UBC-Nepal expedition: upper and lower limb conduit artery shear stress and flow-mediated dilation on ascent to 5,050 m in lowlanders and Sherpa

The study of conduit artery endothelial adaptation to hypoxia has been restricted to the brachial artery, and comparisons with highlanders have been confounded by differences in altitude exposure, exercise, and unknown levels of blood viscosity. To address these gaps, we tested the hypothesis that lowlanders, but not Sherpa, would demonstrate decreased mean shear stress and increased retrograde shear stress and subsequently reduced flow-mediated dilation (FMD) in the upper and lower limb conduit arteries on ascent to 5,050 m. Healthy lowlanders (means ± SD, n = 22, 28 ± 6 yr) and Sherpa ( n = 12, 34 ± 11 yr) ascended over 10 days, with measurements taken on nontrekking days at 1,400 m (baseline), 3,440 m ( day 4), 4,371 m ( day 7), and 5,050 m ( day 10). Arterial blood gases, blood viscosity, shear stress, and FMD [duplex ultrasound of the brachial and superficial femoral arteries (BA and SFA, respectively)] were acquired at each time point. Ascent decreased mean and increased retrograde shear stress in the upper and lower limb of lowlanders and Sherpa. Although BA FMD decreased in lowlanders from 7.1 ± 3.9% to 3.8 ± 2.8% at 5,050 versus 1,400 m ( P < 0.001), SFA FMD was preserved. In Sherpa, neither BA nor SFA FMD were changed upon ascent to 5,050 m. In lowlanders, the ascent-related exercise may favorably influence endothelial function in the active limb (SFA); selective impairment in FMD in the BA in lowlanders is likely mediated via the low mean or high oscillatory baseline shear stress. In contrast, Sherpa presented protected endothelial function, suggesting a potential vascular aspect of high-altitude acclimatization/adaptation. NEW & NOTEWORTHY Upper and lower limb arterial shear stress and flow-mediated dilation (FMD) were assessed on matched ascent from 1,400 to 5,050 m in lowlanders and Sherpa. A shear stress pattern associated with vascular dysfunction/risk manifested in both limbs of lowlanders and Sherpa. FMD was impaired only in the upper limb of lowlanders. The findings indicate a limb-specific impact of high-altitude trekking on FMD and a vascular basis to acclimatization wherein endothelial function is protected in Sherpa on ascent

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Abstract 377: Retrograde Shear Stress does not Alter Endothelial Function in Healthy Subjects

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.377 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Sooraj Shah ◽

Stuart Katz

Keyword(s):

Shear Stress ◽

Endothelial Function ◽

Healthy Subjects ◽

Flow Mediated Dilation ◽

Retrograde Flow ◽

Experimental Conditions ◽

Before And After ◽

Arm Elevation ◽

The Difference ◽

Retrograde Shear

Introduction: Endothelial dysfunction is a precursor and plays a significant role in development of atherosclerosis. Retrograde flow and resulting retrograde shear stress has been shown to adversely affect the endothelial function but the results may be flawed due to experimental conditions. Change in the limb position might result in increase in retrograde flow and adversely affect endothelial function. We hypothesized that elevation of arm above the level of the heart will result in increased retrograde flow and reduced endothelial function as measured by flow mediated dilation (FMD). Methods: We enrolled 27 healthy subjects after obtaining informed consent. Endothelial function was measured by FMD in brachial artery before and after arm elevation with elbow support for 30 minutes in fasting state. Flow velocities were recorded and analyzed at baseline, 10 and 20 minutes after arm elevation and at the end of 30 minutes. Results: The mean retrograde flow velocity was 9.9 ± 7.75 cm/sec at baseline, which increased to 15.8 ± 6.56 cm/sec (p=0.0019) after arm elevation. Out of the 27 subjects 21 (78%) subjects had increase in retrograde flow (20% or more). The difference in FMD change between the groups with increased or no change in retrograde flow was statistically non-significant (p=0.4). Conclusion: In conclusion arm elevation for 30 minutes was associated with statistically significant increase in retrograde flow without significant change in endothelial function in normal healthy subjects. The change in endothelial function between subjects who had augmented retrograde shear and those who did not was statistically not significant.

