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A DISTURBANCE OF
ENDOTHELIAL function is considered as a key event in the
development of atherosclerosis (63). Thus reliable assessment of endothelial function in humans appears highly desirable. With respect to the major endothelial functions, this aim can be
achieved by different approaches: 1) measurement of
morphological and mechanical characteristics of the vascular wall
(intima media thickness, compliance, distensibility, and remodelling
indexes); 2) determination of soluble endothelial
markers (von Willebrandt factor, plasminogen activator, inhibitor
complex thrombomodulin adhesion molecules, and N-oxides);
and 3) measurement of the endothelium-dependent regulation
of vascular tone at focal sites of the circulation. The endothelium is
of essential importance for the maintenance of vascular tone. It
participates in the regulation of blood flow in response to changes in
tissue and organ perfusion requirements. When blood flow increases
through a vessel, the vessel dilates. This phenomenon has been coined
flow-mediated dilatation (FMD). Schretzenmayer (56) was
first to describe this physiological response, and FMD has been
demonstrated subsequently in a number of conduit arteries in vitro and
in vivo, in animals and in humans. This editorial will focus on
pathophysiological aspects and critically evaluate the potential
clinical significance of FMD measurement in humans.
An intact endothelium is crucial for flow-dependent dilatation of
conduit arteries. This has first been demonstrated in femoral arteries
(50, 53) and epicardial arteries (26, 29).
Only in some resistance arteries is FMD mediated, at least in part, independent from the endothelium (7). Shear stress is
mainly determined by blood flow, and its tractive force exerted at a vector perpendicular to the long axis of the vessel. The endothelium acts as a mechanotransducer that senses changes in shear stress and
subsequently modifies the output of dilator factors. Several mediators
have been proposed to be involved in FMD: prostaglandins (28), ATP or an endothelium-derived hyperpolarizing factor
(42), and most importantly nitric oxide (NO)
(30). An increased release of NO in response to increases
in shear stress not only dilates underlying smooth muscle of conduit
arteries but also maintains the concentration of NO constant at the
luminal surface of vascular endothelium despite flow increases
(33). FMD is diminished by reduction in extracellular
calcium and sodium (6) and is improved by magnesium
(60). The FMD response not only depends on the absolute
level but also on the gradient of shear stress, i.e., change per unit
time, and the frequency of changes in amplitude (47). In
human forearm circulation, endothelial responses to blood flow depend
on the characteristics of the flow stimulus. FMD after brief episodes
of hyperemia is almost exclusively mediated by NO, whereas dilatation
during sustained hyperemia is unaffected by NO synthesis inhibition
(44).
The endothelial signaling cascade responsible to convert mechanic
stimuli into the release of vasodilatory molecules has not been fully
clarified. As yet, several mechanisms have been suggested: an
endothelial potassium channel coupled to a pertussis toxin-sensitive G
protein, kininergic mechanisms, sodium-dependent conformational changes
of membrane glycosaminoglycans, and an initial calcium-dependent activation of phospholipase C combined with a longer-lasting
calcium-independent activation of protein kinase C and tyrosine
kinase (6, 47). More recently, it has been demonstrated
that shear stress induces phosphorylation of a serine residue altering
endothelial NO synthase (eNOS) sensitivity to intracellular calcium
levels and thus increasing NO formation (15). FMD
critically depends on the eNOS activity at the level of the conduit
arteries. Brief episodes of reactive hyperemia, as seen with regular
physical exercise, increase the level of shear stress in conduit
arteries. The consecutive increase in constitutive eNOS expression
improves endothelial function and thus FMD (12, 16, 30, 31, 52,
59, 70, 71). But FMD not only depends on NO formation but also
on NO inactivation and the sensitivity of the underlying vascular
smooth muscle for NO. Regular exercise simultaneously induces
upregulation not only of eNOS but also of superoxide dismutase
expression (21). This feed-forward mechanism could prevent
superoxide-mediated inactivation of NO and thus increase shear
stress-dependent FMD.
Endothelial dysfunction is reflected by an impaired FMD response.
In human vasculature, FMD is most often studied in the forearm and
coronary circulation. Principally, a vasodilatory stimulus is applied
to the downstream vascular bed eliciting a flow-dependent dilation of
the upstream conduit vessel. The kind of dilatory stimulus depends on
the vascular bed under investigation.
