.54(0.50–0.93)
0.63(0.54–0.74)
0.78(0.66–0.93)> 23.70.46(0.33–0.67)
0.55(0.47–0.65)
0.72(0.59–0.87)

1.0

Source: Adapted from Manson JE, et al. N Engl J Med 1999;341:650–658.
Numbers in parentheses indicate the confidence interval.

P valuefor Trend< 0.001< 0.001< 0.001© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity

A graded reduction in the relative risk ofcoronary events with increase in the METhours per week was noted (see Table 9.3). The
association between physical activity andmortality risk was somewhat weaker (mortality risk reduction was attenuated), but still
significant, when women who died within thefirst 2 years of follow-up were excluded (seeTable 9.3).
The investigators then sought to assess theattenuating potential effects established risk
factors may have on the association between
physical activity and coronary events. Thus,
the cohort was stratified based on smoking
habits, obesity (BMI), and parental history ofpremature myocardial infarction. For each
respective subgroup, physical activity was
inversely related to the risk of coronary eventsin all strata with no substantial differences in
the impact of physical activity in the loweringrisk (Figure 9.8). These findings support thatphysical activity has a similar attenuating effecton the risk for coronary events even when
amplified by the presence of cardiovascularrisk factors.

Walking and Coronary
Risk Reduction
Approximately 60% of the women in the cohort
engaged in at least 1 hour of walking per week
and only 26% engaged in vigorous activities
requiring ≥ 6 METs and defined vigorous exercise. Thus, the investigators assessed the association between walking and risk of coronary
events by excluding the women who reported
engaging in vigorous activity. An inverse association was again noted between walking hours
per week and the risk for coronary. Women
who walked between 1 to 2.9 hours per week ata brisk pace (≤ 20 minutes/mile), the equivalentof 3.9 to 9.9 MET-hours per week had a 30%
lower relative risk of coronary events when243

compared to the sedentary group (no walk).
The risk for the women who walked for 3 ormore hours per week (≥ 10 MET hr/wk) was
35% lower.
The investigators then sought to determine
if walking pace or exercise intensity was animportant determinant of risk of coronary
events. In a multiple analyses, walking paceemerged as an independent predictor of risk.
The multivariate relative risk for women who
walked at an average pace of 2.0 to 2.9 miles
per hour (20–30 minutes/mile), was 25% lower
risk when compared to women who walked at
an easy pace (< 2.0 miles/hour). The risk of
those who walked briskly or very briskly was
36% (Figure 9.9).
A significant reduction in risk (30% – 35%)
was also observed when walking more than 60
minutes per week (Figure 9.10).
When the investigators examined the combined effect of walking and more vigorous
exercise to the coronary event risk reduction,
they observed that women who engaged inboth walking and vigorous exercise had agreater risk reduction than those participatingin either type of activity alone. When theeffects of walking and vigorous exercise were
examined separately, both were effective inlowering risk. A 14% reduction in risk wasnoted for every 5 MET-hours per week spent
on walking (the equivalent of 1.5 hours of brisk
walk per week). For every 5 MET-hours per
week spent in vigorous exercise (the equivalent of 45 minutes per week of vigorous activities), the risk was lowered by 6%. This suggeststhat the exercise duration is more effective inlowering the risk for coronary events than
exercise intensity.
In the second report of the Women’s HealthStudy, the investigators assessed the association between physical activity and the risk for
cardiovascular disease.30 The cohort consistedof mostly the same cohort as in the previous© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

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Cardiovascular Disease Epidemiology and Physical Activity

Part III

Figure 9.8

Multivariate relative risk of coronary events (nonfatal myocardial infarction
or death from coronary causes) according to quintile group for total physical activity within
subgroups defined according to smoking status (A), body-mass index (B), and presence orabsence of a parental history of premature myocardial infarction (C). For each risk factor,
the reference group is the category at highest risk. Relative risks have been adjusted for thevariables in the full multivariate model.

(A)

Smoking Status

0.20
0.17

0.19
0.15

1

2

3

4

5

(B)

Body-Mass Index

0.65
0.64

0.69
0.54

29

0.82
0.65

0.8

0.88
0.71

1.0

> 29
0.79

3

4

5

0.4

0.0

1

(C)

2

Parental Myocardial Infarction Before Age 60
Yes

0.66

0.44

0.41

0.38

1

2

3

4

0.4

0.0

Low

Quintile Group for Total Physical Activity

Source: From Manson JE, et al. N Engl J Med 1999;341:650–658.

0.34

0.48

0.8

No

0.58

0.87

1.0

1.2

0.75

Relative Risk

1.2

Relative Risk

0.68

0.24
0.17

0.0

Never

0.28
0.20

0.8

0.4

Previously
0.78

0.86

0.84

1.0

Currently

0.29
0.23

Relative Risk

1.2

5
High

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Chapter 9  Cardiovascular Diseases and Physical Activity

Figure 9.9

Figure 9.10

Relative risk for coronary
events in women (n = 72,488) and walking
pace.
1

1.0

Relative Risk

Relative Risk

1.0

Relative risk for coronary
events in women (n = 72,488) and minutesof walking at a pace of 3 or more miles per
hour.

0.75
0.7

0.4

0.64

< 2 mph2–2.9 mph

0.7

0.7

0.4

3+ mph1< 60 min/wk

60–179 min/wk

0.65> 179 min/wk

Source: Adapted from Manson JE, et al. N Engl J Med
1999;341:650–658.

Source: Modified from Manson JE, et al. N Engl J Med
1999;341:650–658.

study, but slightly larger (n = 73,743) and older(50–79 years of age) and all postmenopausal
women.
During the 3.2 years of follow-up, a strong
inverse association was noted between the

total exercise (MET-hours per week) and theage-adjusted risk of coronary heart disease.
Similarly, the age-adjusted risk for cardiovascular disease declined as MET-hours per weekincreased (Table 9.4).

Table 9.4  Relative Risk for Cardiovascular Disease According to Fitness Categories
P valuefor Trend

Fitness Category

1

2

3

4

5

(MET-hr/wk)
CHD
Age-Adjusted
Relative Risk
CVD
Age-Adjusted
Relative Risk
Multivariate
Relative Risk

0–2.4
1.0

2.5–7.2
0.73(0.53–0.99)

7.3–13.4
0.69(0.51–0.95)

13.5–23.3
0.68(0.50–0.93)≥ 23.40.47(0.33–0.67)

1.0

0.83
(0.71–0.95)

0.72(0.62–0.84)

0.63(0.54–0.74)

0.55(0.47–0.65)< 0.001

1.0

0.89(0.75–1.04)

0.81(0.68–0.97)

0.78(0.66–0.93)

0.72(0.59–0.87)< 0.001< 0.001

Source: Adapted from Manson JE, et al. N Engl J Med 2002;347:716–725. Numbers in parentheses indicate
confidence intervals.

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Walking Versus Vigorous
Activity and Cardiovascular Risk
In the second report of the Women’s HealthStudy,30 investigators also assessed the independent effects of intensity and volume of physical activity on the reduction of cardiovascularmortality risk. Similar to the previous study, an
inverse association was observed between thecoronary heart disease and cardiovascular disease mortality with the increase in the METhours per week accumulated during brisk walk.
More specifically, when compared to the sedentary women, the reduction in risk ranged fromapproximately 30% to 40% when engaging ineither walking or more vigorous exercise for atleast 2.5 hours per week (Table 9.5).
The reduction in cardiovascular risk was
greater (63%) for women engaging in both walking and vigorous exercise, suggesting that theexercise intensity may have an independent
effect on risk reduction (Figure 9.11). This is
supported further by the inverse relationshipbetween walking pace and risk reduction. It
also appears that an intensity threshold emerges
at the approximate walking pace of 2 to 3 miles
per hour. When compared to the women who
never or rarely walked, those who walked at
the pace of 2 to 3 miles per hour (20 to 30 minutes per mile); 3 to 4 miles per hour (equivalent

Table 9.5  Relative Risk for Cardiovascular Disease According to Energy
Expenditure by Walking and Vigorous Exercise
P valuefor Trend

Walking

1

2

3

4

5

(MET-hr/wk)
CHD
Age-Adjusted
Relative Risk
CVD
Age-Adjusted
Relative Risk
Multivariate
Relative Risk0
1.0

0.1–2.5
0.71(0.53 – 0.96)

2.6–5.0
0.60(0.44– 0.83)

5.1–10.0
0.54(0.39–0.76)> 10.00.61(0.44–0.84)

1.0

0.88
(0.77–1.01)

0.70(0.60– 0.81)

0.66(0.57–0.77)

0.58(0.49–0.68)< 0.001

1.0

0.91(0.78–1.07)

0.82(0.69–0.97)

0.75(0.63–0.89)

0.68(0.56–0.82)< 0.001
P value

Vigorous Exercise
Minutes/week
CHD
Age-Adjusted
Relative Risk
CVD
Age-Adjusted
Relative Risk
Multivariate
Relative Risk

< 0.004

0
1.0

1–60
1.12
(0.79–1.6)

61–1000.56(0.32– 0.98)

101–1500.73(0.43 –1.25)

> 150
0.58
(0.34– 0.99)

1.0

0.87
(0.72–1.04)

0.73(0.58– 0.92)

0.69(0.53– 0.89)

0.60(0.47– 0.76)< 0.001

1.0

0.91(0.73 –1.12)

0.81(0.63–1.06)

0.85(0.64–1.13)

0.76(0.58–1.0)

0.01

0.008

Source: Adapted from Manson JE, et al. N Engl J Med 2002;347:716–725. Numbers in parentheses indicate
confidence intervals.

