Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

No acute hyperglycemia induced impairment in brachial artery flow-mediated dilation before or after aerobic exercise training in young recreationally active males.

There is some evidence that transient endothelial dysfunction induced by acute hyperglycemia may be attenuated by a single bout of aerobic exercise. However, the impact of aerobic exercise training on acute hyperglycemia-induced endothelial dysfunction has not been explored. The purpose of this study was to determine the impact of aerobic exercise training on the endothelial function response to acute hyperglycemia. Brachial artery flow-mediated dilation (FMD) was assessed in 24 healthy males (21 ± 1 years) pre-, 60 and 90 min post ingestion of 75 g of glucose. Participants completed a four-week control (CON; n = 13) or exercise training (EX; n = 11) intervention. The EX group completed four weeks of cycling exercise (30 min, 4×/week at 65% work rate peak). Cardiorespiratory fitness ([Formula: see text]O2peak) increased and resting HR decreased in EX, but not CON post-intervention (p < 0.001). Glucose and insulin increased (p < 0.001) following glucose ingestion, with no significant difference pre- and post-intervention. In contrast to previous research, FMD was unaffected by glucose-ingestion, pre- and post-intervention in both groups. In conclusion, acute hyperglycemia did not impair endothelial function, before or after exercise training. Relatively high baseline fitness ([Formula: see text]O2peak ~ 46 mL/kg/min) and young age may have contributed to the lack of impairment observed. Further research is needed to examine the impact of exercise training on hyperglycemia-induced impairments in endothelial function in sedentary males and females.

The acute effect of a laboratory shame induction protocol on endothelial function in young, healthy adults.

NEW FINDINGS: What is the central question of this study? Shame is a form of social stress that involves internalizing social devaluations imposed by others. The aim of this study was to determine, for the first time, how acutely experienced shame impacts endothelial function. What is the main finding and its importance? Brachial artery flow-mediated dilatation, an index of endothelial function, was impaired after an intervention that acutely increased self-reported shame. This occurred without increases in cortisol or tumor necrosis factor alpha receptor binding. Frequent or prolonged shame-induced endothelial dysfunction could have important cardiovascular consequences. ABSTRACT: The objective of this study was to examine the impact of a shame induction protocol on endothelial function. Fifteen participants (n = 7 men, n = 8 women) completed both a written shame induction protocol and a control protocol on two different experimental days. Pre- and post-protocol we assessed: (1) endothelial function and arterial shear rate via a standard brachial artery reactive hyperaemia flow-mediated dilatation (FMD) test across two post-intervention time points (15 and 35 min post); (2) perceived shame via the experiential shame scale (ESS); and (3) cortisol and soluble tumor necrosis factor alpha receptor (sTNFαRII) through oral fluid analysis. Shame increased after the shame induction protocol (pre, 2.9 ± 0.6 vs. post, 3.7 ± 0.5, P < 0.001) but not the control protocol (pre, 3.0 ± 0.5 vs. post, 2.8 ± 0.5, P = 0.15; protocol by time interaction, P < 0.001). When all three time points were included in the analysis, %FMD did not change over time. Considering only the lowest post time point, %FMD decreased significantly in response to the shame protocol (pre, 4.8 ± 1.9 vs. post, 3.2 ± 1.6, P < 0.001) but not the control protocol (pre, 4.2 ± 1.8 vs. post, 3.8 ± 1.5, P = 0.45; protocol by time interaction, P = 0.035). Covariation of the shear rate stimulus for FMD did not alter the FMD results. When including both the control and shame protocols, but not the shame protocol alone, increased shame was significantly associated with decreased FMD (r = -0.37, P < 0.046). There were no significant time by protocol interaction effects for cortisol or sTNFαRII. In conclusion, temporary increases in shame might cause transient endothelial dysfunction which, if chronically repeated, could manifest as reduced vasoprotection against atherosclerosis.

The impact of exercise training on endothelial function in postmenopausal women: a systematic review.

