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American Journal of Lifestyle Medicine
http://ajl.sagepub.com/content/3/1_suppl/32S
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DOI: 10.1177/1559827609332348
2009 3: 32S originally published online 19 March 2009 AMERICAN JOURNAL OF LIFESTYLE MEDICINE
Arthur S. Leon
Biological Mechanisms for the Cardioprotective Effects of Aerobic Exercise

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32S
American Journal of Lifestyle Medicine July Aug 2009
Biological Mechanisms for the
Cardioprotective Effects of
Aerobic Exercise
Arthur S. Leon, MD, MS
DOI: 10.1177/1559827609332348. From the Laboratory of Physiological Hygiene and Exercise Science, School of Kinesiology, University of Minnesota, Minneapolis.
Dr Leon is supported in part by the Henry L. Taylor Professorship in Exercise Science and Health Enhancement. For financial disclosure and funding information, see the
Acknowledgments section at the end of the article. Address correspondence to Arthur S. Leon, MD, MS, Laboratory of Physiological Hygiene and Exercise Science, School of
Kinesiology, University of Minnesota, 202 Cooke Hall, 1900 University Avenue SE, Minneapolis, MN 55455; e-mail: leonx002@umn.edu.
For reprints and permissions queries, please visit SAGEs Web site at http://www.sagepub.com/journalsPermissions.nav.
Copyright 2009 The Author(s)
Abstract: Epidemiologic studies have
consistently identified a strong inverse
association between coronary heart
disease (CHD) and regular, predom-
inantly moderate-intensity physical
activity and cardiorespiratory fitness.
Supporting evidence of causative rela-
tionships has been provided by aero-
bic exercise training studies in both
animals and humans. This research
demonstrated multiple plausible cardio-
protective biological mechanisms. These
include direct antiatherosclerotic effects
by improving artery endothelial func-
tion and reducing inflammation and
indirectly via modification of other risk
factor components of the metabolic syn-
drome, by reducing risk of a coronary
thrombotic occlusion (antithrombotic
effects), by decreasing myocardial oxy-
gen demands and increasing its vascu-
lar supply (anti-ischemic effects), and
by improving cardiomyocyte electrical
stability and autonomic nervous system
adaptations (antiarrhythmic effects).
Although much additional research
is needed to better define and estab-
lish optimal dose-response relationships,
clearly these pleotropic effects strongly
suggest that aerobic exercise can atten-
uate the risk of CHD at all stages of the
underlying atherothrombotic process.
Keywords: exercise; physical activity;
physical fitness; atherosclerosis; coronary
heart disease
D
espite a progressive decline in rate
over the past 5 or so decades, cor-
onary heart disease (CHD) remains
the leading cause of death in the United
States, as well as a major contributor to
disability, lost productivity, and medical
expenses. The underlying cause of CHD is
atherosclerosis. This chronic inflammatory
disorder begins during childhood. It is ini-
tiated by multiple risk factors, which cause
dysfunction or injury to artery endothelial
linings. This results in a cascade of
pathophysiological events, including lipid
infiltration, primarily of low-density lipo-
protein (LDL), and its subsequent oxida-
tion. This triggers a progressive inflam-
matory response, resulting in formation
of fibrocalcific plaques, causing progres-
sive coronary stenosis.
1,2
However, acute
coronary events commonly are triggered
by reological disruption of less advanced
lesions, characterized by a thin fibrous
cap over a large, eccentrically located lipid
core and inflammatory cell infiltration (a
so-called vulnerable plaque). Plaque dis-
ruption initiates platelet aggregation and
thrombus formation at the damage site,
causing coronary occlusion, which results
in myocardial ischemic damage and/or a
fatal ventricular tachyarrhythmia.
As is true with most chronic disease
processes, atherosclerosis and resulting
CHD (as well as a strokes and peripheral
artery disease) have a multifactional eti-
ology. Risk factors include nonmodifiable
biological factors (genetics, aging, and
gender differences) and modifiable phys-
iologic and metabolic factors (especially
atherogenic dyslipidemia, hypertension,
and diabetes mellitus) and modifiable
lifestyle-related/behavioral factors (espe-
cially smoking, dietary habits, physical
inactivity and associated reduced physical
fitness, and overweight/obesity).
