Cardiovascular Effects of Exercise Training

Exercise in Cardiovascular Disease
Cardiovascular Effects of Exercise Training

Molecular Mechanisms
Stephan Gielen, MD; Gerhard Schuler, MD; Volker Adams, PhD
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n the natural habitat of our ancestors, physical activity

was not a preventive intervention but a matter of
survival. In this hostile environment with scarce food and
ubiquitous dangers, human genes were selected to optimize aerobic metabolic pathways and conserve energy for
potential future famines.1 Cardiac and vascular functions
were continuously challenged by intermittent bouts of
high-intensity physical activity and adapted to meet the
metabolic demands of the working skeletal muscle under
these conditions.
When speaking about molecular cardiovascular effects of
exercise, we should keep in mind that most of the changes
from baseline are probably a return to normal values. The
statistical average of physical activity in Western societies is
so much below the levels normal for our genetic background
that sedentary lifestyle in combination with excess food
intake has surpassed smoking as the No. 1 preventable cause
of death in the United States.2
Physical activity has been shown to have beneficial
effects on glucose metabolism, skeletal muscle function,
ventilator muscle strength, bone stability, locomotor coordination, psychological well-being, and other organ functions. However, in the context of this review, we will focus
entirely on important molecular effects on the cardiovascular system. The aim of this review is to provide a
birds-eye view on what is known and unknown about the
physiological and biochemical mechanisms involved in
mediating exercise-induced cardiovascular effects. The
resulting map is surprisingly detailed in some areas (ie,
endothelial function), whereas other areas, such as direct
cardiac training effects in heart failure, are still incompletely understood.
For practical purposes, we have decided to use primarily an
anatomic approach to present key data on exercise effects on
cardiac and vascular function. For the cardiac effects, the left
ventricle and the cardiac valves will be described separately;
for the vascular effects, we will follow the arterial vascular
tree, addressing changes in the aorta, the large conduit
arteries, the resistance vessels, and the microcirculation
before turning our attention toward the venous and the
pulmonary circulation (Figure 1).
Cardiac Effects of Exercise

Left Ventricular Myocardium and
Ventricular Arrhythmias
The maintenance of left ventricular (LV) mass and function
depends on regular exercise. Prolonged periods of physical
inactivity, as studied in bed rest trials, lead to significant
reductions in LV mass and impaired cardiac compliance,
resulting in reduced upright stroke volume and orthostatic
intolerance.3 In contrast, a group of bed rest subjects randomized to regular supine lower-body negative pressure treadmill
exercise showed an increase in LV mass and a preserved LV
stoke volume.4 In previously sedentary healthy subjects, a
12-week moderate exercise program induced a mild cardiac
hypertrophic response as measured by cardiac magnetic
resonance imaging.5 These findings highlight the plasticity of
LV mass and function in relation to the current level of
physical activity.
Normal LV Contractile Function
In individuals with normal LV function, exercise-related
cardiac effects may be subdivided into 3 entities: (1) prevention of cardiac pathologies associated with aging; (2) cardiac
adaptation to strenuous regular exercise training resulting in
physiological cardiac hypertrophy commonly known as athletes heart; and (3) prevention of impaired systolic and/or
diastolic cardiac function associated with short-term challenges (eg, ischemia/reperfusion [I/R], doxorubicin).
Prevention of Age-Related Cardiac Pathologies
Oxidative Stress. Theoretically, tissues with fewer cell divisions are more susceptible to cumulative damage by reactive
oxygen species (ROS) than tissues with high replication rates.
In animal models of aging, increased malondialdehyde levels
were observed in sedentary old rats. Although the expression
of antioxidative enzymes such as superoxide dismutase
(SOD) was unchanged,6,7 its enzymatic activity was reduced,8
resulting in a net decline of antioxidative protection. Regular
physical exercise seems to delay the accumulation of ROSmediated cell damage by improving the antioxidative protection in the myocardium. In trained old rats, Rinaldi et al7
found increased myocardial protein expression of MnSOD
and Cu/Zn SOD.
From the Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Leipzig, Germany.
Correspondence to Volker Adams, PhD, Department of Internal Medicine/Cardiology, University of Leipzig, Heart Center, Strumpellstrae 39, 04289
Leipzig, Germany. E-mail adav@medizin.uni-leipzig.de
(Circulation. 2010;122:1221-1238.)
2010 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.110.939959
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September 21, 2010
Figure 1. Summary of exercise-mediated effects on different parts of the cardiovascular system. Max. indicates maximum; HFNEF,
heart failure with normal ejection fraction; ANP, atrial natriuretic peptide; and BNP, brain natriuretic peptide.
Heat Shock Proteins. Heat shock proteins (HSP) are highly

conserved chaperones that are involved in the folding of
newly synthesized or damaged proteins. The overexpression
of HSP70 in cardiomyocytes protects against ischemic damage and is associated with increased cell survival.9 Stressinduced synthesis of HSP70 is reduced in the aged cardiovascular system, consistent with a diminished stress
resistance.10 HSP70 and HSP27 were also elevated in trained
old rats versus sedentary old rats, indicating improved resistance to ischemic insults.7
Cardiomyocyte Apoptosis and Regeneration. Despite the
increase in LV mass generally observed with aging, the
number of cardiomyocytes declines by 30%.11 The exponential increase of cardiomyocyte death by apoptosis or
necrosis and the loss of cardiac regeneration by stem cells
have been discussed as key factors for this decline in cell
number.12,13 The increase in apoptosis may be a consequence
of decreased mitochondrial membrane stability and permeability transition pore formation, which leads to cytochrome c
release into the cytosol, resulting in activation of caspase-3
and -9.12 Exercise training seems to be highly protective
against cardiomyocyte apoptosis by modulating proapoptotic
and antiapoptotic genes.14
Human Functional Data. On the functional level in humans,
cardiac aging is associated with a significant increased wall
stress, decreased elasticity, impaired early LV diastolic relaxation, increased end-systolic LV volume, and reduced contractile reserve.15 Arbab-Zadeh et al16 were able to show that
lifelong physical activity prevents the development of diastolic LV dysfunction in older age. This finding also indicates
that so-called healthy aging is in fact primarily sedentary

