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Review

Endothelial Dysfunction: Cardiovascular Risk Factors, Therapy, and Outcome

, &
Pages 183-198 | Published online: 24 Dec 2022

Abstract

Endothelial dysfunction is a well established response to cardiovascular risk factors and precedes the development of atherosclerosis. Endothelial dysfunction is involved in lesion formation by the promotion of both the early and late mechanisms of atherosclerosis including up-regulation of adhesion molecules, increased chemokine secretion and leukocyte adherence, increased cell permeability, enhanced low-density lipoprotein oxidation, platelet activation, cytokine elaboration, and vascular smooth muscle cell proliferation and migration. Endothelial dysfunction is a term that covers diminished production/availability of nitric oxide and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. Also, when cardiovascular risk factors are treated the endothelial dysfunction is reversed and it is an independent predictor of cardiac events. We review the literature concerning endothelial dysfunction in regard to its pathogenesis, treatment, and outcome.

Introduction

During the last 2 decades, it has been shown that the vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homeostasis. The basic mechanisms involved in atherogenesis indicate that deleterious alterations of endothelial physiology, otherwise known as endothelial dysfunction, represent a key early step in the development of atherosclerosis and are also involved in plaque progression and the occurrence of atherosclerotic complications (CitationAnderson, Gerhard, et al 1995; CitationKinlay and Ganz 1997). Endothelial dysfunction is characterized by reduction of the bioavailability of vasodilators, particularly nitric oxide (NO), and/or an increase in endothelium-derived contracting factors (CitationLerman and Burnett 1992). The resulting imbalance leads to an impairment of endothelium-dependent vasodilation, which is the functional characteristic of endothelial dysfunction. In addition to impaired endothelium-dependent vasodilation, endothelial dysfunction also comprises a specific state of endothelial activation, which is characterized by a proinflammatory, proliferative, and procoagulatory states that favor all stages of atherogenesis (CitationAnderson 1999). Considering the relationship between endothelial dysfunction and atherosclerosis, it is likely that the status of an individual endothelial function may reflect the propensity to develop atherosclerotic disease, and thus may serve as a marker of an unfavorable cardiovascular prognosis. Herein, we review the literature about endothelial dysfunction in regard to its pathogenesis, treatment, and outcome.

Pathophysiology of endothelial dysfunction

The endothelium maintains normal vascular tone and blood fluidity, with no or little expression of proinflammatory factors under normal homeostatic conditions. However, both traditional and novel cardiovascular risk factors including smoking, aging, hypercholesterolemia, hypertension, hyperglycemia, and a family history of premature atherosclerotic disease are all associated with alteration in endothelial function (CitationSorensen et al 1994; CitationGokce and Vits 2002; CitationLibby et al 2002). This results in a chronic inflammatory process accompanied by a loss of antithrombotic factors and an increase in vasoconstrictor and prothrombotic products, in addition to abnormal vasoreactivity, therefore elevating risk of cardiovascular events (CitationBonetti et al 2003) (). More recently, endothelial dysfunction has also been associated with obesity, elevated C-reactive protein, and chronic systemic infection (CitationCelermajer et al 1992; CitationSteinberg et al 1996; CitationThogersen et al 1998; CitationCushman et al 1999; CitationFichtlscherer et al 2000; CitationAl Suwaidi et al 2001; CitationPrasad et al 2002).

Figure 1 The various factors that affect the endothelium and the consequences of endothelial dysfunction.

Figure 1 The various factors that affect the endothelium and the consequences of endothelial dysfunction.

Oxidative stress and endothelial cell dysfunction

Reactive oxygen species (ROS) are generated at sites of inflammation and injury, and at low concentrations can function as signaling molecules participating in the regulation of fundamental cell activities such as cell growth and cell adaptation responses; whereas at higher concentrations, ROS can cause cellular injury and death. The vascular endothelium, which regulates the passage of macromolecules and circulating cells from blood to tissues, is a major target of oxidative stress, playing a critical role in the pathophysiology of several vascular diseases and disorders. Specifically, oxidative stress increases vascular endothelial permeability and promotes leukocyte adhesion, which is coupled with alterations in endothelial signal transduction and redox-regulated transcription factors (CitationLum and Roebuck 2001).

How is endothelial function assessed?

Endothelium-dependent vasodilation can be assessed in the coronary and peripheral circulations. The most relevant methodological issues in the research on endothelial function and dysfunction have recently been published (CitationDeanfield et al 2005). We provide a summary of the available modalities of testing.

Coronary circulation

Noninvasive tests for the assessment of coronary endothelial function that have been described include Doppler echocardiography, positron emission tomography, and phase-contrast magnetic resonance imaging. However, the gold standard test for the evaluation of coronary endothelial function requires invasive quantitative coronary angiography to examine the changes in diameter in response to intracoronary infusions of endothelium-dependent vasodilators such as acetylcholine. Endothelial function of the coronary microvasculature can be assessed with intracoronary Doppler techniques to measure coronary blood flow in response to pharmacological or physiological stimuli (CitationAnderson 1999; CitationAl Suwaidi et al 2001; CitationFarouque and Meredith 2001). Diagnostic coronary angiography is first performed with a standard femoral percutaneous approach, with no nitroglycerin given beforehand. Vasomotor responses to acetylcholine and adenosine are then assessed (CitationAl Suwaidi et al 2001). After the control coronary angiogram has been obtained, a 0.014-inch Doppler guide wire is introduced through an 8-F guiding catheter into the left anterior descending coronary artery. Once baseline flow velocity data are obtained at the position, ie, once a stable Doppler signal is achieved, a bolus of intracoronary adenosine (24–36 μg, from a solution of 6 mg adenosine in 1 L of saline) is administered. Then intracoronary infusion of selective concentrations of acetylcholine (10−6, 10−5, and 10−4 mol/L) is administered for a total of 3 minutes through a 2.2-F Ultrafuse coronary infusion catheter. Symptoms, hemodynamic data, and electrocardiographic and Doppler velocities are recorded at the end of each infusion or bolus injection, followed by selective coronary angiogram. Coronary blood flow is calculated using the formula D2 × APV, where D represents the coronary diameter and APV equals the average peak velocity from Doppler tracing.

Peripheral circulation

Brachial artery ultrasound is a widely used noninvasive measure of endothelial function. Upper-arm occlusion for 5 minutes results in reactive hyperemia after the release of the cuff; the increase in shear stress results in endothelium-dependent flow-mediated vasodilation. Importantly, endothelial dysfunction assessed by this technique correlates with measures of coronary endothelial dysfunction (CitationAnderson, Uehata, et al 1995). Peripheral vascular endothelial function can be assessed by strain-gauge venous impedance plethysmography. This technique examines the change in forearm blood flow in response to direct intraarterial (brachial artery) administration of agonists. Noninvasive measures of arterial compliance and waveform morphology provide a marker of vascular health (CitationDeanfield et al 2005).

Role of endothelial dysfunction in acute coronary syndromes

Endothelial dysfunction may play a fundamental role in the pathogenesis of acute coronary syndromes (CitationLibby 2001). Plaque destabilization, the process that predisposes to rupture of the plaque, results from a complex interplay of inflammatory effects that involve cellular plaque components and various proinflammatory mediators (CitationLibby et al 2002). Endothelial dysfunction is associated with increased oxidative stress (CitationNapoli et al 2001), an important promoter of inflammatory processes. NO may reduce endothelial expression of several inflammatory mediators and adhesion molecules that increase plaque vulnerability (CitationKubes et al 1991; CitationDe Catarina et al 1995; CitationPeng et al 1995; CitationBarnes and Karin 1997). Precipitation of acute coronary syndrome may also involve physical factors related to endothelial dysfunction. Increased vasoreactivity results in local vasoconstriction in response to metabolic and sympathetic stimuli in the area of culprit lesions in patients with unstable angina (CitationBogaty et al 1994). All of these processes may contribute to plaque rupture and hence the development of acute coronary syndrome.