3
Physical inactivity is the most prevalent of
these modifiable risk factors in the United
States, with about two-thirds of Americans
performing little or no discretionary physical
activity (PA) for recreation or job-related PA.
This low level of energy expenditure, along
with an associated relative excess in energy
intake, has resulted in a high and grow-
ing prevalence of obesity and its severity in
both American adults and children. Obesity,
particularly if it is associated with excess vis-
ceral adiposity (as evidenced by increased
abdominal girth), is a major independent
risk factor for the metabolic syndrome, car-
diovascular disease, type 2 diabetes melli-
tus, and several forms of cancer.
4
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American Journal of Lifestyle Medicine
33S
vol. 3 suppl. 1
The inverse association of PA with
risk of CHD has been demonstrated in
both men and women the past 5 or so
decades by an extensive body of epi-
demiologic observational studies. Meta-
analyses of the better quality studies
show that the risk of CHD as well as all-
cause mortality is about twice as likely in
physically inactive as in more active indi-
viduals.
4
In addition, a smaller number
of studies have reported an even stron-
ger inverse association between cardio-
respiratory fitness, as assessed by graded
exercise testing, and risk of CHD and all-
cause mortality.
5
In these studies, there
was more than a 5-fold difference in
CHD rate between the least fit and most
fit members of the cohorts. Furthermore,
it appears from these 2 study approaches
that the largest reduction in relative risk
of CHD occurs in going from an inactive
to a moderately active lifestyle and from
a low to a moderate level of physical
fitness.
6
Strong supporting evidence for the pos-
tulated partial protective effect of PA and
physical fitness against CHD has been
provided by experimental work in ani-
mals and humans. This research has
identified multiple plausible biologi-
cal mechanisms supporting these rela-
tionships. These mechanisms include
anatomic, physiologic, and metabolic
adaptations to aerobic exercise train-
ing. Supporting evidence for these adap-
tations was recently reviewed in depth
in this journal
1
and only will be briefly
summarized here. The reader is referred
to a more detailed article by Leon and
Bronas
1
for references to the findings
discussed below.
These biological mechanisms may be
classified under the following headings:
antiatherosclerotic, antithrombotic, anti-
ischemic, and antiarrhythmic effects.
Below are summarized mechanisms for
each of these 4 categorical adaptations to
regular PA or aerobic exercise.
Antiatherosclerotic Effects
Both morphological assessments of cor-
onary arteries in animals (including mon-
keys) on atherosclerosis-promoting diets
and imaging assessments of human cor-
onary arteries confirm that aerobic exer-
cise training can reduce the progression
or contribute to the partial regression of
atherosclerotic lesions. Multiple mech-
anisms appear to contribute to antiath-
erosclerotic effects of exercise. Exercise
training, by causing recurrent increases
in laminar sheer stress on artery endothe-
lium, improves nitric oxide (NO) synthe-
sis and prolongs its activity. The resulting
improvement in endothelial function
increases vasodilatation and helps pro-
tect the coronaries against both athero-
sclerosis and thrombosis. There also is
growing evidence that exercise training
increases circulating endothelial progen-
itor cells, which participate in repair and
regeneration of damaged endothelium.
Furthermore, exercise training reduces
circulating biomarkers of inflammation,
including C-reactive protein (CRP), a risk
factor related to severity of atherosclerosis.
In addition, exercise training may have
a favorable impact on a number of major
atherogenic risk factors. These include
a reduction in elevated levels of systolic
and diastolic blood pressure and favor-
able impacts on dyslipidemia, insulin sen-
sitivity, and glucose disposal. Furthermore,
a concomitant, even moderate, reduction
in excess body fat, particularly visceral fat,
potentiates the improvement in all of the
above risk factors, which are components
of the proatherogenic, prodiabetic meta-
bolic syndrome.
Antithrombotic Effects
As mentioned, the vast majority of acute
coronary syndromes are initiated by a
thrombus-induced coronary occlusion.
Improved endothelial function, induced
by exercise training, reduces platelet
aggregation and a number of blood-
clotting factors, including fibrinogen, and
it promotes fibrinolysis by increasing activ-
ity of endothelial plasminogen activator.