aging and that the lack of physical activity may be more
relevant to the observed pathologies than aging by itself.
Cardiac Adaptation to Strenuous Exercise and
Cardiac Fatigue
Athletes Heart. In normal individuals, regular high-intensity
physical activity for 5 to 6 hours per week may result in
cardiac adaptations known as athletes heart, resulting in
compensatory myocardial hypertrophy, which is more eccentric in endurance training and more concentric in resistance
training.17 Endurance-trained athletes show mean LV end-diastolic diameters of 53.7 mm compared with 49.6 mm in
normal subjects17; however, 14% of 1309 athletes examined
by Pelliccia et al18 showed LV end-diastolic diameters between 66 and 70 mm. The diagnostic strategies to distinguish
normal LV hypertrophy from hypertrophic cardiomyopathy
are a matter of continuing discussions (reviewed by Fagard19
and Maron20).
LV physiological hypertrophy is caused by a proportional
increase in myocardial cell length and width without evidence
of myocardial hyperplasia in the majority of cases and is
mediated via increased cardiac insulin-like growth factor-1
(IGF-1) expression and activation of phophoinositide-3 kinase (PI3K) (p110).21 Transgenic mice with decreased
cardiac PI3K activity (dnPI3K mice)22 and mice lacking the
p85 subunit of PI3K23 show a reduced basal cardiac size and
an attenuation of exercise-induced myocardial hypertrophy.
Studies by Care` et al24 in exercised rats suggest that
downregulation of cardiac-specific microRNAs (miRNA,
miR-133, and miR-1) is regularly involved in exercise-
Gielen et al
induced cardiac hypertrophy. Reduction of miR-133 levels in

cardiac myocytes caused marked hypertrophy with increased
protein synthesis and fetal gene expression. MiR-1 overexpression, on the other hand, significantly reduced protein
synthesis and fetal gene expression.24 Its hypertrophic effects
are probably mediated via RhoA, Cdc42, and Whsc2, whose
RNA 3 untranslated regions comprise flanking nucleotides
matching miR-133.
The role of miR-1 in physiological hypertrophy was
further elucidated by Elia et al,25 who documented that IGF-1
and IGF-1 receptor are targets of miR-1 and that miR-1 and
IGF-1 are inversely correlated in cardiac hypertrophy.25IGF-1
activation, on the other hand, inhibits the miR-1 transcription
factor Foxo3a via an AKT-dependent pathway, further amplifying its hypertrophic effects.
Using a transgenic mouse model with overexpression of a
constitutively activated AKT (AKT-E40K), Catalucci et al26
confirmed that IGF-1/AKT also improved LV contractility by
phosphorylation of phospholamban at threonine. By translocating to the sarcoplasmatic reticulum, activated AKT can
mediate improved calcium handling by disinhibition of the
sarcoplasmic reticulum Ca2 ATPase pump (SERCA2a)
through phospholamban phosphorylation.
Cardiac plasticity in response to exercise training is
surprisingly rapid. In a rat model of high-intensity interval
treadmill running for 2, 4, 8, and 13 weeks followed by 2 or
4 weeks of detraining, Kemi and colleagues27 identified
cardiomyocyte cell length, diastolic relaxation, and calcium
decay as main factors for the training-induced increase in
VO2max by multiple regression analysis. These trainingrelated cardiac adaptations seem to be dependent on training
intensity.28
Cardiac Fatigue. Prolonged strenuous activity, as in the
Ironman Triathlon, can lead to transient reductions of LV
systolic and diastolic function.29 Several mechanisms are
involved in cardiac fatigue, including changes in preload
conditions, myocardial stunning, 1-receptor desensitization,
and altered cardiac autonomic regulation.30
Preload conditions were highlighted as a potential mechanism by Dawson et al, 31 who demonstrated the lack of
changes in LV function when central venous pressure was
well maintained. However, other researchers with different
training protocols found depressed LV contractile function
unrelated to preload conditions, which confirms the relevance
of intrinsic myocardial damage.32 In a dog model, Vatner and
Hittinger33 demonstrated that prolonged strenuous exercise
can indeed lead to ischemic myocardial dysfunction and
postischemic myocardial stunning in the absence of epicardial coronary stenoses.
Prolonged strenuous exercise results in a 5-fold increase in
circulating catecholamines34 with consecutive desensitization
of 1-adrenoreceptors.35 This results in a blunted chronotropic and inotropic response to dobutamine.32
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approach to I/R protection to exercise is to differentiate

between the mechanisms that are involved in I/R protection
and those that are essential. Mechanisms such as collateral
formation,38 elevated HSP,39,40 increased myocardial cyclooxygenase-2 expression,41 and higher levels of endoplasmic
reticulum stress proteins have all been shown to be not
essential for exercise-mediated I/R protection.42 Therefore,
we will focus on mechanisms found to be a condition sine qua
non for I/R protection. Among these are improved antioxidative protection, changes in mitochondrial metabolism and
protein expression, increased expression of sarcolemmal/
mitochondrial KATP channels, and attenuation of I/Rinduced calpain activation (Figure 2).
Antioxidative Protection. Production of ROS, accumulation
of hydrogen ions, and generation of reactive nitrogen species
play a major role in the complex pathophysiology of I/R
injury,43,44 and the quantity of ROS production critically
depends on the duration of anoxia and reoxygenation.44 The
primary source of ROS in I/R situations seem to be the
mitochondria.45 In animal models, exercise training protects
cardiac myocytes against I/R-induced oxidative stress and the
mitochondria against I/R-associated structural damage.46,47
Several mechanisms for training-induced cardioprotection
are under discussion (Figure 2). There is broad consensus that
increased antioxidative protection by training-induced upregulation of key antioxidative enzymes such as MnSOD,
glutathione peroxidase, and catalase plays an important
role48 50; however, myocardial MnSOD is only increased at
high training intensities. Recent studies have confirmed that
MnSOD is essential for full protection against I/R-induced
myocardial infarction (ie, ischemia 20 minutes) and related
ventricular arrhythmias; however, protection against myocardial stunning seems to work even in the absence of MnSOD.51
Changes in Mitochondrial Metabolism and Protein Expression. Cardiac mitochondria seem to contribute to exerciseinduced protection against I/R injury in several ways, as
follows: (1) Exercise training results in reduced generation of
ROS by cardiac mitochondria52,53; (2) mitochondria isolated
from the myocardium of exercised animals are more resistant
to calcium-induced opening of the mitochondrial permeability transition pore,52 a major proapoptotic stimulus; and (3)
exercise induces a downregulation of mitochondrial monoamine oxidase-A,54 which seems to be a major source of
oxidative stress by H2O2 generation.55 Monoamine oxidase-A
knockout animals are protected from I/R-induced myocardial
damage, highlighting the importance of this pathway for I/R
injury.55
Prevention of Functional Decline After Exposure

to Ischemia
I/R injury is a classic model of an acute cardiac injury with
great clinical relevance in the setting of myocardial infarction
with interventional reperfusion therapy. Human epidemiological data indicate that regular endurance exercise reduces the
risk of death during clinical I/R injury.36
Role of Sarcolemmal/Mitochondrial KATP Channels. Recently,

the sarcolemmal KATP channel has been described as a
potential mechanism for training-induced I/R protection.
Opening the sarcolemmal KATP channel accelerates cardiomyocyte repolarization by increasing K outflow and shortens the action potential.56 As a result of the shorter action
potential, Ca2 overloading is prevented by reducing opening
rates of the L-type Ca2 channel.56
Key Mechanisms for Protection Against I/R Injury. As

