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University of Groningen
Vascular function and cardiovascular diseaseAsselbergs, Folkert
Wouter
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Vascular function and cardiovascular disease: risk stratification
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PART IICoronary vasomotor function
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CHAPTER EIGHT
Clinical impact of vasomotor function assessment
and the role of ACE-inhibitors and statins
F.W. Asselbergs, P. van der Harst, G.A.J. Jessurun,R.A. Tio,
W.H. van Gilst
Provisionally accepted Vascular Pharmacology supplement
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Abstract
Impaired endothelial function is recognised as one of the
earliest events of atherogene-sis. Endothelium dependent vasomotion
has been the principal method to assessendothelial function. In
this article, we will discuss the clinical value of the different
tech-niques to evaluate endothelium dependent vasomotion. To date,
there seems not to be asimple and reliably endothelial function
test to identify asymptomatic subjects atincreased risk for
cardiovascular disease in clinical practice. Recent studies
indicate thatpharmacological interventions, in particular with
ACE-inhibitors and statins, mightimprove endothelial function.
However, there is no solid evidence that improvement ofendothelial
function is a necessity for the observed reduction in
cardiovascular events bythese compounds. Overall, at this moment,
there is no place in clinical practice for theuse of endothelial
function as a method for risk assessment or target of
pharmacologicalinterventions.
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1. Introduction
Since the discovery of the obligatory role for the endothelium
in relaxing arterial smoothmuscles by acetylcholine in
1980(Furchgott & Zawadzki 1980), the endothelium hasbeen the
focus of intensive research. Currently, the endothelium is
recognized to play acrucial role in vascular homeostasis in health
and is considered to be early involved in thepathophysiology of
cardiovascular disease (Moncada & Higgs 1993; Rubanyi 1993;
Ross1999; Davignon & Ganz 2004; Glasser et al. 1996). The
endothelium, a single cell layer ofthe vascular wall, has the
ability to respond to physical, chemical, and neurohumoralstimuli
by the production and release of a variety biological active
substances, e.g. nitricoxide (NO), prostanoids, endothelin,
angiotensin II, thrombomodulin, heparan sul-phate, tissue-type
plasminogen activator (t-PA), plasminogen activator inhibitor-1
(PAI-1), von Willebrand factor (vWF), adhesion molecules and
cytokines. NO, synthesized bythe endothelial NO synthases, is the
most investigated substance released from theendothelium and plays
a pivotal role in endothelium-dependent vasodilatation and
regulation of other protective functions of the endothelium.
Functions of NO includeregulation of vascular smooth muscle cell
tonus and proliferation, blood hemostasis, vas-cular permeability,
inflammatory response, platelet adherence and aggregation,
andendothelial cell-leukocyte interaction (Rubanyi 1993; Moncada
& Higgs 1993; Glasser etal. 1996). In addition, the endothelium
has organ-specific roles that are differentiated forvarious parts
of the body, such as gas exchange in the lungs, control of
myocardial func-tion in the heart or phagocytosis in the liver and
spleen (Vane et al. 1990). A disturbancein the integrity or
function of the endothelium is called endothelial dysfunction. In
this review, we will focus on endothelium dependent vasodilatation
as an measure of endothelial function (mediated predominantly by
NO). We will discuss differentmethods of assessment; prognostic and
clinical implications and pharmacological inter-ventions aimed at
lowering blood pressure and cholesterol, in particular with
ACE-inhibitors and HMG-CoA reductase inhibitors, respectively.
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Figure. 1 Effect of acetylcholine/shear stress, ACE-inhibition,
and statins on vasomotor func-tion. BK: bradykinin, B2: B2-kinin
receptor, ACE: angiotensin converting enzyme, AT:angiotensin, NO:
nitric oxide, O2: superoxide anion, ONOO-: peroxynitrite anion,
eNOS:endothelial Nitric oxide synthase, TXA2: thromboxane A2, PGH2:
prostaglandin H2, PKC:protein kinase C, L-NMMA: L-NG-monomethyl
arginine, BH4: tetrahydrobiopterin,NADH: NADH/NADPH oxidase, DAG:
diacylglycerol, AGE: advanced glycation endprod-uct, ox-LDL:
oxidised low-density lipoprotein, sGC: soluble guanylate cyclase,
cGMP: cyclicguanosine monophosphate.
Upregulation, Downregulation
2. Endothelial dependent vasomotor function
Endothelial cells synthesise NO through NO synthases (e.g. eNOS)
by oxidation of theamino acid L-arginine (figure 1).(Palmer et al.
1988) NO is thought to be the mostimportant endothelial derived
vasodilator. Required cofactors for eNOS functioning arehaem,
calmodulin, tetrahydrobiopterin, flavin mononucleotide and FAD,
andNADPH(Marletta 1993; Fleming & Busse 2003; Albrecht et al.
