Cardiovascular Research 1999 43(3):572-579; doi:10.1016/S0008-6363(99)00152-2
© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Nitric oxide and coronary endothelial dysfunction in humans
Helmut Drexler*
Abteilung Kardiologie, Medizinische Hochschule Hannover, Carl-Neubergstrasse 1, 30625 Hannover, Germany
* Corresponding author. Tel.: +49-511-532-3841; fax: +49-511-532-5412 Drexler.Helmut{at}MH-Hannover.de
Received 20 January 1999; accepted 9 April 1999
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1 Introduction
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The endothelium provides a variety of important functions involved
in the cardiovascular homeostasis. The assessment of endothelial
function in humans has focused primarily on endothelial dependent
vasomotion in response to the release of NO. In particular,
clinical studies have evaluated vasomotor tone following changes
in flow or stimuli for the release of NO from the endothelium,
such as acetylcholine, substance P or serotonin
[1]. However,
NO not only acts as a vasodilating substance but also affects
other functions of the endothelium such as the adhesive properties
of the endothelium with respect to the interaction with leucocytes
and platelets
[2]. Despite the pivotal contribution of in vitro
studies for the elucidation of underlying mechanisms, the clinical
implication of endothelial function can only be appreciated
by studies in humans in vivo, since tissue or cells are exposed
to an artificial environment i.e. lacking the neurohumoral influences
present in vivo. To critically review the role of NO in coronary
endothelial dysfunction in humans the present review focuses
on observations made by the in vivo assessment of endothelial
dependent vascular responses.
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2 Normal endothelial function
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In normal individuals increases in blood flow is associated
with flow-dependent, endothelium-mediated vasodilation
[3] which
is related to the release of NO from the endothelium
[4,5].
Similarly, acetylcholine, bradykinin or substance P elicit endothelium-dependent
dilation of large and small vessels, which, in part, is due
to the stimulated release of NO. However, the effect of acetylcholine,
the most commonly used agent in the clinical setting, is composed
of two divergent actions, that is, vasodilation by the stimulated
release of NO and other vasodilating substances such as EDHF
from the endothelium, and direct vasoconstricting effects on
the underlying vascular smooth muscle, particularly with higher
doses. In contrast to acetylcholine, bradykinin—and possibly
substance P—is likely to play a physiological role. Tissue
bradykinin is inactivated by the endothelial angiotensin-converting
enzyme
[6] and can be released by increased flow
[7]. Endogenous
bradykinin appears to be involved in the regulation of basal
and flow-mediated coronary vasomotor tone in humans
[8]. However
the vasodilator effect of bradykinin involves not only NO but
also PGI
2 and EDHF. Consistent with these observations clinical
studies have shown that short and long-term ACE-inhibition enhances
endothelium-dependent relaxation both in the peripheral and
coronary circulation
[9–11]. There is evidence that NO
is constantly released from the endothelium in humans
[12].
In fact Quyyumi et al. have shown that NO contributes to resting
epicardial and coronary microvascular tone. Despite the absence
of angiografic evidence of arteriosclerosis, the presence of
coronary risk factors is associated with reduced resting and
stimulated bioavailability of NO from the human coronary circulation
[13]. The basal release of NO keeps the vasculature in a ‘dilated
state’ and counteracting the vasoconstrictor forces such
as noradrenalin, angiotensin or endothelin.
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3 Endothelial function in hypercholesterolemia and arteriosclerosis
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The endothelial vasodilator function is impaired in the early
stages of atherosclerosis. For example, impaired endothelial
dependent vasodilation has been noted in large conduit and small
resistance vessels in patients with hypercholesterolemia without
evidence of arteriosclerotic lesions, as assessed by angiography
or intravascular ultrasound
[14,15]. These observations are
consistent with experimental data suggesting that endothelial
dysfunction precedes overt atherosclerosis in experimental models
of hypercholesterolemia and may represent an important early
event predisposing conduit vessels to vasospasm and vasoconstriction.