summarized by Powers et al, 37 the problem of a mechanistic
Attenuation of I/R-Induced Calpain Activation. Calpain is a

calcium-dependent protease with 2 isoforms (calpain I [milli]
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Figure 2. Exercise training has the potential to prevent myocardial damage related to I/R injury. Exercise training induces an upregulation of
key antioxidative enzymes such as MnSOD, glutathione peroxidase (GPX), and catalase. Opening the sarcolemmal (sarco) KATP channel
accelerates cardiomyocyte repolarization by increasing K outflow. As a result of the shorter action potential, Ca2 overloading is prevented
by reducing opening rates of the L-type Ca2 channel. Although not essential for I/R protection, increased levels of HSP72 were observed
after training. HSP72 can prevent apoptotic cell death, likely by interaction with caspase-3. Adapted from Powers et al 37 with kind permission of Springer Science and Business Media. Copyright 2008, Springer Science and Business Media
and calpain II [micro]), which are activated by prolonged

exposure to elevated cytosolic calcium levels and contribute
to myocardial I/R injury.57 French and colleagues58 showed
that calpain inhibition attenuates I/R-induced contractile
myocardial dysfunction. Exercise training reduces I/Rassociated calpain activation, most likely by improved antioxidative protection and prevention of I/R-induced SERCA2a
and phospholamban degradation.58
Thresholds and Time Course of I/R Protection
Training Intensity. In a rat model of 40 minutes per day of
treadmill exercise at 55% to 60% of VO2max for a total time
of 16 weeks, Starnes et al59 were unable to confirm a
significant level of I/R protection. This study therefore
provided evidence for a threshold effect (ie, that a minimum
intensity and duration of exercise have to be exceeded to
benefit from I/R protection). Lennon et al,60 on the other
hand, compared 2 training protocols at 55% and 75% of
VO2max for 60 minutes per day on 3 consecutive days and
did not find any difference in training-induced I/R protection between both groups, indicating that there may not be
a linear dose-response relation between training intensity
and cardioprotection.
Training Duration. Surprisingly, the protective effect is
similar after short-term (3 to 5 days) and long-term (weeks to
months) exercise training.40,46,61 In a trial specifically de-
signed to assess the loss of cardioprotective effects after

training cessation, Lennon et al62 were able to show a
persistence of protection against myocardial stunning for up
to 9 days, but cardioprotection was completely lost at 18 days
after exercise termination.
Systolic Heart Failure
Reduced exercise capacity and early fatigue in chronic heart
failure (CHF) are unrelated to the degree of LV systolic
dysfunction but are determined primarily by peripheral alterations with impaired endothelial function, reduced aerobic
oxidative metabolism in the skeletal muscle, skeletal muscle
atrophy, ventilatory dysfunction, and neurohumoral changes.63 In the context of this review, we will focus on the
cardiac effects of exercise only.
Training Effects on LV Function and Reverse Remodeling
In one of the first small prospective studies of aerobic
endurance training in CHF patients (n12), Sullivan et al64
confirmed that 4 to 6 months of training did not worsen LV
ejection fraction and tended to improve maximal cardiac
output. The extent of the cardiac changes did not, however,
explain the large 23% improvement in peak oxygen uptake so
that peripheral changes in limb perfusion and oxidative
metabolism must account for the larger part of the beneficial
symptomatic training effects.
The first larger prospective randomized study to actually
provide evidence for a training-induced reverse remodeling
Gielen et al
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Figure 3. In systolic heart failure, endurance exercise can induce reverse remodeling with improvement of systolic and diastolic LV
function and reduction of LV end-diastolic diameters. It does so by interfering with the vicious cycle of CHF-associated skeletal muscle
hypoperfusion with increased local ROS and cytokine generation resulting in endothelial function and sympathetic activation, which further increases afterload and worsens LV function. The reverse remodeling is a consequence of peripheral training effects (eg, improved
antioxidative protection in the skeletal muscle, increased parasympathetic tone, improved endothelial function as a result of increased
NO production and bioavailability, and direct cardiac effects related to improved Ca handling, increased PI3K [p110] activity, reduction
of fibrosis, and cardiomyocyte apoptosis). NE indicates norepinephrine; AT II, angiotensin II; ecSOD, extracellular SOD; GPX, glutathione peroxidase; and ox. Phos, oxidative phosphorylation.
came from Hambrecht et al,65 who demonstrated that endurance training led to reverse LV remodeling with modest
improvements of ejection fraction from 30% to 35% and
reductions of LV end-diastolic diameter in a mixed population of subjects with ischemic and dilated cardiomyopathy.
These findings were corroborated by the Exercise in Left
Ventricular Dysfunction and Chronic Heart Failure study.66 A
recent study in our institution indicates that the reverse LV
remodeling occurs as early as 4 weeks after the initiation of
endurance training (unpublished data, 2010).
Mechanisms Explaining Reverse Remodeling in CHF
In the absence of myocardial biopsies for molecular analysis
of myocardial changes induced by training, most authors
interpreted this favorable training effect as secondary to
afterload reduction with reduced resting blood pressure due to
improved endothelial function.65 67 However, animal models
reveal that there are clear direct myocardial effects of training
that are related to signaling pathways of myocardial hypertrophy and fibrosis (Figure 3)
Phosphoinositide-3 Kinase (p110). On the molecular basis,
recent animal studies suggest that activation of PI3K (p110)
is involved in exercise-mediated cardioprotection: In mice
with dilated cardiomyopathy, both swim training and consti-
tutive activation of PI3K (p110, caPI3K) improved survival

by 20%.22 In an aortic banding model of pathological
hypertrophy, caPI3K mice showed a blunted increase in heart
size compared with wild-type mice.22 Levels of interstitial
fibrosis were reduced in caPI3K mice, highlighting the
potential of PI3K as an antifibrotic signal. Another important
downstream effect of PI3K is the protection against apoptotic
cardiomyocyte death via AKT.
Anabolic/Catabolic Balance in the Myocardium. Animal
studies in which an left anterior descending artery ligation
model was used demonstrated a significant upregulation of
components of the ubiquitin-proteasome system as well as
myostatin.68,69 Both of these factors were significantly reduced by exercise training over a period of 4 weeks.68,69
Calcium Handling. Alterations in calcium handling are also
associated with pathological hypertrophy and transition from
hypertrophy to failure: SERCA2a protein levels were reduced
in mouse and dog models of heart failure and were normalized by exercise training.70,71 In addition, exercise training
activates Ca2/calmodulin-dependent protein kinase II, leading to a hyperphosphorylation of phospholamban,72 which in
its phosphorylated form no longer inhibits SERCA2a. In
conjunction with an increased expression of Na-Ca2 ex-
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September 21, 2010
changer,73 this leads to improved calcium cycling and finally

to better cardiomyocyte function. For more detailed information on exercise-induced improvements on the contractile
apparatus and calcium cycling, please see a recent review by
Kemi and Wisloff.74
Neurohormonal Adaptations. An aerobic training program in