NEW FINDINGS: What is the topic of this review? The aim of this systematic review was to evaluate and summarize all published literature examining the impact of various exercise training interventions on endothelial function in postmenopausal women. What advances does it highlight? There was a moderate effect of training on macrovascular and microvascular endothelial function and just under two-thirds of studies demonstrated a significant increase in at least one measure of endothelial function in postmenopausal women. Factors including exercise intensity and duration, vessel type, clinical status, hormone therapy, and menopausal status may influence the effects of training on endothelial function in postmenopausal women. ABSTRACT: Women experience a rapid decline in endothelial function during menopause. Therefore, it is important to explore interventions, such as exercise training, that may prevent endothelial dysfunction in postmenopausal women. The aim of this systematic review was to evaluate and summarize all published literature examining the impact of various exercise training interventions on endothelial function in postmenopausal women. Three electronic databases (MEDLINE, EMBASE and Web of Science) were used to systematically select studies related to exercise training, endothelial function and postmenopausal women. The major initial and secondary update systematic searches yielded 502 unique articles that were screened for eligibility. Thirty-five studies were included in the systematic review. Two-thirds of all studies demonstrated a group-level increase in at least one measure of endothelial function with training. Most studies investigating biomarkers of endothelial function showed improvement in at least one measured biomarker post-training. There was a moderate effect of training on both macrovascular and microvascular endothelial function in observational and randomized intervention studies. Variability in study designs, training protocols and participant characteristics make it difficult to directly compare studies. Factors including exercise intensity and duration, vessel type, clinical status, hormone therapy, and menopausal status may contribute to the inconsistent effects of training on endothelial function in postmenopausal women. Future research is needed in this population to understand the mechanisms driving inter-study and inter-individual differences in training-induced changes in endothelial function.

Reliability of the hyperaemic response to passive leg movement in young, healthy women.

NEW FINDINGS: What is the central question of this study? This is the first study to assess the day-to-day reliability of passive leg movement-induced hyperaemia (PLM-H), an index of lower-limb microvascular function, in young, healthy women. What is the main finding and its importance? Passive leg movement-induced hyperaemia demonstrated good day-to-day reliability, comparable to other common indices of endothelial function, supporting the use of PLM-H to assess lower-limb microvascular function in women. ABSTRACT: Passive leg movement-elicited hyperaemia (PLM-H) provides an index of lower-limb microvascular function. However, there is currently limited information regarding the reliability of PLM-H and no reliability information specific to women. The purpose of this study was to determine the reliability of PLM-H in women on two separate days. Seventeen young, healthy women [22 ± 3 years old (mean ± SD)] participated in two identical visits including three trials of PLM. Using duplex ultrasound, PLM-H was characterized by six indices: peak leg blood flow (LBF) and vascular conductance (LVC), peak change above baseline (Δpeak) for LBF and LVC, and area under the curve above baseline (AUC) during the first 60 s of PLM for LBF and LVC. The results demonstrated good day-to-day reliability of PLM-H characterized as peak LBF [r = 0.84, P < 0.001; intraclass correlation coefficient (ICC) = 0.84; coefficient of variation (CV) = 13.2%], peak LVC (r = 0.82, P < 0.001; ICC = 0.79; CV = 14.4%), Δpeak LBF (r = 0.83, P < 0.001; ICC = 0.82; CV = 17.8%) and Δpeak LVC (r = 0.83, P < 0.001; ICC = 0.80; CV = 16.5%). Characterization of PLM as AUC demonstrated moderate day-to-day reliability: AUC LBF (r = 0.71, P < 0.05; ICC = 0.70; CV = 31.2%) and AUC LVC (r = 0.78, P < 0.001; ICC = 0.74; CV = 27.1%). In conclusion, this study demonstrates that PLM-H has good reliability as an index of microvascular function; however, characterization of PLM-H as peak, Δpeak LBF and LVC is more reliable than AUC.

Individual variation of follicular phase changes in endothelial function across two menstrual cycles.

