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Vascular function and cardiovascular diseaseAsselbergs, Folkert Wouter

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PART IICoronary vasomotor function

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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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8


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.

CLINICAL IMPACT OF VASOMOTOR FUNCTION ASSESSMENT

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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-

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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


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


139


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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