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POINT-COUNTERPOINT

Point: Flow-mediated dilation does reflect nitric oxide-mediated endothelial function

School of Human Movement and Exercise Science
The University of Western Australia

Before you embark on this debate with my redoubtable Canadian friends, you may find it advisable to take something to minimize your cardiovascular risk. I recommend the sensible precaution of a bottle of excellent Australian Shiraz. Pour yourself a generous measure and take a few sips.

Now, if your glass appears half full, you might agree that the abundance of flow-mediated dilatation (FMD) studies in the cardiovascular literature in the past decade is attributable to the seductive idea that it provides a functional bioassay for in vivo endothelium-derived nitric oxide (NO) bioactivity in humans. Impaired NO-mediated endothelial function has gained acceptance as a sentinel atherogenic event (4, 11, 21), so a simple and cheap noninvasive marker of NO "dys"-function may provide a "barometer" of cardiovascular disease risk, which could be used to predict individuals at highest risk of future cardiovascular events (2, 27, 30) or those with less stable advanced lesions (4). It might also be possible to optimize medication and risk factor advice to target directly measured vascular health, rather than surrogates such as blood pressure, lipid levels, or inflammatory markers. Risk reduction is, after all, ultimately dependent on changes in the artery wall and a direct measure of arterial "fitness" would provide a powerful tool. Of course, if your glass seems half empty, it is possible that every physician and scientist with access to an ultrasound machine and a delusion of grandeur is riding the latest research bandwagon. So is the mercury rising or falling on the FMD technique and, crucially, is it NO dependent?

It is true that when Celermajer and colleagues (6) introduced the idea of using cuff occlusion to examine endothelial function by inducing arterial shear stress in 1992, important assumptions were made. It was known at the time that human conduit arteries dilated in response to increased blood flow (1, 18, 23, 24), that in animals this response was dependent on an intact endothelium (20, 25), that shear stress-sensitive ion channels existed in endothelial cells (7, 14, 19), that the physiological stimulus to NO [endothelium-derived relaxing factor (EDRF) at that time] production in animals was shear stress (22) and that infusion of NO antagonists [e.g., N^G-monomethyl-L-arginine (L-NMMA)] decreased FMD in situ (8, 12). Vallance et al. (26) had also established that NO was released basally in humans and in response to pharmacological stimulation. From these atmospherics, it was inferred that the dilator response after cuff deflation was likely to be endothelium dependent and probably NO (EDRF) mediated. Thus, although physiological studies demonstrating NO dependency of the FMD technique had not been performed in humans before the introduction and adoption of the technique, it was a clever idea predicated on sound indicative evidence.

Joannides and colleagues (13) published the first study involving L-NMMA infusion to block NO production after cuff occlusion in humans. They imaged the radial artery for diameter and flow at rest and after 3 min of ischemia induced by a wrist cuff placed distal to the ultrasound probe. L-NMMA, infused into the brachial artery upstream, converted the radial artery FMD response (3.6%) to a constriction (–2.8%). This abolition of FMD by NO blockade occurred in the absence of changes in peak radial artery flow, although L-NMMA decreased the duration of hyperemia, raising the possibility of a confounding nonspecific vasoconstrictor-mediated decrease in radial artery shear stress. This possibility was subsequently ruled out by Lieberman et al. (15), who studied the effect of upper arm cuff occlusion (5 min) on brachial artery FMD in the presence of L-NMMA infused above the ultrasound probe. L-NMMA decreased brachial artery FMD from 21 to 7%, indicating a potent effect of NO inhibition on FMD. Importantly, these investigators also measured the effect of a NO-independent vasoconstrictor (phenylephrine) on FMD. Despite having an equipotent effect on reactive hyperemic forearm blood flow as L-NMMA, phenylephrine did not alter brachial artery FMD, confirming the NO dependence of the FMD response. This study reported relatively high FMD data (21%), possibly due to scanning of the artery below the antecubital fossa, where it is smaller, and the fact that the scanned artery was within the ischemic territory (vide infra). Nonetheless, the authors provided strong evidence that FMD is an endothelium-dependent process, mediated by NO.

In 2001, Doshi et al. (10) specifically investigated the issue of cuff placement on NO dependency of the FMD response. A 5-min cuff occlusion at the wrist, distal to the ultrasound probe placed on the brachial artery, was associated with an 7% FMD response that was abolished (0.14%) by L-NMMA infusion. In response to 5 min of occlusion induced by a cuff placed on the arm above the ultrasound probe, the 12% FMD response was only partially decreased by L-NMMA (7.5%). These data therefore suggested that, whereas NO contributed to FMD under both protocols, placement of the cuff was important; dilation of arteries that have been within the ischemic territory is affected by dilators other than NO and may also be complicated by myogenic responses as a result of the pressure fall inside the artery during occlusion. This important study has resulted in general acceptance of the principle that FMD studies should involve cuff occlusion below the antecubital fossa, with proximal brachial artery imaging.

A final study that deserves mention is that by Mullen et al. (17), which used clever experimental approaches to determine whether characteristics of the flow stimulus modified the mechanisms involved in conduit artery dilatation. Brachial artery infusion of L-NMMA decreased the radial artery diameter response to 5 min of distal wrist cuff occlusion from 5.3 to 0.7%. The L-NMMA infusion had no effect on either the peak or prolonged flow response after cuff deflation. Conversely, after 15 min of wrist cuff inflation, FMD was 9.6% but L-NMMA had no impact on radial artery dilation (9.6 vs. 9.5%). It was also demonstrated that gradual and stepwise increases in blood velocity through the radial artery, induced by stimuli such as hand warming, substantially increased proximal radial artery diameter in a manner that was not L-NMMA sensitive. These elegant physiological studies indicated that different shear stress stimuli, including different periods of ischemia, induce conduit artery dilation that is dependent on different vasodilator mechanisms. Importantly though, it provided further evidence that the widely used FMD approach in humans (9), involving response to a 5-min occlusion induced by a cuff placed downstream from the imaged artery, is almost entirely abolished by L-NMMA and this is not due to a nonspecific vasoconstrictor effect of L-NMMA.

In 2002, an important collaborative guideline was published aimed at standardizing technical approaches to the increasingly popular FMD method (9). The studies detailed above reinforce these guidelines and the use of FMD in humans because they indicate that in response to a period of 5 min of cuff occlusion in the upper limb, where the cuff is placed below the imaging site, FMD is essentially abolished by NO blockade. Under these circumstances, there can be little argument that FMD does reflect NO-mediated endothelial function in humans. It is therefore entirely consistent that FMD measured in this way is impaired by traditional atherosclerotic risk factors (4, 5, 17, 18), predicts future cardiovascular events (3, 30), and is improved by cardioprotective interventions (16, 28), including, for instance, the consumption of wine (29). Cheers!

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