NEW FINDINGS: What is the central question of this study? The purpose of this study was to determine intra-individual reproducibility of follicular phase changes in endothelial function (flow-mediated dilatation) over two menstrual cycles in healthy, premenopausal women. What is the main finding and its importance? Phase changes in endothelial function were not consistent at the individual level across two menstrual cycles, which challenges the utility of interpreting individual responses over one cycle. ABSTRACT: Evidence regarding the impact of menstrual phase on endothelial function is conflicting, and studies to date have examined responses only over a single cycle. It is unknown whether the observed inter-individual variability of phase changes in endothelial function reflects stable, inter-individual differences in responses to oestrogen (E2 ; a primary female sex hormone). The purpose of this study was to examine changes in endothelial function from the early follicular (EF; low-E2 ) phase to the late follicular (LF; high-E2 ) phase over two consecutive cycles. Fourteen healthy, regularly menstruating women [22 ± 3 years of age (mean ± SD)] participated in four visits (EFVisit 1 , LFVisit 2 , EFVisit 3 and LFVisit 4 ) over two cycles. Ovulation testing was used to determine the time between the LF visit and ovulation. During each visit, endothelial function [brachial artery flow-mediated dilatation (FMD)], E2 and progesterone were assessed. At the group level, there was no impact of phase or cycle on FMD (P = 0.48 and P = 0.65, respectively). The phase change in FMD in cycle 1 did not predict the phase change in cycle 2 (r = 0.03, P = 0.92). Using threshold-based classification (2 × typical error threshold), four of 14 participants (29%) exhibited directionally consistent phase changes in FMD across cycles. Oestrogen was not correlated between cycles, and this might have contributed to variability in the FMD response. The intra-individual variability in follicular fluctuation in FMD between menstrual cycles challenges the utility of interpreting individual responses to phase over a single menstrual cycle.

The impact of repeated, local heating-induced increases in blood flow on lower limb endothelial function in young, healthy females.

PURPOSE: The purpose of the present study was to examine the effect of repeated, single leg heating on lower limb endothelial function. METHODS: Macrovascular function was assessed with superficial femoral artery (SFA) reactive hyperemia flow-mediated dilation (RH-FMD) and sustained stimulus FMD (SS-FMD). Calf microvascular function was assessed as the peak and area under the curve of SFA reactive hyperemia (RH). Participants (n = 13 females, 23 ± 2 yrs) had one leg randomized to the single leg heating intervention (EXP; other leg: control (CON)). The EXP leg underwent 8 weeks of single leg heating via immersion in 42.5 â„ƒ water for five 35-min sessions/week. At weeks 0, 2, 4, 6, and 8, SFA RH-FMD, SS-FMD (shear stress increased via plantar flexion exercise), and SFA RH flow were measured. RESULTS: None of the variables changed with repeated, single leg heating (interaction week*limb RH-FMD: p = 0.076; SS-FMD: p = 0.958; RH flow p = 0.955). Covariation for the shear stress stimulus did not alter the FMD results. CONCLUSION: Eight weeks of single leg heating did not change SFA endothelial or calf microvascular function. These results are in contrast with previous findings that limb heating improves upper limb endothelial function.

No impact of acute hyperglycaemia on arterial stiffness in the early and late follicular phases of the menstrual cycle in young females.

NEW FINDINGS: • What is the central question of this study? This is the first study to examine the impact of acute hyperglycaemia on arterial stiffness across the early and late follicular phases of the menstrual cycle. • What is the main finding and its importance? Central and peripheral arterial stiffness were not impacted by acute hyperglycaemia. This indicates that premenopausal women might experience protection against deleterious effects of acute hyperglycaemia, regardless of menstrual cycle phase. This research furthers our understanding of the interaction between nutrient intake, hormonal fluctuation and vascular function in premenopausal women. ABSTRACT: Acute hyperglycaemia may result in transient increases in arterial stiffness. However, research in healthy premenopausal women is lacking, and the impact of menstrual phase [early follicular (EF; low oestrogen) and late follicular (LF; high oestrogen)] on vulnerability to acute hyperglycaemia-induced changes in arterial stiffness is unknown. We hypothesized that an acute hyperglycaemia-induced increase in arterial stiffness in the EF phase would be attenuated in the LF phase. Seventeen healthy, naturally menstruating women [21 ± 1 years of age (mean ± SD)] participated in three experimental visits. During two visits, in the EF and LF phase, arterial stiffness was assessed via central and peripheral (arm and leg) pulse wave velocity (PWV) before and 15, 45, 75 and 105 min after consuming an oral glucose challenge (75 g glucose in 300 ml of solution). Blood samples were taken to assess glucose, insulin, oestrogen and progesterone concentrations. During a third visit in the EF phase, participants ingested 300 ml of water as a time control for PWV. Despite significant increases in blood glucose and insulin (P < 0.001), both central and peripheral arm PWV remained unchanged across time and phase, indicating that neither acute hyperglycaemia nor menstrual phase had an impact on central or peripheral arm arterial stiffness. There was a small effect of phase for peripheral leg PWV, where PWV was lower in the LF phase (P = 0.04, Cohen's d = 0.39); however, and in contrast to recent results in young men, peripheral leg PWV was unaffected by hyperglycaemia. These results suggest that premenopausal women might experience protection from acute hyperglycaemia-induced increases in arterial stiffness.