Endothelial dysfunction and cardiovascular risk factors

Diabetes and endothelial dysfunction

Molecular and cellular basis of endothelial dysfunction in diabetes

Hyperglycemia may lead to intracellular changes in the redox state resulting in depletion of the cellular NADPH pool. Overexpression of growth factors has also been implicated in diabetes with proliferation of both endothelial cells and vascular smooth muscle, possibly promoting neovascularization. Chronic hyperglycemia leads to non-enzymatic glycation of proteins and macromolecules (CitationCalles-Escandon and Cipolla 2001).

The diabetic state is typified by an increased tendency for oxidative stress and high levels of oxidized lipoproteins, especially the so-called small, dense low-density lipoprotein. The high levels of fatty acids and hyperglycemia have also both been shown to induce an increased level of oxidation of phospholipids as well as proteins. In humans it is associated with a prothrombotic tendency as well as increased platelet aggregation, with tumor necrosis factor implicated as a link between insulin resistance, diabetes, and endothelial dysfunction; a hypothesis has been advanced that insulin and/or insulin precursors may be atherogenic (CitationCalles-Escandon and Cipolla 2001).

We have reviewed 22 experimental and clinical studies from 1991 to 2004 that evaluated endothelial dysfunction in diabetic patients; most of these were prospective studies. Diminished capacity of NO synthase to generate NO has been demonstrated experimentally when endothelial cells were exposed either in vitro or in vivo to a diabetic environment (CitationArbogast et al 1982; CitationAanderud et al 1985; CitationKoh et al 1985; CitationLorenzi et al 1986; CitationHattori et al 1991; CitationNordt et al 1993; CitationAvogaro et al 1999; CitationCipolla 1999; CitationSalvolini et al 1999). Most of these studies in humans indicate that endothelial dysfunction is closely associated with microangiopathy and atherosclerosis in diabetic patients.

Endothelial dysfunction in insulin-dependent diabetes mellitus

The association between diabetes and endothelial dysfunction is particularly true in patients with type 1 diabetes who have either early (microalbuminuria) or late (macroalbuminuria) nephropathy. A variety of markers indicate endothelial dysfunction: poor endothelial cell-dependent vasodilation and increased blood levels of von Willebrand factor (vWF), thrombomodulin, selectin, plasminogen activator inhibitor, type IV collagen, and tissue plasminogen activator (t-PA) have been demonstrated in this patient population (CitationYaqoob et al 1993; CitationDosquet et al 1994; CitationMyrup et al 1994; CitationMakimattila et al 1996; CitationHuszka et al 1997; CitationCosentino and Luscher 1998; CitationElhadd et al 1998; CitationMalamitsi-Puchner et al 1998; CitationHuvers et al 1999). While the dysfunction of endothelial cells is considered to be an early marker of vascular disease in type 2 diabetes, it does not seem to fully manifest itself until later in the course of type 1 diabetes (CitationClarkson et al 1996). Furthermore, it has been shown that the levels of vascular cell adhesion molecule-1 were more markedly elevated in type 1 diabetes patients with diabetic retinopathy than in those with micro- or macroalbuminuria, whereas no difference in intracellular adhesion molecule-1 and endothelial leukocyte adhesion molecule-1 levels was apparent regarding the clinical status of diabetic microangiopathy (CitationFasching et al 1996). In diabetic subjects, endothelium-dependent vasodilation correlated inversely with serum insulin concentration but not with glucose concentration, glycosylated hemoglobin, or duration of diabetes (CitationJohnstone et al 1993).

In another study, a significantly raised mean concentration of a free N-terminal fibronectin 30-kDa domain (a marker of endothelial dysfunction) was found in plasma of diabetic patients with proliferative retinopathy as compared with healthy individuals, and a positive correlation was observed between free N-terminal fibronectin and vWF and the degree of albuminuria, suggesting an association between endothelial cell dysfunction and proliferative retinopathy (CitationSkrha et al 1990).

The general consensus is that the occurrence of endothelial cell dysfunction in type 1 diabetes signifies a very high risk of micro- and macroangiopathy, and although the diabetic state predisposes to endothelial cell dysfunction in this disease, it is not sufficient to cause it. It is more likely that other agents (genes, environment) have a role in determining which patients will develop aggressive angiopathy and hence endothelial cell dysfunction. Irrespective of whether endothelial cell dysfunction is a cause or a consequence of vascular injury in type 1 diabetes, it is hoped that therapeutic efforts aimed at restoring endothelial cell function to normal will affect the natural history of vasculopathy in type 1 diabetes (CitationCalles-Escandon and Cipolla 2001).

Endothelial dysfunction in non-insulin-dependent diabetes mellitus

The role of endothelial dysfunction in type 2 diabetes is more complicated than that for type 1. The effects of aging, hyperlipidemia, hypertension, and other factors add to the complexity of the problem. In contrast to the situation with type 1 diabetes, endothelial dysfunction can occur in type 2 diabetes even when patients have normal urinary albumin excretion, a marker of endothelial dysfunction often elevated years before any evidence of microangiopathy becomes evident (CitationJanka 1985; CitationHsueh and Anderson 1992; CitationBloomgarden 1998; CitationDe Mattia et al 1998; CitationNeri et al 1998; CitationWatts and Playford 1998; CitationGazis et al 1999).

There is growing evidence suggesting the coexistence of insulin resistance and endothelial dysfunction. Insulin-induced vasodilation, which is partially mediated by NO release, is impaired in obese individuals who do not have type 2 diabetes but who display insulin resistance (CitationSteinberg et al 1994; CitationFerri et al 1997). Moreover, the obese state, a model of human insulin resistance, is associated with high levels of endothelin in plasma. Plasminogen activator inhibitor concentrations in blood also are high in patients with otherwise uncomplicated obesity (CitationCalles-Escandon et al 1996).

The insulin resistance syndrome encompasses more than a subnormal response to insulin-mediated glucose disposal; patients with this syndrome also frequently display elevated blood pressure, hyperlipidemia, and dysfibinolysis even without any clinically demonstrable alteration in plasma glucose concentrations (CitationSteinberg et al 1994).

The vasodilatory responses to acetylcholine have been shown to be reduced in healthy normoglycemic individuals with a history of type 2 diabetes in one or both parents (relatives), individuals with impaired glucose tolerance, and patients with type 2 diabetes without vascular complications compared with healthy normoglycemic individuals with no history of type 2 diabetes in a first-degree relative (as control). The plasma levels of endothelin-1 were significantly higher in these three groups. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes (CitationCaballero et al 1999).

Low and high physiological hyperinsulinemia have been shown to abolish endothelium-dependent vasodilation, whereas endothelium-independent vasodilation was unaffected. Vitamin C fully restored insulin-impaired endothelial function without affecting endothelium-independent vasodilation (CitationArcaro et al 2002). Other investigators concluded that insulin therapy partly restores insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease (CitationRask-Madsen et al 2001). In other studies in which the long-term effects of insulin glargine on vascular function in patients with type 2 diabetes were investigated, the results seem to support the idea that long-term insulin therapy has beneficial rather than harmful effects on vascular function (CitationPaolisso and Giugliano 1996; CitationVehkavaara and Yki-Jarvinen 2001). A recently performed double-blind, crossover trial of 12 patients with recently diagnosed type 2 diabetes concluded that insulin resistance is a major contributor to endothelial dysfunction in type 2 diabetes, with both endothelial dysfunction and insulin resistance amenable to treatment by rosiglitazone (CitationPistrosch et al 2004). In a more recent study in which the relationship between the angiotensin-converting enzyme (ACE) gene and endothelial dysfunction was investigated, it was concluded that ACE DD genotype is related to endothelium-dependent arterial dilation in the early stage of type 2 diabetes mellitus and in healthy individuals (CitationXiang et al 2004).