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Chapter 9  Cardiovascular Diseases and Physical Activity

Relative risk of CVD according to walking and vigorous activity.

Age-Adjusted Relative Riskof Cardiovascular Disease

Figure 9.11247

p < 0.05 for all comparisons withreference group (RR = 1.00)
1.0

0 min/wk of vigorous exercise
1–100 min/wk of vigorous exercise> 100 min/wk of vigorous exercise

1.00
0.78

0.8

0.70 0.72

0.71

0.6

0.67
0.49

0.43

0.4

0.37

0.2
0.0

2.5
2.6–10.0> 10.0
Energy Expenditure from Walking (MET-hr/wk)

Source: Data from Manson JE, et al. N Engl J Med 1999;341:650–658.

to a brisk walk), and more than 4 miles per hour(very brisk walk) had a 14%, 24%, and 42% relative reduction risk of cardiovascular disease(Figure 9.12).
Once again, the large size of the cohort
allowed the investigators to address several
important questions, including the exercise
intensity, duration, and volume on the risk for
cardiovascular events. In addition, the cohort

Relative risk of CVD according to walking pace.

Relative Risk of
Cardiovascular Disease

Figure 9.12

included a sizable number of African-American
women (n = 5,661) allowing the opportunity
for much needed information in this subgroup.
For the entire cohort, the graded reduction in
the relative risk for coronary heart disease andcardiovascular events with an increase in the
MET-hours per week was evident for total physical activity or walking alone (see Table 9.5).
The risk reduction was similar for Caucasia­n

1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

1.00

Multivariate p for trend = 0.002

1.06
0.86

0.76
0.58

Rarely or< 2 mph
2 to 3 mph
never walk (easy casual) (average)(n = 10,896) (n = 10,690) (n = 30,523)

3 to 4 mph(brisk)(n = 17,555)

Walking Pace (mph) Among Walkers
Source: Adapted from Manson JE, et al. N Engl J Med 1999;341:650–658.

> 4 mph(very brisk)(n = 990)

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and African-American women and for different
age brackets for total physical activity (Figure9.13) or walking alone (Figure 9.14). Similarly,
when the cohort was cate­gorized by body massindex (BMI), fitness was also inversely related
to the cardiovascular mortality for each subgroup (see Figures 9.13 and 9.14).
In summary, the two reports from the Women’s Health Study provided the following
information:
1. Both walking and more vigorous forms of
exercise are associated with an inverse andgraded reduction in the risk for coronary
heart disease and cardiovascular disease.
2. The association is evident in lean andobese Caucasian and African-American
women of different ages.
3. The exercise duration for a substantial
risk reduction in cardiovascular diseaseand coronary heart disease appears to beapproximately 1.5 to 2.5 hours per week.
4. The exercise intensity for similar risk
reduction appears to be at the walking
pace of approximately 20 – 30 minutes
per mile.
Two other studies examined changes inphysical activity status and the mortality risk
in women.32,33 The cohort of the first study consisted of 1,405 Swedish women aged 38 to 60
years who were initially free of major diseases
at baseline. Occupational and leisure-time
physical activity data from the baseline and 6year follow-up examinations were evaluated inrelation to all-cause mortality.
Moderate levels of leisure time and occupational physical activity were associated with
44% and 72% lower mortality risk respectively,
when compared to sedentary women. An insignificant reduction was also observed withhigher occupational or leisure activity levels.
The investigators concluded that decreases inphysical activity as well as low initial levels arestrong risk factors for mortality in women. The

effects and predictive value of physical activity
persist for several years.33
A more recent study32 examined the relationship of changes in physical activity andmortality among older women. This is a prospective study conducted at four U.S. research
centers (Baltimore, MD; Portland, OR; Minneapolis, MN; and Monongahela Valley, PA). The
cohort consisted of 7,553 Caucasian women
aged 65 years or older who were assessed atbaseline (1986 –1988) and at a follow-up visit(1992–1994) and followed for about 6 years.
The all-familiar inverse and graded association between increased physical activity andmortality (all-cause and cardiovascular) also
was evident in this study. The adjusted all-cause
and cardiovascular mortality rate for physically
active women who expanded approximately
1,000 to 1,900 kcal per week was approximately
40% lower when compared to the sedentary
women. In addition, the following findings arenoteworthy:32• Sedentary women who became physically
active between baseline and follow-up
had a 48% and 36% lower all-cause andcardiovascular mortality rate, respectively,
when compared to sedentary women who
were sedentary at both visits.
• Women who were physically active at
both visits also had 32% lower all-cause
mortality and cardiovascular mortality
than sedentary women.
• The associations between changes inphysical activity and reduced mortality
were similar in women with and without
chronic diseases but tended to be weaker
among women aged at least 75 years andamong those with poor health status.
The investigators concluded that increasing
and maintaining physical activity levels could
lengthen life for older women. The effects appear
to be less powerful in women aged at least 75
years and those with poor health status.

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Chapter 9  Cardiovascular Diseases and Physical Activity

Figure 9.13

Relative risk for CVD in women according to total physical activity, by race,

age, and BMI.
Quintile of total MET score

Total Physical Activity

1
LowestRace
1.2

p for trend < 0.001
1.00

1.0

0.82

0.8

2

3

4
5
Highestp for trend = 0.02
1.00
0.81

0.73
0.63

0.6

0.68
0.58

0.55

0.48

0.4

Age-Adjusted Relative Risk of Cardiovascular Disease

0.2
0.0

Caucasian Women (n = 61,574)

African-American Women (n = 5,661)

Age
1.2
1.0
0.8

p for trend < 0.001
1.00

p for trend < 0.001
1.00
0.79

0.68

0.63

0.6

0.54

0.63

0.56

0.45

p for trend < 0.001
1.00
0.93
0.86
0.75
0.64

0.50

0.4
0.2
0.0

50–59 yr (n = 24,803)

60–69 yr (n = 32,127)

70–79 yr (n = 15,856)

p for trend < 0.001
1.00

p for trend = 0.007
1.00
0.96

Body Mass Index
1.2
1.0
0.8
0.6

249

p for trend < 0.001
1.00
0.75

0.84

0.82
0.61 0.60

0.67

0.73

0.71
0.58

0.80
0.65

0.4
0.2
0.0

BMI < 25.0 (n = 30,583)

BMI 25.0–29.9 (n = 24,590)

Source: Adapted from Manson JE, et al. N Engl J Med 2002;347:716–725.

BMI ≥ 30.0 (n = 16,806)

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Cardiovascular Disease Epidemiology and Physical Activity

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Figure 9.14

Age-adjusted relative risk for CVD in women according to energy
expenditure from walking.
Energy expenditure from walking (MET-hr/wk)

Walking

0

Race
1.2

0.1–2.5

2.6–5.0

p for trend < 0.001
1.00

1.0

5.1–10.0> 10.0p for trend = 0.1
1.00 1.00

0.85
0.8

0.70

0.67

0.66

0.73

0.65

0.55

0.6
0.4

Age-Adjusted Relative Risk of Cardiovascular Disease

0.2
0.0

Caucasian Women (n = 61,574)

African-American Women (n = 5,661)

Age
1.2
1.0
0.8
0.6

p for trend < 0.001
1.00
0.78

p for trend < 0.001
1.00
0.91
0.70

0.66

p for trend = 0.004
1.00
0.89
0.78
0.72 0.72

0.49 0.51 0.46

0.49

50–59 yr (n = 24,803)

60–69 yr (n = 32,127)

70–79 yr (n = 15,856)

p for trend < 0.001
1.00
0.90

p for trend < 0.001
1.00

0.4
0.2
0.0

Body Mass Index
1.2
1.0
0.8

p for trend = 0.003
1.00
0.95
0.71

0.75

0.67

0.71

0.79 0.78

0.75
0.64

0.6

0.56 0.59

0.4
0.2
0.0

BMI < 25.0 (n = 30,583)

BMI 25.0–29.9 (n = 24,590)

Source: Adapted from Manson JE, et al. N Engl J Med 2002;347:716–725.

