Nicola D. Hopkins

Shear Stress Mediates Endothelial Adaptations to Exercise Training in Humans

Although episodic changes in shear stress have been proposed as the mechanism responsible for the effects of exercise training on the vasculature, this hypothesis has not been directly addressed in humans. We examined brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men in response to an acute bout of handgrip exercise and across an 8-week period of bilateral handgrip training. Shear stress responses were attenuated in one arm by cuff inflation to 60 mm Hg. Similar increases were observed in grip strength and forearm volume and girth in both limbs. Acute bouts of handgrip exercise increased shear rate (P<0.005) and flow-mediated dilation percentage (P<0.05) in the uncuffed limb, whereas no changes were evident in the cuffed arm. Handgrip training increased flow-mediated dilation percentage in the noncuffed limb at weeks 2, 4, and 6 (P<0.001), whereas no changes were observed in the cuffed arm. Brachial artery peak reactive hyperemia, an index of resistance artery remodeling, progressively increased with training in the noncuffed limb (P<0.001 and 0.004); no changes were evident in the cuffed arm. Neither acute nor chronic shear manipulation during exercise influenced endothelium-independent glyceryl trinitrate responses. These results demonstrate that exercise-induced changes in shear provide the principal physiological stimulus to adaptation in flow-mediated endothelial function and vascular remodeling in response to exercise training in healthy humans.

Impact of Shear Rate Modulation on Vascular Function in Humans

Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline flow-mediated dilation (4.6%, 6.9%, and 6.7%) increased similarly in response to heating, handgrip, and cycling (8.1%, 10.4%, and 8.9%, ANOVA; P<0.001, no interaction; P=0.89). In contrast, cuffed arm antegrade shear rate was lower than in the noncuffed arm for all of the conditions (P<0.05), and the increase in flow-mediated dilation was abolished in this arm (4.7%, 6.7%, and 6.1%; 2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding that may have relevance for the impact of different exercise interventions on vascular adaptation in humans.

Changes in vascular and cardiac function after prolonged strenuous exercise in humans

Prolonged exercise has been shown to result in an acute depression in cardiac function. However, little is known about the effect of this type of exercise on vascular function. Therefore, the purpose of the present study was to investigate the impact of an acute bout of prolonged strenuous exercise on vascular and cardiac function and the appearance of biomarkers of cardiomyocyte damage in 15 male (32 +/- 10 yr) nonelite runners. The subjects were tested on two occasions, the day before and within an hour of finishing the London marathon (229 +/- 38 min). Function of the brachial and femoral arteries was determined using flow-mediated dilatation (FMD). Echocardiographic assessment of cardiac strain, strain rate, tissue velocities, and flow velocities during diastole and systole were also obtained. Venous blood samples were taken for later assessment of cardiac troponin I (cTnI), a biomarker of cardiomyocyte damage. Completion of the marathon resulted in a depression in femoral (P = 0.04), but not brachial (P = 0.96), artery FMD. There was no change, pre- vs. postmarathon, in vascular shear, indicating that the impaired femoral artery function was not related to hemodynamic changes. The ratio of peak early to atrial radial strain rate, a measure of left ventricular diastolic function, was reduced postmarathon (P = 0.006). Postrace cTnI was elevated in 12 of 13 runners, with levels above the recognized clinical threshold for damage in 7 of these. In conclusion, when taken together, these data suggest a transient depression in cardiac and leg vascular function following prolonged intensive exercise.

Does arterial shear explain the magnitude of flow-mediated dilation?: a comparison between young and older humans

Flow-mediated dilatation (FMD) has become a commonly applied approach for the assessment of vascular function and health in humans. Recent studies emphasize the importance of normalizing the magnitude of FMD to its apparent eliciting stimulus, the postdeflation arterial shear. However, the relationship between shear stress and the magnitude of FMD may differ between groups. The aim of this study was to examine the relationship between the brachial FMD and four different indexes of postdeflation shear rate (SR) in healthy children (n = 51, 10 +/- 1 yr) and young (n = 57, 27 +/- 6 yr) and older (n = 27, 58 +/- 4 yr) adults. SR was calculated from deflation (time 0) until 9 s (peak), 30 s (0-30), 60 s (0-60), or until the time-to-peak diameter in each individual (0-ttp). Edge detection and wall tracking of high resolution B-mode arterial ultrasound images were used to calculate the conduit artery diameter. In young adults, the brachial artery FMD demonstrated a significant correlation with the area under the SR curve (SR(AUC)) 0-30 s (r(2) = 0.12, P = 0.009), 0-60 s (r(2) = 0.14, P = 0.005), and 0-ttp (r(2) = 0.14, P = 0.005) but not for the peak SR(AUC) 0-9 s (r(2) = 0.04, P = 0.12). In children and older adults, the magnitude of the brachial artery FMD did not correlate with any of the four SR(AUC) stimuli. These findings suggest that in young subjects, postdeflation SR(AUC) correlates moderately with the magnitude of the FMD response. However, the relationship between FMD and postdeflation shear appears to be age dependent, with less evidence for an association in younger and older subjects. Therefore, we support presenting SR(AUC) stimuli but not normalizing FMD responses for the SR(AUC) when using this technique.