Several therapeutic interventions have been tested in clinical trials with the aim of improving endothelial function in patients with diabetes. Insulin sensitizers may have a beneficial effect in the short and the long term, but the virtual absence of trials with cardiovascular end points precludes any definitive conclusion. Several trials offer optimism that treatment with ACE inhibitors may have a positive effect on the progression of atherosclerosis (CitationO'Driscoll, Green, Rankin, et al 1997; CitationMullen et al 1998; CitationO'Driscoll et al 1999; CitationPrasad et al 2000; CitationHornig et al 2001). Although hypolipidemic agents are widely used, their effect on endothelial function in diabetes is not clear (CitationEvans et al 2000). The role of antioxidant therapy remains controversial ().

Table 1 Modes of therapy of endothelial dysfunction

Endothelial dysfunction in hypertension

Endothelial dysfunction has been documented in both the forearm and coronary beds of patients with essential hypertension. We evaluated 111 patients with normal or mild coronary artery disease by intracoronary Doppler and intravascular ultrasound examination of the left anterior descending coronary artery. Patients were divided into three groups: hypertensive with left ventricular hypertrophy (LVH) (n = 13), hypertensive without LVH (n = 30), and normotensive (n = 68). We found that vessel area and coronary blood flow in patients with LVH were significantly greater than in patients in the other two groups (p < 0.01, p < 0.05); furthermore, the response to both acetylcholine and adenosine was significantly impaired in patients with LVH (CitationHamasaki et al 2000), indicating that endothelium-dependent and -independent vasodilation were impaired in patients with hypertension and LVH.

We have reviewed several other prospective studies that evaluated different aspects of endothelial dysfunction in patients with systemic hypertension; salt-sensitive hypertension is also associated with endothelial dysfunction characterized by defective endothelium-dependent vasodilation. Impairment of the L-arginine-NO pathway may be responsible for this abnormal endothelial response (CitationBragulat et al 2001). Another study found that potassium increases endothelium-dependent vasodilation in essential hypertensive patients (CitationTaddei et al 1994); the same investigator demonstrated impairment of endothelium-dependent vasodilation in renovascular and primary aldosteronism hypertensive patients and indicated that a cyclooxygenase-dependent vasoconstrictor mechanism participated in the blunting of endothelium-dependent vasodilation in essential hypertensive patients (CitationTaddei et al 1993). Other investigators studying the vascular effect of the arginine analog NG-monomethyl-L-arginine have found that patients with essential hypertension have a defect in the endothelium-derived NO system that may at least partly account for both the increased vascular resistance under basal conditions and the impaired response to endothelium-dependent vasodilators (CitationPanza, Casino, et al 1993). Evidence from the same group has led to the conclusion that the endothelial abnormality of patients with essential hypertension is not restricted to the muscarinic receptors (CitationPanza et al 1994) and clinically effective antihypertensive therapy does not restore the impaired endothelium-dependent vasorelaxation in patients with essential hypertension. This indicates that such endothelial dysfunction is either primary, or becomes irreversible once the hypertensive process has become established (CitationPanza, Quyyumi, et al 1993). Another study has shown that the endothelium-dependent vasodilatory response to acetylcholine in the forearm resistance arteries is impaired in patients with essential hypertension (CitationYoshida et al 1991). In contrast, it has also been argued that selective impairment of the responsiveness of the forearm vasculature to muscarinic agonists is not universal in patients with essential hypertension (CitationCockcroft et al 1994).

Endothelial dysfunction and aging

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called “cellular senescence”. Recently, senescent vascular cells have been demonstrated in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of proinflammatory molecules and a decreased level of endothelial NO synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis (CitationMinamino et al 2004).

One widely discussed hypothesis of senescence is the telomere hypothesis. Introduction of telomere malfunction has been shown to lead to vascular dysfunction that promotes atherogenesis, whereas telomere lengthening extends cell lifespan and protects against vascular dysfunction associated with senescence. More recent evidence suggests that telomere-independent mechanisms are implicated in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby promotes vascular inflammation in vitro and in vivo. A large body of data is consistent with cellular senescence contributing to age-associated vascular disorders (CitationMinamino et al 2004).

We reviewed published experimental and clinical studies about aging and endothelial function, most of which were small prospective studies. The hypothesis that oxidative stress, particularly oxidation of tetrahydrobiopterin, may contribute to attenuation of endothelium-dependent relaxation was tested in aged mice using the vasomotor function of isolated carotid arteries by video dimension analyzer, while vascular levels of tetrahydrobiopterin and its oxidation products were measured by high performance liquid chromatography (CitationBlackwell et al 2004). Evidence presented seems to suggest that aging is associated with endothelial dysfunction and reduced arterial elasticity. In addition, reduced arterial elasticity parallels changes in impaired endothelium-dependent vasodilation. It appears that reduced arterial elasticity may be used as a noninvasive measure for the determination of endothelial function (CitationTao et al 2004). Another study concluded that there is a blunted response to acetylcholine with advancing age in both normotensive controls and essential hypertensive patients, suggesting that aging is associated with reduced endothelium-dependent vasodilation in humans (CitationTaddei et al 1995). In normotensive individuals, an earlier primary dysfunction of the NO system and a later production of oxidative stress cause age-related reduction in endothelium-dependent vasodilation. These alterations are similar but anticipated in hypertensive patients compared with normotensive individuals (CitationTaddei et al 2001).

High cholesterol and endothelial dysfunction

Cholesterol is one of the most well established risk factors for premature coronary artery disease (CitationMultiple Risk Factor Intervention Trial Group 1982). Cholesterol levels and coronary artery disease risk show a strong and linear relationship; hypercholesterolemia and high levels of total cholesterol and low-density lipoprotein (LDL) cholesterol result in impaired endothelial function in both peripheral and coronary circulation (CitationCreager et al 1990; CitationCasino et al 1993). Studies concluded that cholesterol levels even in the normal range may be inversely related to endothelium-dependent vasodilation, and this finding has important clinical implications. This suggests that lowering cholesterol levels even when it is within the normal range may improve the production and release of endothelium-dependent NO and hence improve endothelial function (CitationMasumoto et al 2001) (). This idea is supported by recent reports that lowering cholesterol levels enhances endothelium-dependent vasodilation not only in subjects with massively elevated cholesterol levels but also in those with normal cholesterol levels. It is worth noting that lowering of average cholesterol levels in patients with documented coronary artery disease leads to decreased rates of myocardial infarction, and this protective effect may in part be due to improvement in endothelial function (CitationGilligan, Guetta, et al 1994; CitationCasino et al 1995). In addition to lipid-lowering therapy, administration of tetrahydrobiopterin, an essential cofactor for NO production, could restore NO activity in familial hypercholesterolemia (CitationVerhaar et al 1999).

Obesity and endothelial dysfunction

The pathogenesis of vascular disease in obesity remains unclear but probably relates to the effect of the metabolic syndrome (insulin resistance, dyslipidemia, hyperoxidative stress, and hypertension) on the biology of endothelium-derived NO. The notion of increased oxidative stress in central obesity is based on an expansion of the cytosolic triglyceride storage pool in non-adipose tissue (CitationBakker et al 2000). The accumulation of long-chain fatty acyl-coenzyme A esters is hypothesized to inhibit mitochondrial adenosine translocation, with subsequent overproduction of oxygen free radicals such as superoxide. Strong evidence is accumulating that antioxidants may improve insulin resistance and endothelial dysfunction (CitationPaolisso and Giugliano 1996).