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Examining the acute effects of retrograde versus low mean shear rate on flow-mediated dilation

Journal of Applied Physiology ◽

10.1152/japplphysiol.01065.2018 ◽

2019 ◽

Vol 126 (5) ◽

pp. 1335-1342 ◽

Cited By ~ 8

Author(s):

Joshua C. Tremblay ◽

Arman S. Grewal ◽

Kyra E. Pyke

Keyword(s):

Shear Stress ◽

Shear Rate ◽

Endothelial Function ◽

Brachial Artery ◽

Duplex Ultrasound ◽

Flow Mediated Dilation ◽

Relative Contribution ◽

Stress Components ◽

Retrograde Shear

Arterial endothelial function is acutely and chronically regulated by blood flow-associated shear stress. An acute intervention employing modest forearm cuff occlusion to simultaneously increase retrograde and decrease mean brachial artery shear rate for 30 min evokes transient impairments in flow-mediated dilation (FMD). However, the independent influence of the low mean versus the retrograde shear stress components is unclear. Healthy young adults [ n = 24 (12 women, 12 men); 22 ± 2 yr, body mass index = 25 ± 2 kg/m2 (mean ± SD)] completed three laboratory visits within 1 wk. Visits consisted of 45 min of supine rest followed by a brachial artery FMD test (duplex ultrasound) before and after a 30-min intervention: control (shear rate unchanged), cuff (mean shear rate decreased, retrograde shear rate increased), or arterial compression (mean shear rate decreased, no increase in retrograde shear rate). The mean shear rate on the compression visit was targeted to match that achieved on the cuff visit. Cuff and compression trials decreased mean shear rate to a similar extent (cuff: 43 ± 22 s−1, compression: 43 ± 21 s−1; P = 0.850) compared with control (65 ± 21 s−1; both P < 0.001), with the retrograde component elevated only in the former (cuff: −83 ± 30 s−1, compression: −7 ± 5 s−1; P < 0.001). FMD decreased by 29 ± 30% ( P < 0.001) after the cuff intervention and 32 ± 24% ( P < 0.001) after the compression trial but was unchanged on the control visit (−0.3 ± 18%; P = 0.754). This was not altered by accounting for the shear rate stimulus. An increased retrograde shear stress does not appear to be obligatory for the transient reduction in FMD achieved after a 30-min exposure to low mean shear stress. These findings provide novel mechanistic insight on the regulation of endothelial function in vivo. NEW & NOTEWORTHY Low mean and retrograde shear stress are considered atherogenic; however, their relative contribution to the acute regulation of endothelial function in humans is unclear. Matched reductions in mean shear stress (30 min), with and without increases in retrograde shear stress, elicited equivalent reductions in flow-mediated dilation in men and women. These findings afford novel insight regarding the shear stress components governing the acute (dys)regulation of conduit artery endothelial function in vivo.

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Endothelial function and shear stress in hypobaric hypoxia: time course and impact of plasma volume expansion in men

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00597.2020 ◽

2020 ◽

Vol 319 (5) ◽

pp. H980-H994

Author(s):

Joshua C. Tremblay ◽

Philip N. Ainslie ◽

Rachel Turner ◽

Hannes Gatterer ◽

Maja Schlittler ◽

...

Keyword(s):

Shear Stress ◽

Endothelial Function ◽

Plasma Volume ◽

Blood Viscosity ◽

Hypobaric Hypoxia ◽

Volume Expansion ◽

Hypoxic Exposure ◽

Flow Mediated Dilation ◽

Handgrip Exercise ◽

Plasma Volume Expansion

Using a normoxic crossover study design, we examined the impact of hypobaric hypoxia (4 days; altitude equivalent, 3,500 m) and hemoconcentration on blood viscosity, shear stress, and endothelial function. Blood viscosity increased during the hypoxic exposure and was accompanied by elevated resting and exercising arterial shear stress. Flow-mediated dilation stimulated by reactive hyperemia and handgrip exercise was preserved throughout the hypoxic exposure. Plasma volume expansion reversed the hypoxia-associated hemoconcentration and selectively increased handgrip exercise flow-mediated dilation.

