Number 22, 2004
Endothelial Dysfunction

Clinical expression of endothelial dysfunction

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Winston Dunn, Amir Lerman, Vijay Shah
Departments of Medicine and Physiology, Mayo Clinic and Foundation, Rochester, Minnesota, USA
Correspondence: Dr Vijay Shah, GI Research Unit, Alfred 2-435, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA.
Tel: +1 (507) 2555040, fax: +1 (507) 2556318, e-mail:shah.vijay@mayo.edu

Introduction
The endothelium functions to regulate vascular tone by releasing endothelium-derived relaxing (EDRF) and contracting factors. One key relaxing factor is nitric oxide, a free radical signaling gas that promotes vasodilatation, inhibits platelet aggregation, and may thereby inhibit the development of atherosclerosis and arterial thrombosis. Endothelial dysfunction can be readily measured by failure of the endothelium to promote vasodilatation through nitric oxide.
Cardiovascular risk factors commonly lead to a cascade of events that impair endothelial function. Therefore, endothelial dysfunction serves as an integrated index of damage caused by cardiovascular risk factors. Multivariate analysis has shown that it is in fact a composite risk score of conventional risk factors [1,2].
This review will highlight the relevance of endothelial dysfunction to a number of vascular syndromes.

Measuring coronary endothelial dysfunction
The testing of coronary endothelial dysfunction was described by Ludmer et al in 1986 [3]. Acetylcholine is infused into the left anterior descending artery. The coronary artery diameter can be measured with quantitative coronary angiography, and coronary blood flow can be measured with intracoronary flow Doppler. Endothelium-independent responses are induced by administration of nitroglycerin, which directly promotes vasodilatation by acting on smooth muscles. Endothelium-dependent responses are induced by acetylcholine, which promotes the release of nitric oxide from the endothelium, thereby promoting smooth muscle relaxation; this vasodilatation is therefore said to be endothelium-dependent. Without a functional endothelium, acetylcholine causes vasoconstriction in vascular smooth muscle. Thus, with a functional endothelium, administration of acetylcholine results in vasodilatation and an increase in coronary blood flow, whereas with endothelial dysfunction the acetylcholine-mediated vasodilatation and increase in coronary blood flow are attenuated.

Clinical application in coronary artery disease
Since Ludmer's description of the technique, the findings of several studies [410] have supported the concept that measurement of coronary endothelial dysfunction may provide a prognosticator for coronary artery disease (Table I). Al Suwaidi et al [4] conducted a 24-month follow-up study of patients with mild coronary artery disease. The study population consisted of 157 patients with angiographically identified coronary artery lesions, less than 40% stenosis, and no evidence of coronary spasm. Patients were divided into three groups: normal endothelial function, mild endothelial dysfunction, and severe endothelial dysfunction. Interestingly, the distribution of cardiovascular risk factors (eg, age, sex, diabetes mellitus, hypertension, hypercholesterolemia, smoking) was similar between the three groups. Noninvasive studies, including treadmill exercise testing, exercise thallium, and exercise echo cardiograms, were also similar with respect to the prevalence of positive results. Quantitative coronary ultrasound revealed similar prevalences of plaque. During 28 months of follow-up, only patients in the severe endothelial dysfunction group developed cardiac events [4]. Schchinger et al [5] conducted a 7.7-year follow-up study in 147 patients with angiographic evidence of coronary artery disease, and reported similar results. Hasdai et al [11] have also shown that severe coronary endothelial dysfunction is associated with myocardial perfusion defects. Halcox et al [6] generalized the patient population to include those with normal coronary arteries. In their study of 308 patients undergoing coronary catheterization, 132 had coronary artery disease identified by angiography, whereas 176 patients had angiographically normal coronary arteries. These patients were followed for 46 months for cardiovascular events. Although regression analysis showed no significant interaction between coronary artery disease and coronary endothelial dysfunction, in multivariate analysis coronary endothelial function, age, coronary artery disease, and body mass index were all independent risk factors for cardiovascular events [6]. These studies suggest that severe endothelial dysfunction is an independent risk factor for cardiac events in patients with nonobstructive coronary artery disease.

Table I. Clinical studies assessing endothelial dysfunction in vascular disease.

In the Mayo Clinic, more than 700 measurements of coronary endothelial function have been made since 1992. The indication for making these measurements is the finding of a normal coronary artery by angiogram in patients who exhibit symptoms of angina: endothelial dysfunction is found in a significant percentage of these individuals. Normal and abnormal tracings of intracoronary Doppler flow velocity in response to adenosine, obtained for the evaluation of coronary flow reserve, are shown in Figure 1.