We evaluated the association between endothelial function and obesity by angiography in patients (n = 379) with normal or mildly diseased coronary arteries who underwent coronary vascular activity evaluation using intracoronary infusion of acetylcholine. Patients were divided into three groups based on body mass index (BMI): group 1, BMI < 25 (n = 117; normal weight); group 2, BMI 25–30 (n = 149; overweight); and group 3, BMI > 30 (n = 131; obese). Although there were no significant differences between the three groups in regard to other cardiovascular risk factors, the percentage change of coronary blood flow to acetylcholine was significantly lower in the obese patients than in the normal-weight group (85.2% ± 12% in group 1, 63.7% ± 10% in group 2, and 38.1% ± 9.6% in group 3; p = 0.009). Furthermore, by multivariate analysis, overweight and obesity status were independently associated with endothelial dysfunction (CitationAl Suwaidi et al 2001).

Weight loss may improve endothelial function indirectly by improving blood pressure and lipid profile. In a double-blind, placebo-controlled study using orlistat, a lipase inhibitor that prevents fat absorption, and weight loss in 23 patients, CitationBergholm et al (2003) demonstrated that lowering of LDL cholesterol rather than moderate weight loss improved endothelial function. However, further studies are required to confirm these observations.

There are relatively few comparable studies in the literature. Direct measures of the effects of weight loss on endothelial function have been reported to improve endothelium-dependent vasodilation with the use of a very low calorie diet for 2 weeks in obese hypertensive subjects (CitationSasaki et al 2002). Circulating markers of endothelial activation have been reported to be improved in obese subjects after 12 weeks of caloric restriction (800 kcal/day), achieving 9% weight loss (CitationFerri et al 1999), and circulating levels of inflammatory cytokines were similarly reduced in obese women after a 1-year multidisciplinary weight loss program which achieved at least 10% reduction in weight (CitationZiccardi et al 2002). In summary, the available literature suggests beneficial effects of weight loss on a number of axes related to vascular function. Further studies exploring the salient features of the interventions, including the degree of weight loss achieved and the timing of vascular measures in relation to the restoration of a eucaloric diet, are needed to better understand the interactions of obesity and endothelial function.

Smoking and endothelial dysfunction

Cigarette smoking is strongly associated with atherosclerosis and ischemic heart disease but also is a major risk factor for acute coronary thrombosis (CitationChen et al 1995; CitationNjolstad et al 1996). Indeed, 75% of sudden cardiac deaths due to acute thrombosis are in cigarette smokers (CitationBurke et al 1997). Smoking causes endothelial dysfunction, and passive smoking is associated with dose-related impairment of endothelium-dependent dilation in healthy young adults, suggesting early arterial damage (CitationHung et al 1995).

Flow-mediated dilation is significantly impaired in both passive and active smokers when compared with non-smokers. In passive smokers, there is an inverse relationship between the intensity of exposure to tobacco smoke and flow-mediated dilation.

Cigarette smoking is associated with increased platelet thrombus formation. Small areas of denudation and thrombus deposition are a common finding on the surface of atheromatous plaques and are usually subclinical. In the presence of an imbalance in the coagulation or fibrinolytic systems, such microthrombi may propagate, ultimately leading to arterial occlusion (CitationDavies et al 1988; CitationBürrig 1991; CitationCelermajer et al 1996).

Endothelial dysfunction in hyperhomocysteinemia

The nature of the link between homocysteine and cardiovascular disease has not yet been clearly established. Epidemiological studies suggested that even mild elevations of plasma homocysteine are associated with an increased risk of atherosclerosis, including coronary artery disease (CitationBoers et al 1985; CitationClarke et al 1991; CitationStampfer et al 1992). Abnormal metabolism and handling of homocysteine have been demonstrated after a methionine challenge in individuals with premature atherosclerosis, most of whom were heterozygous for cystathionine β-synthase deficiency (CitationClarke et al 1991). Importantly, hyperhomocysteinemia may be a modifiable risk factor for atherosclerosis, as plasma homocysteine levels may be lowered by dietary supplementation with folate and pyridoxine (CitationClarke et al 1991; CitationSelhub et al 1995).

Homocysteine influences multiple vascular responses, including coagulation, platelet function, vascular smooth muscle responses, and endothelial function. Acute infusion of homocysteine has been shown to induce frank endothelial cell damage in primates (CitationHarker et al 1983). Homocysteine alters the production and/or bioactivity of vasoregulatory mediators (CitationQuere et al 1997; CitationZhang et al 1998), including NO, by cultured endothelial cells. Furthermore, homocysteine has been shown to impair endothelium-dependent vasodilation and regulation of blood flow in primates and humans (CitationLentz et al 1996; CitationWoo et al 1997; CitationBellamy et al 1998). The exact mechanisms underlying the beneficial effects of folates on the endothelium remain to be elucidated. Thus far, most studies have focused on the homocysteine-lowering effects of folates; however, more recently the beneficial effects of folate treatment independent of homocysteine lowering have been reported. Potential mechanisms of action include antioxidant actions, effects on cofactor availability, or direct interactions with the enzyme endothelial NO synthase (CitationVerhaar et al 2002).

Endothelial dysfunction as a prominent feature of end-stage renal disease

Recently, several studies demonstrated impairment of (coronary or peripheral, or both) endothelium-dependent vasodilation in patients with moderate renal impairment, as well as in patients with advanced renal impairment treated by hemodialysis (CitationAnnuk et al 2001) or peritoneal dialysis (CitationMiyazaki et al 2000). The reasons for end-stage renal disease patients having signs of endothelial dysfunction are not fully understood but are probably multifactorial. Increased oxidative stress, hyperhomocysteinemia, dyslipidemia, hyperglycemia, hypertension, and retention of L-arginine inhibitors may all be important contributors.

Endothelial dysfunction associated with other diseases

A few scattered articles have described endothelial dysfunction in other diseases, such as pulmonary hypertension (CitationCella et al 2001), hypertrophic cardiomyopathy (CitationDimitrow 2002), multiple organ dysfunction syndrome (CitationAird 2003), acute renal failure (CitationRuschitzka et al 1999), HIV infection (CitationNolan et al 2003), antiphospholipid syndrome (CitationBlum and Simsolo 2004), and hyperprolactinemia (CitationYavuz et al 2003).

Therapy

Endothelial dysfunction is a reversible disorder, and strategies aimed at reducing cardiovascular risk factors, such as cholesterol lowering, antihypertensive therapy, smoking cessation, ACE inhibitor therapy, estrogen replacement therapy in postmenopausal women, supplementation with folic acid, and physical exercise, also translate into an improvement in endothelial health, further supporting the association between risk factors and endothelial dysfunction. Moreover, the observation that several pharmacological interventions that improve endothelial function are associated with a decrease in cardiovascular events independent of risk factor modification supports the concept that cardiovascular risk factors share a common pathway that leads to endothelial dysfunction.

Various forms of therapy have been investigated in medical studies (). The potential benefits associated with L-arginine therapy are presumably mediated by increased NO activity (CitationCreager et al 1992; CitationBoger et al 1998). In addition to improved endothelial function, other changes that have been described include lower plasma endothelin concentrations, increased apoptosis of vascular cells in intimal lesions (leading to regression of atherosclerosis and decreased symptoms), and prevention of the progression of atherosclerotic plaques (CitationRector et al 1996; CitationQuyyumi et al 1997). The endothelium-dependent vasorelaxation with statins results in part from endothelial NO activation. This is independent of the cholesterol-lowering effect of these drugs, although a reduction in oxidized LDL contributes to this response, since oxidized LDL, but not native LDL, down-regulates endothelial NO synthase activity; statins increase the activity of this enzyme independently of lipid lowering. In addition to their effect on NO, statins affect the vasoconstrictor endothelin, further shifting the balance toward vasodilation (CitationO'Driscoll, Green, and Taylor 1997; CitationVita et al 2000).