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Fluctuation in shear rate, with unaltered mean shear rate, improves brachial artery flow-mediated dilation in healthy, young men

Journal of Applied Physiology ◽

10.1152/japplphysiol.00009.2019 ◽

2019 ◽

Vol 126 (6) ◽

pp. 1687-1693 ◽

Cited By ~ 4

Author(s):

Sophie M. Holder ◽

Ellen A. Dawson ◽

Áine Brislane ◽

Jonny Hisdal ◽

Daniel J. Green ◽

...

Keyword(s):

Shear Stress ◽

Shear Rate ◽

Endothelial Function ◽

Brachial Artery ◽

Negative Pressure ◽

Mixed Model ◽

Linear Mixed Model ◽

Flow Mediated Dilation ◽

Conduit Artery ◽

Artery Flow

Increase in mean shear stress represents an important and potent hemodynamic stimulus to improve conduit artery endothelial function in humans. No previous study has examined whether fluctuations in shear rate patterns, without altering mean shear stress, impacts conduit artery endothelial function. This study examined the hypothesis that 30-min exposure to fluctuations in shear rate patterns, in the presence of unaltered mean shear rate, improves brachial artery flow-mediated dilation. Fifteen healthy men (27.3 ± 5.0 yr) completed the study. Bilateral brachial artery flow-mediated dilation was assessed before and after unilateral exposure to 30 min of intermittent negative pressure (10 s, −40mmHg; 7 s, 0 mmHg) to induce fluctuation in shear rate, while the contralateral arm was exposed to a resting period. Negative pressure significantly increased shear rate, followed by a decrease in shear rate upon pressure release (both P < 0.001). Across the 30-min intervention, mean shear rate was not different compared with baseline ( P = 0.458). A linear mixed model revealed a significant effect of time observed for flow-mediated dilation ( P = 0.029), with exploratory post hoc analysis showing an increase in the intervention arm (∆FMD +2.0%, P = 0.008), but not in the contralateral control arm (∆FMD +0.5%, P = 0.664). However, there was no effect for arm ( P = 0.619) or interaction effect ( P = 0.096). In conclusion, we found that fluctuations in shear patterns, with unaltered mean shear, improves brachial artery flow-mediated dilation. These novel data suggest that fluctuations in shear pattern, even in the absence of altered mean shear, represent a stimulus to acute change in endothelial function in healthy individuals. NEW & NOTEWORTHY Intermittent negative pressure applied to the forearm induced significant fluctuations in antegrade and retrograde shear rate, while mean shear was preserved relative to baseline. Our exploratory study revealed that brachial artery flow-mediated dilation was significantly improved following 30-min exposure to intermittent negative pressure. Fluctuations in blood flow or shear rate, with unaltered mean shear, may have important implications for vascular health; however, further research is required to identify the underlying mechanisms and potential long-term health benefits.

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Shear stress and flow-mediated dilation in the normoxic and hypoxic human

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2019-0292 ◽

2019 ◽

Vol 44 (8) ◽

pp. 902-902

Author(s):

Joshua C. Tremblay

Keyword(s):