BMI ≥ 30.0 (n = 16,806)

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Chapter 9  Cardiovascular Diseases and Physical Activity

Two studies in women expressed the mortality risk reduction per 1-MET increase in
exercise capacity.24,28 In both studies, exercise
capacity was assessed by exercise stress test.
In the study by Gulati et al.28, the larger of thetwo, the adjusted mortality risk was 17% lower
for each 1-MET increase in exercise capacity.
This was a relatively greater reduction than has
been reported in men, prompting investigators
to speculate that exercise capacity may havean even greater capacity in predicting risk ofmortality among women than men.
Similar findings were reported by the Lipid
Research Clinic’s prevalence study, where
nearly 3,000 asymptomatic women were followed for up to 20 years.24 The age-adjusted risk
for cardiovascular death for every 1-MET decrement in exercise capacity was 20% higher.
Studies examining the association between physical activity and mortality in women have yielded
similar exercise-related health benefits with thoseobserved in men. There is also some evidence tosupport a greater dose-response association between exercise and mortality risk reduction for
women compared to men. In addition, the recently large studies in women have helped to better define associations between mortality risk andexercise intensity, duration, and frequency.

Physical Activity and Stroke
According to the 1996 U.S. Surgeon General’sReport on Physical Activity and Health, therelationship between exercise and stroke isinconclusive.34 Since that report, several large
studies have been conducted. Their findings
strengthen the suggestion of previous studies
that physical activity may protect people
against strokes.35
The findings from the Physicians’ HealthStudy showed a 14% lower the total risk of251

stroke among men participating in vigorous
exercise five or more times a week.36 Similarly,
in the Harvard Alumni Study total stroke risk in
men who were highly physically active was 18%
lower when compared to sedentary group.37
The Northern Manhattan Study (NOMAS) that
included Caucasian, African American, andHispanics, both men and women showed adecrease in ischemic stroke risk associatedwith physical activity levels across all racial/ethnic and age groups and for each gender.38
Similarly, in the Atherosclerosis Risk in Communities (ARIC) cohort, physical activity was
related to lower risk of ischemic stroke.39
In a Japanese cohort of 73,265 men andwomen, the risk of stroke death in the highest
category of walking and sports participation
was reduced by 29% and 20%, respectively.40
Moderate and high levels of leisure-time activity were associated with significant trends
toward lower risk of stroke in a study of 4,721
men and women in Finland. A smaller but still
significant benefit also was observed withoccupational activity.41
In the Nurses’ Health Study, the risk of total
stroke was graded inversely with the level of fitness.42 The risk was 18%, 26%, and 34% lower forthe three highest physical activity categories
respectively (Figure 9.15). Walking pace and
METs were also associated with lower risk in adose-response manner, independent of the number of hours spent walking (Figure 9.16). Thisfinding supports that exercise intensity has anindependent effect on risk reduction. Anotherimportant finding of the study is that sedentary
women who became active in middle to lateadulthood had approximately 20% reduction inrisk adjusted risk for stroke. This finding
suggest­s that the health benefits of increased
physica­l activity are not attenuated by age. More
importantly, the health benefits can be realizedeven if the individual has been sedentary forsome time. However, it is strongly recommended
that individuals who have been sedentar­y for a© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

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Figure 9.15

Relative risk of stroke in women according to total physical activity reported
in MET-hours/week.

Relative Risk

1.0

1

p = 0.01

0.98
0.82

0.8

0.74
0.66

0.6

0.4

0–2.0

2.1–4.6

4.7–10.4
METs

10.5–21.7> 21.7

Source: Data from Hu F, et al. JAMA 2000;283:2961–2967.

long time consult with a physician prior toembarking on an exercise program.
The association between physical activity
and stroke mortality in middle-aged men fromthe Seven Countries Study (the Corfu cohort),
was assessed after taking into account the presence of left ventricular hypertrophy (LVH).43
The investigators reported that the adoption ofeven a moderate physically active lifestyle was

Figure 9.16

Relative risk of stroke inwomen according to walking pace

Relative Risk

1.0

p < 0.001

1
0.81

0.8

0.6

0.49

0.4

0.2

associated with a significant reduction in therisk of stroke among men with and without
LVH. The impact of physical activity on strokemortality can be appreciated further by thefinding that the risk of stroke in physically
active men with LVH was 49% lower than therisk observed in sedentary men without LVH.
This finding is of particular interest, because
LVH is now considered an independent predictor of coronary heart disease and stroke.44–46
Finally, the findings of a meta-analysis of 31
observational studies conducted mainly in the
United States and Europe support that moderate
and high levels of leisure-time and occupational
physical activity protected against total stroke,hemorrhagic stroke, and ischemic stroke.47< 2 mph2–2.9 mph

3+ mphSource: Data from Hu F, et al. JAMA 2000;283:2961–
2967.

Studies investigating the association between
physical activity and stroke are relatively few andtheir findings are not as compelling as those regarding physical activity and heart diseases.
However, most studies support that moderate
and high levels of leisure-time and occupational
physical activity protected against total stroke.
Furthermore, the evidence is likely to strengthen
as more studies become available.

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Chapter 9  Cardiovascular Diseases and Physical Activity

Chronic Heart Failureand Exercise Training
Prior to the 1980s, exercise or physical activity
was not recommended for individuals withheart failure. The prevailing thinking was thatphysical exertion would cause further deterioration of the already compromised cardiac
function. This notion was challenged by somein the early 1980s. Since then, a systematic
scrutiny on the safety and efficacy of exercise
as a therapeuti­c modality for CHF patients was
pursued.
The findings of early studies were encouraging. Despite the relatively intense exercise programs (80% – 90% of peak oxygen consumption
for 50 – 60 minutes per session), the relatively
small number of patients, and lack of a control
group in some, significant improvements inexercise capacity and no major complications
in patients with moderate or severe left ventricular dysfunction were reported.48–51
These findings provided the incentive forseveral carefully designed, randomized studies, using more moderate exercise intensities.
Overwhelmingly, theses studies supported previous findings. Significant improvements inexercise capacity and peak oxygen consumption were shown after just 8 weeks of stationary bicycle exercise.52,53 A similar program
resulted in improvements in exercise capacity,
peak oxygen consumption, left ventricularfunction, and quality of life.54–56 Several studies
used longer training periods at similar intensities. These studies also yielded significant
improvements both in exercise capacity andpeak oxygen consumption.57–61 Finally, thesafety and efficacy of exercise training for theheart failure patient was confirmed by a relatively large, randomized trial (Chronic Heart
Failure and Graded Exercise Study)62 and amore recent meta analysis comprised of 13
studies that included aerobic and weight training of 2,387 heart failure patients.63

253

Exercise training studies overwhelmingly support
that individuals with heart failure can exercise
safely when exercise is carefully tailored to theirneeds and capacity.

However, exercise implementation in individuals with heart failure was not fully
endorsed, especially in patients with heart failure that resulted from a major heart attack.
Clinical and experimental evidence suggeststhat progressive left ventricular dilation occurs
in the pathogenesis of CHF, particularly after
myocardial infarction.64 This stretching, thinning, and expanding of the affected myo­cardium are influenced by several factors
including ventricular wall stress.65–68 Because
ventricular wall stress increases during phy­sical exercise, the thinking was that thisincreased stress may facilitate the remodelingprocess, exacerbate symptoms, and lead toprogressive deterioration of cardiac function.
Indeed, the findings of two studies supported
that such a remodeling process of the myo­cardium occurs as a result of exercise.69,70
However, the exercise programs implemented
in these studies were too demanding even for
healthy individuals. The programs consistedof morning and evening exercise, five times
per week for 4 weeks.
Subsequent well-designed studies that wererelatively large and had long training periods
revealed that the ejection fraction must be considered when exercise programs are designed
for heart failure individuals.71,72 In a study of 93
individuals who suffered a heart attack, theinvestigators found no deterioration of ventricular function or changes in ventricular cavity
dimensions and significant improvement inejection fraction after 6 months of exercise
training in patients with normal ventricularfunction and ejection fraction > 40%. Conversely, individuals with initial ejection fractio­n© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

