Circulation. 2001;103:e1-e6
(Circulation. 2001;103:e1.)
© 2001 American Heart Association, Inc.
Exercise Training in Coronary Artery Disease and Coronary Vasomotion
S. Gielen, MD;
G. Schuler, MD;
R. Hambrecht, MD
From the Universität Leipzig, Herzzentrum GmbH, Klinik für
Innere Medizin/Kardiologie, Leipzig, Germany.
Correspondence to Priv-Doz Dr med Rainer Hambrecht, Associate Professor of Medicine, Universität Leipzig - Herzzentrum GmbH, Department of Internal Medicine/Cardiology, Russenstr 19, 04289 Leipzig, Germany. E-mail hamr{at}server3.medizin.uni-leipzig.de
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Abstract
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AbstractExercise
training has assumed a major role in
cardiac rehabilitation, mostly
because of its positive effects
on myocardial perfusion in patients
with coronary artery disease.
The mechanisms involved in mediating this
key effect have long
been debated: both regression of coronary artery
stenosis and
improvement of collateralization have been suggested as
potential
adaptations. However, the comparatively minute changes in
luminal
diameter and myocardial contrast staining do not fully explain
the
significant changes in myocardial perfusion. During the last
decade,
endothelial dysfunction was identified as a trigger of
myocardial
ischemia. The impaired production of endothelium-derived
nitric
oxide (NO) in response to acetylcholine and flow leads to
paradoxic
vasoconstriction and exercise-induced ischemia. Recently, it
was
confirmed in humans that training attenuates paradoxic
vasoconstriction
in coronary artery disease and increases coronary
blood flow
in response to acetylcholine. Data from cell-culture and
animal
experiments suggest that shear stress acts as a stimulus for
the
endothelium to increase the transport capacity for L-arginine
(the
precursor molecule for NO), to enhance NO synthase activity
and
expression, and to increase the production of extracellular
superoxide
dismutase, which prevents premature breakdown of
NO. Exercise also
affects the microcirculation, where it sensitizes
resistance arteries
for the vasodilatory effects of adenosine.
These novel findings provide
a pathophysiological framework
to explain the improvement of myocardial
perfusion in the absence
of changes in baseline coronary artery
diameter. Because endothelial
dysfunction has been identified as a
predictor of coronary events,
exercise may contribute to the long-term
reduction of cardiovascular
morbidity and mortality.
Key Words: endothelium exercise coronary disease vasculature microcirculation
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Introduction
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Over the last 2
decades, exercise training has assumed a major
role in both the primary
and secondary prevention of coronary
artery disease (CAD). It increases
physical performance, lifts
the angina threshold in patients with
symptomatic CAD, and improves
myocardial
perfusion.
1 2
However, which mechanisms mediate
the apparent improvement of
myocardial perfusion after training
therapy is a matter of continuing
debate.
Basically, regional myocardial hypoperfusion in CAD
results from a combination of 3 pathogenetic components: (1) vascular
stenosis, (2) microvascular dysfunction, and (3) microrheology
and hemostasis. All 3 components may be affected by exercise training
in patients with stable CAD.
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Regression of Coronary
Atherosclerosis
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The first era of clinical research was guided by the
concept
that the extent of coronary stenosis represented the key
determinant
of myocardial perfusion. In this phase, which paralleled
the
expansion of interventional cardiology, the angiographically
visible
static coronary stenosis was regarded as the therapeutic
target.
This led to the hypothesis that exercise training would result
in
a net regression of coronary stenoses. Three prospective, randomized
intervention
studies have been published assessing the influence of
exercise
training in combination with cholesterol lowering on the
progression
of CAD. They share not only the "regression
hypothesis," but
also a methodological approach of quantitative
coronary angiography.
The Lifestyle Heart Trial analyzed the effect of lifestyle
changes, including a strictly vegetarian diet, stress-management
techniques, smoking cessation, and 3 hours of exercise training per
week, on the degree of coronary artery stenosis. In the intervention
group, a regression of coronary artery stenoses from 40±17% to
38±17% was observed; in the control group, stenoses increased from
43±16% to 46±19%
(P=0.001).3
This difference was even more pronounced at 5-year follow-up. At that
point, the intervention group had a 3.1% regression of stenoses (in
percent of relative coronary stenosis) compared with an 11.8%
progression in the usual care group; this regression was associated
with a 2.5-fold risk reduction in cardiac
events.4
In the Stanford Coronary Risk Intervention Project, 300
patients with CAD were randomly assigned to receive either the usual
care or multifactorial risk reduction, including a low-fat diet,
lipid-lowering medication, and exercise training. Serial coronary
angiograms on a yearly basis showed an attenuation of disease
progression in the intervention arm, with a decline in minimal luminal
diameter by 0.024±0.067 mm/year compared with a regression of
0.045±0.073 mm/year in the control group
(P<0.02).5
Over the study period of 4 years, 25 cardiac events occurred in the
intervention group and 44 occurred in the control group.