Assessment of endothelial vasodilator function at different stages of coronary artery disease indicated that a progressive deterioration of endothelial function emerges, including early impairment of acetylcholine-induced vasodilator responses followed by reduced flow-dependent vasodilation [16]. Studies in patients with hypercholesterolemia type IIa, moderately elevated serum cholesterol levels and angiographically smooth coronary arteries revealed a significant endothelial dysfunction of large coronary arteries and coronary microcirculation [14]. In patients with hypercholesterolemia, even angiographically smooth coronary arteries show a striking vasoconstriction in response to intracoronary infusion of acetylcholine. Although no coronary lesions can be detected by angiographic standards in some of those patients it is conceivable that intimal hyperplasia and structural alterations of the vascular wall might have been present. Patients with hypercholesterolemia and normal coronary arteries often have focal intimal thickening and structural remodelling of the vascular wall [17]. Whether or not the basal release of NO is affected remains controversial: while some studies have indicated a preserved response to L-NMMA in the peripheral vasculature of hypercholesterolemic patients as compared to normal individuals in vitro studies have suggested that basal release of NO is impaired in coronary artery disease [18]. Impaired endothelial vasodilator function is reversible, i.e. by short-term administration of by L-arginine, the precursor of NO [19,20] or following removal of LDL-cholesterol (see below).
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4 Endothelial function in the coronary micrcocirculation
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Impaired endothelium-dependent relaxation is not confined to
epicardial coronary arteries but emerges in the coronary microcirculation
particularly in hypercholesterolemic subjects
[14,16] while
endothelium-independent vasodilators exert maximal increases
in coronary blood flow in hypercholesterolemia. There is experimental
evidence that under these circumstances, flow-dependent dilation
of the coronary microvasculature is abolished
[21]. Since this
mechanism of dilation of resistance vessels may be involved
in the increased flow, i.e. during states of increased flow
such as reactive hyperemia, the impaired endothelial function
of the coronary microvasculature in humans may have important
implications for subjects with hypercholesterolemia. Moreover,
the endothelial modulation of factors such as sympathetic stimulation
or platelets and its releasing substances (thromboxane and serotonin)
is altered. With normal endothelial function, the release of
NO may be associated with vasodilation (counterbalancing the
direct vasoconstricting effects of serotonin and thromboxan),
however, in the face of a defective endothelial mediated vasodilation,
inappropriate coronary vasoconstriction may emerge promoting
platelet activation and aggregation.
In general, the degree of endothelial dysfunction of coronary microvasculature correlates with total serum cholesterol levels [22]. However, if the analysis is confined to patients with hypercholesterolemia (rather than to patients with a wide range of serum cholesterol levels) the ratio of LDL/HDL appears to correlate more closely than total serum cholesterol levels with endothelium-dependent dilation in the coronary circulation [23]. Based on the presumed functions of HDL and their relationship to the efficiency of reverse cholesterol transport in subjects with normal and increased LDL levels (for review see [24]), serum levels of HDL cholesterol may be an important determinant for endothelial function and exert protective effects on coronary endothelial function in patients with hypercholesterolemia. Similarly, oxidized LDL or the ability to oxidize LDL (as measured by lagtime) appears to be more closely related to endothelium-dependent dilation in resistance arteries and coronary conduit arteries respectively [25,26]. Preliminary observations suggest that severe endothelial dysfunction as determined by acetylcholine-induced coronary blood flow responses are associated with increased risk for future coronary events [27].
