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      Adjusting Flow-Mediated Dilation for Shear Stress Stimulus Allows Demonstration of Endothelial Dysfunction in a Population with Moderate Cardiovascular Risk

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          Background/Aims: Although normalization of brachial artery flow-mediated dilation (FMD) to individual shear stress (FMD:shear stress ratio) has been proposed to improve this measure of endothelial function, the clinical utility of FMD normalization has not yet been demonstrated. We tested (1) whether following conventional 5-min forearm occlusion, the FMD:shear stress ratio would discriminate a population with moderate cardiovascular risk (MR) from a low-risk (LR) population, and (2) whether the dose-response profile relating shear stress to FMD would be different between the 2 populations. Methods: Five different magnitudes of reactive hyperemia-induced shear stress were applied to 20 MR and 20 LR subjects by manipulating forearm cuff occlusion duration. Brachial artery diameters and velocities were measured via high-resolution ultrasound. To quantify the hyperemic stimulus, shear stress area under the curve was individually calculated for the duration of time-to-peak dilation. Results: Following 5-min of forearm occlusion, FMD:shear stress ratio (p = 0.041), but not FMD (p = 0.286), discriminated MR from LR. The slope of the shear stress-FMD regression line was lower in MR compared to the LR (p <0.001). Conclusion: The FMD:shear stress ratio distinguished reduced endothelial function in a population with MR. The dose-response profile of the shear stress-FMD relationship appears to differ between populations of distinct cardiovascular risk.

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          Most cited references 24

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          Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery

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            The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function.

            Endothelium-dependent flow-mediated dilatation (FMD) describes the vasodilatory response of a vessel to elevations in blood flow-associated shear stress. Nitric oxide (NO), one of many vasoactive substances released by the endothelium in response to shear stress, is of particular interest to researchers as it is an antiatherogenic molecule, and a reduction in its bioavailability may play a role in the pathogenesis of vascular disease. The goal of many human studies is to create a shear stress stimulus that produces an NO-dependent response in order to use the FMD measurements as an assay of NO bioavailability. The most common non-invasive technique is the 'reactive hyperaemia test' which produces a large, transient shear stress profile and a corresponding FMD. Importantly, not all FMD is NO mediated and the stimulus creation technique is a critical determinant of NO dependence. The purpose of this review is to (1) explain that the mechanisms of FMD depend on the nature of the shear stress stimulus (stimulus response specificity), (2) provide an update to the current guidelines for FMD assessment, and (3) summarize the issues that surround the clinical utility of measuring both NO- and non-NO-mediated FMD. Future research should include (1) the identification and partitioning of mechanisms responsible for FMD in response to various shear stress profiles, (2) investigation of stimulus response specificity in coronary arteries, and (3) investigation of non-NO FMD mechanisms and their connection to the development of vascular disease and occurrence of cardiovascular events.
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              Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension.

              Endothelial dysfunction in the setting of cardiovascular risk factors such as hypercholesterolemia, diabetes mellitus, chronic smoking, as well hypertension, is, at least in part, dependent of the production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO). ROS-producing enzymes involved in increased oxidative stress within vascular tissue include NADPH oxidase, xanthine oxidase, and mitochondrial superoxide producing enzymes. Superoxide produced by the NADPH oxidase may react with NO, thereby stimulating the production of the NO/superoxide reaction product peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, therefore switching an antiatherosclerotic NO producing enzyme to an enzyme that may accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and also occurs within the smooth muscle cell layer. Increased superoxide production has important consequences with respect to signaling by the soluble guanylate cyclase and the cGMP-dependent kinase I, which activity and expression is regulated in a redox-sensitive fashion. The present review will summarize current concepts concerning eNOS uncoupling, with special focus on the role of tetrahydrobiopterin in mediating eNOS uncoupling.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2009
                30 June 2009
                : 46
                : 6
                : 592-600
                aKinesiology and bApplied Health Science, Indiana University, Bloomington, Ind., cHealth and Kinesiology, Purdue University, West Lafayette, Ind., and dMedicine, Indiana University, Indianapolis, Ind., USA
                226227 J Vasc Res 2009;46:592–600
                © 2009 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 2, References: 34, Pages: 9
                Research Paper


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