In the Heidelberg Regression Study, 113 patients with
documented CAD were randomly assigned to a bifactorial intervention
with a low-fat diet and regular physical exercise or to a control
group. This regimen was effective in halting the progression of
coronary atherosclerosis.6
After 1 year, the mean luminal diameter was unchanged in the training
group (0.0±0.038 mm), but it decreased in the usual care group by
0.13±0.045 mm (P<0.05). At
6-year follow-up, the progression of CAD was still significantly
retarded in the training
group.7 In a retrospective
analysis, a correlation between exercise-associated energy expenditure
and change in minimal stenosis diameter revealed that a regression of
coronary stenosis may only be expected when using >2200 kcal/week,
which is equivalent to 5 to 6 hours of regular physical exercise per
week.8 This finding makes the
regression of coronary stenoses an unlikely mechanism to explain the
improved myocardial perfusion in the majority of patients who undergo
exercise training.
In summary, multifactorial lifestyle changes, including
reducing cholesterol and improving exercise training, can attenuate the
progression of coronary stenoses. However, the comparatively small
morphometric changes observed in coronary diameter make it difficult
for this factor to explain the substantial increase in myocardial
perfusion and angina threshold associated with training interventions.
From todays perspective, it may be that the use of intravascular
ultrasound, which permits a more accurate assessment of plaque volume
than conventional angiography, would have yielded different
results.
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Formation of Collaterals
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As with epicardial vessels, the first scientific
approach to
the microcirculation was led by the search for a
morphological
correlate: collateral formation. Evidence from animal
studies
suggested that long-term intensive physical exercise led
to
an improvement in coronary
collateralization.
9 10
Neill et
al
11 found an
increase in collateralization after 5 to 8 weeks
of training in dogs on
the basis of microsphere injections.
However, no difference in
epicardial collaterals was apparent
angiographically.
In humans, data derived from clinical studies are equally
controversial. In a subgroup analysis of an 8-week exercise training
trial in ischemic cardiomyopathy involving 23 patients, Belardinelli et
al12 found a significant
increase in coronary collateralization as quantified by visual
classification of the retrograde filling of the infarct-related
vessel.
In the Heidelberg Regression Study, which involved patients
with stenotic CAD and preserved left ventricular function, however, no
increase in angiographically visible collateralization was observed in
long-term follow-up after 1 year of exercise
training.13 It may well be
that (1) angiography is not sensitive enough to detect the formation of
small intramyocardial collateral vessels that will be recruited only
during exercise and (2) the stimuli for collateralization are different
in patients with stenotic CAD and stable angina pectoris and
postinfarction patients with complete vessel occlusion and reduced left
ventricular function.
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Endothelial Dysfunction in Coronary Conduit
Vessels
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The last decade witnessed a paradigm shift in the
pathophysiological
concept of CAD. With the growing knowledge about
endothelial
function came the awareness that the luminal diameter of
epicardial
vessels is highly dynamic in response to mechanical
(flow-related)
or agonist-mediated (endogenous or pharmacological)
stimuli.
Alterations in coronary vascular endothelial function were
first described in 1986, when Ludmer et
al14 observed a paradoxical
vasoconstriction of atherosclerotic segments after infusing
acetylcholine into the left coronary artery of patients with atypical
chest pain. The observation that major coronary risk factors are
associated with coronary endothelial dysfunction even before
circumscript stenoses are visible has led to the concept that
endothelial dysfunction occurs at the early stages of atherosclerosis
as a conditio sine qua non for
atherogenesis.
Pathophysiology of Endothelial
Dysfunction
Coronary vasomotion is influenced by mechanical and
agonist-mediated stimuli, both of which converge on endothelial nitric
oxide (NO) synthesis/release as the final common pathway.
Endothelial dysfunction occurs as a result of decreased bioactive NO
concentrations at vascular smooth muscle cells.