Celermajer and colleagues (9) introduced a unique setup to
study FMD noninvasively and reliably in human forearm circulation. An
increase in flow through the brachial artery is induced by causing
postischemic dilatation in the downstream vascular bed of the
distal forearm. This is achieved by inflating a cuff placed around the
proximal forearm to suprasystolic pressure producing a ischemia
in the distal vascular bed. After the release of the cuff pressure, a
sudden increase of blood flow into the dilated vascular bed occurs. The
subsequent increase in shear stress in the upstream conduit artery
cause a dilatation of the brachial artery, which can be assessed by an
ultrasound device. As a control the response of the brachial artery to
sublingual glycerol trinitrate (GTN) is recorded. The duration and the
amplitude of brachial artery dilatation upon GTN is somewhat more
pronounced than during FMD (+15% vs. +10%). With increasing number of
cardiovascular risk factors, smooth muscle dysfunction becomes apparent
and thus GTN response is progressively impaired independently from
endothelial dysfunction (1). This has to be considered
when studying patients with either coronary or systemic atherosclerosis.
A variety of stimuli acutely influence FMD: a single high-fat meal and
postprandial lipemia (19, 66), mental stress, and most
probably by catecholamines (23), circulating levels of estrogen and progesterone (62), smoking (37),
acute changes in glucose (32), and changes in sodium and
calcium (6). Acute increases in oxidative stress occurring
during hemodialysis have also been reported to be related to impaired
brachial artery FMD (43). In contrast, the FMD response
appears to be independent from whole blood viscosity (45).
Furthermore, diurnal variation in regulation of vascular tone are
well known. Thus FMD measurement enables clinical physiologists to
sensitively assess acute changes in endothelial function in humans.
However, in followup studies assessing therapeutic interventions on
endothelial function, patients have to be matched and a study protocol
must be standardized for the aforementioned potential impact factors on FMD.
In general, these precautions concerning patient selection and study
conditions in measurement of brachial artery reactivity also apply to
the coronary circulation. Dilatation of coronary resistance vessels to
induce increases in shear stress in the upstream epicardial arteries
can be achieved by metabolic stimuli such as exercise or pacemaker
stimulation. Alternatively, this can be mimicked by selective infusion
of adenosine (69) or papaverine (68) into the
midportion of the epicardial artery and simultaneous quantification of
FMD in the proximal segment of the artery under investigation. In this
segment, endothelium-dependent changes in tone are detected mainly by
quantitative computer-supported analysis.
It is still not clear whether or not the endothelial dysfunction of the
coronary circulation is a focal or a systemic disturbance of the
vasculature that occurs simultaneously in other territories of the
circulation. Assessment of FMD in epicardial arteries is a much more
invasive approach compared with FMD measurement in the brachial artery.
Therefore, several studies addressed the issue that brachial artery FMD
measurement may represent a surrogate for diagnostic evaluation of
coronary circulation in patients with evident coronary artery disease
(CAD) or those individuals at risk for CAD. In these studies (3,
39, 46, 57), the endothelium-dependent (3) as well
as the endothelium-independent (49) dilatation in the
forearm circulation was determined in patients with CAD. A close
correlation of endothelial function in the human coronary and
peripheral vasculature has been demonstrated in some but not all
studies (2, 38). It has also been shown that a high
percentage of patients with unstable angina pectoris had concurrent
endothelial dysfunction of the brachial artery in the ultrasound scan.
Interestingly, the disturbance of endothelial function was reversible
after treatment of acute coronary syndrome (18). However,
the patient numbers studied so far are too small to permit a
statistically confirmed statement with regard to the specificity and
sensitivity of brachial artery FMD measurement to predict endothelial
dysfunction and CAD in the coronary vasculature.
There is ample evidence that FMD measurement sensitively detects
endothelial dysfunction in hyperlipidemia, arterial hypertension, and
diabetes, all considered as major cardiovascular risk factors. FMD in the brachial artery is impaired by elevated levels of
cholesterol, whereas the plasma level of triglycerides does not affect
FMD (55, 65). The extent of endothelial dysfunction
depends on the total cholesterol level (58). In arterial
hypertension, an altered bioactivity of NO is involved in endothelial
dysfunction of coronary and peripheral circulation (34,
35). Sustained arterial hypertension blunts FMD in conduit
arteries in peripheral (17) and coronary circulation
(4, 20, 61). The degree of coronary endothelial
dysfunction depends on the severity and duration of arterial
hypertension as indexed by the degree of left ventricular hypertension
(25, 27). Endothelial dysfunction in conduit arteries and
the microvasculature is also frequently seen in diabetes mellitus
(13). FMD in epicardial vessels is reduced in diabetic
individuals (48). Hyperglycemia blunted endothelium-dependent vasodilation in conduit (32) and
resistance vessels (67). Thus, in humans, FMD measurement
not only enables to reliable diagnose endothelial dysfunction
associated with the major atherogenic risk factors but also to quantify
the degree of endothelial dysfunction in relation to the severity of
hyperlipedemia, hypertension, and diabetes.