Shear Stress ◽

Endothelial Function ◽

High Altitude ◽

Blood Viscosity ◽

Short Term Exposure ◽

Low Shear Stress ◽

High Altitude Natives ◽

Low Levels ◽

The Impact ◽

Low Shear

The endothelium is a single cell layer that plays a critical role in determining the health and function of blood vessels. Endothelial function is shaped by shear stress, the frictional force exerted by the speed of blood flow, and the thickness (viscosity) of the blood. Exposure to shear stress that reverses direction back-and-forth impairs endothelial function in young men. Whether women are equally susceptible to this perturbation and the isolated impact of a low level of shear stress with and without reversal of shear had not been investigated. Hypoxia, the low levels of oxygen that are experienced at high altitude, has been shown to influence flow reversal and impair endothelial function. However, no previous study had accounted for the changes in blood thickness, and hence shear stress that occur at high altitude. This may be especially important in the context of excessive erythrocytosis, a high-altitude disease characterized by exceptionally thick blood and increased cardiovascular risk. This thesis examined (i) whether there are sex differences in the impact of exposure to low and reversing shear stress on endothelial function; (ii) whether isolated low shear stress impairs endothelial function; (iii) the impact of reversing shear stress on endothelial function in short-term exposure to low levels of oxygen and after trekking to 5050 m in the Himalayas; and (iv) the role of high levels of blood viscosity on endothelial function in high-altitude natives in Cerro de Pasco, Peru (4330 m), with excessive erythrocytosis. We identified that (i) premenopausal women have some protection against reductions in endothelial function after being exposed to reversing shear stress; (ii) isolated low shear stress impaired endothelial function; (iii) short-term exposure to low levels of oxygen and sustained high-altitude exposure reduced endothelial function, while superimposing reversing shear stress had no effect; and (iv) high levels of hemoglobin and blood viscosity contributed to lower endothelial function in Andean high-altitude natives with excessive erythrocytosis. Altogether, this dissertation advances our understanding of how the components of shear stress (the pattern, magnitude, and blood viscosity) impact endothelial function in humans under normoxic (normal levels of oxygen) and hypoxic (low levels of oxygen, such as high-altitude) conditions.

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Flow-mediated dilation stimulated by sustained increases in shear stress: A useful tool for assessing endothelial function in humans?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00534.2017 ◽

2017 ◽

pp. ajpheart.00534. ◽

Cited By ~ 10

Author(s):

Joshua C Tremblay ◽

Kyra Ellen Pyke

Keyword(s):

Shear Stress ◽

Endothelial Function ◽

Flow Mediated Dilation

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Endothelial dysfunction following prolonged sitting is mediated by a reduction in shear stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00943.2015 ◽

2016 ◽

Vol 310 (5) ◽

pp. H648-H653 ◽

Cited By ~ 61

Author(s):

Robert M. Restaino ◽

Lauren K. Walsh ◽

Takuma Morishima ◽

Jennifer R. Vranish ◽

Luis A. Martinez-Lemus ◽

...

Keyword(s):

Shear Stress ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Internal Control ◽

Popliteal Artery ◽

Local Heating ◽

Underlying Mechanism ◽

Flow Mediated Dilation ◽

Prolonged Sitting ◽

Artery Flow

We and others have recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanism(s) remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow-induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 10 young healthy men, bilateral measurements of popliteal artery flow-mediated dilation were performed before and after a 3-h sitting period during which one foot was submerged in 42°C water (i.e., heated) to increase blood flow and thus shear stress, whereas the contralateral leg remained dry and served as internal control (i.e., nonheated). During sitting, popliteal artery mean shear rate was reduced in the nonheated leg (pre-sit, 42.9 ± 4.5 s−1; and 3-h sit, 23.6 ± 3.3 s−1; P < 0.05) but not in the heated leg (pre-sit, 38.9 ± 3.4 s−1; and 3-h sit, 63.9 ± 16.9 s−1; P > 0.05). Popliteal artery flow-mediated dilation was impaired after 3 h of sitting in the nonheated leg (pre-sit, 7.1 ± 1.4% vs. post-sit, 2.8 ± 0.9%; P < 0.05) but not in the heated leg (pre-sit: 7.3 ± 1.5% vs. post-sit, 10.9 ± 1.8%; P > 0.05). Collectively, these data suggest that preventing the reduction of flow-induced shear stress during prolonged sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus these findings are consistent with the hypothesis that sitting-induced leg endothelial dysfunction is mediated by a reduction in shear stress.

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Does habitual endurance exercise protect endothelial function against acute exposure to oscillatory shear stress?