Global Reach 2018: reduced flow-mediated dilation stimulated by sustained increases in shear stress in high-altitude excessive erythrocytosis.

Excessive erythrocytosis [EE; hemoglobin concentration (Hb) ≥ 21 g/dL in adult men] is a maladaptive high-altitude pathology associated with increased cardiovascular risk and reduced reactive hyperemia flow-mediated dilation (FMD); however, whether a similar impairment occurs in response to more commonly encountered sustained increases in shear stress [sustained stimulus (SS)-FMD] over a range of overlapping stimuli is unknown. We characterized SS-FMD in response to handgrip exercise in Andeans with and without EE in Cerro de Pasco, Peru (4,330 m). Andean highlanders with EE (n = 17, Hb = 23.2 ± 1.2 g/dL) and without EE (n = 23, Hb = 18.7 ± 1.9 g/dL) performed 3 min of rhythmic handgrip exercise at 20, 35, and 50% of maximum voluntary contraction (MVC). Duplex ultrasound was used to continuously record blood velocity and diameter in the brachial artery, and blood viscosity was measured to accurately calculate shear stress. Although baseline shear stress did not differ, Andeans with EE had 22% lower shear stress than Andeans without at 50% MVC (P = 0.004). At 35 and 50% MVC, SS-FMD was 2.1 ± 2.0 and 2.8 ± 2.7% in Andeans with EE compared with 4.1 ± 3.4 and 7.5 ± 4.5% in those without (P = 0.048 and P < 0.001). The stimulus-response slope (∆shear stress vs. ∆diameter) was lower in Andeans with EE compared with Andeans without (P = 0.028). This slope was inversely related to Hb in Andeans with EE (r2 = 0.396, P = 0.007). A reduced SS-FMD in response to small muscle mass exercise in Andeans with EE indicates a generalized reduction in endothelial sensitivity to shear stress, which may contribute to increased cardiovascular risk in this population.NEW & NOTEWORTHY High-altitude excessive erythrocytosis (EE; hemoglobin concentration ≥ 21 g/dL) is a maladaptation to chronic hypoxia exposure and is associated with increased cardiovascular risk. We examined flow-mediated dilation (FMD) in response to sustained elevations in shear stress achieved using progressive handgrip exercise [sustained stimulus (SS)-FMD] in Andean highlanders with and without EE at 4,330 m. Andeans with EE demonstrated lower SS-FMD compared with those without. Heightened hemoglobin concentration was related to lower SS-FMD in Andeans with EE.

The influence of acute hyperglycaemia on brachial artery flow-mediated dilatation in the early and late follicular phases of the menstrual cycle.