2003). NO is continuous-ly produced by eNOS in the healthy
endothelium in certain amounts in response to shearand pulsatile
stretch of the vascular wall. The production of NO can be increased
bymany physiological stimuli, such as hypoxia, increase blood flow
or shear stress, andpharmacological stimuli such as acetylcholine,
bradykinine, adenosine triphosphate,adenosine diphosphate,
thrombin, serotonin, histamine and substance P (Luscher
&Vanhoutte 1990). NO released from the endothelium in turn
stimulates the solubleguanylate cyclase in the vascular smooth
muscle cells, resulting in an increase in the for-
CHAPTER EIGHT
126
DAG
NOeNOS
Receptor
Acetylcholine
sGC
L-arginine
cGMP
TXA2
Contraction
Cyclooxygenase
AT1 receptor
AT II
Contraction
ACE
AT I
ACE-inhibition
B2
BK
TX receptor
PGH2
PKC
Relaxation
O2-
Smooth muscle cell
Hyperglycemia (AGEs)
Ox-LDL
L-NMMAShear stress
Arachidonic acid ONOO-
Statins
NADH
+
+
++
+
BH4
+ -
-
-
-- +
+
+
+-
K+channel
- -
-+
Endothelial cell
-
AT1 receptor
ProefschriftFolkert25-11-04.qxd 25-11-2004 12:41 Pagina 126
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mation of cyclic GMP (Rapoport & Murad 1983; Rapoport et al.
1983; Draznin et al.1986). Activation of cyclic GMP-dependent
protein kinases alters the phosphorylationstate of various proteins
and cascades, subsequently resulting in the decrease in
vasculartonus through either a decrease in intracellular free
calcium concentrations, calciumdesensitization, and/or thin
filament regulation, or a combination of these processes (seeRefs
(Lincoln et al. 2001; Hofmann et al. 2000) for reviews).In addition
to NO, other endothelial-derived factors contribute to
vasorelaxation, e.g.prostacyclin and endothelium-derived
hyperpolarizing factor (non-NO and non-prostaglandin mechanism). In
contrast to NO, EDHF is predominantly present in small-er
resistance arteries and less in large conduit vessels.(McGuire et
al. 2001) The relevanceof non-NO dependent mechanisms is well
established in animal and experimental mod-els, but its clinical
assessment and importance is still subject of investigation.
3. Assessment of endothelium dependent vasomotor function
Endothelium dependent vasodilatation has grown to be the read
out of endothelial func-tioning based on the assumption that
impaired endothelium dependent vasomotionreflects impaired NO
production and other of its protective properties. In
1980,Furchgott and Zawadzki demonstrated that relaxation of
isolated rabbit thoracic aortaand other blood vessels by
acetylcholine was dependent on the presence of
endothelium(Furchgott & Zawadzki 1980). In the absence of
endothelium acetylcholine caused vaso-constriction through a direct
effect on the muscarinic receptors of the vascular smoothmuscle
cells. Similar experiments confirmed the presence of endothelium
dependentvasomotor function in human isolated internal mammary
arteries, a vessel widely usedfor coronary bypass surgery
(Schoeffter et al. 1988). It has been suggested that thedecreased
endothelium dependent vasorelaxation in saphenous venous segments
toacetylcholine, compared to mammary artery segments, can explain
the differences ingraft patency after bypass (Luscher et al. 1988;
Yang et al. 1989; Werner et al. 1990;Tadjkarimi et al. 1992). In
isolated human coronary arteries, obtained from hearts of car-diac
transplant patients, the endothelium dependent vasomotor function
in response tosubstance P, bradykinin, and Ca+-ionophore A23187 of
atherosclerotic arteries wasattenuated (Forstermann et al.
1988).Abnormal vasomotor response to acetylcholine can also be
demonstrated in vivo in thecatheter laboratory using quantitative
angiography. In patients with coronary athero-sclerosis in the left
anterior descending coronary artery, acetylcholine induced
vasocon-striction (Ludmer et al. 1986). In subsequent studies,
progressive impairment ofendothelial dependent vasomotor function
was demonstrated in coronary arteries ofpatients with different
early stages of atherosclerosis (Zeiher et al. 1989; Zeiher et
al.1991b) and traditional risk factors (Vita et al. 1990; Zeiher et
al. 1991a; Antony et al.1994; Nitenberg et al. 1995; Quyyumi et al.
1995).However, coronary endothelial testing during catheterization
is invasive, not withoutrisk, and time consuming (Tio et al. 2002).
Assessment of endothelial function in thebrachial artery could be a
solution to some of these limitations. Endothelial
dependentvasomotor function can be assessed in peripheral arteries
by using intra-arterial infu-sions of pharmacologic stimuli, like
acetylcholine, to enhance NO release. During venousocclusion strain
gauge plethysmography total forearm blood flow (FBF) and thus
vaso-
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motor function can be calculated by measuring increase in
forearm volume over timeafter infusion of acetylcholine (Wilkinson
& Webb 2001; Hokanson et al. 1975; Stroes etal. 1995; Stroes et
al. 1997). Indeed, impairment of endothelial function as assessed
byFBF is also associated with cardiovascular risk factors,
including hypercholesterolaemia,diabetes mellitus and cigarette
smoking (Chowienczyk et al. 1992; Makimattila et al.1999; Heitzer
et al. 1996). In addition, we found a significant correlation
between theendothelium dependent vasodilatation in the coronary and
brachial artery after acetyl-choline infusion in patients referred
for a first diagnostic angiogram (Monnink et al.2002). Venous
occlusion plethysmography in the brachial artery consists of less
risk com-pared to assessment of the coronary artery, but is still
not suitable in asymptomaticpatients due to its invasive
approach.Since impaired NO release in humans can be demonstrated by
an impaired vasomotorresponse to eNOS activation, it can also be
demonstrated by physiological stimuli, suchas exercise- (Gordon et
al. 1989) or cold-pressor testing (Nabel et al. 1988; Zeiher et
al.1989). Another physiological stimulus, blood flow, allows
non-invasive assessment ofendothelial dependent vasodilatation.