Fibrate therapy also improves fasting and postprandial endothelial function in patients with type 2 diabetes. The mechanism for this may be an increase in high-density lipoprotein and an attenuation of postprandial lipemia and the associated oxidative stress (CitationEvans et al 2000).

Folate improves endothelial dysfunction by reducing the serum levels of homocysteine. Elevated levels of homocysteine promote endothelial dysfunction by their toxic effects on the endothelium, probably mediated by an increase in oxidative stress and inhibition of NO production (CitationVerhaar et al 1999).

More recently, the HOPE (Heart Outcome Prevention Evaluation) trial assessed the role of an ACE inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure. Ramipril significantly reduced the rate of death, myocardial infarction, and stroke in a broad range of high-risk patients who did not have a low ejection fraction or heart failure, thus suggesting that the use of ACE inhibitors may prevent the progression of initially clinically silent atherosclerosis (CitationDagenais et al 2001).

Even more recently, the insulin sensitizer thiazolidinediones were found to improve endothelial function in diabetic patients (CitationTack et al 1998; CitationPistrosch et al 2004).

Although various interventions have been shown to be associated with improvement in endothelial function, little is currently known about the clinical and prognostic effects of therapeutic improvement in endothelial function. Cholesterol lowering with statins and therapy with ACE inhibitors are also associated with a reduction of myocardial ischemia in patients with coronary artery disease. Moreover, the improvement in coronary endothelial function by L-arginine supplementation has been associated with a reduction in anginal symptoms. Taken together, these findings point out the clinical significance of therapeutic improvement in coronary endothelial function.

Prognostic value of endothelial dysfunction

To date, 14 published studies have examined the value of endothelial dysfunction in prognosis. Five of these assessed coronary endothelial dysfunction and the remainder evaluated brachial endothelial function. Three of these studies were retrospective analyses and the rest were prospective studies (). We retrospectively evaluated the long-term outcome of patients (n = 157) with normal or mildly diseased coronary arteries who underwent coronary vascular reactivity evaluation. Patients were divided into three groups according to their response to intracoronary acetylcholine: a normal endothelial function group, a mild endothelial dysfunction group, and a moderate-to-severe endothelial dysfunction group. We found there were no significant differences between the various groups in regard to traditional cardiovascular risk factors. At a mean follow-up of 28 months, six patients in the moderate-to-severe endothelial dysfunction group developed cardiac events, suggesting that endothelial dysfunction is an independent predictor for the development of cardiac events (CitationAl Suwaidi et al 2000).

Table 2 Studies on the prognostic effect of coronary and peripheral endothelial dysfunction

Since the publication of our findings, several other investigators have reported similar findings in patients with obstructive coronary artery disease and peripheral vascular disease. This seems to show the importance of evaluating the function of endothelial cells as an independent predictor in all patients with or without coronary artery disease in either peripheral or coronary blood vessels.

Future perspectives

The future will witness increasing interest in finding reliable methods of testing endothelial function; several large noninvasive studies are needed to determine the predictive value of brachial ultrasound testing as a potential predictor of cardiovascular disease. As the measures of endothelial dysfunction become clinically applicable, this may translate into improved methods of risk assessment that help in predicting, preventing, and treating cardiovascular disease. Inflammatory markers, such as C-reactive protein, will probably find their way into risk assessment; several therapeutic strategies aimed at improving endothelial function in a variety of cardiovascular disease states are under investigation. The future holds great promise.