patients with CHF regularly reduces the resting heart rate,
which indicates a reduction in sympathoadrenergic drive.
This has also been confirmed for serum catecholamine levels:
Coats et al75 showed a 16% reduction of radiolabeled norepinephrine secretion after 8 weeks of training. This reduction in
adrenergic tone was accompanied by an increase in heart rate
variability. In addition to the reduction in circulating catecholamines, Braith et al76 described a 25% to 30% reduction
of angiotensin II, aldosterone, arginine vasopeptide, and atrial
natriuretic peptide after 4 months of walking training in
patients with CHF.
In a rat model of ischemic CHF, the beneficial training
effects on local neurohumoral balance were analyzed in the
noninfarcted LV myocardium. Xu and colleagues77 found a
significant reduction of myocardial angiotensin-converting
enzyme mRNA expression and AT1-receptor expression after
8 weeks of treadmill training. This finding is of special
importance given the fact that 90% of angiotensin II is
produced locally in the myocardium and implies that local
angiotensin II levels are significantly reduced by training.
This reduction also translates into reduced fibrogenesis, as
indicated by reduced tissue inhibitor of metalloproteinase-1
expression with unchanged matrix metalloproteinase
(MMP)-1 expression and reduced collagen volume fraction in
the exercised animals.77
Diastolic Heart Failure
Heart failure with normal ejection fraction is a comparatively
new disease category that includes patients who display the
typical clinical, physiological, and neurohormonal heart failure phenotype in the absence of reduced LV ejection fraction.78 Thus far, no specific pharmaceutical therapy for heart
failure with normal ejection fraction has been found. However, a number of clinical and experimental studies indicate a
protective and curative role of exercise training for this
disease entity.
Protective Effects
It is well established in sports physiology that endurance
training improves LV diastolic filling at rest and during
exercise.79 Endurance exercise interventions improve early
diastolic relaxation at all ages in healthy individuals, but in
the presence of an elevated atrial filling rate in elderly
patients, this could be normalized.80 A landmark study for the
preventive effects of lifelong physical activity against agerelated diastolic dysfunction was published by Arbab-Zadeh
et al in 2004.16 They were able to show with invasive
measurement of LV pressure-volume relations that senior
athletes did not exhibit any degree of diastolic dysfunction
compared with young healthy sedentary controls.
Curative Effects
Patients after myocardial infarction and with preexistent
abnormal relaxation patterns benefit from endurance training,
as shown by Yu et al.81 Although data on training effects in

patients with diabetes mellitus derived from small studies are
still controversial,82,83 data on patients with established heart
failure with normal ejection fraction are convincingly
positive.84
CHF with systolic dysfunction is associated primarily with
significant diastolic dysfunction. Prospective randomized
training studies confirmed that as early as after 4 weeks of
endurance training, diastolic dysfunction is significantly improved with reduced E/E ratio (unpublished data, 2010).
Molecular Mechanisms
In diastolic heart failure, calcium homeostasis is affected by
a reduced expression of SERCA2a,85 which is the key player
for calcium reuptake into the sarcoplasmic reticulum and is
regulated in its activity by phospholamban and sarcolipin and
increased diastolic calcium leakage via the ryanodine receptors.86,87 Phospholamban affects both the calcium affinity of
SERCA and its calcium reuptake rates. Animal studies in
healthy rats indicate that endurance training can increase both
SERCA and phospholamban expression,73 a finding that was
confirmed in a mouse model of sympathetic hyperactivityinduced heart failure (congenic 2A/2C-adrenoceptor knockout mice).88 No data are available with regard to trainingassociated effects on calcium leakage. On the structural level,
12 weeks of treadmill training in old Fischer 344 rats did not
affect collagen volume fraction but significantly reduced
collagen cross-links by advanced glycation end-products.89
Cardiac Valves
Aortic Valve Sclerosis/Stenosis
Currently, no effective therapy to prevent calcified aortic
valve disease is established. Calcified aortic valve disease
confers significant morbidity and mortality as the severity of
disease progresses.90
Degenerative calcified aortic valve disease and atherosclerosis share similar mechanisms (ie, clinical risk factors and
histopathological features). Pathological examinations of diseased aortic valves showed areas of subendothelial thickening
with the disruption of the basement membrane, accumulation
of inflammatory infiltrates, and calcium deposits.91,92 It is
well accepted that regular physical exercise prevents the
progression of atherosclerosis by modulating endothelial
function or oxidative stress.93,94 Using low-density lipoprotein receptor knockout mice, we recently demonstrated that
regular exercise training as primary prevention prevents the
development of aortic valve sclerosis.95 It has been proposed
that apoptosis of endothelial cells and myofibroblasts in the
valve,96 elastin degradation and collagen synthesis by MMPs
and/or cathepsin,97 increased oxidative stress,98 and enhanced
osteogenesis99 contribute to aortic valve degeneration. In
consequence, procalcific gene expression such as bone morphogenetic protein 2 (BMP2), CBFA1/Runx2 (runt-related
transcription factor 2), and osteocalcin was amplified.98 The
activation of BMP2 and CBFA1/Runx2, particularly in the
noncalcified valve tissue, reflects an early stage of transdifferentiation of myofibroblast to a more osteoblast-like
phenotype.100
Gielen et al
In the low-density lipoprotein receptor knockout mouse
model, regular exercise attenuated the deleterious elevation of
oxidative stress and reduced expression of BMP2, Runx2,
and osteoblast differentiation marker. Additionally, the disruption of the aortic valve endothelium was prevented.95
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metabolic control is dominant in small resistance arteries, in

which the myogenic response to increased perfusion pressure
is also most pronounced. Although the effects of exercise on
the microcirculation and the capillary bed have been studied
extensively, little is known about the training-induced mechanism of vascular changes in the venous circulation.
Vascular Effects of Exercise
It has been said that one is as old as ones arteries. In view

of the supreme importance of endothelium in arterial function, I should like to modify this statement by saying that one
is as old as ones endothelium.101 Perhaps Rudolf Altschul
himself would be surprised to see to what extent his prophetic
words have become scientific consensus half a century later.
There are several reasons why endothelial research became so
significant for todays mechanistic concepts of exercisemediated cardiovascular effects: (1) Endothelial dysfunction
has been found to be a condition sine qua non for atherogenesis (ie, an obligatory initial step in early atherosclerosis).102
Thus, prevention of endothelial dysfunction will necessarily
prevent atherosclerosis development. (2) The presence of
endothelial dysfunction predicts future cardiovascular
events.103,104 Hence, endothelial function measurements were
proposed as a surrogate end point in clinical research.105 (3)
Endothelial function can be assessed by a large variety of
methods in both animal and human studies. Surgical/invasive
methods include organ bath measurements of arterial rings
harvested in animals or during aortocoronary bypass surgery
in humans and catheter-based assessment of acetylcholineinduced vasodilatation with angiography of the target vessel.
Noninvasive methods such as brachial/radial ultrasound,
magnetic resonance imaging, and venous occlusion plethysmography permit serial studies comparing endothelial function before and after an exercise intervention. These classic
methodologies are increasingly supplemented by commercial
semiautomatic devices using, for example, digital pulse
amplitude tonometry to measure microvascular function.106
It is beyond the scope of this article to provide in-depth
review of endothelial function in health and disease. We will
focus on 2 important aspects of vascular research in exercise
physiology: (1) the heterogeneity of molecular mechanisms
involved in vasomotor function along the vascular bed and
(2) the molecular mechanisms for exercise-mediated improvements of vascular endothelial function with special
emphasis on clinical studies in overt heart disease (coronary
artery disease and heart failure).
Differential Effects on Different Parts of the