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5 Potential mechanisms for the development of endothelial dysfunction
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The underlying mechanisms by which risk factors such as hypercholesterolemia
or hypertension impair endothelium-dependent relaxation remain
to be elucidated. Several possible mechanisms were proposed
including: (a) reduced synthesis of NO (b) altered membrane
receptor coupling mechanisms affecting the release of NO and
(c) impaired diffusion or augmented destruction of NO in the
vessel wall. Native LDL lipoprotein has been shown to increase
endothelial cell NO synthase generation of superoxide anion
[28]. The inhibitory effect of oxidized LDL (presumed to be
accumulated in the vascular wall of patients with hypercholesterolemia)
may be derived from its ability to interfere with the receptor-operated
release of
L-arginine from intracellular stores or the synthesis
of the amino acid
[29]. Alternatively, high-affinity arginine
transport into endothelial cells may be impaired by lysophosphatidylcholine,
a component of of oxidized LDL
[30,31]; in fact a caveolar complex
exists between the cationic acid transporter 1, endothelial
NO synthase and caveolin
[32]. In addition, hypercholesterolemia
in patients is associated with increased plasma and tissue levels
of asymmetrical dimethyl-
L-arginine (ADMA), inhibiting the NO
synthase to generate NO
[33]. Thus, in hypercholesterolemia,
the intracellular availability of
L-arginine may become a rate-limiting
factor for the production of NO. Conceivably, hypercholesterolemia
may alter the intracellular pathway for
L-arginine or affect
the stimulated release of NO. Hypercholesterolemia may also
affect the NO synthase to produce superoxide radicals which
in turn would be able to inactivate NO
[28]. The improvement
of endothelium-dependent dilation within the human coronary
circulation following the administration of
L-arginine would
be consistent with the hypothesis that by providing the substrate
for synthesis of NO, an enhanced formation of NO emerges restoring
endothelium-dependent dilation. Notably,
L-arginine augmented
endothelium-dependent dilation in the coronary microcirculation
of patients with hypercholesterolemia but not in control subjects.
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6 Functional consequences of impaired NO availability in coronary arteries
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The loss of flow-dependent dilation in atherosclerotic segments
may favor vasoconstriction at sites where vasodilation could
ordinarily occur upon an increase in flow. Such an impaired
response to increased flow may in part explain the abnormal
vasomotor responses to physiological stimuli in daily life such
as exercise, mental stress or exposure to cold environment.
Under normal conditions, flow-mediated dilation represents the
major mechanism by which the epicardial vessels respond to stimuli,
e.g. exercise, that increase myocardial work and oxygen demand.
NO mediated, shear-induced dilatation opposes the myogenic vasoconstriction
elicited by increases in pressure
[34,35]. Endothelial modulation
of factors such as sympathetic stimulation or platelets and
its releasing substances (thromboxane and serotonin) is altered.
In the face of endothelial dysfunction, the vessel is more sensitive
to the constrictor effects of norepinephrine. Indeed, Vita et
al. have shown that patients with evidence of coronary endothelial
dysfunction as assessed by acetylcholine, intracoronary infusion
of phenylephrine was associated with increased coronary vasoconstriction
as compared to normal individuals
[36]. Similarly, exercise
or exposure to cold activates the sympathetic nervous system
and increases circulating levels of catecholamines. Sympathetic
activation is also accompanied by complex reflex mechanisms
including increases in heart rate and blood pressure thereby
enhancing myocardial oxygen demand. In patients with normal
coronary arteries exercise and exposure to cold produce dilation
of epicardial coronary arteries
[37]. In contrast, patients
with arteriosclerotic coronary arteries demonstrate ‘paradoxical’
epicardial coronary vasoconstriction in response to exercise,
cold pressure test or mental stress
[38–40] despite similar
effects on central hemodynamics or plasma levels of catecholamines.
In such patients there is a close relationship between endothelial
function and response of the identical coronary segment to the
cold pressure test. Coronary vasoconstriction is usually observed
only in segments with acetylcholine-induced epicardial coronary
vasoconstriction (indicating endothelial dysfunction). Moreover,
sympathetic activation is an important trigger mechanism of
myocardial ischemia in patients with coronary artery disease
and stable angina. There is evidence that exercise induces dynamic
vasoconstriction at the site of arteriosclerotic lesions
[40].
Conceivably, inappropriate vasoconstriction due to endothelial vasodilator dysfunction of atherosclerotic epicardial arteries may play an important role in triggering myocardial ischemia in patients with (intermediate) coronary stenoses. Even though the extent of coronary vasoconstriction elicited by sympathetic activation is usually less than 25 to 30%, such an increase in arterial tone may be sufficient to convert a non-flow-limiting into a critical stenosis with ensuing decreases in blood flow; i.e. in intermediate coronary lesions of 50–70%. Thus, in coronary lesions with stenoses between 50 and 70% (luminal diameter) an abnormal vasoconstrictor response due to the loss of endothelium-mediated vasodilation may account for the mismatch between myocardial oxygen supply and demand, with other words, a link may exist between endothelial vasodilator dysfunction at the site of the stenosis and myocardial ischemia and explain episodes of angina associated with daily life activities.