Flow-mediated vasodilatation (FMD) in thebrachial artery measures
the diameter of the brachial artery at rest and during
reactivehyperaemia with high-resolution ultrasound and has been
widely used for quantifyingendothelium dependent vasodilatation
(Celermajer et al. 1992; Raitakari & Celermajer2000). Anderson
et al. (Anderson et al. 1995b) demonstrated a relation between
coronaryartery endothelium-dependent vasomotor responses to
acetylcholine and the FMD.There was a positive predictive value of
95% between an abnormal brachial artery dilata-tion and coronary
endothelial dysfunction. However, the sensitivity for detecting
coro-nary endothelial dysfunction was only 49%. Besides
quantitative angiography, FBF andFMD, there are some other methods,
such as positron emission tomography (Bottcher etal. 1999) and
transthoracic doppler echocardiograpy (Iliceto et al. 1991; Hozumi
et al.1998), but these are currently not commonly used and only
small sample sizes have beenreported. To date, non-invasive
assessment of the flow-mediated vasodilatation withultrasound seems
to be the most attractive method to assess endothelium
dependentvasodilatation because of its safety and the potential to
measure vascular functionrepeatedly over time.
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Table 1. Prognostic studies of coronary and peripheral
endothelial function
Study n Extent of CAD Design Method Cut-off value Events, n
Follow-up, Result
months
Suwaidi 157 < 40% stenosis prospective CEDV -20 % 6 28
+(Suwaidi et al. 2000)
Schachinger 147 1 VD prospective CEDV 0 % 16 92 +(Schachinger et
al. 2000)
Hollenberg 73 < 50% stenosis prospective CEDV 5 % 14 9
+(Hollenberg et al. 2001)
Halcox 308 Mild to moderate retrospective CEDV 0 % 35 46
+(Halcox et al. 2002)
Targonski 503 < 30 % stenosis retrospective CEDV 20 % 25 16
+(Targonski et al. 2003)
von Mering 163 75 % normal prospective CEDV 0 %* 58 48 +(von
Mering et al. 2004) or mild VD
Asselbergs 277 0-3 VD prospective CEDV 0 % 24 47 -(Asselbergs et
al. 2004)
Schindler 130 0 VD prospective CPT 0 % 26 45 +(Schindler et al.
2003)
Nitenberg 128 0 VD retrospective CPT 0 % 27 45 +(Nitenberg et
al. 2004)
Perticone 225 Unknown prospective FBF Tertiles 29 32 +(Perticone
et al. 2001)
Heitzer 281 1-3 VD prospective FBF Median 91 54 +(Heitzer et al.
2001)
Neunteufl 73 0-3 VD prospective FMD 10 % 27 12 +(Neunteufl et
al. 2000)
Gokce (Gokce et al. 2002) 187 Unknown Prospective FMD Tertiles
45 1 +
Gokce (Gokce et al. 2003) 199 Unknown prospective FMD Tertiles
35 14 +
Chan (Chan et al. 2003) 152 Unknown prospective FMD FMD/NMD
ratio 22 34 +
Brevetti 131 Unknown prospective FMD median 39 23 +(Brevetti et
al. 2003)
Fathi (Fathi et al. 2004) 444 Unknown prospective FMD Tertiles
49 24 -
CAD: coronary artery disease, CEDV: coronary endothelial
dependent vasodilatation, CPT: cold-pressor testing, FMD: flow
mediated vasodilatation, NMD: nitroglycerin mediated
dilation
*In the multivariate analysis, no cut-off value was used, but
the change in diameter after acetylcholine infusion was
continu-
ously entered into the model.
4. Prognostic value of endothelium dependent vasomotor
function
To our knowledge, no studies have been published on the
prognostic value of endothe-lial dependent vasodilation of isolated
human vascular segments. However, several studies (table 1) have
investigated the prognostic value of endothelium
dependentvasodilatation in the coronary artery as assessed at the
catheter laboratory. Suwaidi et al.(Suwaidi et al. 2000) were the
first to report that endothelial dysfunction is associatedwith
increased cardiac events in 157 patients with mild coronary artery
disease (CAD)during a 2.3-year follow-up. This finding was
confirmed by Schächinger et al.(Schachinger et al. 2000) who
studied 147 patients with mild CAD during a median follow-up of 7.7
years. Since these two studies had a relatively small number of
events
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(6 and 16, respectively) it was not considered as sufficiently
convincing evidence.However, Halcox et al. (Halcox et al. 2002)
provided similar data, retrospectively, aboutthe predictive value
of coronary endothelial dependent function in a study in
308patients with mild to moderate CAD and even in patients with
angiographically normalcoronary arteries, with a follow up of 46
months (35 events). Another retrospective studydemonstrated an
independent association between coronary endothelial function
andcerebrovascular events in patients without obstructive coronary
artery disease at an earlystage of atherosclerosis (Targonski et
al. 2003). More recently, the Women’s IschemiaSyndrome Evaluation
(WISE) Study investigated the prognostic value of coronary
vas-cular dysfunction in 163 women referred for diagnostic
angiogram for evaluatingmyocardial ischemia (von mering et al.
2004). Seventy-five percent had no or mild coro-nary artery disease
and the degree of coronary artery disease and the change in
diameterafter intracoronary acetylcholine infusion were both
predictive for cardiovascular events.Unfortunately, it is unclear
how many events occurred in the group with mild and in thegroup
with severe coronary artery disease. Fifty-eight (36%) of these
so-called lower-riskwomen had a cardiovascular event during a
follow-up period of 48 months and theWISE study has thereby the
highest event rate of all studies listed in table 1. We studied277
patients referred for a first coronary angiogram (Asselbergs et al.