254

Part III

Cardiovascular Disease Epidemiology and Physical Activity< 40% and ventricular dilation had more significant ventricular enlargement, with increased
infarct size, and more pronounced distortion in
the shape of the ventricle. However, this wasevident in both the exercise and no exercisegroups. In fact, the exercise group tended tohave less ventricular dilation and a substantial
increase in ejection fraction from 35% to 39%.
Although these findings were not statisticallysignificant, they suggest that exercise training
is not responsible for the increased deterioration in myocardial function observed in HF
patients with relatively low EF. In fact, exercise may lessen the deterioration of left ventricular function over time.72 Similar benefits
were reported in patients with reduced ven­
tricular function (EF of 26% to 38%) who exercised daily for 2 months at moderate intensities.
The program resulted in a 26% increase in exercise capacity and no deleterious effects on left
ventricular volume, function, or myocardialwall thinning regardless of the size of theinfarct area.71
Despite the efficacy and safety of moderate
to high exercise intensities, the use of lower
exercise intensities may be preferred for several reasons: (1) Low and moderate intensity
exercise carry a relatively low risk for cardiac
complications and musculoskeletal injuries;(2) patients are more likely to participate andsustain a lower than higher intensity exercise;and (3) physicians may feel more comfortableadvising patients to pursue a low-intensity versus a high-intensity exercise program.
The efficacy of low-intensity exercise
trainin­g for the CHF patient has been demonstrated by several studies. These studies foundthat improvements in peak oxygen uptake andpeak workload were comparable to thosereported with much higher exercise inten­
sities. Additionally, the relatively lower left
ventricular wall stress during low exercise
intensities decreases the risk for left ventricu-

lar enlargement that may occur in heart failure
individuals.73,74
Relatively small exercise training studies provide
strong evidence that exercise capacity and cardiac function improve with carefully conducted
exercise programs. The limited evidence suggesting that exercise training also can reduce therisk of mortality in individuals with heart failure isencouraging but this theory awaits the confirmation of large clinical trials.

Mechanisms for
Improvement by
Exercise Training
The mechanisms for such improvements are
not fully understood. The reduction in cardiac
output was originally thought to be the determining factor in the exercise capacity of the
CHF patient. However, indices of resting cardiac function such as left ventricular ejection
fraction and hemodynamic measurements arepoorly correlated with peak exercise performance or maximal oxygen consumption.75,76
Attention shifted to changes in skeletal muscle
and vascular pathophysiology to explain the
impaired exercise tolerance in such patients.
Skeletal muscle atrophy is a common phenomenon in CHF patients occurring early in thecourse of the disease.77,78 Improvements inexercise capacity following muscle strength
gains78–80 and positive correlations between
muscle mass and peak oxygen uptake in CHF
patients78 support that muscle atrophy may be
involve at least in part in the poor exercise
capacity of heart failure patients.
In a recent study, Hambrecht et al.81 notedsignificant improvements in endothelial-© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity

mediate­d vasodilation of the peripheral vasculature, peripheral blood flow, and peak V̇O2
following 24 weeks of moderate-intensity aerobic exercise training. These favorable findings
are attributed to the increased formation andrelease of endothelial relaxing factors in
response to increased shear stress induced bypulsatile blood flow. Similarly, endothelial
function was improved after 4 weeks of handgrip exercise. Collectively, these findings suggest that long-term physical training restores
impaired endothelial function,81,82 reverses theneurohormonal activation, and ameliorate the255

autonomic derangement observed in CHF
patients.51,53 It is now generally accepted thatphysical work capacity in these patients isdetermined by the interaction of cardiovascular and musculoskeletal and hormonal factors(Figure 9.17).

Exercise Training andMortality in Heart Failure
Encouraging findings on the rate of CHF progression, morbidity, and mortality have been

Figure 9.17

Schematic representation of muscular, cardiorespiratory, andneurohormonal changes in heart failure. Patients with heart failure are likely to adopt a
sedentary lifestyle. Consequently, there is a deterioration of skeletal muscle and aerobic
capacity, fostering an even more sedentary lifestyle and thus further deterioration of
muscular and cardiorespiratory functions.
Heart Failure

Skeletalmuscle atrophy

Patient adapts
sedentary lifestyle

Diminishedaerobic capacity

Muscular Changes

Cardiorespiratory Changes

Neurohormonal Changes• Diminished CO• Diminished EF• Diminished aerobic
work capacity• Chronotropic
incompetence• Decreased heart ratevariability• Increase in NE levels• Increase in endothelin
levels• Reduction in aerobic
enzyme content• Reduction in mitochondrial
volume content• Reduction in percent
of type I fibers• Increase in percent
of type II fibers• Decrease capillarization• Early onset of anaerobic
metabolism

Schematic representation of muscular, cardiorespiratory, and neurohormonal changes in heart failure.
Patients with heart failure are likely to adapt sedentary lifestyle. Consequently, there is deterioration ofskeletal muscle and aerobic capacity, fostering an even more sedentary lifestyle and thus further
deterioration of muscular and cardiorespiratory functions.

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Cardiovascular Disease Epidemiology and Physical Activity

Part III

reported by a small randomized and wellcontrolle­d trial.83 Belardinelli et al. randomized 99 middle-aged patients with stable CHF(88 males and 11 women) with EF ≤ 40% into
exercise and no exercise groups. After 14months of aerobic training, the exercise group
had lower total and cardiac mortality and hospital readmission for heart failure (Figure 9.18).
In addition, the quality of life improved in
the exercise group. The findings of a metaanalysi­s of nine randomized trials totaling 801
patients also support a significant reduction in
mortality and hospital admissions are significantly reduced after exercise training in HF
patients.84
Until recently, the impact of exercise training on clinical outcomes in patients with heart
failure had not been studied extensively. The
findings of a large trial (n = 2,331) on exercise
and heart failure (HF-ACTION trial) that wererecently published support that exercise

Survival (%)

Figure 9.18

reduced all-cause mortality and hospitalization
by 11% in patients assigned to the exercisegroup compared to those in the non-exercisegroup.85 Although this can be viewed as a modest reduction, several factors should be considered. First, the 11% reduction was in addition
to the reduction achieved by the state-of-theart medical/device management of heart failure
patients. Second, in addition to heart failure, asubstantial number of the participants in thisstudy had several comorbidities that madetheir capacity and ability to exercise on a regular basis very difficult. Consequently, the volume of exercise for these individuals wasseverely compromised. When the investigators
examined those who were able to exercise, thefindings were more impressive. More specifically, the average reduction in all-cause mortality and hospitalization was 16% and up to 27%
for cardiovascular disease mortality and heart
failure hospitalization.85

Exercise training and mortality in heart failure patients.
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

Cardiac Deaths

Exercise

No Exercise
log rank = 6.24
0

200

400

600

800
1,000
Time (days)

1,200

1,400

1,600

1,800

Number of Patients at Risk
No Exercise

49

46

43

42

41

37

29

29

29

29

Exercise

50

50

48

48

48

45

42

41

41

41

Source: From Belardinelli R, et al. Circulation 99:1173–1182.

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Chapter 9  Cardiovascular Diseases and Physical Activity

Conclusions• The current literature overwhelmingly
supports that carefully designed
exercise programs are well tolerated
and beneficial to patients with stable
heart failure.
• Exercise of low to moderate intensity
should be preferred because it isequally beneficial, carries a lower
risk for muscular and cardiovascularcomplications, and is better tolerated
by the patients than high intensity
exercise.
• Both the cardiovascular and muscularsystems are inextricably linked in thepathophysiology of CHF. Improvements
observed in exercise capacity following
exercise training may be the cumulative
result of hemodynamic, histological, andbiochemical changes.
• Improvement in work performance
following aerobic and strength training
exercises are similarly impressive. Thissuggests that decreased blood flow may
be the precursor of all the pernicious
manifestations of CHF. Future work in thisarea should consider exercise programs
that enhance both aerobic and anaerobic
pathways. The benefits of such exercise
programs may be additive and therefore
more beneficial to the CHF patient thaneither exercise mode alone.
• Endothelial dysfunction has been
implicated in CHF at least in part due todiminished blood flow. Recent trials
support that regular physical activity
improves endothelial function and work
capacity in CHF patients.
• Carefully designed exercise training
programs may be the intervention required
to reverse the deleterious effects ofendothelial dysfunction. The recently

257

published findings of a large trial (HFACTION) support that adequate exercise
training increases survival in patients withheart failure.