With the use of invasive testing with intracoronary application of
acetylcholine, several studies demonstrated that endothelial dysfunction in CAD may be reversible (40, 64), which
raises the possibility that progression of atherosclerosis may be
slowed. This underscores the need for a sensitive and reproducible
testing of endothelial function in clinical routine and therapeutic
follow-up studies. Brachial artery FMD measurement may represent such a noninvasive diagnostic alternative to the acetylcholine test. In
patients with CAD, improvement of brachial artery FMD has already been
proven after long-term therapy with ascorbic acid,
angiotensin-converting enzyme inhibitors, ciprofibrate, and
L-arginine (2, 10, 19, 24, 38).
Brachial artery reactivity has been successfully used to
investigate the genetic influence on early arterial physiology that may
be relevant to later clinical disease. Intrauterine and childhood factors also appear to influence brachial artery FMD. Recent data indicate that FMD positively and significantly correlates with birth
weight. This relation was not altered by adjustment for childhood body
build, parity, cardiovascular risk factors, social class, or ethnicity
(36). Furthermore, an increased carotid stiffness is
associated with low birth weight (41). Thus growth in
utero and other so far not identified genetic determinants may be
associated with long-term changes in vascular function that are
manifest by the first decade of life. These factors may influence the
long-term risk of cardiovascular disease.
In adulthood, endothelial dysfunction has been implicated as a key
event in the pathogenesis of atherosclerosis. FMD is impaired with
progressive atherosclerosis (14, 71). Furthermore, there is some evidence that a reduced FMD in epicardial arteries predicts cardiovascular event rates (54). Measurement of brachial
artery FMD is a noninvasive diagnostic procedure. This easily allows assessment of endothelial function also in offspring or in first-degree relatives from patients with evident atherosclerosis. Healthy young
adults with a family history of premature CAD have impaired FMD,
even in the absence of other risk factors (11). This
impaired brachial artery FMD not only coincides but also correlates
with a greater intima-media thickness (IMT) of the common carotid
artery, indicating early functional and structural changes of vascular endothelium in offspring of patients with premature CAD
(22). Similar results were obtained in first-degree
relatives of patients with type 2 diabetes (5). Thus FMD
measurement enables us to potentially identify patients at risk for
atherosclerotic complications. This not only underscores the prognostic
impact of endothelial dysfunction but also provides a rationale for
future risk stratification of patients.
Not only endogenous, but also environmental factors, may impair
vascular function. Measuring brachial artery FMD, it has been demonstrated that passive smoking impairs endothelial function in
humans (8). However, the interindividual susceptibility to
endogenous and environmental risk factors may vary considerably and may
at least in part be determined genetically. The combined determination
of FMD and single nucleotid polymorphisms of target genes involved in
atherosclerosis in large patient populations may provide us with new
insights into the pathogenesis of early atherosclerosis.
The underlying physiological mechanisms of FMD have been
investigated extensively in various experimental models. In humans, the
measurement of FMD has been widely adopted to explore endothelial function. Alterations in FMD have been documented in almost all of the
major cardiovascular risk factors. The assumption that focal
measurement of brachial artery FMD predicts endothelial dysfunction and
CAD deserves further investigation. There are also needs for
standardization of FMD measurement facilitating studies in large
patient populations and comparison of data from different laboratories.
Likewise, with IMT measurement, an international consensus for normal,
borderline, and pathological reference values in FMD measurement is
necessary. Recently, a new automated analysis systems was introduced
for the boundary detection of the brachial artery wall reducing
variability and analysis time of FMD measurement (51). In
the future, improved techniques of FMD measurement will enable
clinicians to measure FMD in large-scale trials, and thus to further
proof a causal relation between endothelial dysfunction and the major
clinical endpoints cardiovascular mortality and morbidity. Thus FMD may
become not only a biomarker but a valuable surrogate of endothelial
dysfunction in clinical routine. In parallel, new developments in the
field of DNA array technologies will help to identify target genes
important for different phases of atherosclerosis. The combined
measurement of FMD and IMT together with the characterization of
differential gene expression will develop clinical diagnoses of
vascular diseases from the mere angiographic to the more functional and
genomic approach with the perspectives to evaluate new strategies in
risk stratification and treatment.
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ACKNOWLEDGEMENTS |
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A part of this work was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Ke 405 4/1 and 4/3) and by the Biomedizinisches Forschungszentrum der Heinrich Heine Universität Düsseldorf.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Kelm, Medizinische Klinik und Poliklinik B, Klinik für Kardiologie, Pneumologie und Angiologie, Moorenstr. 5, 40225 Düsseldorf, Germany (E-mail: kelm{at}med.uni-duesseldorf.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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