2004). In contrastto other studies, we did not exclude patients
with advanced atherosclerosis who werecandidates for
revascularization. This might explain why we were unable to
demonstrateprognostic value of coronary endothelium dependent
vasomotor function. Furthermore,discontinuing vasoactive medication
before the coronary angiogram in this study mayconfound this
finding. It might have been the case that non-responders to
cardioprotec-tive medication experienced events. Unfortunatly, how
previous studies dealt withvasoactive medication prior to
endothelium assessment is not clear. Two other studiesreported that
endothelial vasomotor function of the coronary artery in response
to cold-pressor testing have prognostic value in patients with
normal coronary angiograms(Schindler et al. 2003; Nitenberg et al.
2004). Collectively, the above studies indicate thatcoronary
vasomotor function in patients with an increased cardiovascular
risk profilecan predict future cardiovascular events. However,
measuring endothelial function incoronary arteries is only
justifiable in high-risk patients and therefore does not add
anyvalue to primary prevention programs.Only recently, the
prognostic value of peripheral assessment of endothelial
dependentvasodilatation by FBF in response to intra-arterial
acetylcholine infusion was demon-strated (Perticone et al. 2001;
Heitzer et al. 2001). In patients with initially untreated
anduncomplicated essential hypertension and in patients with
documented coronary arterydisease forearm endothelial dysfunction
appeared a marker for future cardiovascularevents (Perticone et al.
2001; Heitzer et al. 2001). Non-invasive assessment of
peripheralendothelial dependent vasodilatation by FMD might also be
a marker for increased car-diovascular risk (Kuvin et al. 2001).
Two studies have reported a significant (modest-strong) relation
with impaired endothelial dependent relaxation in the coronary
arteriesand brachial arteries (Anderson et al. 1995a; Takase et al.
1998). However, the results ofFBF and FMD may not be analogous
(Eskurza et al. 2001; Monnink et al. 2002) andreproducibility of
FMD can be poor. (Hijmering et al. 2001; Monnink et al.
2002).Neunteufl et al. (Neunteufl et al. 1997) demonstrated that
FMD measurements are inde-pendently associated with the
angiographic extent of CAD. Interestingly, the same groupfound a
relation between endothelial function measured by the FMD and need
for car-
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diac revascularization (Neunteufl et al. 2000). Gokce et al.
demonstrated in a prospectivestudy that an impaired FMD predicts
short-term and long-term cardiovascular eventsafter vascular
surgery (Gokce et al. 2003; Gokce et al. 2002). In another report
it wasshown that functional integrity following arterial bypass
surgery was preserved, whichmay partially explain the long term
beneficial outcome after arterial graft surgery(Amoroso et al.
2000). However, in a recent study, involving a relatively large
number ofpatients (n=444) at relatively high risk, Fathi et al,
investigated whether FMD measure-ments have an additional value in
predicting mortality and cardiovascular morbidity relative to other
predictors of outcome (Fathi et al. 2004). Although they found in
univariate analysis that the most disturbance of FMD had greater
subsequent cardiacmorbidity and mortality than those with normal or
mildly abnormal FMD, in multi-variate analysis this could be
independently predicted by intima medial thickness (IMT)and LV mass
rather than FMD. Only in a subgroup undergoing stress testing, FMD
pro-vided additional information (along with IMT and LV mass).When
considering the above, it should be noted that studies
demonstrating prognosticvalue of coronary vasodilation have
predominantly been performed in patients withmild to moderate CAD.
In patients with more severe CAD, peripheral endothelial func-tion
testing was used to investigate its predictive value. This
discrepancy in study designsmay suggest that endothelium dependent
vasodilatation test for assessment of endothe-lium function can
only be assessed in vessels with intact endothelium, e.g. the
brachial orcoronary artery with mild atherosclerosis. To visualise
this conception, figure 2 shows acoronary artery without
obstructive coronary artery disease and an intact endotheliallayer.
In contrary to mild coronary artery disease, the endothelium is
damaged or oblit-erated in coronary arteries with severe
atherosclerosis and plaques (figure 3). Therefore,we hypothesize
that coronary endothelial function testing might not be a powerful
diag-nostic modality in patients with advanced atherosclerosis. In
addition, use or non-use ofvasoactive mediation introduces an
important potential confounder since non-respon-ders to vasoactive
medication might continue to have diminished endothelium vasomo-tor
function in contrast to responders. In this respect, discontinuing
medication mightprovide a better information of the intrinsic
health of the endothelium, while continu-ing medication probably
provides better information of the endothelium function in‘real
life’, when events do occur. Which of these two situations provides
the strongestprognostic information still remains to be
elucidated.In summary, most of the aforementioned studies
demonstrate a predictive value ofendothelial function in patients
independent of traditional cardiovascular risk factors.Whether or
not this is truly independent or additive, in all situations
remains to be estab-lished. Furthermore, most studies were
retrospective in nature, with few events and per-formed in selected
patient populations only. Invasive endothelial function measured
byintracoronary or intrabrachial acetylcholine infusion does not
seem to have future as pri-mary prevention tool considering their
risk and costs. Nevertheless, these tests continueto have value for
academic reasoning and assessing vascular response to
therapeuticintervention over time in symptomatic or high-risk
patients. The FMD assessment ofendothelial dependent vasomotor
function seems to be the most attractive candidatesince it can
safely be applied to large and asymptomatic patients. However,
disadvantagesof FMD are the high variability, its modest
association with coronary endothelial func-tion and lack of
standardisation between centres.