Is the ratio of flow-mediated dilation and shear rate a statistically sound approach to normalization in cross-sectional studies on endothelial function?

It has been deemed important to normalize flow-mediated dilation (FMD), a marker of endothelial function, for between-subject differences in the eliciting shear rate (SR) stimulus. Conventionally, FMD is divided by the area under the curve of the SR stimulus. In the context of a cross-sectional comparison across different age cohorts, we examined whether this ratio approach adhered to established statistical assumptions necessary for reliable normalization. To quantify brachial artery FMD and area under the curve of SR, forearm cuff inflation to suprasystolic pressure was administered for 5 min to 16 boys aged 10.9 yr (SD 0.3), 48 young men aged 25.3 yr (SD 4.2), and 15 older men aged 57.5 yr (SD 4.3). Mean differences between age groups were statistically significant (P < 0.001) for nonnormalized FMD [children: 10.4% (SD 5.4), young adults: 7.5% (SD 2.9), older adults: 5.6% (SD 2.0)] but not for ratio-normalized FMD (P = 0.10). Moreover, all assumptions necessary for reliable use of ratio-normalization were violated, including regression slopes between SR and FMD that had y-intercepts greater than zero (P < 0.05), nonlinear and unstable relations between the normalized ratios and SR, skewed data distributions, and heteroscedastic variance. Logarithmic transformation of SR and FMD before ratio calculation improved adherence to these assumptions and resulted in age differences similar to the nonnormalized data (P = 0.03). In conclusion, although ratio normalization of FMD altered findings about age differences in endothelial function, this could be explained by violation of statistical assumptions. We recommend that exploration of these assumptions should be routine in future research. If the relationship between SR and FMD is generally found to be weak or nonlinear or variable between samples, then ratio normalization should not be applied.

Relationships between measures of fitness, physical activity, body composition and vascular function in children.

BACKGROUND The prevalence of obesity and physical inactivity in Western countries has increased rapidly. Both are modifiable risk factors for cardiovascular disease. Atherosclerosis begins in childhood and endothelial dysfunction is its earliest detectable manifestation. METHODS We assessed flow-mediated dilation (FMD) in 129 children (75 female; 10.3+0.3 yrs; 54 male; 10.4; 0.3 yrs). FMD was normalised for differences in the eliciting shear rate stimulus between subjects (SR(AUC)). Fitness was assessed as peak oxygen uptake during an incremental treadmill exercise test (V O(2)peak). Body composition was measured using a dual-energy X-ray absorptiometry (DEXA) scan. Physical activity (PA) was assessed using Actigraph accelerometers. The cohort was split into tertiles according to FMD% and also FMD% corrected for SR(AUC) to gain insight into the determinants of vascular function. RESULTS Across the cohort, significant correlations were observed between FMD%/SR(AUC) and DEXA percentage fat (r=-0.23, p=0.009) and percentage lean mass (r=0.21, p=0.008), and also with PA performed at moderate-to-high intensity (r=0.363, p=0.001). For children in the lowest FMD%/SR(AUC) tertile, a stronger relationship with all PA measures was observed, particularly with high intensity PA (r=0.572, P=0.003). Regression analysis revealed that high intensity PA was the only predictor of impaired FMD%/SR(AUC). CONCLUSIONS These data suggest that traditional risk factors for CHD in adult populations impact upon vascular function in young people. Furthermore, it appears that individuals with impaired FMD may benefit from performing high intensity PA, whereas no relationships exist between FMD and lower intensities of PA or between PA and FMD in those subjects who possess preserved vascular function a priori.

The impact of baseline diameter on flow-mediated dilation differs in young and older humans