NEW FINDINGS: What is the central question of the study? This is the first study to examine the impact of acute hyperglycaemia on endothelial function [flow-mediated dilatation (FMD)] in premenopausal women across the early and late follicular (EF and LF) phases of the menstrual cycle. What is the main finding and its importance? Flow-mediated dilatation was impaired 90 min after glucose ingestion, with no significant difference between phases. This indicates that women are susceptible to acute hyperglycaemia-induced endothelial dysfunction in both the EF and LF phases of the menstrual cycle, despite potentially vasoprotective elevations in estradiol levels during the LF phase. ABSTRACT: Acute hyperglycaemia transiently impairs endothelial function in healthy men when assessed via flow-mediated dilatation (FMD). However, research in female participants is lacking, and the impact of menstrual phase [early follicular (EF) and late follicular (LF)] on vulnerability to acute hyperglycaemia-induced endothelial dysfunction is unknown. Seventeen healthy, naturally menstruating women [21 ± 1 years old (mean ± SD)] participated in three visits. During two visits (EFGlucose and LFGlucose ), brachial artery FMD was assessed before and 60, 90 and 120 min after an oral glucose challenge (75 g glucose). During an additional EF visit, participants ingested 300 ml of water (EFTimeControl ). Blood glucose and insulin increased 30 min after glucose ingestion (P < 0.001), with no difference between phases. Flow-mediated dilatation did not change in EFTimeControl (P = 0.748) but was reduced 90 min after glucose ingestion (Pre, 8.5 ± 2.5%; Post90, 6.6 ± 2.4%, P = 0.001; Cohen's d = 0.82), with no difference between phases (main effect of phase, P = 0.506; phase by time interaction, P = 0.391). To account for individual variability in the time course of the impact of hyperglycaemia, the maximal hyperglycaemia-induced impairment in FMD was determined in each participant and compared between phases, revealing no significant phase differences (EFGlucose , -3.1 ± 2.8%; LFGlucose , -2.4 ± 2.1%, P = 0.181; d = 0.34). These results indicate that, similar to findings in men, acute hyperglycaemia results in FMD impairment in young women. We did not detect significant protection from acute hyperglycaemia-induced endothelial dysfunction in the LF 'high-oestrogen' phase in this sample, and further research is needed to examine the potential for a protective effect of oestrogen exposure, including oral contraceptive pills and hormone replacement therapy.

Ramp and step increases in shear stress result in a similar magnitude of brachial artery flow-mediated dilation.

PURPOSE: There is evidence that the endothelium is responsive to both the rate and magnitude of increases in shear stress. However, whether flow-mediated dilation stimulated by sustained increases in shear stress (SS-FMD) is rate sensitive in humans is unknown. The purpose of this investigation was to test whether ramp (gradual) and step (instantaneous) increases in shear stress elicit disparate SS-FMD. METHODS: Young, healthy men (n = 18, age = 22 ± 2 years, body mass index = 25 ± 3 kg m-2) performed two 11-min bouts of rhythmic handgrip exercise; one with a 5.5-min ramp-increase in shear stress and one with an immediate step increase in shear stress. Ramp increases in shear stress were achieved through incremental increases in handgrip exercise intensity [increases of 4% maximum voluntary contraction (MVC) every 30 s for 5.5 min, ending at 44% MVC] and step increases in shear stress were achieved through a combination of arterial compression and commencing handgrip exercise at 44% MVC. RESULTS: Shear rate was greater in the step versus ramp protocol in minutes 1-6, but not different thereafter. Similarly, SS-FMD was greater in the step versus ramp protocol during minutes 2-6, but similar in minutes 7-11 (minute 11: ramp 8.7 ± 4.6%; step 9.4 ± 3.6%; P = 0.343). SS-FMD continued to increase over time with maintenance of a steady shear stress stimulus (step minutes 2-11: 0.51 ± 0.36% min-1; ramp minutes 7-11: 0.64 ± 0.57% min-1; P = 0.259). CONCLUSIONS: These findings indicate that in the brachial artery of humans, the magnitude of SS-FMD is determined by the magnitude and duration, but not the rate, of increases in shear stress.

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

Investigations of human conduit artery endothelial function via flow-mediated vasodilation (FMD) have largely been restricted to the reactive hyperemia (RH) technique, wherein a transient increase in shear stress after the release of limb occlusion stimulates upstream conduit artery vasodilation (RH-FMD). FMD can also be assessed in response to sustained increases in shear stress [sustained stimulus (SS)-FMD], most often created with limb heating or exercise. Exercise in particular creates a physiologically relevant stimulus because shear stress increases, and FMD occurs, during typical day-to-day activity. Several studies have identified that various conditions and acute interventions have a disparate impact on RH-FMD versus SS-FMD, sometimes with only the latter demonstrating impairment. Indeed, evidence suggests that transient (RH) and sustained (SS) shear stress stimuli may be transduced via different signaling pathways, and, as such, SS-FMD and RH-FMD appear to offer unique insights regarding endothelial function. The present review describes the techniques used to assess SS-FMD and summarizes the evidence regarding 1) SS-FMD as an index of endothelial function in humans, highlighting comparisons with RH-FMD, and 2) potential differences in shear stress transduction and vasodilator production stimulated by transient versus sustained shear stress stimuli. The evidence suggests that SS-FMD is a useful tool to assess endothelial function and that further research is required to characterize the mechanisms involved and its association with long-term cardiovascular outcomes. NEW & NOTEWORTHY Sustained increases in peripheral conduit artery shear stress, created via distal skin heating or exercise, provide a physiologically relevant stimulus for flow-mediated dilation (FMD). Sustained stimulus FMD and FMD stimulated by transient, reactive hyperemia-induced increases in shear stress provide distinct assessments of conduit artery endothelial function.