Low Extremity Arterial
Disease and Exercise
As discussed in Chapter 8, the progressive
development of atherosclerotic lesions ultimately in the arteries of the lower extremities
leads to significant stenosis of the arteries
involved. Consequently, blood flow distal tolesions is significantly impaired leading toleg pain, numbness, cold legs or feet, andmuscle pain in the thighs, calves, or feet. Thisis known as low extremity arterial disease(LEAD).
Individuals with this condition lead a sedentary lifestyle. Consequently, the deterioration of cardiorespiratory and muscularfunctions is accelerated and a decline in theoverall health and quality of life for the LEAD
patient ensues. In addition, LEAD patients
often suffer from comorbidities, including
hypertension, diabetes mellitus, dyslipidemia,
and coronary artery disease. National healthorganizations including the American Heart
Association, the American College of Sports
Medicine, and the Centers for Disease Control
and Prevention strongly recommend that
increased physical activity alone or as an
adjunct to pharmacologic therapy should be
implemented for the prevention and management of cardiovascular disease and the aforementioned comorbidities and risk factors.86,87
Treatment for intermittent claudication(pain or cramping in legs when walking or
exercising) thus should include lifestylechanges for positive modification of the traditional cardiovascular disease risk factors.
Exercise training should be an integral part of© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

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Cardiovascular Disease Epidemiology and Physical Activity

Table 9.6  Summary of Select Studies Reporting Improvements in Peak V̇O2 and/orWork Capacity in CHF Patients Following Exercise Training
Reference

N

NYHA
Class

Esani et al.49
Sullivan et al.51
Lee et al.50
Coats et al.52
Coats et al.53

15
12
18
11
17

I
II, III
I–IV
II, III
II, III

Belardinelli et al.54
Belardinelli et al.55
Belardinelli et al.56
Hambrecht et al.58

55
46
43
22

II, III
II, III
II, III
II, III

Wielenga et al.62
Demopoulos et al.74
Belardinelli et al.73

81
16
27

II–III
II–IV
II, III

Kiilavuori et al. 61
Koch et al.79
Minnotti et al.80
Mancini et al.78
Hambrecht et al.81

20
25
5
8
20

II–III
N/A
II–III
I–IV
II–III

Hornig et al.82

19

III

Belardinelli et al83
Jugdutt et al.70

99
13

Jette et al.69

39

Giannuzi et al.72

95

II–IV
15 wkspost-MI; notrandomized
10 wkspost-MI;EF < 30%
I, II

Dubach et al.71

25

N/A

Improvements
Peak V̇O2 ; work capacity
Peak V̇O2 ; work capacity
Peak V̇O2 ; work capacity
Peak V̇O2 ; work capacity
Reduction in NE spillover; sympathetic tone
withdrawal and increased vagal tone
Peak V̇O2 ; work capacity
Peak V̇O2 ; work capacity; LV function; quality of life
Peak V̇O2 ; work capacity; LV function
Improvements in aerobic enzyme and mitochondria
content; peak V̇O2; work capacity
Exercise time; anaerobic threshold; quality of life
Aerobic work; peak V̇O2
Improvements in aerobic enzymes and mitochondria
content
Aerobic work capacity; heart rate variability
Muscle strength; work capacity; quality of life
Forearm muscle strength and endurance
Respiratory muscle endurance and strength
Endothelial function; peripheral blood flow; work
capacity; peak V̇O2
Endothelial function; peripheral blood flow; work
capacity; peak V̇O2
Improved survival, peak V̇O2 and quality of life
Deterioration in global and regional ventricularfunction
Aerobic work capacity; peak V̇O2; EF improved insome but not all patients and worsened in one
Aerobic work capacity; peak V̇O2 improved inpatients with EF > 40%; no changes in ventricular
cavity dimensions; exercise patients with EF < 40%
had less deterioration than controls
Aerobic work capacity and peak V̇O2 improved; nodeterioration in ventricular performance

Source: Data are from Kokkinos, et al. American Heart Journal 2000;140:21–28.

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Chapter 9  Cardiovascular Diseases and Physical Activity

such therapeutic approach. An exercise training program of low to moderate intensity
can attenuate the deleterious effects of theaforementioned comorbidities associated with
LEAD. It is an attractive and conservative alternative therapy for these patients. For example,
walking, the preferred form of exercise for
LEAD patients, has a relativel­y low risk–benefi­tratio; it is also relevant to daily living, inexpensive, easily implemented to large populations,contributes to the overall health, can be usedalone or as an adjunct to pharmacotherapy,
and does not interfere with the surgical possibility that may be deemed necessary in the
future. In addition, the well-recognized local
vasodilatory effects of exercise and the preservation of lean body tissue can only be of benefit
to these patients.

 Exercise Therapy Findings
The well-known local vasodilation and the consequent increase in blood flow that occurs in
the exercising muscle encouraged investigators to assess the possible therapeutic effectsof structured exercise programs for LEAD
patients. Scientific assessment in patients withmild and moderate claudication began in the
1960s.
Primarily, two exercise training protocols
have been used extensively. One requires thepatient to walk to the onset of pain (claudication), rest until the pain subsides, and repeat
this intermittent walking several times. The
other protocol is similar with the exceptionthat the patients walk until near-maximal or
maximal claudication is reached.
Without exception, exercise training studies
involving LEAD patients yielded substantial
and clinically significant improvements inwalking distance to the onset of pain or maximal pain.88–102 A meta-analysis of 21 studies
revealed that following exercise rehabilitation,
the average walking distance to onset of clau-

259

dication increased by 179% and the distance tomaximal claudication by 122%.90 Significant
increases in peak oxygen uptake along withimprovements in maximal and pain-free walking time also have been reported.91
There is evidence of a synergistic effectwhen exercise is combined with pharma­cologic
therapy. After 6 months of either antiplatelet
therapy, exercise therapy, or a combination of
antiplatelet therapy plus exercise, walking distance improved in all groups. However, thegreatest improvements were observed in the
combined therapy group. Pain-free and maximal walking distances increased by 120% and105% in the combined therapy group, 90% and
86% in the exercise alone group, and only 35%
and 38% in the antiplatelet-only group.98
Exercise training following reconstructive
arterial surgery also merits special attention. In
one study, patients were randomized to reconstructive surgery, exercise alone, or reconstructive surgery plus exercise. Performance wasassessed at baseline and 48 weeks followingintervention. The symptom-free and maximal
walking distance in the exercise alone groupincreased by 179% and 151%, respectively. In
the surgery-only group, the increase was 376%
in the symptom-free distance and 173% in the
maximal walking distance. In the group with a
combination of surgery with exercis­e, symptom-free and maximal walking distanceincreased by 698% and 263%, respectively.97
The findings of the two studies presented(arterial reconstructive surgery and the antiplatelet therapy) support that the implementation of a well-designed exercise program as an
adjunct to either therapy can significantly
improve the outcome for the LEAD patient.
Exercise rehabilitation is now recommended
and implemented as the first line of therapy for
LEAD patients in stage I and II alone, or in conjunction with medical therapy and after reconstructive arterial surgery in patients withsignificant hemodynamic improvements.

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Cardiovascular Disease Epidemiology and Physical Activity

Without exception, exercise training studies involving LEAD patients have yielded substantial
and clinically significant improvements in walking distance to the onset of pain or maximal
pain. There is also string evidence of a synergistic effec­t when exercise is combined with phar­macologic therapy and/or after reconstructive
arterial surgery.

 Exercise Mode
The mode of exercise for most studies is walking combined with some other forms of leg
exercise such as running, cycling, stair climbing, dancing, jumping, and other dynamic andstatic leg exercises.90 Two studies used walking
alone and two other studies combined andcompared walking with resistance (strength)
training.92,100 Walking appears to be superior toother forms of exercise training, especiallywhen the exercise protocol requires thatpatients perform intermittent bouts of walking
to near-maximal or maximal pain.89 Althoughboth studies reported that resistance training
was inferior to walking and no additional benefits to the patient were noted when the walking
program was supplemented with resistancetraining, in some cases, muscle weakness cancompromise walking performance. Thus, thepossible therapeutic effects of an exercise program that combines aerobic and resistance
exercise for the LEAD patient should not bedismissed.

Intensity
The intensity of the exercise programs is notwell described in any of the studies. It is estimated that only 16% of patients who do notexperience pain at rest can walk a distance of
1,000 meters or more on a flat surface at 4 km/
hr or 2.5 miles/hr.103 Collectively, this information from available studies supports an exer-

cise intensity of approximately 2 to 4 mph
walking speed on a flat surface.104

Frequency, Duration,and Length of Training
Most evidence supports that exercising threeor more sessions per week yields greater
improvements in claudication distance whencompared with fewer than three times per
week.90 Most studies also support that the exercise duration should be between 30 to 60 minutes per session. Improvements in the onset of
claudication pain and maximal claudication
pain walking distances are significant inpatients exercising 30 or more minutes per session when compared to those exercising less.
It thus appears that most improvements inphysical performance for LEAD patients occur
when exercising for at least 90 minutes per
week. However, the interaction between duration and frequency cannot be discerned fromthe existing literature.
Noticeable improvements in walking distance can be observed even after 4 weeks oftraining. However, longer training periods areclearly more successful. Greater improvements
in walking distances were associated stronger
with the length of training lasting 6 months or
longer.90

Potential Mechanisms
The mechanisms responsible for the exerciseinduced improvements in walking distanceremain illusive. The compromised blood flow
to the lower extremities in LEAD patients andthe well-known vasodilation and consequent
increase in blood flow in the exercising muscle
deserve special attention. However, the decline
in physical performance observed in LEAD
patients is likely the collective outcome ofdeterioration on several physiologic systems.
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Chapter 9  Cardiovascular Diseases and Physical Activity

in the functional capacity of these patients are
the result of favorable changes in several ofthese systems.