References

  • AanderudSKraneHNordoyAInfluence of glucose, insulin and sera from diabetic patients on the prostacyclin synthesis in vitro in cultured human endothelial cellsDiabetologia19852864143905474
  • AirdWCThe role of the endothelium in severe sepsis and multiple organ dysfunction syndromeBlood200310137657712543869
  • Al SuwaidiJHamasakiSHiganoSTLong-term follow-up of patients with mild coronary artery disease and endothelial dysfunctionCirculation20001019485410704159
  • Al SuwaidiJHiganoSTHolmesDRObesity is an independent predictor of coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteriesJ Am Coll Cardiol200137152311345360
  • AndersonTJAssessment and treatment of endothelial dysfunction in humansJ Am Coll Cardiol199934631810483941
  • AndersonTJElsteinEHaberHComparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study)J Am Coll Cardiol20003560610636260
  • AndersonTJGerhardMDMeredithITSystemic nature of endothelial dysfunction in atherosclerosisAm J Cardiol19957571B74B7801869
  • AndersonTJUehataAGerhardMDClose relation of endothelial function in the human coronary and peripheral circulationsJ Am Coll Cardiol1995261235417594037
  • AndrewsNPPrasadAQuyyumiAAN-acetylcysteine improves coronary and peripheral vascular functionJ Am Coll Cardiol2001371172311153725
  • AnnukMLindLLindeTImpaired endothelium-dependent vasodilation in renal failure in humansNephrol Dial Transplant200116302611158404
  • ArbogastBWLeeGMRaymondTLIn vitro injury of porcine aortic endothelial cells by very-low-density lipoproteins from diabetic rat serumDiabetes19823159396819172
  • ArcaroGCrettiABalzanoAInsulin causes endothelial dysfunction in humans: sites and mechanismsCirculation20021055768211827922
  • AvogaroACaloLPiarulliFEffect of acute ketosis on the endothelial function of type 1 diabetic patients: the role of nitric oxideDiabetes199948391710334319
  • BakkerSJIjzermanRGTeerlinkTCytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction and beta-cell failure?Atherosclerosis2000148172110580166
  • BarnesPJKarinMNuclear factor-κ: a pivotal transcription factor in chronic inflammatory diseasesN Engl J Med19973361066719091804
  • BellamyMFMcDowellIFWRamseyMWHyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adultsCirculation1998981848529799203
  • BergerRStanekBHulsmannMEffects of endothelin A receptor A blockade on endothelial function in patients with chronic heart failureCirculation2001103981611181473
  • BergholmRTiikkainenMVehkavaaraSLowering of LDL cholesterol rather than moderate weight loss improves endothelium-dependent vasodilatation in obese women with previous gestational diabetesDiabetes Care20032616677212766091
  • BijlstraPJSmitsPLuttermanJAEffect of long-term angiotensin-converting enzyme inhibition on endothelial function in patients with the insulin-resistance syndromeJ Cardiovasc Pharmacol199525658647596136
  • BlackwellKASorensonJPRichardsonDMMechanisms of aging-induced impairment of endothelium-dependent relaxations – role of tetrahydrobiopterinAm J Physiol Heart Circ Physiol2004287H24485315319209
  • BloomgardenZTEndothelial dysfunction, neuropathy and the diabetic foot, diabetic mastopathy, and erectile dysfunctionDiabetes Care19982118399538990
  • BlumASimsoloCThe antiphospholipid syndrome and endothelial functionIsr Med Assoc J20046556815373316
  • BoersGHSmalsAGTrijbelsFJHeterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial diseaseN Engl J Med1985313709154033695
  • BogatyPHackettDDaviesGVasoreactivity of the culprit lesion in unstable anginaCirculation1994905118026037
  • BogerRHBode-BogerSMSzubaAAsymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemiaCirculation199898184279799202
  • BonettiPOLermanLOLermanAEndothelial dysfunction a marker of atherosclerotic riskArterioscler Thromb Vasc Biol20032316812588755
  • BragulatEde la SierraAAntonioMTEndothelial dysfunction in salt-sensitive essential hypertensionHypertension200137444811230316
  • BrevettiGSilvestroADi GiacomoSEndothelial dysfunction in peripheral arterial disease is related to increase in plasma markers of inflammation and severity of peripheral circulatory impairment but not to classic risk factors and atherosclerotic burdenVasc Surg2003383749
  • BrevettiGSilvestroASchianoVEndothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure indexCirculation20031082093814530195
  • BurkeAPFarbAMalcolmGTCoronary risk factors and plaque morphology in men with coronary artery disease who died suddenlyN Engl J Med19973361276829113930
  • BürrigKFThe endothelium of advanced arteriosclerotic plaques in humansArterioscler Thromb1991111678891657131
  • CaballeroAEAroraSSaouafRMicrovascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetesDiabetes19994818566210480619
  • Calles-EscandonJBallorDHarvey-BerinoJAmelioration of the inhibition of fibrinolysis in elderly, obese subjects by moderate energy intake restrictionAm J Clin Nutr1996647118669417
  • Calles-EscandonJCipollaMDiabetes and endothelial dysfunction: a clinical perspectiveEndocr Rev200122365211159815
  • CardilloCCampiaUKilcoyneCMImproved endothelium-dependent vasodilation after blockade of endothelin receptors in patients with essential hypertensionCirculation2002105452611815427
  • CasinoPRKilcoyneCMCannonROImpaired endothelium-dependent vascular relaxation in patients with hypercholesterolemia extends beyond the muscarinic receptorAm J Cardiol1995754047528464
  • CasinoPRKilcoyneCMQuyyumiAAThe role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patientsCirculation199388254178252665
  • CelermajerDSAdamsMRClarksonPPassive smoking and impaired endothelium-dependent arterial dilatation in healthy young adultsN Engl J Med199633415048531969
  • CelermajerDSSorensenKEGoochVMNoninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosisLancet19923401111151359209
  • CellaGBellottoFTonaFPlasma markers of endothelial dysfunction in pulmonary hypertensionChest200112012263011591565
  • ChambersJCUelandPMObeidOAImproved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteineCirculation200010224798311076820
  • CheethamCCollisJO'DriscollGLosartan, an angiotensin type 1 receptor antagonist, improves endothelial function in noninsulin-dependent diabetesJ Am Coll Cardiol2000361461611079643
  • ChenLChesterMKaskiJCClinical factors and angiographic features associated with premature coronary artery diseaseChest199510836497634868
  • ChouEJKeevilJGAeschlimannSEffect of ingestion of purple grape juice on endothelial function in patients with coronary heart diseaseAm J Cardiol200188553511524068
  • CipollaMJElevated glucose potentiates contraction of isolated rat resistance arteries and augments protein kinase C-induced intracellular calcium releaseMetabolism19994810152210459567
  • ClarkeRDalyLRobinsonKHyperhomocysteinemia: an independent risk factor for vascular diseaseN Engl J Med19913241149552011158
  • ClarkeSCSchofieldPMGraceAATamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosisCirculation2001103149750211257075
  • ClarksonPCelermajerDSDonaldAEImpaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levelsJ Am Coll Cardiol19962857398772741
  • CockcroftJRChowienczykPJBenjaminNPreserved endothelium-dependent vasodilatation in patients with essential hypertensionN Engl J Med1994330108138127338
  • CosentinoFLuscherTFEndothelial dysfunction in diabetes mellitusJ Cardiovasc Pharmacol199832Suppl 3S54619883749
  • CreagerMACookeJPMendelsohnMPImpaired vasodilation of forearm resistance vessels in hypercholesterolemic humansJ Clin Invest199086228342195060
  • CreagerMAGallagherSIGirerdXJL-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humansJ Clin Invest1992901248531401062
  • CushmanMLumaitreRNKullerLHFibrinolytic activation markers predict myocardial infarction in the elderly. The cardiovascular health studyArterioscler Thromb Vasc Biol199919493810073948
  • DagenaisGRYusufSBourassaMGEffects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation StudyCirculation2001104522611479247
  • DaviesMJWoolfNRowlesPMMorphology of the endothelium over atherosclerotic plaques in human coronary arteriesBr Heart J198860459643066389
  • DeanfieldJDonaldAFerriCEndothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of HypertensionJ Hypertens20052371715643116
  • De CatarinaRLibbyPPengHBNitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokinesJ Clin Invest1995966087542286
  • De MattiaGBraviMCLaurentiOReduction of oxidative stress by oral N-acetyl-L-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetesDiabetologia199841139269833950
  • DeSouzaCAShapiroLFClevengerCMRegular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy menCirculation20001021351710993851
  • DimitrowPPCoronary endothelial dysfunction in patients with hypertrophic cardiomyopathyChest2002121137411948083
  • DosquetCWautierMPGuillausseauPJMonokines and endothelial cell proliferation in patients with diabetes mellitusDiabetes Metab1994203742
  • DuffySJKeaneyJFJrHolbrookMShort- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery diseaseCirculation2001104151611447078
  • DupuisJTardifJCCernacekPCholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trialCirculation19999932273310385495
  • ElhaddTAKhanFKirkGInfluence of puberty on endothelial dysfunction and oxidative stress in young patients with type 1 diabetesDiabetes Care199821199069802756