UBC-Nepal Expedition: imposed oscillatory shear stress does not further attenuate flow-mediated dilation during acute and sustained hypoxia.

Experimentally induced oscillatory shear stress (OSS) and hypoxia reduce endothelial function in humans. Acute and sustained hypoxia may cause increases in resting OSS; however, whether this influences endothelial susceptibility to further increases in OSS is unknown. Healthy lowlanders ( n = 15, 30 ± 6 yr; means ± SD) participated in three OSS interventions: two interventions at sea level [normoxia and after 20 min of normobaric hypoxia (acute hypoxia, 11% O2)] and one intervention 5-7 days after a 9-day ascent to 5,050 m (sustained hypoxia). OSS was provoked in the brachial artery using a 30-min distal cuff inflation (75 mmHg). Endothelial function was assessed before and after each intervention by reactive hyperemia flow-mediated dilation (FMD). Shear stress magnitude and patterns were obtained via Duplex ultrasound. Baseline retrograde shear stress and OSS were greater in acute hypoxia versus normoxia ( P < 0.001), and OSS was elevated in sustained hypoxia versus normoxia ( P = 0.011). The intervention further augmented OSS during each condition. Preintervention FMD was decreased by 29 ± 48% in acute hypoxia and by 25 ± 31% in sustained hypoxia compared with normoxia ( P = 0.001 and 0.026); these changes correlated with changes in baseline mean and antegrade shear stress. After the intervention, FMD decreased during normoxia (-41 ± 26%, P < 0.001) and was unaltered during acute or sustained hypoxia. Therefore, a 30-min exposure to OSS reduced FMD during normoxia, a condition with an unchallenged, healthy endothelium; however, imposed OSS did not appear to worsen endothelial function during acute or sustained hypoxia. Exposure to an altered magnitude and pattern of shear stress at baseline in hypoxia may contribute to the insensitivity to further acute augmentation of OSS. NEW & NOTEWORTHY We investigated whether the endothelium remains sensitive to experimental increases in oscillatory shear stress in acute (11% O2) and sustained (2 wk at 5,050 m) hypoxia. Hypoxia altered baseline shear stress and decreased endothelial function (flow-mediated dilation); however, exposure to experimentally induced oscillatory shear stress only impaired flow-mediated dilation in normoxia.

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.

The impact of menstrual phase on brachial artery flow-mediated dilatation during handgrip exercise in healthy premenopausal women.