Anti-Ischemic Effects
Myocardial ischemia is induced by an
imbalance between myocardial oxygen
(MVO
2
) demands and its supply via the
coronary circulation. An exercise training-
induced improvement in maximal oxygen
uptake (VO
2
max) has a favorable impact
on both sides of the MVO
2
demand-
supply equation. MVO
2
demands are
reduced at rest and during submaximal
physical exertion by a reduction in heart
rate and systolic blood pressure (and
hence the so-called rate-pressure product).
In addition, it reduces MVO
2
demands by
improving efficiency and capacity of the
heart as a pump, as well as by peripheral
adaptations in skeletal muscle.
Aerobic exercise training also has been
shown to improve MVO
2
supply by sev-
eral mechanisms. These include extending
the diastolic period of peak coronary flow
by slowing the heart rate and by improv-
ing endothelial-induced vasodilatation of
coronary resistance vessels by increas-
ing NO synthesis and activity. In addi-
tion, moderate-intensity aerobic exercise
improves arterial compliance/elasticity,
thereby reducing aging-related arterial
stiffness. Furthermore, exercise training
can increase the luminal area of conduit
arteries by remodeling (arteriogenesis).
In addition, animal studies have demon-
strated exercise-induced increases in myo-
cardial capillary density, analogous to the
angiogenesis demonstrated in skeletal
muscle in both animals and humans.
Antiarrhythmic Effects
Lethal ventricular tachyarrhythmias, often
the initial presenting symptom of CHD,
are responsible for about two-thirds
Differentiation is needed between
transient effects of each acute
exercise session and true chronic
adaptations to training.
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34S
American Journal of Lifestyle Medicine July Aug 2009
of CHD-related deaths among Americans
older than age 35 years. Vigorous physical
exertion (>6 metabolic equivalent [MET]
intensities) transiently increases risk of
sudden cardiac death (SCD), as compared
to risk at rest or during more moderate
PA. Possible mechanisms for exertion-
induced SCD include increased MVO
2

demands in the presence of coronary ste-
rosis, increased sympathetic activity, coro-
nary spasm, or disruption of a vulnerable
plaque. However, excess risk of SCD dur-
ing vigorous PA is markedly lower in
those who exercise regularly. This most
likely is related to the reduced rate-
pressure product and MVO
2
demands
and/or its improved supply; direct cardio-
myocyte adaptations, improving electrical
stability of the heart; and reduced sympa-
thetic and increased vagal stimulation of
the heart. These latter training effects can
be demonstrated by increased heart rate
variability and a decrease in the sympa-
thetic component of the heart rateblood
pressure baroreceptor response to stimuli
following exercise training.
Conclusion
Much additional research is required
to confirm and further elucidate these
apparent cardioprotective effects of exer-
cise and to identify possible additional
mechanisms. Differentiation is needed
between transient effects of each acute
exercise session and true chronic adapta-
tions to training. In addition, there is
a need to better define the optimal
dose-response relationship for producing
and maintaining specific exercise-induced
adaptations.
7
There also is evidence of
considerable interindividual variabil-
ity in responsiveness to the same train-
ing prescription, as demonstrated in the
HERITAGE Family Study.
8
Based on a considerable body of
knowledge, reduced risk of CHD can be
obtained by the current public health rec-
ommendation of 30 to 60 minutes a day
on most days of the week of either con-
tinuous or intermittent moderate-intensity
PA, such as brisk walking. However, to
obtain the full gamut of cardioprotective
effects of exercise, it appears from the
currently available evidence that a formal,
more rigorous aerobic exercise training
program to significantly increase VO
2

max appears to be required (eg, 20 to
60 minutes at least 3 times per week at
60% to 90% of VO
2
max).
Acknowledgments
Appreciation is expressed to Ms Linda
Estrem for preparation of this manuscript.
No conflict of interest was delcared by
the author. This material was presented
at the 3rd Annual Building Healthy
Lifestyles Conference sponsored by
Arizona State University in Mesa, Arizona
(February 28 to March 1, 2008). The con-
ference was supported by the National
Heart, Lung, and Blood Institute (NIH-
NHLBI: 1R13HL091657-01). The content
is solely the responsibility of the authors
and does not necessarily represent the
official views of the National Institutes
of Health; National Heart, Lung, and
Blood Institute; or Arizona State
University.
AJLM
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