  • ENCORE I StudyEffect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery disease: the ENCORE I Study (Evaluation of Nifedipine and Cerivastatin on Recovery of Coronary Endothelial Function)Circulation2003107422812551866
  • EvansMAndersonRAGrahamJCiprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitusCirculation20001011773910769276
  • FarouqueHMMeredithITThe assessment of endothelial function in humansCoron Artery Dis2001124455411696683
  • FaschingPVeitlMRohacMElevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitusJ Clin Endocrinol Metab1996814313178954033
  • FerriCBelliniCDesideriGCirculating endothelin-1 levels in obese patients with the metabolic syndromeExp Clin Endocrinol Diabetes1997105Suppl 238409288542
  • FerriCDesideriGValentiMEarly up regulation of endothelial adhesion molecules in obese hypertensive menHypertension1999345687310523328
  • FichtlschererSRosenbergerGWalterDHElevated C-reactive protein level and impaired endothelial vasoreactivity in patients with coronary artery diseaseCirculation20001021000610961964
  • FuentesFLopez-MirandaJSanchezEMediterranean and low-fat diets improve endothelial function in hypercholesterolemic menAnn Intern Med200113411151911412051
  • GazisAWhiteDJPageSREffect of oral vitamin E (α-tocopherol) supplementation on vascular endothelial function in type 2 diabetes mellitusDiabet Med1999163041110220204
  • GilliganDMGuettaVPanzaJASelective loss of microvascular endothelial function in human hypercholesterolemiaCirculation19949035418026018
  • GilliganDMQuyyumiAACannonROIIIEffects of physiologic levels of estrogen on coronary vasomotor function in postmenopausal womenCirculation1994892545518205663
  • GokceNKeaneyJFJrHunterLMRisk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective studyCirculation200210515677211927524
  • GokceNKeaneyJFJrHunterLMPredictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular diseaseJ Am Coll Cardiol20034117697512767663
  • GokceNVitsJALoscalzoJSchaferAIThrombosis and hemorrhageClinical manifestation of endothelial dysfunction2002Philadelphia, PALippincott Williams & Wilkins685706
  • GoodfellowJBellamyMFRamseyMWDietary supplementation with marine omega-3 fatty acids improves systemic large artery endothelial function in subjects with hypercholesterolemiaJ Am Coll Cardiol2000352657010676668
  • GuthikondaSSinkeyCBarenzTXanthine oxidase inhibition reverses endothelial dysfunction in heavy smokersCirculation20031074162112551865
  • HalcoxJPSchenkeWHZalosGPrognostic value of coronary vascular endothelial dysfunctionCirculation2002106653812163423
  • HamasakiSAl SuwaidiJHiganoSTAttenuated coronary flow reserve and vascular remodeling in patients with hypertension and left ventricular hyperatrophyJ Am Coll Cardiol20003516546010807473
  • HarkerLAHarlanJMRossREffect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboonsCirc Res19835373196640860
  • HattoriYKasaiKNakamuraTEffect of glucose and insulin on immunoreactive endothelin-1 release from cultured porcine aortic endothelial cellsMetabolism19914016591988773
  • HeitzerTSchlinzigTKrohnKEndothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery diseaseCirculation20011042673811723017
  • Hernandez-PereraOPerez-SalaDNavarro-AntolinJEffects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cellsJ Clin Invest19981012711199637705
  • HornigBLandmesserUKohlerCComparative effect of ACE inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutaseCirculation200110379980511171786
  • HsuehWAAndersonPWHypertension, the endothelial cell, and the vascular complications of diabetes mellitus [clinical conference]Hypertension199220253631639468
  • HungJLamJYTLacosteLCigarette smoking acutely increases platelet thrombus formation in patients with coronary artery disease taking aspirinCirculation199592243267586342
  • HusainSAndrewsNPMulcahyDAspirin improves endothelial dysfunction in atherosclerosisCirculation199897716209498533
  • HuszkaMKaplarMRejtoLThe association of reduced endothelium derived relaxing factor-NO production with endothelial damage and increased in vivo platelet activation in patients with diabetes mellitusThromb Res199786173809175238
  • HuversFCDe LeeuwPWHoubenAJEndothelium-dependent vasodilatation, plasma markers of endothelial function, and adrenergic vasoconstrictor responses in type 1 diabetes under near-normoglycemic conditionsDiabetes1999481300710342820
  • JankaHUPlatelet and endothelial function tests during metformin treatment in diabetes mellitusHorm Metab Res Suppl19851512022934311
  • JohnstoneMTCreagerSJScalesKMImpaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitusCirculation1993882510168080489
  • KaufmannPAGnecchi-RusconeTdi TerlizziMCoronary heart disease in smokers. Vitamin C restores coronary microcirculatory functionCirculation20001021233810982536
  • KinlaySGanzPRole of endothelial dysfunction in coronary artery disease and implications for therapyAm J Cardiol19978011-I16-I9205012
  • KohMSMajewskiBBRhodesELDiabetic serum stimulates the proliferation of endothelial cells in cultureDiabetes Res1985228794075699
  • KubesPSuzukiMGrangerDNNitric oxide: an endogenous modulator of leukocyte adhesionProc Natl Acad Sci U S A199188465151675786
  • LeferAMCampbellBShinY-KSimvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat heartsCirculation19991001788410402448
  • LentzSRSobeyCGPiegorsDJVascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemiaJ Clin Invest1996982498690798
  • LermanABurnettJCJrIntact and altered endothelium in regulation of vasomotionCirculation199286Suppl IIIIII-12III-191424046
  • LibbyPCurrent concepts of the pathogenesis of the acute coronary syndromesCirculation20011043657211457759
  • LibbyPRidkerPMMaseriAInflammation and atherosclerosisCirculation200210511354311877368
  • LissinLWCookeJPPhytoestrogens and cardiovascular healthJ Am Coll Cardiol20003514031010807439
  • LorenziMMontisanoDFToledoSHigh glucose induces DNA damage in cultured human endothelial cellsJ Clin Invest19867732253944257
  • LumHRoebuckKAOxidant stress and endothelial cell dysfunctionAm J Physiol Cell Physiol2001280C7194111245588
  • MakimattilaSVirkamakiAGroopPHChronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitusCirculation1996941276828822980
  • Malamitsi-PuchnerASarandakouATziotisJSerum levels of basic fibroblast growth factor and vascular endothelial growth factor in children and adolescents with type 1 diabetes mellitusPediatr Res19984487359853920
  • ManciniGBJHenryGCMacayaCAngiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing Endothelial Dysfunction) StudyCirculation199694258658759064
  • MasumotoAHirookaYHironagaKEffect of pravastatin on endothelial function in patients with coronary artery disease (cholesterol-independent effect of pravastatin)Am J Cardiol2001881291411728357
  • MatherKJVermaSAndersonTImproved endothelial function with metformin in type 2 diabetes mellitusJ Am Coll Cardiol2001382131211738325
  • McFarlaneRMcCredieRJBonneyMAAngiotensin converting enzyme inhibition and arterial endothelial function in adults with type 1 diabetes mellitusDiabet Med19991662610229295
  • MinaminoTMiyauchiHYoshidaTThe role of vascular cell senescence in atherosclerosis: antisenescence as a novel therapeutic strategy for vascular agingCurr Vasc Pharmacol20042141815320515
  • MiyazakiHMatsukaHItabeHHemodialysis impairs endothelial function via oxidative stress. Effects of vitamin E-coated dialyzerCirculation20001011002610704167
  • ModenaMGBonettiLCoppiFPrognostic role of reversible endothelial dysfunction in hypertensive postmenopausal womenJ Am Coll Cardiol2002405051012142118
  • MullenMJClarksonRDonaldAEEffect of enalapril on endothelial function in young insulin-dependent diabetic patients: a randomized, double blind studyJ Am Coll Cardiol199831133059581728
  • Multiple Risk Factor Intervention Trial GroupMultiple Risk Factor Intervention Trial: risk factor changes and mortality resultsJAMA19822481465777050440
  • MyrupBMathiesenERRonnBEndothelial function and serum lipids in the course of developing microalbuminuria in insulin-dependent diabetes mellitusDiabetes Res1994263397664535
  • NapoliCde NigrisFPalinskiWMultiple roles of reactive oxygen species in the arterial wallJ Cell Biochem2001826748211500945
  • NeriSBrunoCMLeottaCEarly endothelial alterations in non-insulin-dependent diabetes mellitusInt J Clin Lab Res19982810039689551
  • NeunteuflTHeherSKatzenschlagerRLate prognostic value of flow-mediated dilation in the brachial artery of patients with chest painAm J Cardiol2000862071010913483
  • NjolstadIArnesenELund-LarsenPGSmoking, serum lipids, blood pressure, and sex differences in myocardial infarction: a 12-year follow-up of the Finnmark studyCirculation19969345068565161
  • NolanDWattsGFHerrmannSEEndothelial function in HIV-infected patients receiving protease inhibitor therapy: does immune competence affect cardiovascular risk?QJM2003968253214566037
  • NordtTKKlassenKJSchneiderDJAugmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysisArterioscler Thromb199313182288241103
  • O'DriscollGGreenDMaioranaAImprovement in endothelial function by angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitusJ Am Coll Cardiol19993315061110334415
  • O'DriscollGGreenDRankinJImprovement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitusJ Clin Invest1997100678849239416
  • O'DriscollGGreenDTaylorRRSimvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 monthCirculation1997951126319054840