NEW FINDINGS: What is the central question of this study? The aim of this study was to determine the influence of menstrual phase on flow-mediated dilatation in response to sustained, exercise-induced increases in shear stress. What is the main finding and its importance? We showed, for the first time, that in healthy, premenopausal women the flow-mediated dilatation stimulated by exercise-induced increases in shear stress did not fluctuate across two phases of the menstrual cycle, despite significant fluctuations in oestrogen. This suggests that endothelial function is not consistently augmented in the high-oestrogen phase. Flow-mediated dilatation (FMD) in response to a sustained shear-stress stimulus (e.g. via handgrip exercise; HGEX) is emerging as a useful tool for assessing endothelial function; however, the impact of menstrual phase on HGEX-FMD is unknown. The purpose of this study was to determine whether HGEX-FMD fluctuates with cyclical changes in oestrogen concentrations over two discrete phases (low and high oestrogen) of the menstrual cycle. Brachial artery (BA) diameter and blood velocity were assessed with two-dimesional and Doppler ultrasound, respectively. Shear stress was estimated using shear rate (SR = BA blood velocity/BA diameter). Participants (12 healthy, regularly cycling women, 21 ± 2 years of age) completed two experimental visits: (i) low oestrogen (early follicular, EF); and (ii) high oestrogen (late follicular, LF). Reactive hyperaemia-stimulated FMD (RH-FMD) and HGEX-FMD (6 min of handgrip exercise) were assessed during each visit. Results are mean values ± SD. Oestrogen increased from the EF to LF phase (EF, 33 ± 9 pg ml-1 ; LF, 161 ± 113 pg ml-1 , P = 0.003). However, neither the SR stimuli (HGEX, P = 0.501; RH, P = 0.173) nor the FMD responses differed between phases (EF versus LF: HGEX-FMD, 4.8 ± 2.8 versus 4.6 ± 2.2%, P = 0.601; RH-FMD, 7.9 ± 4.3 versus 6.4 ± 3.1%, P = 0.071). These results extend existing RH-FMD findings indicating that not all women experience fluctuations in FMD with the menstrual cycle. Further research is needed to investigate the mechanisms that underlie variability in the impact of menstrual phase on FMD.

The influence of vitamin C on the interaction between acute mental stress and endothelial function.

PURPOSE: To determine whether orally administered vitamin C attenuates expected mental stress-induced reductions in brachial artery endothelial function as measured by flow-mediated dilation (FMD). METHODS: Fifteen men (21 ± 2 years) were given 1000 mg of vitamin C or placebo over two visits in a randomized, double-blinded, within-subject design. Acute mental stress was induced using the Trier Social Stress Test (TSST). Saliva samples for cortisol determination and FMD measures were obtained at baseline, pre-TSST, and 30 and 90-min post-TSST. An additional saliva sample was obtained immediately post-TSST. Cardiovascular stress reactivity was characterized by changes in heart rate (HR) and mean arterial pressure (MAP). RESULTS: A significant stress response was elicited by the TSST in both conditions [MAP, HR, and salivary cortisol increased (p < 0.001)]. Overall FMD did not differ pre- vs. post-stress (time: p = 0.631) and there was no effect of vitamin C (condition: p = 0.792) (interaction between time and condition, p = 0.573). However, there was a correlation between cortisol reactivity and changes in FMD from pre- to post-stress in the placebo condition (r 2 = 0.66, p < 0.001) that was abolished in the vitamin C condition (r 2 = 0.02, p = 0.612). CONCLUSION: Acute mental stress did not impair endothelial function, and vitamin C disrupted the relationship between cortisol reactivity and changes in FMD post-stress. This suggests that acute mental stress does not universally impair endothelial function and that reactive oxygen species signaling may influence the interaction between FMD and stress responses.

The impact of a cold pressor test on brachial artery handgrip exercise-induced flow-mediated dilation.

It is unknown how endothelial-dependent flow-mediated dilation (FMD) stimulated by a sustained, exercise-induced increase in shear stress (EX-FMD) is affected by a simultaneous sympathoexcitatory painful stimulus. The purpose of this study was to examine the impact of a cold pressor test (CPT) on brachial artery EX-FMD elicited by a handgrip exercise-induced increase in shear stress. Participants were healthy males (age 21±2 years) (n=28; 16 Experimental group, 12 Control). Brachial artery diameter and blood velocity were measured using echo and Doppler ultrasound, respectively. Shear stress was estimated by shear rate (shear rate = blood velocity / diameter) and targeted to reach 75 s(-1) in each of two EX-FMD trials in all subjects. In the Experimental group, the second EX-FMD trial was accompanied by simultaneous foot immersion in ice water (simultaneous CPT). The shear rate stimulus did not differ between groups (p=0.823) or trials (p=0.726) (group × trial interaction: p=0.646) (average exercise shear rate (mean ± SD): 67.6±6.2 s(-1)). The CPT (experienced during EX-FMD trial 2 in the Experimental group) increased mean arterial pressure (p<0.001) and heart rate (p=0.002) relative to the Control group. %EX-FMD was not different between groups (p=0.508) or trials (p=0.592) (group × trial interaction: p=0.879) (EX-FMD: Experimental group trial 1: 5.4±3.4%, trial 2: 5.6±2.6%; Control group trial 1: 6.0±3.7%, trial 2: 6.4±2.2%). In conclusion, the CPT did not impact concurrent EX-FMD, and this indicates that an acute painful stimulus does not interfere with conduit artery FMD responses during exercise in young healthy men.