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Figure. 2 Coronary artery without obstructive coronary artery
disease and an intactendothelial layer. Reproduced with permission
of AC van der Wall (Academic MedicalCenter, Amsterdam).
Figure. 3 Coronary artery with a microthrombus centrally
located, the endothelium is dam-aged or obliterated at the site of
injury. The black arrows indicate adjacent endothelial
cells.Reproduced with permission of AC van der Wall (Academic
Medical Center, Amsterdam).
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5. Intervention on endothelium dependent vasomotor function
Numerous studies have reported the beneficial effects of several
physiological and phar-macological interventions on endothelial
function (Hambrecht et al. 2000; Husain et al.1998; Noon et al.
1998; Quyyumi 1998; Levine et al. 1996; Gokce et al. 1999; Andrews
etal. 2001; Lieberman et al. 1994; Gerhard et al. 1998; Saitta et
al. 2001). Among these, ACE-inhibitors and HMG CoA reductase
inhibitors (statins) are most extensively investigatedin
experimental and clinical setting. Both drugs have repeatedly been
demonstrated to bevery effective in decreasing cardiovascular
events in high-risk populations. Therefore,this review is limited
to the effects of these drugs on endothelial function.
5.1 Hypertension, ACE-inhibitors and endothelium dependent
vasomo-tor function
It has been repeatedly shown that hypertension impairs
endothelium dependent vaso-motor function in animal models as well
as human studies (for reviews see (Lind et al.2000; Vanhoutte 1996)
Impairment of endothelium dependent vasodilatation has
beenextensively documented in hypertensive subjects with several
methods and in differentarteries (Linder et al. 1990; Panza et al.
1990; Treasure et al. 1992; Brush, Jr. et al. 1992;Panza et al.
1995; Iiyama et al. 1996; Li et al. 1997). It has not yet been
fully elucidatedwhether impaired endothelium dependent
vasodilatation causes hypertension or viceversa. Nevertheless,
antihypertensive treatment with ACE-inhibitors,
calcium-channelblockers, angiotensin 2 receptor blockers,
betablockers and diuretics can improveendothelium dependent
vasodilatation in animal experimental models of hypertension(Clozel
et al. 1990; Novosel et al. 1994; Rodrigo et al. 1997; Hayakawa et
al. 1997;Vanhoutte et al. 1993; Finta et al. 1993). In humans, it
has also been demonstrated thatimprovement in endothelial function
may be obtained after antihypertensive therapyand, in addition,
clearly identifies patients who possibly have more favourable
prognosis(Modena et al. 2002). The most potent improvement of
endothelium function might beobtained by ACE-inhibitors. ACE
inhibitors not only prevent the production ofangiotensin II from
angiotensin I, but also stimulates the production of
bradykinin.Bradykinin contributes to the effects of ACE inhibitors
in clinical setting (Gainer et al.1998). Several pathways are
activated by both actions, which are illustrated in figure
1.Indeed, treatment with ACE-inhibitors has been shown to improve
endothelial functionin humans (table 2) (Rajagopalan et al. 1996;
Antony et al. 1996; Prasad et al. 2000b;Cheetham et al. 2000). The
Brachial Artery Normalisation of Forearm Function(BANFF) study was
designed to compare the effect of ACE-inhibition with quinapril
orenalapril, angiotensin II blockade with losartan, and
calcium-channel blocking therapywith amlodipine on FMD in 80
patients with CAD (Anderson et al. 2000). The authorsdemonstrated
that only quinapril improved FMD after eight weeks of treatment
inpatients with CAD. These results were in concordance with other
studies comparingenalapril and quinapril. Moreover, the beneficial
effect of quinapril was confirmed instudies using FMD, FBF, and
coronary endothelial function (table 2). Only Benacceraf(Benacerraf
et al. 1999) et al. did not demonstrate a beneficial effect of
quinapril inpatients with CAD. Nevertheless, quinapril improved FBF
in healthy subjects in thisstudy. The discrepancy found in the
BANFF study between quinapril and losartan sug-
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gest an important role of kinins in endothelium dependent
vasodilatation, as losartandid not augment FMD. However, despite
extensive experimental evidence and the stud-ies using quinapril,
the beneficial effects of other ACE-inhibitors on endothelial
functionin humans are more inconsistent (table 2). Benazepril only
augmented FMD in hyper-tensive patients with a FMD
-
Table 2. Overview of human studies investigating the effect of
ACE-inhibitors on endothe-lial function
Study Patient N Method ACE- Follow-up Result
characteristics inhibitor
Mancini (Mancini et al. 1996) CAD 105 CEDV quinapril 6 months
+
Prasad (Prasad et al. 2000a) Coronary sclerosis 56 CEDV
enalapril Immediately after infusion +
or risk factors
Antony (Antony et al. 1996) Hypertension 10 CPT perindopril
Immediately after infusion +
Hirooka (Hirooka et al. 1992) Hypertension 12 FBF captopril
Acute +
Kiowski (Kiowski et al. 1993) Hypertension 10 FBF cilazapril 5
months -
Creager (Creager & Roddy 1994) Hypertension 44 FBF captopril
7-8 weeks -
enalapril -
Iwatsubo (Iwatsubo et al. 1997) Hypertension 26 FBF temocapril 6
months +