Potential Mechanisms for
the Physical Activity–Related
Reduction in Cardiovascular Risk
The mechanisms for the inverse association
between physical activity and the risk of cardiovascular disease and cardiovascular mortality are not completely understood. It has beenlong suspected and is likely that the favorable
modification physical activity or exercise
exerts on several established cardiovascularrisk factors translates to the cardioprotection
observed. Evidence for this is provided by arecent prospective study that included 27,055
apparently healthy women.105 The investigators
assessed several metabolic and hemodynamic
parameters and inflammatory biomarkers.
They also recorded the presence of hypertension and diabetes, and the self-reported physical activity levels of these women. After a meanfollow-up period of almost 11 years, the investigators noted a linear decrease in risk for
CVD events with higher physical activity levels.
The relative risk reductions risk for women
who expanded 200 to 599 kcal per week was
27% lower when compared to those expanding
less that 200 kcal. The relative risk was 32%
and 41% lower for those women who expanded
600 to 1,499, and 1,500 or more kcal/wk,
respectively.
The same investigators then assessed thecontribution of risk factors to lower risk. Differences in known risk factors explained alarge proportion (59.0%) of the observed
inverse association. They concluded that theinverse association between physical activity
and CVD risk is mediated mostly by known risk
factors, particularly inflammatory factors andblood pressure, and to a lesser by lipids, bodycomposition (BMI), and diabetes.

261

Author’s Note
Since the early 1950s, a plethora of scientificevidence has accumulated to support that increased physical activity and exercise lower therisk of cardiovascular disease and overall morbidity and mortality. Study findings are eloquently
summarized in a 2002 editorial entitled “Survivalof the Fittest.”106 In it, Dr. Gary Balady stated,“During the past 15 years, many long-term epidemiologic studies have shown an unequivocal
and robust relation of fitness, physical activity,and exercise to reduced mortality overall andfrom cardiovascular causes and reduced cardiovascular risk.”
Our next challenge is no longer to prove thatphysical activity or exercise protects against premature death. It isn’t even to define the kind of
exercise needed, how much, or of what intensity.
Although research must continue to define theseissues for different populations and diseases, themost compelling challenge is to promote a physically activity lifestyle for people of all ages.

Summary• Epidemiologic studies support a strong
inverse relationship between physicalexercise and coronary heart disease risk.
This evidence provided the basis to seek
answers as to kind of exercise, duration,
intensity, and volume needed to reduce therisk of heart disease.
• Physical fitness assessed by a treadmill
or bike test allows a more precise
quantification of fitness and its association
with mortality. The most striking findingsof these studies are: (1) the inverse,
graded, and independent association
between the volume of physical activity
and mortality risk; and (2) the relatively
low intensity and volume of physicalactivity required to achieve substantial
reduction in mortality risk.

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262

Part III

Cardiovascular Disease Epidemiology and Physical Activity• The exercise components of intensity andduration are also inversely associated withthe risk of coronary heart disease
independent of exercise volume.
• Some evidence supports that intensity may
be more strongly associated with risk
reduction. However, it is more likely that athreshold for exercise intensity andduration must be achieved before healthbenefits are realized.
• A number of observational studies
support that moderate and high levels of
leisure-time and occupational physicalactivity protected against total stroke,hemorrhagic stroke, and ischemic stroke.
• Exercise for the heart failure patients was
not recommended until recently for thefear that it may worsen the condition.
However, well-designed studies that
tailored their exercise programs have
proven that heart failure patients cantolerate exercise well.
• A number of these small studies provide
strong evidence that well-designed
exercise training studies yield significant
and favorable changes in cardiac function
and structure for the heart failure patients.
• Recent evidence from a large randomized
trial supports that exercise training
reduces hospitalization and mortality inthese patients.
• Well-designed exercise programs canbe beneficial for individuals with low
extremity arterial disease.
• Walking distance can be improved
substantially following such programs.
Exercise can be used in adjunct topharmacologic therapy or surgery.
Such approaches provide even greater
improvements in walking distance forsuch individuals.
• Recent evidence supports that the
cardiovascular risk reduction observedwith increased levels of physical activity is

mediated by the favorable effects physicalactivity exerts on several cardiovascularrisk factors. More specifically, most of
the reduction is mediated by favorable
changes in inflammatory factors and bloodpressure and to a lesser by lipids, bodycomposition (BMI), and diabetes.

References
1. Morris JN, Heady JA, Raffle PA, et al. Coronary heart-disease and physical activity ofwork. Lancet 1953;265(6796):1111–1120.
2. Leon AS Physical activity levels and coronary heart disease. Analysis of epidemiologic and supporting studies. Med Clin North
Am 1985;69(1):3–20.
3. Powell KE, Thompson PD, Caspersen CJ,
Kendrick JS. Physical activity and the incidence of coronary heart disease. Annu Rev
Public Health 1987;8:253–287.
4. Paffenbarger RS, Hale WE. Work activity andcoronary heart mortality. N Engl J Med
1975;292(11):545–550.
5. Brunner D, Mandis G, Modan, M, Levin S.
Physical activity at work and the incidenceof myocardial infarction, angina pectoris
and death due to ischemic heart disease. An
epidemiological study in Israeli collective
settlements (kibbutzim). J Chronic Dis
1974;27(4):217–233.
6. Punsar S, Karvonen MJ. Physical activity andcoronary heart disease in populations fromeast and west Finland. Adv Cardiol 1976;
18(0):196–207.
7. Paffenbarger RS Jr, Wing AL, Hyde RT. Physical activity as an index of heart attack risk incollege alumni. Am J Epidemiol 1978;
108(3):161–175.
8. Paffenbarger RS Jr, Hyde RT, Wing AL, Hsieh
CC. Physical activity, all-cause mortality, andlongevity of college alumni. N Engl J Med
1986;314(10):605–613.
9. Paffenbarger RS Jr, Hyde RT, Wing AL, et al.
The association of changes in physicalactivit­y level and other lifestyle characteris-© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity
tics with mortality among men. N Engl J
Med 1993;328(8):538–545. (see comments)
10. Kohl HW 3rd. Physical activity and cardiovascular disease: evidence for a dose response. Med Sci Sports Exerc 2001;33(6Suppl):S472–S483; discussion S493–S494.
11. Lee IM, Paffenbarger RS Jr. Do physical activity and physical fitness avert premature
mortality? Exerc Sport Sci Rev 1996;24:
135–171.
12. Paffenbarger RS Jr, Hyde RT. Exercise in theprevention of coronary heart disease. Prev
Med 1984;13(1):3–22.
13. Lee IM, Skerrett PJ. Physical activity and allcause mortality: what is the dose-response
relation? Med Sci Sports Exerc 2001;33(6Suppl):S459–S471; discussion S493–S494.
14. Kujala UM, Kaprio J, Sarna S, Koskenvuo M.
Relationship of leisure-time physical activity
and mortality: the Finnish twin cohort.
JAMA 1998;279(6):440–444.
15. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr,
et al. Physical fitness and all-cause mortality.
A prospective study of healthy men andwomen. JAMA 1989;262(17):2395–2401.
16. Blair SN, Kohl HW 3rd, Barlow CE, et al.
Changes in physical fitness and all-cause
mortality. A prospective study of healthy
and unhealthy men. JAMA 1995;273(14):1093–1098.
17. Blair SN, Kampert JB, Kohl HW 3rd, et al.
Influences of cardiorespiratory fitness andother precursors on cardiovascular disease
and all-cause mortality in men and women.
JAMA 1996;276(3):205–210.
18. Lakka TA, Venäläinen JM, Rauramaoa R, etal. Relation of leisure-time physical activity
and cardiorespiratory fitness to the risk ofacute myocardial infarction. N Engl J Med
1994;330(22):1549–1554.
19. Sandvik L, Erikssen J, Thaulow E, et al.
Physical fitness as a predictor of mortality
among healthy, middle-aged Norwegian men.
N Engl J Med 1993;328(8):533–537.
20. Tanasescu M, Leitzmann MF, Rimm EB, et al.
Exercise type and intensity in relation tocoronary heart disease in men. JAMA 2002;
288(16):1994–2000. (see comment)