Notably, coronary vasomotor tone may be further enhanced by humoral factors released from activated platelets during ischemia, plaque rupture or simply during circadian peaks of platelet aggregability. A recent study has shown that intracoronary infusion of serotonin resulting in concentration equivalent to those during platelet activation caused severe epicardial coronary vasoconstriction in patients with coronary artery disease and endothelial dysfunction whereas coronary diameters increased in normal subjects [41,42]. Thus, the vasomotor response to serotonin is dependent on the integrity of the endothelium. Platelet-mediated vasoconstriction may only occur if the endothelium is dysfunctional. Importantly, the intact endothelium plays an important role in maintaining the balance between proaggregatory and antiaggregatory behaviour of platelets since both NO and prostaglandins inhibit platelet aggregation and adhesion. Hence, defective endothelial function prediposes to the deposition of platelets. Indeed, increased platelets adhesion has been demonstrated in human arteriosclerotic arteries. Vice versa, stimulation of NO release from the vascular endothelium promotes inhibition of platelet aggregation in the human circulation and this inhibitory effect is attenuated in patients with atherosclerosis [43].
Taken together, with normal endothelial function, the release of NO may be associated with vasodilation (counterbalancing the direct vasoconstricting effects of serotonin and thromboxan), however, in the face of a defective endothelial mediated vasodilation, inappropriate coronary vasoconstriction may emerge promoting platelet activation and aggregation [44].
Since experimental data suggest that the endothelium plays an important role in maintaining vascular structure [45], the impaired basal release of atherosclerotic coronary arteries as demonstrated in vitro may have long-term implications concerning vascular remodelling of coronary arteries. Since NO interferes with the action and synthesis of endothelin, the lack of NO activity may favor the vascular expression of endothelin. Indeed, increased circulating and tissue endothelin immunoreactivity has been observed in patients with coronary artery disease [46]. In fact, the expression of endothelin in the coronary circulation is increased in humans with coronary endothelial dysfunction [47].
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7 Risk factors and endothelial function
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Except for smoking whose impact on epicardial endothelial function
remains somewhat controversial, all known risk factors are associated
with endothelial dysfunction of epicardial coronary arteries.
Studies by Vita et al.
[48] and Yasue et al.
[49], indicate
that the loss of endothelium-dependent vasodilation correlates
with the presence of elevated serum cholesterol, male sex, family
history of coronary artery disease, and age in angiographically
normal coronary arteries. Elevated high-density lipoprotein
levels may have a protective effect on endothelial function
of epicardial coronary arteries
[50]. Even a family history
of premature coronary disease has been shown to be associated
with impaired endothelial dependent dilation in young healthy
subjects
[51]. The more risk factors present, the more likely
the coronary arteries were to constrict. However, the presence
of a single coronary risk factor, such as hypercholesterolemia
or hypertension, is sufficient to impair endothelium-dependent
vasomotion in angiographically normal coronary arteries. By
multivariate analysis, the presence of arteriosclerotic lesions
has been reported to be an independent predictor for impaired
blood flow responses to acetylcholine. This analysis suggests
that mild (non-flow-limiting) arteriosclerotic lesions are accompanied
by impaired endothelium-dependent dilation of coronary resistance
vessels. However, a dissociation between the impairment of endothelium-dependent
relaxation of conductance and resistance vessels has been reported,
suggesting that the presence of different mechanisms underlying
the endothelial dysfunction in these two arterial territories
may exist.
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8 Effect of cholesterol lowering by statins on endothelial dysfunction
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Several longterm studies have applied lipid lowering drugs for
several months and evaluated endothelial function before and
after this intervention in patients with coronary artery disease
and hypercholesterolemia. Leung et al.