O’Driscoll Type I DM 9 FBF enalaprilat / Acute infusion / 1
month + / + (O'Driscoll et al. 1997a) enalapril
Haefeli (Haefeli et al. 1997) Healthy volunteers 44 FBF
quinapril Immediately after infusion +
enalapril -
Taddei (Taddei et al. 1998) Hypertension 20 FBF lisinopril 6-8
hours / 1 month / +/+
12 months
Millgard J (Millgard et al. 1998) Hypertension 23 / 5 FBF
captopril 1 hour / 3 months +
O’Driscoll (O'Driscoll et al. 1999) Type II DM 10 FBF enalapril
4 weeks +
Benacerraf (Benacerraf et al. 1999) CAD 26 FBF quinapril
Immediately after infusion -
Lee (Lee et al. 1999) Hyperlipidaemia 40 FBF lisinopril 6 months
+
Houben (Houben et al. 2000) Hypertension 12 FBF quinapril
Immediately after +
enalapril infusion -
Higashi (Higashi et al. 2000) Hypertension 296 FBF any ACEi >
24 weeks +
Butler (Butler et al. 1999) Smokers 23 FBF lisinopril 8 weeks
+
Nagy (Nagy et al. 1998) Hypertension 21 FMD benazepril 2 hours/
1 month - / -
Mullen Type 1 DM 91 FMD enalapril 12 / 24 months - / -(Mullen et
al. 1998)et al. (1998)
Hornig (Hornig et al. 1998) CHF 15 FMD quinapril Immediately
after +
enalapril L-NMMA -
Wilmink (Wilmink et al. 1999) Healthy volunteers 30 FMD
quinapril 2 weeks +
McFarlane (McFarlane et al. 1999) Type 1 DM 20 FMD perindopril
12 weeks -
Arcaro G, (Arcaro et al. 1999) Microalbuminuric 9 FMD captopril
/ 1 week / 1 week +/+
type 1 DM enalapril
Anderson CAD 80 FMD quinapril 8 weeks +(Anderson et al. 2000) et
al. (2000) enalapril -
Esper (Esper et al. 2000) CAD with hyper 38 FMD enalapril 8
weeks +
cholesterolemia
Bae (Bae et al. 2001) CAD 39 FMD lisinopril 2 hours -
Bots (Bots et al. 2002) coronary artery 345 FMD perindopril 3
years ? (not
disease completed)
EF: endothelial function, CAD: coronary artery disease, CHF:
chronic heart failure, DM: diabetes mellitus,
FBF: Forearm Blood Flow assessed by venous occlusion
plethysmography, FMD: endothelium dependent Flow-mediated
vasodilatation of the brachial artery, CPT: cold-pressor test,
CEDV: coronary endothelium dependent vasodilatation
after infusion of acetylcholine, L-NMMA: L-NG-monomethyl
arginine, ACEi: ACE-inhibitor.
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5.2 Effects of cholesterol lowering therapy and HMG CoA
reductaseinhibitors on endothelium dependent vasomotor function
Effects of hypercholesterolemia on endothelial function have
also been extensively studied. Numerous studies indicate
cholesterol to be an independent predictor forendothelial
dysfunction and to have an inverse correlations with endothelium
depend-ent vasodilatation with different methods of assessment and
in different arteries (Creageret al. 1990; Vita et al. 1990;
Drexler & Zeiher 1991; Celermajer et al. 1992; Chowienczyket
al. 1992; Casino et al. 1993; Seiler et al. 1993; Shiode et al.
1996; Voors et al. 1997).Several explanations can account for the
decreased endothelial function in hypercholes-terolemia. (Oxidized)
LDL cholesterol can decrease eNOS activity at several levels,
suchas downregulation mRNA (Liao et al. 1995), inhibition of
membrane signal transduction(Liao 1994) and NO inactivation (Galle
et al. 1991). In addition, increased vascularoxidative stress is
associated with hypercholesterolemia and could further diminish
theavailability of NO (Ohara et al. 1993). Evidence for causality
in humans was provided byseveral LDL apheresis studies. A single
LDL apheresis can result in LDL reductions of 40-90% within 3
hours. In hypercholesterolemia patients improvement of
endothelialdependent vasodilatation could be demonstrated directly
after LDL apheresis in thecoronary artery (Mellwig et al. 1998;
Igarashi et al. 2004) and forearm vessel (FBF)(Tamai et al. 1997).
A reduction of triglycerides showed no such correlation. This
stud-ies strongly supports the concept that hypercholesterolemia in
itself causes endothelialdysfunction that can be immediately
reversed by an acute aggressive reduction of serumcholesterol.Only
very few studies investigated pharmacological interventions on
endotheliumdependent vasorelaxation not using statins. Treatment
with cholestyramine in hyper-cholesterolaemic patients resulted in
a 29% reduction in total cholesterol after 6 monthsand a
significant improvement of acetylcholine induced vasomotor response
of the coro-nary artery (Leung et al. 1993). Treatment with
gemfibrozil resulted in improvement in10 subjects with DM, but had
no effect in 100 subjects with LDL
-
effect on serum cholesterol levels was detectable. The time
course of cholesterol loweringat the beginning and end of treatment
disassociated from alterations of vascular func-tion. Therefore,
these data support the existence of cholesterol-independent effects
ofstatins in humans. Similar, pravastatin improved endothelial
dependent vasodilatationafter 3 days of treatment in
normocholesterolemic CAD patients (Masumoto et al. 2001).This
improvement in endothelial function was completely blocked by
coinfusion of theNO synthase inhibitor L-NMMA, thus seems to be
attributable to a potentiation ofeNOS activity. After menopause,
most healthy women show an impairment of peripher-al
vasodilatation. 10 days of atorvastatin treatment improved
endothelium-dependentvasodilatation in postmenopausal
normocholesterolemic women, without affectingserum lipoproteins.