The combined influence of fat consumption and repeated mental stress on brachial artery flow-mediated dilatation: a preliminary study.

Experienced separately, both acute mental stress and high-fat meal consumption can transiently impair endothelial function, and the purpose of the present study was to investigate their combined impact. On four separate days, 10 healthy men (23 years old) underwent brachial artery flow-mediated dilatation (FMD) tests, before and hourly for 4 h post-consumption of a high-fat (HFM; 54 g fat) or low-fat meal (LFM; 0 g fat; each meal ∼ 1000 calories), with hourly mental stress (mental arithmetic, speech) or control (counting) tasks (conditions HFM+S, LFM+S, HFM and LFM). Data are presented as means ± SD. Plasma triglycerides increased and remained elevated after the high-fat but not the low-fat meal (P = 0.004) and were not affected by mental stress (P = 0.329). Indices of stress reactivity increased during mental stress tasks (mean arterial pressure, ∼ 20 mmHg; heart rate, ∼ 22 beats min(-1); salivary cortisol, ∼ 2.37 nmol l(-1); and plasma noradrenaline, ∼ 0.17 ng ml(-1)) and were not influenced by meal (P > 0.05). There was no effect of the type of meal on FMD (P = 0.562); however, FMD was 4.5 ± 0.5% in the control conditions and 5.8 ± 0.6% in the mental stress conditions (P = 0.087), and this difference was significant when normalized for the shear stress stimulus (FMD/area under the curve of shear stress, P = 0.045). Overall, these preliminary data suggest that postprandial FMD was augmented with mental stress irrespective of meal type. These results are contrary to previous reports of impaired endothelial function after mental stress or fat consumption independently and highlight the need to further investigate the mechanisms underlying the interactions between these factors.

Can a combination of handgrip exercise and prolonged forearm occlusion elicit a maximal brachial artery FMD response?

INTRODUCTION: The upper limit of brachial artery (BA) flow-mediated dilation (FMD) has not been thoroughly interrogated, and long duration occlusion + handgrip exercise may create larger shear stress stimuli than previous manipulations. PURPOSE: To determine whether novel combinations of occlusion + handgrip exercise can extend the range of FMD stimulus-response relationship characterization and permit identification of a BA-FMD response ceiling. METHODS: Ten healthy subjects performed eight reactive hyperemia (RH) FMD trials: 5, 10, and 15 min of occlusion (5RH, 10RH, 15RH); 5, 10 and 15 min of occlusion + 3-min ischemic exercise (IE) (5IE, 10IE, 15IE); 10 and 15 min of occlusion + 3-min IE + 4-min post-occlusion exercise (PE) (10IEPE, 15IEPE). Shear stress was estimated as shear rate (SR = blood velocity/BA diameter; (ultrasound assessment)) (SR stimulus = area under the curve (AUC) until peak diameter). Data are mean ± SE. RESULTS: There were no differences in SR-AUC among IE and IEPE trials (p > 0.70), however, IE consistently increased the SR-AUC (IE + IEPE trial average 17,845.1 ± 2,023.3 a.u.) vs. the 5RH and 10RH trials (4,943.0 ± 428.4 a.u., 6,800.6 ± 805.9 a.u.) (p < 0.05). The %FMD ranged from 7.3 ± 0.8% (5RH) to 19.1 ± 2.0% (15IEPE) (p < 0.001) with no differences among IE and IEPE trials (p > 0.16). FMD increased with increasing SR-AUC (all subjects, all trials: r(2) 0.36, p < 0.001) CONCLUSIONS: The stimulus created by brief (5 min) occlusion + ischemic exercise was not significantly enhanced by prolonging occlusion or continuing to exercise post-occlusion. The FMD response did not clearly plateau with increasing stimulus magnitude; however, the FMD capacity was shown to be more than double the FMD magnitude that was elicited with a standard 5-min occlusion test.