[52] were the first to
assess endothelium-dependent and -independent dilation of coronary
epicardial arteries before and 6 months following a lipid-lowering
regimen, consisting of dietary restrictions and oral treatment
with cholestyramin. A decrease in plasma cholesterol of approximately
30% was achieved at follow-up, in comparison to baseline. Before
treatment, intracoronary coronary infusion of acetylcholine
causes severe vasoconstriction of epicardial arteries, whereas
a moderate vasodilation was observed at follow-up. Intracoronary
infusion of nitroglycerine elicited a similar degree of vasodilation
at baseline and follow-up. Egashira et al. studied a small group
of nine hypercholesterolemia patients before and after treatment
with pravastatin, an inhibitor of HMG-CoA reductase
[53]. The
acetylcholine-induced vasoconstriction of the epicardial artery
was less and the the acetylcholine-induced increases in coronary
blood flow were greater after pravastatin. In a normocholesterolemic
control group the effects of acetylcholine were similar before
and after 8 months. Thus, the lipid lowering intervention (272
to 187 mg/dl) was associated with an improvement of endothelial
function of coronary conduit and resistance vessels. Two controlled
trials have yielded similar beneficial effects of HMG-CoA reductase
inhibitors on endothelial function in the coronary circulation
[54,55]. In one of the latter trials, the incidence of angina
was reduced
[55]. Moreover, short-term (3 month) cholesterol
lowering decreases the size and severity of perfusion abnormalities
as assessed by positron emission tomography after dipyradamole
in hypercholesterolemic patients with coronary artery disease
[56], myocardial ischemia, angina pectoris
[57–59] and
improves coronary flow
[60]. The rapid improvement in myocardial
perfusion is unlikely to be attributed to regression of epicvaridal
coronary lesions. In fact, seminal studies by Brown et al. have
clearly shown that the extent of lesion regression is minimal
and if it occurs takes years to be measureable
[61]. Conceivably,
improvement of endothelial function has contributed to the improved
coronary perfusion following cholesterol lowering with statins
[60]. The improvement in endothelial function may not only be
related to reduction of LDL-cholesterol but to a specific upregulation
of the synthesis of NO synthase by statins which increase the
mRNA for the endothelial NO synthase
[62]. In addition, prolonged
treatment with statins may reduce vascular radical formation.
Interestingly, longterm therapy with probucol over 1 year combined
with lovastatin was more effective than lovastain given alone
in improving endothelial dysfunction of epicardial coronary
arteries
[55]. Since probucol acts as an antioxidant with minor
effects on lipid plasma levels, these clinical observations
are consistent with experimental data suggesting that inactivation
of NO may play a prominant role in hypercholesterolemia, diabetes
and arteriosclerosis.
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9 Inactivation of NO as a cause of endothelial dysfunction
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Hypercholesterolemia, diabetes mellitus or heart failure are
all associated with increased oxidative stress, either due to
increased radical formation and/or decreased radical scavenging
enzyme activity (see
Fig. 1). Superoxide anions production may
be enhanced by stimulation of the NADPH oxidase in response
to angiotensin II
[63,64]. Antioxidants such as vitamin C or
E, PEG-SOD or probucol have been applied clinically to test
the concept that inactivation of NO may play a prominant role
in cardiovascular disorders. In fact, the water soluble antioxidant
vitamin C has been shown to improve endothelium-dependent dilation
(and availability of NO) in patients with hypercholesterolemia,
hypertension, diabetes or coronary artery disease. Importantly,
vitamin C improves endothelium-dependent vasomotor capacity
after acute administration
[65] and improves myocardial perfusion
during long-term therapy
[66], again implying that increased
oxidative stress contributes to endothelial dysfunction in hypertensive
patients with coronary artery disease. Moreover, evidence has
been presented that a weak glutathione related enzymatic antioxidant
is present in human atherosclerotic lesions
[67], while intracoronary
infusion of reduced glutathione improves endothelial vasomotor
response to acetylcholine in the human coronary circulation
[68]. Furthermore
L-2 oxothiazolidine-4-carboxylic acid, which
augments intracellular glutathione, improves endothelial-dependent
relaxation in patients with coronary artery disease
[69]. The
impressive and instant improvement of NO availability following
administration of antioxidants supports the role of oxygen species
in the impaired endothelial dependent relaxation in coronary
artery disease and its risk factors and are consistent with
the notion, that the cellular redox state may be an important
regulator of endothelium-derived NO. Interestingly, low plasma
ascorbic acid independently predicts the presence of an unstable
coronary syndrome
[70] which would support the role of impaired
endothelial dysfunction in the clinical setting of angina. Moreover,
the activity of superoxide dismutase in the extracellular space
(EC SOD) or in vascular smooth muscle cells (Cu/Zn SOD) may
play an important role in keeping the balance between radical
formation and scavenging.