  • PanzaJACasinoPRKilcoyneCMRole of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertensionCirculation1993871468748491001
  • PanzaJACasinoPRKilcoyneCMImpaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor levelJ Am Coll Cardiol1994231610167515084
  • PanzaJAQuyyumiAACallahanTSEffect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertensionJ Am Coll Cardiol1993211145518459069
  • PaolissoGGiuglianoDOxidative stress and insulin action: is there a relationship?Diabetologia199639357638721784
  • PengHBLibbyPLiaoJKInduction and stabilization of IκBα by nitric oxide mediates inhibition of NF-κBJ Biol Chem199527014214197775482
  • PerticoneFCeravoloRPujiaAPrognostic significance of endothelial dysfunction in hypertensive patientsCirculation2001104191611447085
  • PistroschFPassauerJFischerSIn type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose controlDiabetes Care2004274849014747233
  • PrasadATupas-HabibTSchenkeWHAcute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosisCirculation200010123495410821809
  • PrasadAZhuJHalcoxJPPredisposition to atherosclerosis by infections. Role of endothelial dysfunctionCirculation20021061849012105156
  • QuereIHillaire-BuysDBrunschwigJEffects of homocysteine on acetylcholine- and adenosine-induced vasodilation of pancreatic vascular bed in ratsBr J Pharmacol199712235179313946
  • QuyyumiAADakakNDiodatiJGEffect of L-arginine on human coronary endothelium-dependent and physiologic vasodilationJ Am Coll Cardiol199730122079350919
  • Rask-MadsenNIhlemannTKrarupEInsulin therapy improves insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart diseaseDiabetes20015026111811679442
  • RectorTSBankAJMullenKARandomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failureCirculation1996932135418925582
  • RuschitzkaFShawSGygiDEndothelial dysfunction in acute renal failureJ Am Soc Nephrol1999109536210232680
  • RyanMMcInerneyDOwensDDiabetes and the Mediterranean diet: a beneficial effect of oleic acid on insulin sensitivity, adipocyte glucose transport and endothelium-dependent vasoreactivityQJM200093859110700478
  • SalvoliniERabiniRAMartarelliDA study on human umbilical cord endothelial cells: functional modifications induced by plasma from insulin-dependent diabetes mellitus patientsMetabolism199948554710337852
  • SasakiSHigashiYNakagawaKA low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertensionAm J Hypertens200215302911991214
  • SchächingerVBrittenMBZeiherAMPrognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart diseaseCirculation2000101189990610779454
  • SchindlerTHHoringBBuserPTPrognostic value of abnormal vasoreactivity of epicardial coronary arteries to sympathetic stimulation in patients with normal coronary angiogramsArterioscler Thromb Vasc Biol20032349550112615687
  • SelhubJJacquesPFBostomAGAssociation between plasma homocysteine concentrations and extracranial carotid-artery stenosisN Engl J Med1995332286917816063
  • SessoHDGazianoJMBuringJECoffee and tea intake and the risk of myocardial infarctionAm J Epidemiol199914916279921961
  • SkrhaJVackovaIKvasnickaJPlasma-free N-terminal fibronectin 30-kDa domain as a marker of endothelial dysfunction in type 1 diabetes mellitusEur J Clin Invest19902017162112482
  • Skyrme-JonesRAO'BrienRCBerryKLVitamin E supplementation improves endothelial function in type I diabetes mellitus: a randomized, placebo-controlled studyJ Am Coll Cardiol2000369410210898419
  • Skyrme-JonesRAO'BrienRCLuoMEndothelial vasodilator function is related to low-density lipoprotein particle size and lowdensity lipoprotein vitamin E content in type 1 diabetesJ Am Coll Cardiol200035292910676672
  • SorensenKECelermajerDSGeorgakopoulosDImpairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein (a) levelJ Clin Invest1994935058282821
  • StampferMJMalinowMRWillettWCA prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physiciansJAMA1992268877811640615
  • SteinJHCarlssonCMPapcke-BensonKThe effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemiaJ Am Coll Cardiol20013818061311738278
  • SteinbergHOBrechtelGJohnsonAInsulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide releaseJ Clin Invest199494117298083357
  • SteinbergHOChakerHLeamingRObesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistanceJ Clin Invest1996972601108647954
  • StuhlingerMCTsaoPSHerJHHomocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginineCirculation200110425697511714652
  • TackCJOngMKLuttermanJAInsulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazoneDiabetologia199841569769628275
  • TaddeiSMatteiPVirdisAEffect of potassium on vasodilation to acetylcholine in essential hypertensionHypertension199423485908144217
  • TaddeiSVirdisAGhiadoniLAge-related reduction of NO availability and oxidative stress in humansHypertension200138274911509489
  • TaddeiSVirdisAMatteiPVasodilation to acetylcholine in primary and secondary forms of human hypertensionHypertension1993216 Pt 2929338505103
  • TaddeiSVirdisAMatteiPAging and endothelial function in normotensive subjects and patients with essential hypertensionCirculation199591198177895356
  • TaoJJinYFYangZReduced arterial elasticity is associated with endothelial dysfunction in persons of advancing age: comparative study of noninvasive pulse wave analysis and laser Doppler blood flow measurementAm J Hypertens200417654915288882
  • TeragawaHKatoMKurokawaJKEndothelial dysfunction is an independent factor responsible for vasospastic anginaClin Sci (Lond)20011017071311724660
  • ThogersenAMJanssonJBomanKHigh plasminogen activator inhibitor and tissue plasminogen activator level in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factorCirculation199898224179826309
  • ThompsonLPPinkasGWeinerCPChronic 17 beta-estradiol replacement increases nitric oxide-mediated vasodilation of guinea pig coronary microcirculationCirculation20001024455110908218
  • ThorneSMullenMJClarksonPEarly endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginineJ Am Coll Cardiol199832110159669257
  • TingHHTimimiFKHaleyEAVitamin C improves endothelium dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemiaCirculation1997952617229193429
  • VehkavaaraSYki-JarvinenH3.5 years of insulin therapy with insulin glargine improves in vivo endothelial function in type 2 diabetesArterioscler Thromb Vasc Biol2001243253014684428
  • VenkovCDRankinABVaughanDEIdentification of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial functionCirculation199694727338772695
  • VerhaarMCStroesERabelinkTJFolates and cardiovascular diseaseArterioscler Thromb Vasc Biol20022261311788454
  • VerhaarMCWeverRMFKasteleinJJPEffects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia: a randomized placebo-controlled trialCirculation1999100335810421591
  • VitaJAYeungACWinnifordMEffect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery diseaseCirculation20001028465110952951
  • WakatsukiAOkataniYIkenoueNEffect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogenCirculation20011041773811591613
  • WalkerHADeanTSSandersTAThe phytoestrogen genistein produces acute nitric oxide-dependent dilation of human forearm vasculature with similar potency to 17β-estradiolCirculation20011032586211208686
  • WangBYHoHKLinPSRegression of atherosclerosis: role of nitric oxide and apoptosisCirculation19999912364110069793
  • WassmannSLaufsUStamenkovicDRaloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide productionCirculation200210520839111980689
  • WattsGFPlayfordDADyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: a hypothesisAtherosclerosis199814117309863535
  • WebbCMGhateiMAMcNeillJG17 beta-estradiol decreases endothelin-1 levels in the coronary circulation of postmenopausal women with coronary artery diseaseCirculation200010216172211015337
  • WebbCMMcNeillJGHaywardCSEffects of testosterone on coronary vasomotor regulation in men with coronary heart diseaseCirculation19991001690610525487
  • WooKSChookPLolinYIHyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humansCirculation199796254249355891
  • XiangGDHeYSDaiXJAngiotensin-converting enzyme gene and the brachial artery endothelial dysfunction in type 2 diabetes without angiopathyZhonghua Yi Xue Yi Chuan Xue Za Zhi200421355915300633
  • YaqoobMPatrickAWMcClellandPRelationship between markers of endothelial dysfunction, oxidant injury and tubular damage in patients with insulin-dependent diabetes mellitusClin Sci (Colch)199385557628287643
  • YatacoARCorrettiMCGardnerAWEndothelial reactivity and cardiac risk factors in older patients with peripheral arterial diseaseAm J Cardiol199983754810080432
  • YavuzDDeyneliOAkpinarIEndothelial function, insulin sensitivity and inflammatory markers in hyperprolactinemic premenopausal womenEur J Endocrinol20031491879312943520
  • YokoyamaIMomomuraS-IOhtakeTImprovement of impaired myocardial vasodilatation due to diffuse coronary atherosclerosis in hypercholesterolemics after lipid-lowering therapyCirculation19991001172210402439
  • YoshidaMImaizumiTAndoSImpaired forearm vasodilatation by acetylcholine in patients with hypertensionHeart Vessels19916218231800481
  • ZhangFSlungaardAVercellottiGMSuperoxide-dependent cerebrovascular effects of homocysteineAm J Physiol1998274R1704119608025
  • ZiccardiPNappoFGiuglianoGReduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one yearCirculation2002105804911854119