Vascular Bed
The vasomotor responsiveness is not uniformly distributed
along the arterial tree. Four basic mechanisms have been
identified to regulate vascular tone in response to local
metabolic demand in the downstream vascular territory: (1)
endothelium-mediated flow-induced vasodilatation, (2) myogenic control, (3) metabolic vasodilatation, and (4) sympathetic control.107,108 The relative contribution of these mechanisms to vasodilatation is different in different
microdomains of the coronary vascular tree. Endotheliumdependent vasodilatation is most relevant in small conduit
and resistance arteries down to 150 m of diameter108;
Aorta
Although the aorta is a standard vessel to quantify changes in
endothelial function in animal experiments involving small
rodents, it is rarely a target vessel in human vascular research.
The composition of the extracellular matrix has changed
through the evolution of species and is influenced by pulse
pressure amplitude and wall tension. In fact, there seems to be
a universal elastic modulus that determines the relative
proportion of elastic lamellae, collagen fibers, and smooth
muscle cells in the aortic wall.109 Aging, coronary artery
disease, and myocardial infarction are often accompanied by
increased aortic stiffness and reduced compliance.110,111
Among healthy individuals, high-intensity exercise led to
vascular remodeling with up to 51% enlarged brachial conduit artery area and reduced distal aortic cross-sectional areas
(up to 8%), whereas aortic distensibility remained unchanged.112 However, endurance and strength training have
opposite effects on aortic compliance and vascular stiffness;
in an elegant study, Otsuki et al113 measured plasma
endothelin-1, nitric oxide (NO), and arterial stiffness in
young, healthy endurance-trained versus strength-trained
men. They demonstrated that aortic pulse-wave velocity as an
established index of vascular stiffness was significantly
increased in strength athletes and reduced in endurance
athletes versus healthy controls.113 Strength athletes displayed elevated endothelin-1 levels that correlated with aortic
pulse-wave velocity. Reductions of aortic stiffness after
endurance training were confirmed in patients with hypertension114 and coronary artery disease.115
Large Arterial Conduit Vessels
Conduit vessels 2 to 4 mm in diameter are the preferred target
vessels in clinical research because they may be assessed
readily by either noninvasive of invasive methods. After the
first description of coronary endothelial dysfunction,116 it was
quickly recognized that coronary endothelial function
could serve as a stress index integrating the cardiovascular
effects of risk factors and may provide pivotal diagnostic
and prognostic information in patients with coronary heart
disease.103
Exercise and Conduit Vessel Vasomotor Function in
Coronary Artery Disease
The clinical effects of endurance exercise training on coronary endothelial function were first studied in humans by
Hambrecht et al117: A 4-week endurance training program
was effective in attenuating the paradoxical arterial vasoconstriction in epicardial conduit vessels by 54% and increased
average peak flow velocity by 78% in response to intracoronary acetylcholine infusion. The improvements in coronary endothelial function were partially lost during a consecutive 5-month home-based endurance training program at
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Figure 4. The majority of exercise effects on the vascular endothelium are mediated by intermittent increases of laminar shear stress
associated with increased cardiac output during physical exertion. On the luminal side of the endothelial cells, direct signaling can
occur through deformation of the glycocalyx. This shear stressinduced signal can activate calcium ion channels, phospholipase activity leading to calcium signaling, prostaglandin I2 (PGI2) release, and cAMP-mediated smooth muscle cell relaxation. VEGF receptor 2
(VEGFR2) located at the luminal surface can associate with vascular endothelial cadherin, [beta]-catenin, and PI3K to phosphorylate Akt
and induce AKT-mediated eNOS phosphorylation, which leads to higher NO production. Mechanical forces are also transmitted by the
cytoskeleton to adhesion sites, where transmembrane integrins bound to the extracellular matrix serve as a focus for deformation. This
integrin-mediated pathway leads to the activation of Rasmitogen-activated protein kinase activity. In turn, Ras releases nuclear
factor-B (NFB) from its cytosolic inhibitor and thus enables its translocation to the nucleus, where it binds to the promoters of multiple target genes, including the eNOS gene. Increased NO synthesis in response to shear stress induces extracellular SOD (ecSOD) in a
feed-forward fashion to inhibit the degradation of NO by ROS with consecutive formation of the toxic peroxynitrite. Akt indicates protein kinase B; PECAM-1, platelet endothelial cell adhesion molecule-1; Ras, small GTPase; ONOO, peroxynitrite; and AA, Arachidonic
acid. Reprinted from Davies et al 121 with permission of the publisher. Copyright 2008, Cambridge University Press.
lower intensity, and changes were related to daily training

durations.118
In a subsequent study examining training effects on the
peripheral conduit artery function, Gokce et al119 measured
brachial and femoral artery endothelial function in patients
with coronary artery disease before and after a 10-week leg
exercise program. They documented significant improvement
in endothelium-dependent, flow-mediated dilation in conduit
arteries of the leg but not the arm and hypothesized that
training effects could be limited to the trained limb. This may,
however, also depend on the distribution of endothelial
dysfunction and the intensity of the training program because
Linke et al120 were able to confirm improved radial artery
endothelial function after pure bicycle ergometer training in
patients with CHF.
Mechanosensors in the Vascular Wall
Arteries are exposed to 2 main forces: radial strain as a result
of the blood pressure wave that is propagated along the
arterial tree and laminar shear stress as a result of the
frictional forces caused by antegrade blood flow. Whereas

increased radial strain (eg, as a result of arterial hypertension)
increases the atherogenic risk, laminar shear stress as a result
of pulsatile continuous blood flow is a potent survival signal
for endothelial cells.
On the molecular level, laminar shear stress affects multiple signaling pathways121 (Figure 4), which include the PI3K,
extracellular signal-regulated kinase 5 (also known as
mitogen-activated protein kinase 7), and NO pathways.122
Endothelial cells must therefore express specific mechanotransducers that convert physical stress into biochemical
signals. The cytoskeleton plays an important part in the
sensing of shear stress, and high strain is observed at the
luminal and basal membrane. In addition, cellular adhesion
proteins such as platelet endothelial cell adhesion molecule-1,
vascular endothelial cadherin, and the transmembrane tyrosine kinase vascular endothelial growth factor receptor-2
(KDR) were found to mediate biochemical responses to
flow. Vascular endothelial growth factor receptor-2 activates
Gielen et al
PI3K, which is essential for AKT-mediated phosphorylation
and activation of endothelial NO synthase (eNOS).123 In
contrast to laminar shear stress, the atherogenic flow patterns
include turbulent or disturbed flow, low flow, gradients, and
flow reversal. These conditions are associated with high rates
of endothelial cell proliferation and apoptosis, increased
production of ROS, and increased expression of inflammatory markers inducing a preatherosclerotic vascular phenotype.122 In the presence of additional atherogenic risk factors,
such as hypertension, dyslipidemia, and diabetes mellitus,
atherogenesis is significantly accelerated.
NO Generation in the Endothelium