Inquiry@Queen's Undergraduate Research Conference Proceedings ◽

10.24908/iqurcp.13322 ◽

2019 ◽

Author(s):

A. S. Grewal ◽

J. C. Tremblay ◽

N. Preobrazenski ◽

B. J. Gurd

Keyword(s):

Physical Activity ◽

Shear Stress ◽

Endothelial Function ◽

Endurance Exercise ◽

Lower Limb ◽

Rest Period ◽

Oscillatory Shear ◽

Acute Exposure ◽

Before And After ◽

Oscillatory Shear Stress

Introduction: Acute exposure to increases in oscillatory shear stress (increased retrograde shear stress and decreased mean shear stress) reduces flow-mediated dilation (FMD). This impairment may be mediated via increased oxidative stress. Habitual endurance exercise training results in increased antioxidant protection. However, it is currently unknown whether these adaptations protect against oscillatory shear stress-induced impairments in FMD. Purpose and Hypothesis: The purpose of this study is to determine whether lower limb endurance-trained athletes have protection against oscillatory shear stress-induced impairments in FMD compared to sedentary individuals. It is hypothesized that athletes will have a preserved FMD after an acute oscillatory shear stress intervention, compared to their sedentary counterparts. Methods: Healthy, young adult volunteers (18-29 years old) will be screened for physical activity (PA) through a physical activity recall questionnaire. 12 sedentary individuals (<3h of structured PA/week) and 12 lower limb endurance athletes will be recruited to participate. All participants will complete a VO2 peak test to objectively measure cardiorespiratory fitness. Participants will visit the laboratory twice in the same week for vascular testing. Both 90-minute visits will begin with 45 minutes of supine rest, followed by a brachial artery FMD test before and after 30 minutes of either imposed oscillatory shear stress (forearm cuff inflated to 70 mmHg) or a 30 min rest period (control). Significance: This will be the first study to investigate whether endurance-trained athletes are resistant to oscillatory shear-stress induced impairments in endothelial function. This will provide insight into mechanism contributing to the vasoprotective effects of habitual endurance exercise.

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Evidence of a limb- and shear stress stimulus profile-dependent impact of high-intensity cycling training on flow-mediated dilation

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2019-0151 ◽

2020 ◽

Vol 45 (2) ◽

pp. 135-145

Author(s):

Trevor J. King ◽

Kyra E. Pyke

Keyword(s):

Shear Stress ◽

Endothelial Function ◽

Endurance Training ◽

Training Group ◽

Lower Limbs ◽

Stress Profile ◽

Flow Mediated Dilation ◽

Post Intervention ◽

The Impact ◽

Cycling Training

Lower limb endurance training can improve conduit artery flow-mediated dilation (FMD) in response to transient increases in shear stress (reactive hyperemia; RH-FMD) in both the upper and lower limbs. Sustained increases in shear stress recruit a partially distinct transduction pathway and elicit a physiologically relevant FMD response (SS-FMD) that provides distinct information regarding endothelial function. However, the impact of training on SS-FMD is not well understood. The purpose of this study was to determine the impact of cycling training on handgrip exercise-induced brachial artery (BA) FMD (BA SS-FMD) and calf plantar-flexion-induced superficial femoral artery (SFA) FMD (SFA SS-FMD). RH-FMD was also assessed in both arteries. Twenty-eight young males were randomized to control (n = 12) or training (n = 16) groups. The training group cycled 30 min/day, 3 days/week for 4 weeks at 80% heart rate reserve. FMD was assessed in the BA and SFA before and after the intervention via Duplex ultrasound. Results are means ± SD. Training did not impact SS-FMD in either artery, and SFA RH-FMD was also unchanged (p > 0.05). When controlling for the shear rate stimulus via covariate analysis, BA RH-FMD improved in the training group (p = 0.05) (control – pre-intervention: 5.7% ± 2.4%, post-intervention: 5.3% ± 2.4%; training – pre-intervention: 5.4% ± 2.5%, post-intervention: 7.2% ± 2.4%). Thus, endurance training resulted in nonuniform adaptations to endothelial function, with an isolated impact on the BA’s ability to transduce a transient increase in shear stress. Novelty Training did not alter SS-FMD in the arm or leg. RH-FMD was augmented in the arm only. Thus training adaptations were limb- and shear stress profile-specific.

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