BackgroundNormalization of brachial artery flow-mediated dilation (FMD) to individual shear stress area under the curve (peak FMD:SSAUC ratio) has recently been proposed as an approach to control for the large inter-subject variability in reactive hyperemia-induced shear stress; however, the adoption of this approach among researchers has been slow. The present study was designed to further examine the efficacy of FMD normalization to shear stress in reducing measurement variability.MethodsFive different magnitudes of reactive hyperemia-induced shear stress were applied to 20 healthy, physically active young adults (25.3 ± 0. 6 yrs; 10 men, 10 women) by manipulating forearm cuff occlusion duration: 1, 2, 3, 4, and 5 min, in a randomized order. A venous blood draw was performed for determination of baseline whole blood viscosity and hematocrit. The magnitude of occlusion-induced forearm ischemia was quantified by dual-wavelength near-infrared spectrometry (NIRS). Brachial artery diameters and velocities were obtained via high-resolution ultrasound. The SSAUC was individually calculated for the duration of time-to-peak dilation.ResultsOne-way repeated measures ANOVA demonstrated distinct magnitudes of occlusion-induced ischemia (volume and peak), hyperemic shear stress, and peak FMD responses (all p < 0.0001) across forearm occlusion durations. Differences in peak FMD were abolished when normalizing FMD to SSAUC (p = 0.785).ConclusionOur data confirm that normalization of FMD to SSAUC eliminates the influences of variable shear stress and solidifies the utility of FMD:SSAUC ratio as an index of endothelial function.

This study supports the hypothesis that RPE increases similarly in relation to relative distance, regardless of the distance performed, and it suggests that the perception of effort has scalar properties.

The endothelium plays an integral role in the development and progression of atherosclerosis. Hemodynamic forces, particularly shear stress, have a powerful influence on endothelial phenotype and function; however, there is no clear consensus on how endothelial cells sense shear. Nevertheless, multiple endothelial cell signal transduction pathways are activated when exposed to shear stress in vitro. The type of shear, laminar or oscillatory, impacts which signal transduction pathways are initiated as well as which subsequent genes are up- or down-regulated, thereby influencing endothelial phenotype and function. Recently, human studies have examined the impact of shear stress and different shear patterns at rest and during exercise on endothelial function. Current evidence supports the theory that augmented exercise-induced shear stress contributes to improved endothelial function following acute exercise and exercise training, whereas retrograde shear initiates vascular dysfunction. The purpose of this review is to examine the current theories on how endothelial cells sense shear stress, to provide an overview on shear stress-induced signal transduction pathways and subsequent gene expression, and to review the current literature pertaining to shear stress and shear patterns at rest as well as during exercise in humans and the related effects on endothelial function.

Atherosclerotic cardiovascular disease (CVD) was proposed to be a postprandial phenomenon as early as 1979 (1). Impairment of the vascular endothelium is now felt to be a key central component of the initiation and progression of atherogenesis (2). Oxidative stress is harmful at multiple steps in atherogenesis, including direct contributions to endothelial function. Through such mechanisms, oxidative stress appears to mediate postprandial vascular dysfunction (3-6).Platelet aggregation, coagulation, fibrinolysis and vascular tone are regulated by the endothelium in its role in the defence against atherogenesis and atherosclerosis. Nitric oxide (NO) is arguably the most important mediator of these functions. The left panel of Figure 1 illustrates NO synthesis and function. The synthesis of NO from l-arginine, molecular oxygen and electrons carried by NADPH is catalysed by the endothelial nitric oxide synthase (eNOS), and dependent on other cofactors [tetrahydrobiopterin (BH 4 ), flavin adenine dinucleotide and flavin mononucleotide]. eNOS can be activated by shear stress from arterial blood flow, insulin and small molecule agonists [i.e. acetylcholine (ACh)]. Insulin and shear stress work through calcium-independent signalling pathways mediated in part by phosphatidylinositol-3-kinase (PI-3 kinase), whereas ACh works through a calcium-dependent pathway (7).The right panel of Figure 1 illustrates how the NO role in protecting the endothelium is compromised in postprandial lipaemia. Superoxide radical (O 2 ) )accumulates as a result of excess mitochondrial lipid oxidation. NO is the kinetically preferred scavenger for O 2 ) (8) because scavenging by NO occurs at an extremely rapid rate; three times faster than the interaction with other antioxidants (i.e. superoxide dismutase) (9). The reaction between O 2 ) and NO S U M M A R YAims: Postprandial lipaemia-induced endothelial dysfunction is felt to be mediated by increases in oxidative stress. In this review, we have examined the cross-sectional relationships found among these three variables. Methods: We found 20 studies conducted by 16 independent investigative teams through a Medline search from 1980 to 2008; studies were required to report correlations between at least two of the three variables of interest in studies of humans. This review is divided into (i) discussions on the biomarkers and other measures of postprandial lipaemia, oxidative stress and endothelial function; (ii) associations reported among the three variables; and (iii) other considerations including alternative intervention studies.Results: Triglycerides and free fatty acids are robust and well-standardised biomarkers of lipaemia. Measures of oxidative stress ranged from electron spin techniques to measures of lipid peroxidation and are limited by lack of standardisation. Brachial artery flow-mediated dilatation is the most commonly used measure of endothelial function. The associations between postprandial lipaemia and oxidative stress and between postprandial lipaemia and endothelial functi...