A key component of intact endothelial function is a functional
eNOS. Located in the luminal endothelial cell membrane, it
produces NO from L-arginine. By diffusion, the short-lived
NO reaches the vascular smooth muscle cells in the media
and causes relaxation via cyclic guanosine monophosphatedependent pathways. Potential mechanisms of endothelial
dysfunction are (1) reduced eNOS substrate and cofactor
availability (eg, reduction of L-arginine levels, increase of the
competitive eNOS inhibitor asymmetrical dimethylarginine
[ADMA])124; (2) a reduced quantity and activity of eNOS and
inactivation of NO by ROS125; and (3) vascular regeneration
by endothelial progenitor cells (EPCs).126
Exercise and eNOS Substrate/Cofactor Availability. Another
enzyme also responsible for the generation of ROS in the
vascular is NO synthase. Under a number of pathological
conditions, the enzymatic reduction of molecular oxygen by
eNOS is no longer coupled to L-arginine oxidation, resulting
in production of superoxide rather than NO.127 A number of
mechanisms have been reported to contribute to eNOS
uncoupling, including tetrahydrobiopterin (BH4) deficiency,
shortage of L-arginine or HSP90, eNOS dephosphorylation on
threonine residue 495, or elevated ADMA levels.127 With
respect to the BH4 concentration, cell culture studies provided
the first evidence that increased shear stress dramatically
increases BH4 levels.128 This result was confirmed in an
aortocaval fistula model in the rat, wherein aortic blood flow
is enhanced proximal but decreased distal to the fistula,129 as
well as in a rat exercise training model.130 In addition, for
circulating levels of ADMA, a beneficial effect of exercise
training was documented.131
Exercise, eNOS Activity, and Oxidative Stress. To assess
molecular changes in NO production in human arterial
conduit vessels, we randomized patients with coronary artery
disease scheduled for elective coronary artery bypass graft
surgery to 4 weeks of endurance training or control and
harvested left internal mammary artery tissue not needed for
bypass grafting.132 Patients in the training group had 2-fold
higher eNOS protein expression and 4-fold higher eNOS
Ser1177 phosphorylation levels in left internal mammary
artery endothelium. A linear correlation was confirmed between Akt phosphorylation and phospho-eNOS levels and
between phospho-eNOS and Delta mean peak blood flow
velocity.
NO bioavailability is also influenced by ROS-mediated
breakdown. In animal and human studies, exercise train-
1229
ing programs resulted in an increased vascular expression

of antioxidative enzymes, such as SOD, catalase, and
glutathione peroxidase133135 and a reduced expression of
ROS-generating enzymes such as nicotinamide adenine
dinucleotide phosphate (NAD[P]H) oxidase and xanthine
oxidase.94,136 Nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase expression and activity are
regulated mainly by the dominant influence of angiotensin
II type 1 receptor activation by inducing a rapid rac1
translocation to the cell membrane.137 In addition, a
4-week exercise training program in patients with coronary
artery disease resulted in a significantly lower expression
of angiotensin II type 1 receptor compared with a sedentary control group.94
Exercise and EPCs.
The first description of postnatal vasculogenesis and the
characterization of EPCs derived from adult bone marrow
changed our concept of vascular plasticity in health and
disease.138 In addition to EPCs, mesenchymal stem cells also
possess the potential for vascular regeneration.139 Both mesenchymal stem cells and EPCs are mobilized from the bone
marrow in response to ischemia, exercise, and neurohormonal
factors (eg, vascular endothelial growth factor [VEGF],
placental growth factor) and critically contribute to maintaining the integrity of the endothelial cell layer. EPC number and
function correlate with the number of cardiovascular risk
factors and disease severity and predict cardiovascular events
and death from cardiovascular causes.140
It is a matter of continuing debate whether training-induced
flow changes or ischemia induction is required to stimulate
EPC release. In 2 clinical studies, we demonstrated that an
increase in circulating EPCs was only achieved in response to
exercise-induced ischemia, whereas matrigel assays indicated
improved EPC function in nonischemic training, as
well.141,142 Other authors showed exercise-related EPC increase also in the absence of ischemia.143,144 Prolonged
strenuous exercise (half-marathon, marathon, or spartathlon),
however, showed no change or a significant increase in
circulating progenitor cells.145148
The principal mechanism of EPC mobilization from the
bone marrow seems to depend on the activation of eNOS in
the presence of several mobilizing factors such as VEGF149 or
placental growth factor.150 Gene-targeting studies using either
MMP-2151 or MMP-9152 knockout mice demonstrated that the
presence of MMPs is crucial in ischemia-induced mobilization of EPCs and hence neovascularization. At the molecular/
cellular level, the following scenario for the mobilization is
proposed (Figure 5): Under steady state conditions, progenitor cells reside in a niche of the bone marrow, bound to
stroma cells via adhesion molecules such as vascular cell
adhesion molecule/very late antigen-4.153 Signal-induced upregulation of MMP-9 results in a release of sKitL, conferring
signals that enhance mobility of progenitor cells into a
vascular-enriched niche favoring liberalization of the cells
into the circulation.154 How can we explain the exerciseinduced mobilization of EPCs? In several studies, it was
demonstrated that exercise increases the concentration of
NO,132 which in turn can activate MMP-9 in bone marrow,155
1230
Circulation
September 21, 2010
Figure 5. A model for mobilization of circulating progenitor cells from the bone marrow by increased shear stress induced by exercise.
Increased laminar shear stress results in an activation of eNOS, resulting in an increase of NO. Subsequently, MMP-9 and MMP-2 are
activated, resulting in the release of sKitL. SKitL confers signals enhancing mobility of circulating progenitor cells. Along with stromalderived factor-1 (SDF-1 gradient, the circulating progenitor cells are mobilized into the peripheral circulation. CPC indicates circulating progenitor cells; VCAM-1, vascular cell adhesion molecule-1; and VLA4, very late antigen-4.
leading to enhanced mobilization of progenitor cells, as