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Fig. 1 Balance between radical formation and radical scavenging is dependent on the activity of enzymes systems generating superoxide anions in the vascular wall such as the NADPH oxidase, and radical scavenging enzymes such as the different isoforms of superoxide dismutases. There is evidence that the NAD(P)H oxidase is activated by angiotensin and may exceed the capacity of SODs to scavenge radicals resulting in increased oxidative stress and inactivation of NO.
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Vitamin E is thought to protect LDL from oxidation within the
vascular wall. However, the clinical observations with vitamin
E on the effect on endothelium-dependent relaxation are conflicting.
In our experience the beneficial effect of longterm vitamin
E treatment on endothelium-dependent dilation is confined to
patients with increased levels of autoantibodies against oxidized
LDL suggesting that vitamin E works only in those patients whose
endogenous oxygen stress defence mechanisms cannot cope with
the generation of oxygen radicals produced
[71].
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10 Peripheral endothelial function as a surrogate for the coronary circulation
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The assessment of endothelial function in the coronary circulation
can only be achieved by cardiac catherization and interventional
techniques including Doppler flow measurements. In the last
7–8 years several investigators have used a non-invasive
approach, introduced by Deanfields group, to identify patients
at risk by determining endothelial function in peripheral arteries,
mostly in the brachial artery. Whether or not the evaluation
of endothelial function in the forearm represents a useful surrogate
to predict the development of atherosclerosis in humans (i.e.
for the clinically more important coronary and cerebral circulation)
is an open but a relevant question, given the limitations to
evaluate the latter circulatory beds. A comparison of flow-dependent
dilation in the brachial artery and acetylcholine-induced coronary
vascular response demonstrated a reasonable relationship, although
different stimuli for release of NO were used
[72]. However,
the sensitivity for detecting coronary endothelial dysfunction
was only 49% in that study
[72]. It is unclear whether or not
determination of the same stimuli in the brachial and coronary
artery would provide better sensitivity. However, an even more
important issue is whether endothelial dysfunction of the brachial
artery predicts risks for future coronary events (rather than
simply the presence of coronary arteriosclerosis). Large-scale
clinical studies are needed to address this important clinical
question.
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11 Conclusions
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In summary clinical studies have been able to evaluate endothelial-dependent
vasomotor capacity in the coronary circulation in patients with
risk factors and/or evidence of coronary artery disease. There
is clear evidence that endothelial-dependent vasodilation is
impaired in coronary artery disease and this functional alteration
is associated with impaired myocardial perfusion and ischemia.
Thus, improvement of endothelial vasodilator capacity is a clinically
relevant target for therapy and may prevent clinical symptoms
of ischemia. Whether or not prevention of endothelial function
has prognostic implications is an important question and remains
to be determined. Several interventions have been effective
in restoring endothelial vasodilator responses such as lipid
lowering, antioxidants or ACE-inhibitors. Further studies should
be able to elucidate whether the overall clinically benefical
effects of these interventions are related to improvement of
endothelial function which includes much more then vasodilator
capacity, i.e. attenuation of leucocyte adhesion, prevention
of platelet aggregation or favoring profibrinolytic activity.
Time for primary review 21 days.
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1 Introduction
2 Normal endothelial function