Curriculum in cardiology
Detection of endothelial dysfunction with brachial artery ultrasound scanning

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Abstract

The role of the endothelium in human disease recently has become the focus of intense scientific investigation. Impaired endothelial function is associated with a number of disease states, including cardiovascular disease (CVD) and its major risk factors. Endothelial dysfunction precedes overt vascular disease by years and may itself be a potentially modifiable CVD risk factor. Although no gold standard for the measurement of endothelial function exists, the measurement of flow-mediated dilation (FMD) in the brachial artery, assessed with Doppler ultrasonography, is the most studied method and shows the most promise for clinical application. It is a well-tolerated, noninvasive, and low-risk procedure. Brachial artery FMD after transient vascular occlusion may serve as an index of nitric oxide bioavailability, and its impairment correlates with coronary arterial abnormalities. These factors, with the wide availability of vascular ultrasound scanning in clinical practice, make brachial artery FMD an attractive screening tool for endothelial dysfunction. Present limitations of this procedure include the lack of a consensus definition of normal FMD and the variability among centers in both procedural technique and image analysis. However, these limitations are likely to be overcome with increasing experience and advances in technology, and with further refinements, the measurement of brachial artery FMD will likely become the clinical technique of choice for the evaluation of endothelial disease.

Section snippets

Normal endothelium

The vascular endothelium is a monolayer of highly specialized cells that regulates the complex vascular milieu, acting as both a barrier to and facilitator of interactions between the plasma and the vessel. The endothelium accomplishes this goal through the expression of diverse molecules in response to a variety of mechanical and chemical stimuli (Table I). Of these factors, nitric oxide (NO) is essential. NO is produced by the endothelium from L-arginine via a constitutive form of nitric

Endothelial dysfunction

Normal arterial function depends on the complex interplay between endothelium-derived molecules and the vascular milieu. Endothelial dysfunction refers to altered vasoactive, anticoagulant, and anti-inflammatory properties, and dysregulated vascular growth remodeling that results from a loss of NO bioactivity in the endothelium. A reduction in NO activity may be caused by 1) decreased eNOS expression (decreased transcription and/or message stability); 2) insufficient substrate (L-arginine) or

Clinical implications of endothelial dysfunction

Increased NO degradation by ROS and impaired EDV is associated with established cardiovascular risk factors, including hyperlipidemia, cigarette smoking, diabetes mellitus, and hypertension, and an increasing number of diseases (Table II). 11 Importantly, endothelial dysfunction in peripheral arteries correlates with the presence of coronary artery endothelial dysfunction12, 13 and angiographically proven coronary artery disease (CAD).12, 14 In addition, patients with coronary endothelial

Assessment of endothelial function

Endothelial function has been assessed in the literature with a variety of invasive and noninvasive surrogate assays (Table III). Elevation of serum markers (eg, adhesion molecules, selectins, C-reactive protein) has been associated with endothelial dysfunction and its risk factors, but distinguishing between endothelial stimulation and endothelial damage is difficult.6 In addition, assays measuring NO activity in plasma and urine exist, but are heavily affected by dietary habits.16 As a

Brachial artery flow-mediated vasodilation

The measurement of brachial artery flow-mediated vasodilation (FMD) was first described by Anderson and Mark in 198920 and began to see clinical research application in the early 1990s.2 Blood flow through the brachial artery is increased in response to transient hyperemia, which is provoked by inducing postischemic dilation of distal vascular beds. Ischemia is induced by the inflation of an arterial occlusion cuff, positioned on the proximal or mid-forearm. After cuff deflation, brachial

Clinical value of brachial artery flow-mediated vasodilation

Several lines of data suggest that brachial artery FMD may soon have a role beyond the research laboratory. First, brachial artery FMD appears to be a suitable surrogate for coronary arterial reactivity.26 Takase et al13 compared brachial artery FMD to coronary endothelial dysfunction measured angiographically after adenosine triphosphate infusion in 15 patients with suspected CAD. There was a strong correlation between abnormal coronary and brachial FMD (r = 0.78, P < .001), implying that

Limitations of brachial artery FMD

Although the measurement of brachial artery FMD is a noninvasive index of endothelial function with an established relationship to CAD (and its risk factors) and is associated with a panoply of clinical entities, technique- and patient-related limitations and the lack of a “gold-standard” test for endothelial function presently preclude its widespread use as a clinical screening tool.

Technically, measurement of brachial artery diameter can be difficult. Vessel sizes are generally in the 3 to 5

Ongoing studies

Several ongoing clinical trials may help define a clinical application for brachial artery ultrasound scanning. Brachial artery FMD is measured in the Cardiovascular Health Study (CHS), a National Heart, Lung, and Blood Institute study of cardiovascular risk involving >5000 subjects. The subjects in this study, which should be completed in 2005, are being prospectively observed for coronary events. The Multi-ethnic Studies of Atherosclerosis (MESA) trial, which started in 1999, is another

Conclusion

The endothelium is a complex organ that serves as the final common target for a variety of pathophysiologic mechanisms related to CVD. Endothelial dysfunction precedes overt clinical disease, making the endothelium an attractive target for early, preventative pharmacotherapy. Although improvement of endothelial dysfunction has not been shown to result in clinical benefit, prospective trials with firm clinical end points have yet to be performed, in part because of the lack of an accurate,

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