Flow-mediated dilation (FMD) has become a commonly applied approach for the assessment of vascular function and health, but methods used to calculate FMD differ between studies. For example, the baseline diameter used as a benchmark is sometimes assessed before cuff inflation, whereas others use the diameter during cuff inflation. Therefore, we compared the brachial artery diameter before and during cuff inflation and calculated the resulting FMD in healthy children (n=45; 10+/-1 yr), adults (n=31; 28+/-6 yr), and older subjects (n=22; 58+/-5 yr). Brachial artery FMD was examined after 5 min of distal ischemia. Diameter was determined from either 30 s before cuff inflation or from the last 30 s during cuff inflation. Edge detection and wall tracking of high resolution B-mode arterial ultrasound images was used to calculate conduit artery diameter. Brachial artery diameter during cuff inflation was significantly larger than before inflation in children (P=0.02) and adults (P<0.001) but not in older subjects (P=0.59). Accordingly, FMD values significantly differed in children (11.2+/-5.1% vs. 9.4+/-5.2%; P=0.02) and adults (7.3+/-3.2% vs. 4.6+/-3.3%; P<0.001) but not in older subjects (6.3+/-3.4% vs. 6.0+/-4.2%; P=0.77). When the diameter before cuff inflation was used, an age-dependent decline was evident in FMD, whereas FMD calculated using the diameter during inflation was associated with higher FMD values in older than younger adults. In summary, the inflation of the cuff significantly increases brachial artery diameter, which results in a lower FMD response. This effect was found to be age dependent, which emphasizes the importance of using appropriate methodology to calculate the FMD.

Seven-Day Remote Ischemic Preconditioning Improves Local and Systemic Endothelial Function and Microcirculation in Healthy Humans

BACKGROUND Ischemic preconditioning (IPC) protects tissue against ischemia-induced injury inside and outside ischemic areas. The purpose was to examine the hypothesis that daily IPC leads to improvement in endothelial function and skin microcirculation not only in the arm exposed to IPC but also in the contralateral arm. METHODS Thirteen healthy, young, normotensive male individuals (aged 22±2 years) were assigned to 7-day daily exposure of the arm to IPC (4×5 minutes). Assessment of brachial artery endothelial function (using flow-mediated dilation (FMD)) and forearm microcirculation (cutaneous vascular conductance (CVC) at baseline and during local heating) was performed before and after 7 days to examine the local (i.e., intervention arm) and remote (i.e., control arm) effect of IPC. We repeated the assessment tests 8 days after the intervention (Post+8). RESULTS FMD increased after repeated IPC (P = 0.03) and remained significantly elevated at Post+8 in the intervention (5.0±2.2%, 6.1±2.2%, and 6.6±2.3%) and contralateral arms (5.4±2.2%, 6.0±2.2%, and 7.5±2.2%). Forearm CVC also increased following repeated IPC (P = 0.006) and remained elevated at Post+8 in both arms (intervention: 0.12±0.03, 0.14±0.04, 0.16±0.04 mV/mm Hg; contralateral: 0.14±0.04, 0.015±0.04, 0.17±0.07). No interaction between IPC arm and time was evident for FMD and CVC (both P > 0.05). IPC intervention did not alter CVC responses to local heating (P > 0.05). CONCLUSIONS Daily exposure to IPC for 7 days leads to local and remote improvements in brachial artery FMD and resting skin microcirculation that remain after cessation of the intervention and beyond the late phase of protection. These findings may have clinical relevance for micro- and macrovascular improvements.

Physical activity, cardiorespiratory fitness, and clustered cardiometabolic risk in 10- to 12-year-old school children: The REACH Y6 study

(1) Investigate whether clustered cardiometabolic risk score, cardiorespiratory fitness (CRF), sedentary time (ST), and body mass index Z‐scores (BMI Z‐scores), differed between participants that met and did not achieve ≥60 min of daily moderate to vigorous intensity physical activity (MVPA). (2) Compare clustered cardiometabolic risk score, BMI Z‐score, ST, and MVPA by CRF status.

Endothelial Function and Carotid Intima-Medial Thickness in Adolescents with Type 2 Diabetes Mellitus

OBJECTIVE We assessed the effect of type 2 diabetes mellitus and obesity on flow-mediated dilation (FMD) and endothelial-dependent vasodilation and carotid intima-medial thickness (cIMT) in young people. STUDY DESIGN Adolescents were recruited in 3 groups: subjects with type 2 diabetes mellitus (n = 15), subjects who were obese and non-insulin resistant (n = 13), and lean control subjects (n = 13). Body mass index was similar in subjects with obesity and subjects with type 2 diabetes mellitus, but higher compared with that of lean control subjects (both P < .001). Brachial artery FMD and cIMT were assessed by using Duplex ultrasound scanning imaging. RESULTS There were no significant differences in brachial or common carotid arterial diameters in the groups. cIMT was significantly greater in the group with type 2 diabetes mellitus (0.54 ± 0.01mm) compared with both the lean control (0.46 ± 0.02 mm, P < .001) and obese control (0.46 ± 0.02 mm, P < .01) groups. FMD was significantly decreased in the group with type 2 diabetes mellitus (7.98% ± 0.54%) compared with the lean group (10.40% ± 1.00%, P < .05). CONCLUSIONS Measures of vascular health were impaired in adolescents with type 2 diabetes mellitus compared with lean and obese adolescents who were not insulin resistant. Measures of arterial function and structure may provide pre-clinical measures of cardiovascular disease in young people at elevated risk.