depicted above. As soon as the EPCs are circulating, the most
important factors for tissue engraftment of the mobilized cells
are the local concentration of stromal-derived factor-1 and
its cell receptor CXCR4.156 This notion is further supported
by the observation that mice lacking CXCR4 die in utero
because of defects in vascular development.157 Although the
animal data make shear stressinduced NO generation a
likely mechanism for NO-mediated EPC mobilization, animal
experiments with ischemic exercise are still lacking. Therefore, the aforementioned controversy still awaits experimental resolution.
Exercise and Plaque Regression in CAD
Although it is high on the agenda in lipid research, plaque
regression ceased to be a research focus of exercise research
in recent years. Two decades ago, a series of angiographic
long-term follow-up studies documented that regular endurance exercise training can retard the progression of coronary
atherosclerosis158,159 or even reduce stenosis diameter if
combined with lipid-management techniques of smoking
cessation and other lifestyle interventions.160,161 Surprisingly,
not a single study has addressed exercise-mediated changes in
plaque volume by intravascular ultrasound thus far to control
the findings of the early regression studies with a more
accurate technique, which also permits insight into changes of

plaque composition.
Arterial Resistance Vessels
Larger and medium-sized resistance vessels (150 m) are
exposed to the predominant influence of endotheliummediated vasodilatation, whereas smaller arterioles are subject to metabolic and myogenic control. The vasomotor state
of the distal microvasculature is influenced by the dominant
effects of local myocardial metabolic demands.
Metabolic Control
In principle, all concepts for metabolic control of resistance
vessel diameter are based on the presence of an oxygen/metabolic sensor coupled to vascular smooth muscle cell tension
to control vascular tone.162 Four models are currently under
discussion, as follows:
1. An oxygen sensor in the vessel wall leads to production
of the vasodilatory prostaglandin G2 in response to
decreases in PO2.163 There is evidence for prostaglandin-mediated vasodilation via KATP channels.164
2. Adenosine serves as a myocardial oxygen sensor because it is generated at an accelerated rate when oxygen
supply-to-demand relationship falls.165
3. Carbon dioxide production, which in turn leads to tissue
acidosis, is known to increase coronary flow.166 Acido-
Gielen et al
1231
Figure 6. In the microcirculation, several pathways for metabolic vasodilation have been described. PO2-dependent regulation represents hypoxic coronary flow control; metabolic rate of oxygen (MRO2) dependent regulation represents normoxic coronary flow control. Under hypoxemic conditions, Ca2i is increased in endothelial cells, leading to phospholipase activation with consecutive generation of prostaglandins and cAMP-mediated metabolic vasodilation. Alternatively, ATP release either from erythrocytes or from the
working skeletal muscle activates the adenosine purinergic A2A receptor, resulting in activation of the KATP channel with potassium loss
and hyperpolarization of the vascular smooth muscle cell. As a consequence, voltage-gated Ca2 channels (VGCC) are opened, and
Ca2i is decreased with vascular relexation and vasodilation. Acidosis can directly influence the opening probability of the KATP channel. Exercise increases the adenosine sensitivity, resulting in larger metabolic vasorelaxation. Hb indicates hemoglobin; AC, adenylate
cyclase; and PGI2, prostaglandin I2. Adapted from Deussen et al 162 with kind permission of Springer Science and Business Media.
Copyright 2006, Springer Science and Business Media
sis in turn increases the sensitivity of adenosine A2A

receptors.
4. Erythrocyte ATP release may cause vasodilatation, as
documented in studies confirming the necessity of
erythrocytes to mediate vasodilation under hypoxic
conditions.167
All vasodilatory stimuli converge on the activation of the
KATP channels, the opening of which leads to vascular
smooth muscle cell hyperpolarization and reduced activation
of voltage-gated calcium channels (Figure 6).
Exercise training increases resistance vessel sensitivity and
maximal responsiveness to adenosine. This has been confirmed in dogs and miniature swine in vivo.168,169 In humans,
adenosine-induced microvascular function improved by 29%
after exercise training, as assessed by coronary flow reserve
ratio in response to intracoronary adenosine infusion. With
regard to the different mechanisms described above, no data
are currently available to describe exercise-mediated specific
changes.
Myogenic Control
It is well established in porcine animal models of treadmill
training that myogenic vasoconstriction to increases in perfusion pressure (particularly 40 mm Hg) is augmented after
exercise.170 Evidence is accumulating that L-type voltagegated calcium channels and protein kinase C determine
myogenic tone under physiological conditions.171 Korzick et
al172 demonstrated that increased myogenic tone in trained
pigs involves changes in protein kinase C- expression and
phosphorylation, which augment the depolarization-related
opening of voltage-gated calcium channels in smooth muscle
cells and increase of intracellular calcium.
Angiogenesis and Microcirculation
In the cardiac muscle, White et al173 conclusively showed in
a porcine model of exercise training that training increases
the total vascular bed cross-sectional area by up to 37% after
16 weeks. In humans, changes in cardiac vascularization are
difficult to assess.
More data, however, are available for the skeletal muscle.
In addition to an effect on metabolic alterations and the
1232
Circulation
September 21, 2010
Figure 7. A model depicting exerciseinduced angiogenesis in the peripheral

