The influence of sex and maturation on carotid and vertebral artery hemodynamics and associations with free-living (in)activity in 6-17-year-olds.

We explored the influence of sex and maturation on resting cervical artery hemodynamics (common carotid artery, CCA; internal carotid artery, ICA; and vertebral artery, VA), free-living physical activity, and sedentary behavior in children 6-17 yr of age. In addition, we investigated the relationship between physical activity, sedentary behavior, and cervical artery hemodynamics. Seventy-eight children and adolescents, girls (n = 42; mean age, 11.4 ± 2.5 yr) and boys (n = 36; mean age, 11.0 ± 2.6 yr), completed anthropometric measures, duplex ultrasound assessment of the cervical arteries, and wore an activPAL accelerometer to assess physical activity (indexed by steps/day) and sedentary behavior for 7 days. The ICA and VA diameters were similar between prepubertal and pubertal groups, as was volumetric blood flow (Q); however, the CCA diameter was significantly larger in the pubertal group (P < 0.05). Boys were found to have larger diameters in all cervical arteries than girls, as well as higher QCCA, QICA, and global cerebral blood flow (P < 0.05). The pubertal group was more sedentary (100 min/day more; P < 0.05) and took 3,500 fewer steps/day than the prepubertal group (P < 0.05). Shear rate (SR) and Q of the cervical arteries showed no relationship to physical activity or prolonged bouts of sedentary behavior; however, a significant negative relationship was apparent between total sedentary time and internal carotid artery shear rate (ICASR) after covarying for steps/day and maturation (P < 0.05). These findings provide novel insight into the potential influence sedentary behavior may have on cerebrovascular blood flow in healthy girls and boys.NEW & NOTEWORTHY Cerebral blood flow is known to change with age; however, assessing these age-related changes is complex and requires consideration of pubertal status. This, to our knowledge, is the first study to investigate the influence of sex and maturation on resting cervical artery hemodynamics and subsequently explore associations with physical activity and sedentary behavior in healthy children and adolescents. Our findings suggest that habitual sedentary behavior may influence cervical artery hemodynamics in youth, independent of physical activity, maturation, and sex.

UBC-Nepal Expedition: Haemoconcentration underlies the reductions in cerebral blood flow observed during acclimatization to high altitude.

NEW FINDINGS: What is the central question of this study? The aim was to evaluate the degree to which increases in haematocrit alter cerebral blood flow and cerebral oxygen delivery during acclimatization to high altitude. What is the main finding and its importance? Through haemodilution, we determined that, after 1 week of acclimatization, the primary mechanism contributing to the cerebral blood flow response during acclimatization is an increase in haemoglobin and haematocrit. The remaining contribution to the cerebral blood flow response during acclimatization is likely to be attributable to ventilatory acclimatization. ABSTRACT: At high altitude, an increase in haematocrit (Hct) is achieved through altitude-induced diuresis and erythropoiesis, both of which result in increased arterial oxygen content. Given the impact of alterations in Hct on oxygen content, haemoconcentration has been hypothesized to mediate, in part, the attenuation of the initial elevation in cerebral blood flow (CBF) at high altitude. To test this hypothesis, healthy men (n = 13) ascended to 5050 m over 9 days without the aid of prophylactic acclimatization medications. After 1 week of acclimatization at 5050 m, participants were haemodiluted by rapid saline infusion (2.10 ± 0.28 l) to return Hct towards pre-acclimatization values. Arterial blood gases, Hct, global CBF (duplex ultrasound) and haemodynamic variables were measured after initial arrival at 5050 m and after 1 week of acclimatization at high altitude, before and after the haemodilution protocol. After 1 week at 5050 m, the Hct increased from 42.5 ± 2.5 to 49.6 ± 2.5% (P < 0.001), and it was subsequently reduced to 45.6 ± 2.3% (P < 0.001) after haemodilution. Global CBF decreased from 844 ± 160 to 619 ± 136 ml min-1 (P = 0.033) after 1 week of acclimatization and increased to 714 ± 204 ml min -1 (P = 0.045) after haemodilution. Despite the significant changes in Hct, and thus oxygen content, cerebral oxygen delivery was unchanged at all time points. Furthermore, these observations occurred in the absence of any changes in mean arterial blood pressure, cardiac output, arterial blood pH or oxygen saturation pre- and posthaemodilution. These data highlight the influence of Hct in the regulation of CBF and are the first to demonstrate experimentally that haemoconcentration contributes to the reduction in CBF during acclimatization to altitude.

UBC-Nepal Expedition: Cerebrovascular Responses to Exercise in Sherpa Children Residing at High Altitude.

Understanding the process of successful adaptation to high altitude provides valuable insight into the pathogenesis of conditions associated with impaired oxygen uptake and utilization. Prepubertal children residing at low altitude show a reduced cerebrovascular response to exercise in comparison to adults, and a transient uncoupling of cerebral blood flow to changes in the partial pressure of end-tidal CO2 (PETCO2); however, little is known about the cerebrovascular response to exercise in high-altitude native children. We sought to compare the cerebral hemodynamic response to acute exercise between prepubertal children residing at high and low altitude. Prepubertal children (n = 32; 17 female) of Sherpa descent (Sherpa children [SC]) at high altitude (3800 m, Nepal) and maturational-matched (n = 32; 20 female) children (lowland children [LLC]) residing at low altitude (342 m, Canada). Ventilation, peripheral oxygen saturation (SpO2), PETCO2, and blood velocity in the middle and posterior cerebral arteries (MCAv and PCAv) were continuously measured during a graded cycling exercise test to exhaustion. At baseline (BL), PETCO2 (-19 ± 4 mmHg, p < 0.001), SpO2 (-6.0% ± 2.1%, p < 0.001), MCAv (-12% ± 5%, p = 0.02), and PCAv (-12% ± 6%, p = 0.04) were lower in SC when compared with LLC. Despite this, the relative change in MCAv and PCAv during exercise was similar between the two groups (p = 0.99). Linear regression analysis demonstrated a positive relationship between changes in PETCO2 with MCAv in SC (R2 = 0.13, p > 0.001), but not in LLC (R2 = 0.03, p = 0.10). Our findings demonstrate a similar increase in intra-cranial perfusion during exercise in prepubertal SC, despite differential BL values and changes in PETCO2 and SpO2.