Furthermore, the effect was potentiated by L-arginine and bluntedby
L-NMMA, strongly suggesting an association with increased NO
production by statintreatment (Mercuro et al. 2002). Recently, it
was demonstrated that impaired endothelialfunction caused by
cigarette smoking could be improved by statin treatment in
normo-cholesterolemic smokers, without associations between
baseline lipid levels and changein lipid levels (Beckman et al.
2004).These studies all suggests that statins probably exerts a
direct action on the arterialendothelium independently of (serum)
cholesterol levels. However, in diabetic subjectsresults are less
consistent (table 3). (Sheu et al. 1999; Sheu et al. 2001; van de
Ree et al.2001; Duffy et al. 2001; van Etten et al. 2002;
Economides et al. 2004; van Venrooij et al.2002) In diabetic
studies, endothelial function seems not to be associated with an
tradi-tional lipid variable, in contrast to studies of nondiabetic
subjects (Vogel et al. 1996;Toikka et al. 1999; van Venrooij et al.
2002) (Cosentino & Luscher 1998). Interestingly, inelderly type
2 diabetic patients 3 days of cerivastatin treatment did not result
in changein lipid concentrations, but did improve the FMD and this
was associated with anincrease in plasma NOx and decrease of
oxidant markers (Tsunekawa et al. 2001). Thus,whether in diabetic
subjects, hyperglycemia is the principle cause of endothelial
dys-function resistant to statin therapy remains to be further
elucidated.In contrast to several studies investigating peripheral
endothelial function in normocho-lesterolemic patients, two
placebo-controlled randomised studies failed to show animprovement
on coronary endothelial function after 6 months of treatment with
sim-vastatin and cerivastatin, the CARATS and the ENCORE study
(Vita et al. 2000; 2003).The improvement of coronary endothelial
function in the placebo group might haveresulted in the regression
to the mean phenomenon. Both groups assessed the effects onthe most
constrictive segment. However, when all coronary segments were
analysed, thisphenomenon disappeared. Taken all together, more
positive than negative studies havebeen published for each method
of endothelial function testing (table 3). The currentlyavailable
studies strongly suggest that treatment of hypercholesterolemia can
restoreendothelial dysfunction. At the moment, conflicting clinical
evidence of statin therapyexists on endothelium dependent effects
beyond cholesterol lowering. Furthermore, nostudy has demonstrated
whether improvement of endothelium dependent vasodilata-tion is a
necessity for the efficacy of statin treatment.
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Table 3. Overview of human studies investigating the effect of
statins on endothelial func-tion.
Study Patient n Method Statin Follow-up Result
characteristics
Egashira (Egashira et al. 1994) hypercholesterolemia 9 CEDV
pravastatin 6 months +
Treasure (Treasure et al. 1995) CAD 23 CEDV lovastatin 12 days /
5.5 months - / +
Anderson (Anderson et al. 1995a) Cholesterol 49 CEDV lovastatin
1 year +
(4.7-7.2 mmol/l) cholestyramide
probucol
Houghton (Houghton et al. 2000) Normal coronary 6 CEDV
pravastatin 6 months -
arteries
Vita (Vita et al. 2000) CAD 60 CEDV simvastatin 6 months -
Penny (Penny et al. 2001) Hypercholesterolemia 29 CEDV
lovastatin 18 months +*
ENCORE (2003) CAD 343 CEDV cerivastatin 6 months -
Wassmann (Wassmann et al. 2003) Angina pectoris 27 CEDV
pravastatin 24 hours +
O'Driscoll Cholesterol 10 FBF simvastatin 4 weeks / 3 months + /
+(O'Driscoll et al. 1997b) (6.0-10.0 mmol/l)
Perticone (Perticone et al. 2000) hypercholesterolemia 40 FBF
atorvastatin 1 month +
John (John et al. 2001) hypercholesterolemia 37 FBF cerivastatin
2 weeks +
Duffy (Duffy et al. 2001) hypercholesterolemia 26 FBF
simvastatin After L-NMMA -
van de Ree (van de Ree et al. 2001) Type 2 DM 17 FBF simvastatin
6 weeks -
Laufs (Laufs et al. 2001) Healthy male 28 FBF atorvastatin 48
hours +
Mercuro (Mercuro et al. 2002) Postmenopausal 28 FBF atorvastatin
10 days +
women
van Etten (van Etten et al. 2002) Type 2 DM 44 FBF atorvastatin
4 weeks -
Wassmann Normocholesterolemic 18 FBF atorvastatin 6 weeks
+(Wassmann et al. 2004) with increased
cardiovascular risk
Vogel (Vogel et al. 1996) Hypercholesterolemia 7 FMD simvastatin
12 weeks +
Neunteufl (Neunteufl et al. 1998) hypercholesterolemic 7 FMD
simvastatin 20 weeks +
vitamin E
Simons (Simons et al. 1998) hypercholesterolemia 32 FMD
atorvastatin 30 weeks +
simvastatin + +
cholestyramine
Sheu (Sheu et al. 1999) Type 2 DM with 21 FMD simvastatin 24
weeks -
hypercholesterolemia
Dupuis (Dupuis et al. 1999) ACS 60 FMD pravastatin 6 weeks +
Jarvisalo (Jarvisalo et al. 1999) CAD 45 FMD statins After at
least +
3 months of statins