skeletal muscle. A central player for
enhanced capillary density, VEGF can be
activated either by PGC-1 or by hypoxia-inducible transcription factor 1 (HIF1) because of local hypoxia or a reduction in energy equivalents. TF indicates
transcription factor.
catabolic/anabolic balance within the skeletal muscle, exercise also affects the vascularization of the skeletal muscle. It
has been known for a long time that endurance exercise
training induces a significant increase in muscle capillaries in
either animals or humans.174,175 This process is largely
coordinated by soluble factors emanating from tissues in need
of vascularization. One of the best factors to study in this
scenario is VEGF. It is a powerful activator of endothelial
proliferation and is crucial for nearly all forms of neovascularization.176 With respect to exercise training, several studies
showed that VEGF transcription in skeletal muscle is increased by short-term177 as well as endurance training.142 It is
thought that local skeletal muscle hypoxia stabilizes the
transcription factor hypoxia inducible factor-1, leading to
the induction of VEGF. However, this concept must be
questioned because the deletion of hypoxia inducible
factor-1 in the skeletal muscle increases rather than decreases capillary density.178
In recent years, the transcriptional coactivator peroxisome
proliferator-activated receptor- coactivator (PGC)-1 has
been regarded as an important exercise-mediated regulator of
VEGF transcription. Mice lacking PGC-1 in their skeletal
muscle failed to increase capillary density in response to
exercise training.179 The central role of PGC-1 is furthermore supported by the observation that transgenic expression
of PGC-1 in skeletal muscle dramatically increases capillary
density.180 The mechanism by which PGC-1 induces VEGF
transcription appears to involve the coactivation of the orphan
nuclear receptor ERR.180 Which signals are upstream of
PGC-1 mediating the exercise-induced angiogenesis? One
pathway is the exercise-dependent modulation of high-energy
phosphates and the concomitant activation of AMP-activated
protein kinase.181 However, if this pathway is only responsible for basal VEGF expression and capillarization and not for
exercise-induced angiogenesis is still an ongoing discussion.182 In addition to activation of AMPK, the activation of
the p38MAPK (Mitogen-activated protein kinase) pathway
by exercise training also leads to the activation of PGC-1.183
Last but not least, the increased production of ROS by
exercise training can also contribute to the induction of
PGC-1.184 Therefore, one may summarize that endurance
exercise by activating PGC-1 via AMPK or p38MAPK or
ROS leads to an enhanced transcription of VEGF, finally
resulting in angiogenesis (Figure 7).
Venous Circulation
Compared with the arterial bed, the venous circulation has
received less attention in vascular research, particularly with
regard to training effects. The reasons are diverse, ranging
from methodological problems to underestimation of the
physiological relevance of venous function.185
Key parameters of venous function such as venous capacitance, which reflects the blood volume stored in the venous
system, and venous compliance, which represents the change
in volume in response to a change in pressure, change with
aging, posture, and physical activity. Aging alters the composition of the venous wall, resulting in lower venous
compliance in sedentary senior individuals.186 In both young
and elderly endurance-trained men, however, venous compliance was 70% to 120% higher compared with their sedentary
age-matched counterparts. It is currently unclear whether
these changes are primarily the result of factors such as
increased venous NO availability and decreased venous
smooth muscle tone, sympathetic -adrenergic vasomotor
control, or structural effects on elastin-to-collagen ratio.
Gielen et al
Immobilization, as tested in bed rest studies, demonstrated
a significant decline in venous capacitance after 52 days,
which was not affected by resistive vibration exercise.187
Venous compliance remained unaffected.
In patients with heart failure, exercise forearm venous
capacitance and venous outflow, as measured by strain-gauge
plethysmography, are significantly reduced and seem to be
related to maximal walking distance.188 Although the methodology of strain-gauge plethysmography was used in a
number of studies to examine training effects on vascular
function,189,190 changes of venous capacitance induced by
training have not been reported thus far. From animal
experiments, we know that the capillary domain area values
for venular capillaries were significantly decreased after 4
weeks of training.191
Pulmonary Circulation
Pulmonary hypertension is a frequent accompanying problem
in heart failure or valvular heart disease. Similar to heart
failure, exercise has long been regarded as detrimental and
was discouraged in pulmonary hypertension because of the
fear of fatal cardiovascular compromise.
Human Data
The first reports on training effects on pulmonary pressure
came from aerobic training studies in patients with stable
CHF. Lee et al192 were the first to demonstrate the lack of any
exercise-induced rise in resting pulmonary artery pressure in
patients with CHF, a finding confirmed by Dubach et al193 18
years later. In a large prospective randomized study involving
73 patients with CHF, Hambrecht et al65 were finally able to
demonstrate that pulmonary vascular resistance at rest and at
peak exercise was decreased after 6 months of endurance
training.
Just recently, the first clinical study in patients with stable
precapillary pulmonary hypertension confirmed that 15
weeks of endurance exercise are effective in significantly
improving 6-minute walking distance on top of optimal
medical therapy.194
Animal Experiments
The first rat model of pulmonary hypertension to be used with
exercise training was hypobaric hypoxia. Rats were trained
for 4 and 6 weeks under hypobaric hypoxia (equivalent to
altitudes of 2500 and 5500 m). Kashimura et al196 found that
the increase in resting mean pulmonary arterial pressure with
increasing equivalent altitude was lower in the 2 trained
groups than in the control group and greater after 6 than after
4 weeks of exercise.195 In a follow-up study, they showed that
6 weeks of training can attenuate the hypoxia-induced and
angiotensin IIinduced PH. These findings were extended by
Favret et al,197 who demonstrated that exercise training
improved lung gas exchange and attenuated acute hypoxic
pulmonary hypertension but did not prevent pulmonary hypertension of prolonged hypoxia.
In rabbits, it was soon documented that treadmill exercise
improved acetylcholine-induced endothelium-dependent vasodilatation not only in aortic rings but also in precontracted
pulmonary artery rings,198 a finding that could not be reproduced in Sprague-Dawley rats, however.199 A possible expla-
1233
nation for the discrepant results can be derived from 2 studies

by Johnson et al.200,201 Whereas long-term training enhanced
endothelium-dependent vasorelaxation in pulmonary arteries
by mechanisms of increased reliance on NO and reduced
production of a prostanoid constrictor in miniature swine with
surgically induced chronic coronary artery occlusion, it did
not alter pulmonary vasorelaxation in normal pigs.200 However, short-term 1-week training was effective in improving
bradykinin-induced vasorelaxation and in increasing pulmonary artery eNOS protein expression. SOD remained unchanged.201 In essence, training-induced changes in pulmonary vasomotion are modified by preexistent endothelial
dysfunction and by training duration.
In a rat model, Handoko et al202 induced compensated and
progressive pulmonary hypertension using different doses of
monocrotaline. Only the compensated pulmonary hypertension animals benefited from exercise training with increased
exercise tolerance and right ventricular capillarization,
whereas animals with progressive right ventricular failure had
reduced cardiac output and died prematurely from right
ventricular failure.
Conclusion
To summarize, cardiac effects of exercise include an improved protection against I/R injury primarily as a result of
higher antioxidative protection and improved LV diastolic
and systolic function in chronic heart failure due to favorable
changes in neurohormonal state, activation of PI3K (p110)
attenuating pathological hypertrophy, normalization of cardiomyocyte calcium handling, and inhibition of the catabolic
ubiquitin-proteasome system.
Vascular effects are based on improved endotheliummediated flow-induced vasodilatation in conduit arteries and
larger resistance arteries, higher myogenic control, and increased metabolic vasodilatation in small resistance arteries.
Vascular regeneration by mobilization of endothelial progenitor cells is augmented by exercise. Recently, improved
endothelial vasodilatation has also been confirmed in the
pulmonary artery.
Extending our concept of molecular mechanisms of exercise is essential to further optimize training interventions with
regard to their clinical efficacy and to identify novel targets
for pharmaceutical intervention. However, certain areas (ie,
microcirculation and the venous system) are still incompletely understood and merit further molecular studies. Residual incomplete molecular understanding should not prevent the clinical use of training interventions with established
clinical benefit.
Sources of Funding
Dr Gielen is supported by the Deutsche Forschungsgemeinschaft,
grant GI535/11.
Disclosures
None.
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KEY WORDS: coronary disease
endothelium
exercise
myocardium
Cardiovascular Effects of Exercise Training: Molecular Mechanisms

Stephan Gielen, Gerhard Schuler and Volker Adams
Circulation. 2010;122:1221-1238
doi: 10.1161/CIRCULATIONAHA.110.939959
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