One session of remote ischemic preconditioning does not improve vascular function in acute normobaric and chronic hypobaric hypoxia.

NEW FINDINGS: What is the central question of this study? It is suggested that remote ischemic preconditioning (RIPC) might offer protection against ischaemia-reperfusion injuries, but the utility of RIPC in high-altitude settings remains unclear. What is the main finding and its importance? We found that RIPC offers no vascular protection relative to pulmonary artery pressure or peripheral endothelial function during acute, normobaric hypoxia and at high altitude in young, healthy adults. However, peripheral chemosensitivity was heightened 24 h after RIPC at high altitude. Application of repeated short-duration bouts of ischaemia to the limbs, termed remote ischemic preconditioning (RIPC), is a novel technique that might have protective effects on vascular function during hypoxic exposures. In separate parallel-design studies, at sea level (SL; n = 16) and after 8-12 days at high altitude (HA; n = 12; White Mountain, 3800 m), participants underwent either a sham protocol or one session of four bouts of 5 min of dual-thigh-cuff occlusion with 5 min recovery. Brachial artery flow-mediated dilatation (FMD; ultrasound), pulmonary artery systolic pressure (PASP; echocardiography) and internal carotid artery (ICA) flow (ultrasound) were measured at SL in normoxia and isocapnic hypoxia (end-tidal PO2 maintained at 50 mmHg) and during normal breathing at HA. The hypoxic ventilatory response (HVR) was measured at each location. All measures at SL and HA were obtained at baseline (BL) and at 1, 24 and 48 h post-RIPC or sham. At SL, RIPC produced no changes in FMD, PASP, ICA flow, end-tidal gases or HVR in normoxia or hypoxia. At HA, although HVR increased 24 h post-RIPC compared with BL [2.05 ± 1.4 versus 3.21 ± 1.2 l min-1  (% arterial O2 saturation)-1 , P < 0.01], there were no significant differences in FMD, PASP, ICA flow and resting end-tidal gases. Accordingly, a single session of RIPC is insufficient to evoke changes in peripheral, pulmonary and cerebral vascular function in healthy adults. Although chemosensitivity might increase after RIPC at HA, this did not confer any vascular changes. The utility of a single RIPC session seems unremarkable during acute and chronic hypoxia.

Adenosine receptor-dependent signaling is not obligatory for normobaric and hypobaric hypoxia-induced cerebral vasodilation in humans.

Hypoxia increases cerebral blood flow (CBF) with the underlying signaling processes potentially including adenosine. A randomized, double-blinded, and placebo-controlled design, was implemented to determine if adenosine receptor antagonism (theophylline, 3.75 mg/Kg) would reduce the CBF response to normobaric and hypobaric hypoxia. In 12 participants the partial pressures of end-tidal oxygen ([Formula: see text]) and carbon dioxide ([Formula: see text]), ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), CBF (duplex ultrasound), and intracranial blood velocities (transcranial Doppler ultrasound) were measured during 5-min stages of isocapnic hypoxia at sea level (98, 90, 80, and 70% [Formula: see text]). Ventilation, [Formula: see text] and [Formula: see text], blood pressure, heart rate, and CBF were also measured upon exposure (128 ± 31 min following arrival) to high altitude (3,800 m) and 6 h following theophylline administration. At sea level, although the CBF response to hypoxia was unaltered pre- and postplacebo, it was reduced following theophylline (P < 0.01), a finding explained by a lower [Formula: see text] (P < 0.01). Upon mathematical correction for [Formula: see text], the CBF response to hypoxia was unaltered following theophylline. Cerebrovascular reactivity to hypoxia (i.e., response slope) was not different between trials, irrespective of [Formula: see text] At high altitude, theophylline (n = 6) had no effect on CBF compared with placebo (n = 6) when end-tidal gases were comparable (P > 0.05). We conclude that adenosine receptor-dependent signaling is not obligatory for cerebral hypoxic vasodilation in humans.NEW & NOTEWORTHY The signaling pathways that regulate human cerebral blood flow in hypoxia remain poorly understood. Using a randomized, double-blinded, and placebo-controlled study design, we determined that adenosine receptor-dependent signaling is not obligatory for the regulation of human cerebral blood flow at sea level; these findings also extend to high altitude.

Hypoxemia, oxygen content, and the regulation of cerebral blood flow.

This review highlights the influence of oxygen (O2) availability on cerebral blood flow (CBF). Evidence for reductions in O2 content (CaO2 ) rather than arterial O2 tension (PaO2 ) as the chief regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O2 sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in CaO2 . We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in CaO2 and thus maintain cerebral O2 delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that CaO2 has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower CaO2 during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regulation during changes in O2 content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP, deoxyhemoglobin nitrite reductase activity, and the downstream interplay of several vasoactive factors including adenosine and epoxyeicosatrienoic acids. The emerging picture supports the role of deoxyhemoglobin (associated with changes in CaO2 ) as the primary biological regulator of CBF. The mechanisms for vasodilation therefore appear more robust during hypoxemic hypoxia than during changes in CaO2 via hemodilution. Clinical implications (e.g., disorders associated with anemia and polycythemia) and future study directions are considered.