NO concentrations can be affected by alterations at the
following different steps of its pathway: (1) availability of the
precursor molecule L-arginine; (2) alterations of NO synthesis rate, as
determined by endothelial NO synthase (eNOS) conformational changes,
expression, or genetic polymorphism; and (3) differences in NO
breakdown velocity related to reactive oxidative species (ROS) once it
is released.15
L-Arginine
The availability of L-arginine at the active site of
eNOS depends on several factors: (1) exogenous supply with L-arginine
or endogenous L-arginine synthesis; (2) intracellular accumulation of
L-arginine, which depends on active cytokine-regulated transmembranous
transport16 ; (3)
intracellular degradation of L-arginine by arginase to ornithine and
urea; and (4) the presence of the antagonist asymmetric dimethyl
arginine, which blocks NO synthesis from L-arginine. Asymmetric
dimethyl arginine is present in patients with peripheral vascular
disease17 and chronic renal
failure.18
To date, it remains unclear which of these mechanisms are
involved in the development of endothelial dysfunction in coronary
atherosclerosis, and clinical data are also contradictory. Although
L-arginine supplementation improves vascular function in
hypercholesterolemia and chronic heart
failure,19 20 21
it has no effect in patients with stable
CAD.22
eNOS
The activity of eNOS can be altered in response to
short-term stimuli by conformational changes. Michel and
Feron23 proposed that eNOS
association with caveolin suppresses the enzyme activity in the
unactivated endothelial cell. Agonist activation increases
intracellular calcium concentration via cGMP-dependent mechanisms, thus
promoting calmodulin binding to eNOS and dissociation from caveolin.
The activated eNOS-calmodulin complex synthesizes NO until
[Ca2+]i
decreases below a level necessary to sustain calmodulin binding.
Calmodulin dissociates, and the inhibitory eNOS-caveolin complex
reforms.24
Because NO is released via plasmalemmal caveolae, eNOS is
targeted to this subcellular compartment by enzyme
acylation,25 which may occur
as reversible palmitoylation or irreversible myristoylation. Prolonged
eNOS activation leads to depalmitoylation of the enzyme, translocation
away from the caveolae, phosphorylation, and rebinding of the
inhibitory caveolin.23 It
remains unclear how this regulation of enzymatic activity is affected
by the pathological conditions of endothelial dysfunction.
More is known about long-term conditions like exposure to
high levels of tumor necrosis factor-
, oxidized LDL, and hypoxia,
all of which have been shown to lower eNOS expression in cultured
endothelial cells.26 In
atherosclerosis, eNOS expression is significantly reduced, indicating
that this downregulation may be an important factor for the
pathogenesis of endothelial
dysfunction.27
Genetic polymorphisms of eNOS were recently described as
prevalent in certain patients (eg, in hypertensive
Japanese).28 However,
whether polymorphisms of eNOS result in alterations of enzyme activity
remains controversial.
NO Breakdown
Atherosclerosis and endothelial dysfunction are
associated with increased levels of ROS (ie, ·OH,
H2O2).29
These highly reactive radicals accelerate the extracellular degradation
of secreted NO by forming peroxynitrite. Adventitial NADPH oxidases
produce quantities of superoxide high enough to affect endothelial
function.30 This mechanism
has been confirmed in CAD in intervention studies with antioxidants.
For example, in patients with CAD, the long-term administration of
ascorbic acid (vitamin C), a natural radical scavenger, reverses
endothelial
dysfunction.31
However, the underlying mechanism is more complex.
Vascular smooth muscle cells produce and set free a potent
antioxidative enzyme, the extracellular superoxide dismutase (ecSOD),
which is reduced in CAD and correlates with flow-dependent vasodilation
of the radial artery in
vivo.32 In human aortic
smooth muscle cell cultures and organoid cultures of mouse aorta, the
NO donor diethylenetriamine-NO (DETA-NO) enhances ecSOD
expression in a time- and dose-dependent
fashion.33 This finding is
consistent with the hypothesis that endothelium-derived NO stimulates
the expression and release of ecSOD from vascular smooth muscle cells.
Training seems to have similar effects on
ecSOD.33 34
Shear Stress and Endothelial Function:
Experimental Data
Shear stress is an important component of exercise, and
it affects vascular NO concentrations on all 3 levels responsible for
the development of endothelial dysfunction discussed above.
L-Arginine
Shear stress increases the velocity of the endothelial
high-affinity/low-capacity transport system for
L-arginine.35 This ensures
substrate availability as the rate-limiting step of eNOS, which
generates ROS in the absence of L-arginine.