263

21. Balady GJ, Larson MG, Vasan RS, et al. Usefulness of exercise testing in the predictionof coronary disease risk among asymptomatic persons as a function of the Framingham
risk score. Circulation 2004;110(14):1920–1925.
22. Dorn J, Naujton J, Imamura D, Trevisan M.
Results of a multicenter randomized clinical
trial of exercise and long-term survival in
myocardial infarction patients: the National
Exercise and Heart Disease Project(NEHDP). Circulation 1999;100(17):1764–1769.
23. Goraya TY, Jacobsen SJ, Pellikka PA, et al.
Prognostic value of treadmill exercise testing in elderly persons. Ann Intern Med
2000;132(11):862–870.
24. Mora S, Redberg RF, Cui Y, et al. Ability of
exercise testing to predict cardiovascularand all-cause death in asymptomatic women:
a 20-year follow-up of the lipid research clinics prevalence study. JAMA 2003;290(12):1600–1607. (see comment)
25. Myers J, Kaykha A, George S, et al. Fitness
versus physical activity patterns in predicting mortality in men. Am J Med 2004;
117(12):912–918.
26. Myers J, Prakash M, Froelicher V, et al. Exercise capacity and mortality among men
referred for exercise testing. N Engl J Med
2002;346(11):793–801. (see comment)
27. Kokkinos P, Myers J, Kokkinos JP, et al. Exercise capacity and mortality in black and whitemen. Circulation 2008;117(5):614–622.
28. Gulati M, Pandey DK, Arnsdorf MF, et al.
Exercise capacity and the risk of death inwomen: the St James Women Take Heart
Project. Circulation 2003;108(13):1554–
1559. (see comment)
29. Kushi LH, Fee RM, Folsom AR, et al. Physical activity and mortality in postmenopausal
women. JAMA 1997;277(16):1287–1292. (seecomment)
30. Manson JE, Greenland P, La Croix AZ, et al.
Walking compared with vigorous exercise
for the prevention of cardiovascular eventsin women. N Engl J Med 2002;347(10):716–
725. (see comment)© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

264

Part III

Cardiovascular Disease Epidemiology and Physical Activity

31. Manson JE, Hu FB, Rich-Edwards JW, et al.
A prospective study of walking as comparedwith vigorous exercise in the prevention ofcoronary heart disease in women. N Engl J
Med 1999;341(9):650–658.
32. Gregg EW, Cauley JA, Stone K, et al. Rela­
tionship of changes in physical activity andmortality among older women. JAMA 2003;
289(18):2379–2386.
33. Lissner L, Bengtsson C, Bjökelund C, Wendel
H. Physical activity levels and changes inrelation to longevity. A prospective study ofSwedish women. Am J Epidemiol 1996;143(1):54–62.
34. United States Department of Health andHuman Services: a report by the Surgeon
General, 1996. Historical document (1999)
available at www.nku.edu/~lipping/PHE125/
A%20Report%20of%20the%20Surgeon%20Ge
neral.doc. Accessed March 15, 2009.
35. Kiely DK, Wolf PA, Cupples LA, et al. Physical activity and stroke risk: the Framingham
Study. Am J Epidemiol 1994;140(7):608–620.
(see erratum)
36. Lee IM, Henneken CH, Berger K, et al. Exercise and risk of stroke in male physicians.
Stroke 1999;30(1):1–6.
37. Lee IM, Paffenbarger RS Jr. Physical activity
and stroke incidence: the Harvard Alumni
Health Study. Stroke 1998;29(10):2049–2054.
38. Sacco RL, Gan R, Boden-Albala B, et al. Leisure-time physical activity and ischemic
stroke risk: the Northern Manhattan Stroke
Study. Stroke 1998;29(2):380–387.
39. Evenson KR, Rosamond WD, Cai J, et al.
Physical activity and ischemic stroke risk.
The atherosclerosis risk in communities
study. Stroke 1999;30(7):1333–1339.
40. Noda H, Iso H, Toyoshima H, et al. Walking
and sports participation and mortality fromcoronary heart disease and stroke. J Am Coll
Cardiol 2005;46(9):1761–1767.
41. Hu G, Sarti C, Jousilahti P, et al. Leisure time,
occupational, and commuting physical activity and the risk of stroke. Stroke 2005;
36(9):1994–1999.
42. Hu FB, Stampfer MJ, Colditz GA, et al.
Physical activity and risk of stroke inwomen. JAMA 2000;283(22):2961–2967.
(see comments)
43. Pitsavos C, Panagiotakos DB, Crysohoou C,
et al. Physical activity decreases the risk ofstroke in middle-age men with left ventricular hypertrophy: 40-year follow-up (1961–
2001) of the Seven Countries Study (theCorfu cohort). J Hum Hypertens 2004;18(7):495–501.
44. Benjamin EJ, Levy D. Why is left ventricular
hypertrophy so predictive of morbidity
and mortality? Am J Med Sci 1999;317(3):168–175.
45. Levy D, Garrison RJ, Savage, DD, et al. Prognostic implications of echocardiographicallydetermined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;
322(22):1561–1566. (see comments)
46. Rodriguez CJ, Sacco RL, Sciacca RR, et al.
Physical activity attenuates the effect ofincreased left ventricular mass on the risk ofischemic stroke: the Northern Manhattan
Stroke Study. J Am Coll Cardiol 2002;
39(9):1482–1488.
47. Wendel-Vos GC, Schuit AJ, Feskens EJ, et al.
Physical activity and stroke. A meta-analysis
of observational data. Int J Epidemiol 2004;
33(4):787–798.
48. Conn EH, Williams RS, Wallace AG. Exercise
responses before and after physical conditioning in patients with severely depressed
left ventricular function. Am J Cardiol
1982;49(2):296–300.
49. Ehsani AA. Adaptations to training in patientswith exercise-induced left ventricular dysfunction. Adv Cardiol 1986;34:148–155.
50. Lee AP, Ice R, Blessey R, Sanmarco ME.
Long-term effects of physical training
on coronary patients with impaired ventricular function. Circulation 1979;60(7):1519–1526.
51. Sullivan MJ, Higginbotham MB, Cobb FR.
Exercise training in patients with severe left
ventricular dysfunction. Hemodynamic andmetabolic effects. Circulation 1988;78(3):506–515.
52. Coats AJ, Adamopoulos S, Meyer TE, et al.
Effects of physical training in chronic heart© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity
failure. Lancet 1990;335(8681):63–66. (seecomments)
53. Coats AJ, Adamopoulos S, Radaelli A, et al.
Controlled trial of physical training in chronic heart failure. Exercise performance,
hemodynamics, ventilation, and autonomic
function. Circulation 1992;85(6):2119–2131.
(see comments)
54. Belardinelli R, Georgiou D, Cianci G, et al.
Exercise training improves left ventricular
diastolic filling in patients with dilated cardiomyopathy. Clinical and prognostic implications. Circulation 1995;91(11):2775–2784.
55. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Effects of exercise training on left
ventricular filling at rest and during exercise in patients with ischemic cardiomyopathy and severe left ventricular systolic
dysfunction. Am Heart J 1996;132(1 Pt 1):
61–70.
56. Belardinelli R, Georgiou D, Ginzton L, et al.
Effects of moderate exercise training on
thallium uptake and contractile response to
low-dose dobutamine of dysfunctional myocardium in patients with ischemic cardio­
myopathy. Circulation 1998;97(6):553–561.
57. Goebbels U, Myers J, Dziekan G, et al. A randomized comparison of exercise training inpatients with normal vs. reduced ventricularfunction. Chest 1998;113(5):1387–1393.
58. Hambrecht R, Fiehn E, Yu J, et al. Effects ofendurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic
heart failure. J Am Coll Cardiol 1997;29(5):1067–1073.
59. Hambrecht R, Niebauer J, Fiehn E, et al.
Physical training in patients with stablechronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles. J Am Coll Cardiol
1995;25(6):1239–1249.
60. Keteyian SJ, Levine AB, Brawner CA, et al.
Exercise training in patients with heart failure. A randomized, controlled trial. Ann
Intern Med 1996;124(12):1051–1057.
61. Kiilavuori K, Sovijärvi A, Näveri H, et al.
Effect of physical training on exercise capa-