The aim of this investigation was to establish whether changes in oxidative stress and endothelial function following acute aerobic exercise are dose-dependent. Ten healthy trained men completed four exercise sessions: 50% VO(2peak) for 30 min (moderate intensity moderate duration, MIMD), 50% VO(2peak) for 60 min (moderate intensity long duration, MILD), 80% VO(2peak) for 30 min (high intensity moderate duration, HIMD), and 80% VO(2peak) for the time to reach the caloric equivalent of MIMD (high intensity short duration, HISD). Thiobarbituric acid reactive substances (TBARS) were measured as an index of oxidative stress and brachial artery flow-mediated dilation (FMD) was assessed as an index of endothelial function. Variables were measured at baseline, immediately post-exercise, 1 and 2 h post-exercise. Both HIMD (14.2 ± 2.5 μmol/L) and HISD (14.7 ± 1.9 μmol/L) TBARS differed from MIMD (11.8 ± 1.5 μmol/L) immediately post-exercise. TBARS increased from pre to immediately post-exercise for HIMD (12.6 ± 2.1 vs.14.2 ± 2.5 μmol/L) and HISD (12.3 ± 2.8 vs. 14.7 ± 1.9 μmol/L). Both MIMD (7.2 ± 2.2%) and HISD (7.6 ± 2.7%) FMD immediately post-exercise were greater than HIMD (4.7 ± 2.2%). An increase of FMD from pre to immediately post-exercise was found for MIMD (5.0 ± 2.5 vs. 7.2 ± 2.2%) and HISD (5.9 ± 2.4 vs. 7.6 ± 2.7%). These data suggest that acute exercise-induced TBARS are exercise intensity-dependent whereas FMD appears to improve following energy expenditure equivalent to 30 min 50% VO(2peak), regardless of intensity or duration.

The purpose of this study was to compare hemodynamic and blood analyte responses to reduced central venous pressure (CVP) and pulse pressure (PP) elicited during graded lower body negative pressure (LBNP) to those observed during graded blood loss (BL) in conscious humans. We hypothesized that the stimulus-response relationships of CVP and PP to hemodynamic responses during LBNP would mimic those observed during BL. We assessed CVP, PP, heart rate, mean arterial pressure (MAP), and other hemodynamic markers in 12 men during LBNP and BL. Blood samples were obtained for analysis of catecholamines, hematocrit, hemoglobin, arginine vasopressin, and blood gases. LBNP consisted of 5-min stages at 0, 15, 30, and 45 mmHg of suction. BL consisted of 5 min at baseline and following three stages of 333 ml of hemorrhage (1,000 ml total). Individual r(2) values and linear regression slopes were calculated to determine whether the stimulus (CVP and PP)-hemodynamic response trajectories were similar between protocols. The CVP-MAP trajectory was the only CVP-response slope that was statistically different during LBNP compared with BL (0.93 ± 0.27 vs. 0.13 ± 0.26; P = 0.037). The PP-heart rate trajectory was the only PP-response slope that was statistically different during LBNP compared with BL (-1.85 ± 0.45 vs. -0.46 ± 0.27; P = 0.024). Norepinephrine, hematocrit, and hemoglobin were all lower at termination in the BL protocol compared with LBNP (P < 0.05). Consistent with our hypothesis, LBNP mimics the hemodynamic stimulus-response trajectories observed during BL across a significant range of CVP in humans.

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.

SummarySedentary activity is a modifiable life-style behavior and a key component in the etiology of atherosclerotic cardiovascular disease (ACVD). US adults and children spend more than half their waking time in sedentary pursuits. Sedentary activity has been shown to result in impaired insulin sensitivity, impaired metabolic function and attenuated endothelial function, which are classic markers of ACVD. Sedentary activity is defined as ‘sitting without otherwise being active.’ This behavior promotes reduced muscular activity of the lower extremities which decreases leg blood flow, increases blood pooling in the calf, augments mean arterial pressure, and deforms arterial segments resulting in low mean shear stress (SS). SS activates distinct physiological mechanisms which have been proposed to be protective against ACVD; specifically through a SS-induced endothelium-derived nitric oxide mechanism. Reduced bioavailability of nitric oxide creates a pro-oxidant milieu resulting in increased oxidative stress. There is sufficient evidence which demonstrates that endothelial function is attenuated in the presence of oxidative stress. Sedentary activity results in low SS in the lower extremities which may result in increased oxidative stress and impaired endothelial function. This review furthers the use of sitting as model to study the effects of inactivity, discusses possible physiological mechanisms and suggests future directions.