eNOS
As early as 60 minutes after the initiation of
shear stress, bovine aortic endothelial cells produce 13 times more NO
compared with baseline
conditions.36 This increase
seems to be mediated by both short-term enhancement of eNOS activity
and the activation of eNOS expression. Shear stress leads to eNOS
phosphorylation on serine residues independent from increases in
[Ca2+]i, which may
modulate enzyme activity.36
Recently, a shear stressactivated signal transduction cascade
involving phosphatidyl-inositol-3-kinase and the serine/threonine
kinase Akt has been identified; it causes
[Ca2+]i-independent
eNOS phosphorylation and
activation.37 38
A considerable increase of eNOS expression has been
demonstrated in endothelial cell-culture experiments after 6 hours of
exposure to laminar shear
stress.39 40 This
is consistent with animal studies of exercise training in dogs, which
documented increased eNOS expression and NO production in coronary
conduit41 and resistance
vessels.42 Increases in NOS
expression are proportional to the extent of laminar shear stress
applied, but they are abolished by turbulent
flow.40
However, the presence of 2 alleles of the eNOS gene seems to
be necessary to increase eNOS expression in response to exercise
training. In mice heterozygotic for a loss of the eNOS gene, no
increased eNOS protein expression could be observed in the aorta,
whereas wild-type eNOS+/+ mice had a
2.5±0.4-fold
increase.34
NO Breakdown
It has long been enigmatic why exercise training, which
increases total oxygen uptake and in turn the production of
ROS,43 can improve
endothelial function. As mentioned above, it was recently shown that
endothelium-derived NO increases the expression of ecSOD in vascular
smooth muscle cells.33 In
the same publication, the authors demonstrated that exercise training
increased both eNOS and ecSOD in wild-type mice, whereas ecSOD remained
unchanged in mice lacking eNOS. This suggests that the effect of
training on ecSOD is mediated by endothelium-derived
NO.
Effects of Exercise Training on Endothelial
Dysfunction in Conduit Vessels
In a recently published prospective clinical study, 19
patients with coronary endothelial dysfunction, as documented by
acetylcholine-induced vasoconstriction, were prospectively randomized
to a training (10 patients) or control group (9 patients). At baseline
and after 4 weeks, endothelium-mediated vasodilation was assessed after
intracoronary infusions of acetylcholine (0.072, 0.72, and 7.2 µg per
minute). The average peak flow velocity was measured using a Doppler
wire, and vessel diameter was assessed by quantitative coronary
angiography.
At baseline, both groups had similar constrictive responses
to acetylcholine. After 4 weeks of intensive physical training,
acetylcholine-induced coronary artery constriction was attenuated by
54% after the administration of 7.2 µg/min acetylcholine (from
-0.41±0.05 to -0.19±0.07 mm;
P<0.05 versus control). In
training patients, the change in average peak flow velocity in response
to 7.2 µg/min acetylcholine increased from 78±16% at the initial
study to 142±28% after 4 weeks
(P<0.01 versus
control).44 This trial
documented, for the first time, that exercise training attenuates
paradoxical vasoconstriction in response to acetylcholine and improves
the endothelial function of coronary conduit vessels in patients with
CAD.
While the study by Hambrecht et
al44 enrolled patients with
nonocclusive stable CAD, Griffin et
al45 used an animal model of
subacute coronary occlusion by amaroid constrictor in pigs to assess
the effects of 16 weeks of exercise training on endothelium-dependent
vasorelaxation after long-term coronary occlusion. Even in artery
segments distal to the constrictor, they observed a markedly enhanced
NO-mediated relaxation, which basically confirmed the results in
patients with nonstenotic CAD.
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Coronary Resistance Vessels and
Microcirculation
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Microvascular Dysfunction in CAD
Small coronary arteries with an internal diameter <300
µm
are a major component of the regulation of coronary vascular
resistance
and the distribution of coronary flow. It has been shown
that
the responsiveness to endothelium-derived relaxing factors changes
from
the proximal to the distal part of dog coronary arteries.
cGMP-mediated
vasodilators like NO, nitrates, and atrial natriuretic
peptide
preferentially dilate proximal conductance arteries. Resistance
arteriesin
contrast to epicardial conduit arteriesare exposed to
more
than just circulating or platelet-derived neurohormones. The
vasomotor
state of the distal microvasculature is influenced by the
dominant
effects of local myocardial metabolic
demands.
46 Altman et
al
47 reported that
NG-nitro-l-arginine,
a NO synthase inhibitor,
did not substantially impair the coronary
vasodilation associated
with the increased myocardial oxygen
requirements produced by
exercise in conscious dogs. Under these
conditions, adenosine,
which is a by-product of the breakdown of ATP,
the main energy
source of myocardial contraction, is formed at an
accelerated
rate.
48 Among
all metabolic factors described so far, adenosine
seems to be the most
relevant clinically.