Rashid (Rashid & Touchon 1999) CAD 8 FMD simvastatin 3 / 6
months + / +
Mullen (Mullen et al. 2000) Type 1 DM 84 FMD atorvastatin 6
weeks +
Tsunekawa (Tsunekawa et al. 2001) Type 2 DM 27 FMD cerivastatin
3 days +
3 months
Sheu (Sheu et al. 2001) Type 2 DM with 12 FMD simvastatin 12
weeks +
hypercholesterolemia
Malik (Malik et al. 2001) hyperlipidemia 29 FMD fenofibrate 10
weeks -
atorvastatin -
Stein (Stein et al. 2001) hypercholesterolemia 37 FMD
pravastatin 6 months -
17 simvastatin -
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Table 3. Continued
Study Patient n Method Statin Follow-up Result
characteristics
Van Venrooij Type 2 diabetes 133 FMD atorvastatin 10mg 30 weeks
-
atorvastatin 80mg -
Dogra (Dogra et al. 2002) Nephrotic syndrome 10 FMD any statin
12 weeks +
Omori (Omori et al. 2002) Healthy volunteers 30 FMD cerivastatin
1h/3h/6h/12h -/+/-/-
de Jongh (de Jongh et al. 2002) FH 69 FMD simvastatin 28 weeks
+
Vita (Vita et al. 2003) CAD 51 FMD Atorvastatin 36 hours -
van Haelst (van Haelst et al. 2003) FH 35 FMD simvastatin 6
weeks -
Economides Diabetes Type 1/2 40 FMD atorvastatin 12 weeks
+(Economides et al. 2004)
Beckman (Beckman et al. 2004) Cigarette smokers 20 FMD
atorvastatin 4 weeks +
Healthy controls 20 -
EF: endothelial function, CAD: coronary artery disease, CHF:
chronic heart failure, DM: diabetes mellitus, FBF: Forearm
Blood Flow assessed by venous occlusion plethysmography, FMD:
endothelium dependent Flow-mediated vasodilatation of
the brachial artery, CEDV: coronary endothelium dependent
vasodilatation after infusion of acetylcholine, ACS: acute
coro-
nary syndromes, FH: familial hypercholesterolemia, L-NMMA:
L-NMMA: L-NG-monomethyl arginine. *Improvement only
in the most constricted segments
5.3 Clinical Implications of therapeutic interventions on
endothelialdependent vasomotor function
Improvement of endothelial function can be induced by statin
therapy and possible ACEinhibitors. Like aspirin (Husain et al.
1998; Noon et al. 1998; Quyyumi 1998), statins andACE inhibitors
definitely improve cardiovascular prognosis concomitantly
withendothelial dependent vasomotor function. However, endothelial
function can also beimproved with other pharmacological
interventions, such as vitamins/antioxidants(Levine et al. 1996;
Gokce et al. 1999; Andrews et al. 2001; Title et al. 2000) and
hormonereplacement therapy (Lieberman et al. 1994; Gerhard et al.
1998; Saitta et al. 2001) butwithout positive effects on clinical
outcomes (2002; Yusuf et al. 2000; Nelson et al. 2002;Liem et al.
2003; Lange et al. 2004). Thus, improvement of endothelial function
is notnecessarily a good surrogate marker of risk reduction. The
clinical value of persistentendothelial dysfunction after
initiation of a well proven treatment has not been wellestablished.
Currently, only one study reported the lack of change in FMD in
response toblood pressure lowering therapy could predict
cardiovascular events in 400 post-menopausal hypertensive women
(Modena et al. 2002).
6. Conclusions
In this paper, we reviewed the most commonly used methods to
assess endothelialdependent vasomotor function. It is conceivable
to assume that endothelial dependentvasodilatation is of prognostic
value for future cardiovascular events. Non-invasiveassessment of
the flow-mediated vasodilatation with ultrasound seems to be the
most
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attractive method to assess endothelium dependent vasodilatation
in low-risk andasymptomatic patients because of its safety and the
potential to measure vascular func-tion repeatedly. However,
studies aimed at the prognostic value were only performed
inselected patients referred for evaluation of cardiovascular
disease. Consequently, thesedata cannot be extrapolated to the
general population. In addition, the assessment offlow-mediated
dilatation is a sophisticated and expensive procedure, which may
only beuseful for academic reasoning towards new diagnostic and
treatment modalities.Secondly, we discussed blood pressure and
cholesterol lowering interventions, in partic-ular with ACE
inhibitors and statins, on endothelium dependent vasodilatation,
whichseems beneficial in small sample sizes. Currently, large
randomised population basedprospective studies on treatment of
endothelial function with statins or ACE inhibitorsin low risk
patients are lacking. Improvement of endothelial dependent
vasodilatationcould, theoretically, exert a beneficial effect on
clinical outcome. However, several inter-ventions improving
endothelial function did not improve clinical outcome and
thereforeit remains questionable whether improvement of endothelial
function is a necessity toimprovement in cardiovascular
prognosis.
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