Measuring forearm flow mediated vasodilatation
Despite its prognostic value, measurement of coronary endothelial function is very invasive. In the 1990s, less invasive ultrasonographic measurement of brachial artery endothelial function was developed, in line with evidence that endothelial dysfunction in peripheral vessels correlates well with that in the coronary artery [12,13]. An ultrasound system with two-dimensional imaging, color and spectral Doppler, internal electrocardiographic monitoring, and high frequency vascular tranducer are needed for the measurement. After a baseline resting image and blood flow have been recorded, a blood pressure cuff is placed either above the antecubital fossa or on the forearm and inflated to at least 50mm above the systolic blood pressure, to occlude the blood vessel. The occlusion causes vasodilatation of the downstream resistance vessel. After deflation of the cuff, there is a transient high flow state (reactive hyperemia). At the brachial artery level, the endothelium responds to an increase in blood flow, as sensed by increased shear stress, by releasing nitric oxide, and subsequently results in vasodilatation. This endothelium-dependent phenomenon is known as flow-mediated vasodilatation. An ultrasound image of the brachial artery is recorded from 30 seconds before to 2 minutes after deflation of the cuff. The flow-mediated vasodilatation is reported as either absolute change or percentage change in diameter. Despite its utility, this method has technical and interpretive limitations. For details, refer to the American College of Cardiology guidelines [14].
The prognostic indications of forearm endothelial function quickly expanded. Neunteufl et al [7] showed that a reduced brachial artery flow-mediated vasodilatation response to reactive hyperemia (less than 10% increase) in patients with angina is correlated with increased death, myocardial infarction, or a need for revascularization. Heitzer et al [8] showed that a reduced brachial artery blood flow response to adrenocorticotrophic hormone in patients with coronary artery disease diagnosed by angiogram was associated with increased death, myocardial infarction, need for revascularization, and ischemic stroke. Thus, assessment of forearm endothelial dysfunction may allow for expansion of the utilization of endothelial dysfunction.

Clinical applications of measurement of endothelial dysfunction

Clinical application in hypertension
In patients with hypertension, endothelial dysfunction is a predictor of adverse outcome. Perticone et al [9] conducted a 31.5-month follow-up study in 225 never-treated patients with hypertension. Patients were stratified into three groups on the basis of their percentage increase in forearm blood flow from basal: group 1, 30184%; group 2, 185333%; group 3, 339760%. In group 1, the relative risk for cardiovascular events was 2.084 times that of group 3 (P=0.0049). In multivariate analysis, the only independent predictors of cardiovascular events were mean 24-hour ambulatory blood pressure and the peak percent increase in forearm blood flow. Thus, measuring endothelial function may allow clinicians to identify a subgroup of patients at greatest risk, in whom aggressive treatment is warranted.
Endothelial dysfunction may be used to identify normotensive people who have a genetic predisposition to cardiovascular disease. Normotensive individuals with a family history of hypertension have a significantly depressed forearm endothelial function index, calculated as the ratio between endothelium-dependent and endothelium-independent vasodilatation. Likewise, healthy individuals reporting at least one parent suffering from myocardial infarction showed a significantly lower EDV than individuals without such a family history. A prospective follow-up study will be necessary to determine whether endothelial dysfunction in normal individuals is indeed predictive of future hypertension and myocardial infarction [15].

Clinical application in congestive heart failure
Congestive heart failure is also related to endothelial dysfunction. The relationship of disease severity to the level of endothelial dysfunction was investigated by Bank et al [16], who found that endothelial dysfunction measured by the forearm blood flow response to methacholine was present and near maximum in mild congestive heart failure. Thus endothelial dysfunction per se, rather than disease severity index, may serve as an early disease marker in congestive heart failure. Another finding by Bank et al [16] was that both endothelium-dependent and endothelium-independent vasodilatation were impaired in congestive heart failure. The same finding was reported by Maguire et al [17] and Negrao et al [18], suggesting that both endothelium and smooth muscle are dysfunctional in congestive heart failure.

Clinical application in hypercholesterolemia and obesity
Data from the early 1990s had shown that endothelium-dependent vasodilatation is impaired in patients with hypercholesterolemia [1921]. More recent studies have shown that hypertriglyceridemia further impairs endothelial function in patients with and without hypercholesterolemia [22,23]. In contrast, an increased high-density lipoprotein concentration in patients with hypercholesterolemia improves endothelial function [24]. Obesity also adversely affects endothelial function in normotensive and hypertensive patients, suggesting that obesity is an independent risk factor for endothelial dysfunction [25].

Clinical application in noncardiologic conditions such as portal hypertension and cirrhosis
The concept of endothelial dysfunction has been a focus of clinical research not only in cardiology but also in noncardiologic conditions. For example, cirrhosis of the liver is often accompanied by the morbid complication of portal hypertension. A component of portal hypertension occurs through endothelial dysfunction and subsequent vasoconstriction within the hepatic sinusoids, and this may represent a target for treatment of portal hypertension in humans through approaches that aim to supplement the generation of nitric oxide in the liver [26].

Marker for therapeutic response and implication for future studies
Improvement in endothelial function has been used as a surrogate marker of therapeutic response. Studies have shown that it can be achieved through exercise in patients with coronary artery disease [27], congestive heart failure [28], and type 2 diabetes mellitus [29], although the effect obtained through exercise in healthy individuals remains controversial [30]. Conversely, smoking [31] and high-fat meals [32] adversely affect endothelial function. In common with measurement of weight, blood pressure, and cholesterol, measurement of endothelial function can perhaps be used as a feedback to encourage and monitor therapeutic lifestyle change.
Analysis of endothelial function is now a frequent end point of research studies. A study that measures endothelial dysfunction, a surrogate marker of cardiovascular events, does not have as much power as a study that uses cardiovascular events as an end point. However, a study that measures endothelial dysfunction can be reasonably accomplished in a few months, whereas one that uses cardiovascular events as an end point will usually take years. Thus analysis of endothelial dysfunction has both clinical and research utility.

Conclusion
Studies have shown that endothelial dysfunction may be a predictor of cardiovascular events. It can be measured in the coronary artery and brachial artery, and the results are closely correlated with each other. The relevant study population includes those with coronary artery disease, hyperlipidemia, hypertension, and obesity, and healthy individuals. Future expansion of the practise of clinical measurement of endothelial dysfunction in humans will be determined by continued studies aimed at establishing its clinical utility, and by continued technical advances aimed at improving its ease of use and applicability.

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REFERENCES

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