Effects of Exercise Training on the
Microcirculation
Exercise training increases resistance vessel
sensitivity and maximal responsiveness to adenosine in dogs in
vivo.49 These results also
suggest that training alters the responses of coronary artery smooth
muscle to metabolic vasodilators. In line with this hypothesis, Muller
et al50 found an increased
myogenic response of coronary resistance arteries from exercise-trained
swine for intraluminal pressures >40 mm Hg. After exercise training,
adenosine-mediated arteriolar permeability for porcine serum albumin
increased by 65%, indicating a higher vascular
permeability.51
Long-term exercise training induces functional and
morphological changes in the microvasculature. White et
al52 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. As a
consequence, vascular resistance decreases and maximal flow reserve
rises.
Hambrecht et al44
assessed changes in microvascular function by measuring the coronary
flow reserve ratio in response to adenosine. Training patients had a
29% increase in coronary flow reserve after exercise training (from
2.8±0.2 to 3.6±0.2;
P<0.01 versus control), which
also indicated an enhanced sensitivity of the coronary microcirculation
to adenosine.
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Microrheology and Platelet Function
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Blood viscosity can be reduced and microrheology
improved by
exercise training in healthy subjects and patients with
peripheral
vascular
disease.
53 However, in
patients with CAD and impaired
left ventricular function, training
failed to have any significant
effect on blood
viscosity.
54 The reasons for
the different
responses to exercise in these subgroups remain
obscure.
Short-term bouts of strenuous exercise may have thrombogenic
side effects because platelet number and activity are
increased.55 Long-term
exercise training, however, attenuates this potentiation of platelet
function and increases platelet cGMP
content.56 Physical training
seems to suppress coagulability, as indicated by the decrease in
fibrinogen, factor VIII:C, von Willebrand factor, factor VII:C, and
thrombin-antithrombin III complex and the prolongation of activated
partial thromboplastin time. The decrease of anticoagulatory factors
like plasminogen, tissue plasminogen activator antigen,
2-plasmin inhibitor, plasminogen activator
inhibitor-1, and plasmin-
2PI complex after physical training may
result from decreased
coagulability.57 In summary,
a net reduction of thrombogenic risk in CAD by exercise training has
been documented.
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Future Aspects
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Despite the encouraging results of high-intensity
exercise training
on coronary endothelial function, any training
intervention
must be embedded in a comprehensive risk factor management
as
a secondary prevention strategy. In most cases, the pathogenesis
of
endothelial dysfunction can be linked to the presence of
one or more of
the following coronary risk factors, all of which
have been shown to be
associated with impaired endothelium-dependent
vasodilation: diabetes
mellitus,
58
hypercholesterolemia,
59
arterial hypertension,
60 and
smoking (both active
61 and
passive
62 ). Given the
prevalence of these risk factors, it still must
be determined if
adequate therapy for the risk factor (eg, statins
for
hypercholesterolemia) is effective in restoring endothelial
dysfunction
to normal or whether additive effects are to be
expected in combination
with training.
A further open question that might influence future
guidelines of exercise training in CAD is the dose-response
relationship between the training intensity and the effects on coronary
vasomotion. Is there a threshold of either training intensity/duration
or trained muscle mass that must be surmounted to achieve improved
endothelium-dependent vasodilation?
Recently, the first reports about a possible association
between endothelial dysfunction and the frequency of clinical events
were
published.63 64
Further prospective studies are needed to establish whether endothelial
dysfunction is an independent prognostic marker. If so, exercise
training may be promoted from a symptomatic intervention to a
preventive strategy with long-term prognostic
benefits.
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Conclusion
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Protagonists of exercise training in patients with
coronary
atherosclerosis have long faced the dilemma of how to explain
the
improvement of myocardial perfusion. Regression of coronary
atherosclerosis
and collateral formation have been favorite theories.
However,
angiographic techniques have thus far failed to document any
significant
increase in coronary collaterals at rest. Although the net
regression
of stenotic lesions may be achieved with high-intensity
exercise
training, it is unlikely that plaque regression causes
the significant
improvement in myocardial perfusion, which is seen much
earlier
than changes in baseline luminal diameter.
Keeping these limitations in mind, exercise training
enhances myocardial perfusion by increasing both eNOS and ecSOD
expression, thus attenuating the premature breakdown of NO by ROS.
These increases in both local NO production and half-life improve
endothelium-dependent vasodilation in response to flow or
acetylcholine. It is reasonable to suppose that these functional
changes occur rather rapidly after the initiation of an exercise
training program, although no studies are available on their precise
time course. Anatomic changes like augmentation of the capillary bed
and slowing of the progression of coronary atherosclerosis will require
more extended periods of training
(Figure
).

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Figure 1. Suggestion for a possible time course of exercise traininginduced mechanisms of enhancing myocardial perfusion. Halftones denote elements that are still under discussion.
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