265

city and gas exchange in patients with chronic heart failure. Chest 1996;110(4):985–991.
62. Wielenga RP, Huisveld IA, Bol E, et al. Safety
and effects of physical training in chronic
heart failure. Results of the Chronic Heart
Failure and Graded Exercise study(CHANGE). Eur Heart J 1999;20(12):872–879.
63. Smart N, Marwick TH. Exercise training forpatients with heart failure: a systematic
review of factors that improve mortality andmorbidity. Am J Med 2004;116(10):714–716.
64. Gaudron P, Eilles C, Kugler I, Ertl G. Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential
mechanisms and early predictors. Circulation 1993;87(3):755–763.
65. Braunwald E. Optimizing thrombolytic therapy of acute myocardial infarction. Circulation 1990;82(4):1510–1513.
66. Braunwald E, Pfeffer MA. Ventricular enlargement and remodeling following acute
myocardial infarction: mechanisms andmanagement. Am J Cardiol 1991;68(14):
1D–6D.
67. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications.
Circulation 1990;81(4):1161–1172.
68. Pfeffer MA, Braunwald E. Ventricularenlargemen­t following infarction is a modifiable process. Am J Cardiol 1991;68(14):127D–131D.
69. Jette M, Heller R, Landry F, Blümchen G.
Randomized 4-week exercise program inpatients with impaired left ventricular function. Circulation 1991;84(4):1561–1567.
70. Jugdutt BI, Michorowski BL, Kappagoda CT.
Exercise training after anterior Q wave myocardial infarction: importance of regional
left ventricular function and topography.
J Am Coll Cardiol 1988;12(2):362–372.
71. Dubach P, Myers J, Dziekan G, et al. Effect of
exercise training on myocardial remodelingin patients with reduced left ventricularfunction after myocardial infarction: application of magnetic resonance imaging. Circulation 1997;95(8):2060–2067.

© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

266

Part III

Cardiovascular Disease Epidemiology and Physical Activity

72. Giannuzzi P, Tavazzi L, Temporelli PL, et al.
Long-term physical training and left ventricular remodeling after anterior myocardial
infarction: results of the Exercise in Anterior
Myocardial Infarction (EAMI) trial. EAMI
Study Group. J Am Coll Cardiol 1993;22(7):1821–1829.
73. Belardinelli R, Georgiou D, Scocco V, et al.
Low intensity exercise training in patientswith chronic heart failure. J Am Coll Cardiol 1995;26(4):975–982.
74. Demopoulos L, Bijou R, Fergus I, et al. Exercise training in patients with severe congestive heart failure: enhancing peak aerobic
capacity while minimizing the increase inventricular wall stress. J Am Coll Cardiol
1997;29(3):597–603.
75. Franciosa JA, Park M, Levine TB. Lack ofcorrelation between exercise capacity andindexes of resting left ventricular performance in heart failure. Am J Cardiol 1981;
47(1):33–39.
76. Szlachcic J, Massie BM, Kramer BL, et al.
Correlates and prognostic implication of
exercise capacity in chronic congestive
heart failure. Am J Cardiol 1985;55(8):1037–1042.
77. Lipkin DP, Jones DA, Round JM, PooleWilso­n PA. Abnormalities of skeletal muscle
in patients with chronic heart failure. Int J
Cardiol 1988;18(2):187–195. (see comment)
78. Mancini DM, Walter G, Reichek N, et al.
Contributio­n of skeletal muscle atrophy toexercise intolerance and altered muscle
metabolism in heart failure. Circulation
1992;85(4):1364–1373. (see comment)
79. Koch M, Douard H, Broustet JP. The benefitof graded physical exercise in chronic heart
failure. Chest 1992;101(5 Suppl):231S–235S.
80. Minotti JR, Johnson EC, Hudson TL, et al.
Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest
1990;86(3):751–758.
81. Hambrecht R, Fiehn E, Wiegl C, et al. Regularphysical exercise corrects endothelial dysfunction and improves exercise capacity inpatients with chronic heart failure. Circulation 1998;98(24):2709–2715. (see comments)

82. Hornig B, Maier V, Drexler H. Physical training improves endothelial function inpatients with chronic heart failure. Circulation 1996;93(2):210–214.
83. Belardinelli R, Georgiou D, Cianci G, Purcaro A, et al. Randomized, controlled trial of
long-term moderate exercise training inchronic heart failure: effects on functional
capacity, quality of life, and clinical outcome.
Circulation 1999;99(9):1173–1182.
84. Piepoli MF, Davos C, Francis DP, et al. Exercise training meta-analysis of trials inpatients with chronic heart failure (ExTraMATCH). BMJ 2004;328(7433):189.
85. O’Connor CM, Ehellan DJ, Lee KL, et al. Efficacy and safety of exercise training inpatients with chronic heart failure: HFACTION Randomized Controlled Trial.
JAMA 2009;301(14):1439–1450.
86. Fletcher GF, Balady GJ, Amsterdam EA, etal. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association.
Circulation 2001;104(14):1694–1740.
87. Pate RR, Pratt M, Blair SN, et al. Physicalactivity and public health. A recommendation from the Centers for Disease Control
and Prevention and the American Collegeof Sports Medicine. JAMA 1995;273(5):402–407.
88. Alpert JS, Larsen OA, Lassen NA. Exercise
and intermittent claudication. Blood flow inthe calf muscle during walking studied by
the xenon-133 clearance method. Circulation 1969;39(3):353–359.
89. Carter SA, Hamel ER, Paterson JM, et al.
Walking ability and ankle systolic pressures:
observations in patients with intermittent
claudication in a short-term walking
exercis­e program. J Vasc Surg 1989;10(6):642–649.
90. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA 1995;274(12):975–980.
91. Hiatt WR, Regensteiner JG, Hargarten ME,
et al. Benefit of exercise conditioning forpatients with peripheral arterial disease.

© Jones and Bartlett Publishers, LLC. NOT FOR SALE OR DISTRIBUTION

Chapter 9  Cardiovascular Diseases and Physical Activity
Circulation 1990;81(2):602–609. (seecomments)
92. Hiatt WR, Wofel EE, Meier RH, Regensteiner
JG, et al. Superiority of treadmill walking
exercise versus strength training for patientswith peripheral arterial disease. Implications
for the mechanism of the training response.
Circulation 1994;90(4):1866–1874.
93. Hillestad LK. The peripheral blood flow inintermittent claudication. VI. Plethysmographic studies. The blood flow response to
exercise with arrested and with free circulation. Acta Med Scand 1963;174:671–685.
94. Hillestad LK. The peripheral blood flow inintermittent claudication. V. Plethysmographic studies. The significance of the calf bloodflow at rest and in response to timed arrestof the circulation. Acta Med Scand 1963;
174:23–41.
95. Hillestad LK. The peripheral blood flow inintermittent claudication. IV. The significance of the claudication distance. Acta Med
Scand 1963;173:467–478.
96. Larsen OA, Lassen NA. Effect of daily muscular exercise in patients with intermittent claudication. Lancet 1966;2(7473):1093–1096.
97. Lundgren F, Dallöf AG, Lundholm K, et al.
Intermittent claudication–surgical reconstruction or physical training? A prospective
randomized trial of treatment efficiency.
Ann Surg 1989;209(3):346–355.
98. Mannarino E, Pasqualini L, Innocente S, etal. Physical training and antiplatelet treatment in stage II peripheral arterial occlusive267

disease: alone or combined? Angiology
1991;42(7):513–521.
99. Regensteiner JG, Meyer TJ, Krupski WC, etal. Hospital vs. home-based exercise rehabilitation for patients with peripheral arterial
occlusive disease. Angiology 1997;48(4):291–300.
100. Regensteiner JG, Steiner JF, Hiatt WR.
Exercise training improves functional status
in patients with peripheral arterial disease.
J Vasc Surg 1996;23(1):104–115.
101. Skinner JS, Strandness DE Jr. Exercise andintermittent claudication. II. Effect of physical training. Circulation 1967;36(1):23–29.
102. Skinner JS, Strandness DE Jr. Exercise andintermittent claudication. I. Effect of repetition and intensity of exercise. Circulation
1967;36(1):15–22.
103. Ekroth R, Dahllöf AG, Gundevall B, et al.
Physical training of patients with intermittent claudication: indications, methods, andresults. Surgery 1978;84(5):640–643.
104. Ainsworth BE, Haskell WL, Leon AS, et al.
Compendium of physical activities: classification of energy costs of human physicalactivities. Med Sci Sports Exerc 1993;25(1):71–80. (see comment)
105. Mora S, Cook N, Buring JE, et al. Physicalactivity and reduced risk of cardiovascular
events: potential mediating mechanisms.
Circulation 2007;116(19):2110–2118.
106. Balady G. Survival of the fittest—more evidence (editorial). N Engl J Med 2002;347(4):288–290.