Manipulation of iron status on cerebral blood flow at high altitude in lowlanders and adapted highlanders.

Cerebral blood flow (CBF) increases during hypoxia to counteract the reduction in arterial oxygen content. The onset of tissue hypoxemia coincides with the stabilization of hypoxia-inducible factor (HIF) and transcription of downstream HIF-mediated processes. It has yet to be determined, whether HIF down- or upregulation can modulate hypoxic vasodilation of the cerebral vasculature. Therefore, we examined whether: 1) CBF would increase with iron depletion (via chelation) and decrease with repletion (via iron infusion) at high-altitude, and 2) explore whether genotypic advantages of highlanders extend to HIF-mediated regulation of CBF. In a double-blinded and block-randomized design, CBF was assessed in 82 healthy participants (38 lowlanders, 20 Sherpas and 24 Andeans), before and after the infusion of either: iron(III)-hydroxide sucrose, desferrioxamine or saline. Across both lowlanders and highlanders, baseline iron levels contributed to the variability in cerebral hypoxic reactivity at high altitude (R2 = 0.174, P < 0.001). At 5,050 m, CBF in lowlanders and Sherpa were unaltered by desferrioxamine or iron. At 4,300 m, iron infusion led to 4 ± 10% reduction in CBF (main effect of time p = 0.043) in lowlanders and Andeans. Iron status may provide a novel, albeit subtle, influence on CBF that is potentially dependent on the severity and length-of-stay at high altitude.

Impact of Oxygen Supplementation on Brachial Artery Hemodynamics and Vascular Function During Ascent to 5,050 m.

Vizcardo-Galindo, Gustavo A., Connor A. Howe, Ryan L. Hoiland, Howard H. Carter, Christopher K. Willie, Philip N. Ainslie, and Joshua C. Tremblay. Impact of oxygen supplementation on brachial artery hemodynamics and vascular function during ascent to 5,050 m. High Alt Med Biol. 24:27-36, 2023.-High-altitude trekking alters upper limb hemodynamics and reduces brachial artery vascular function in lowlanders. Whether these changes are reversible with the removal of hypoxia is unknown. We investigated the impact of 20 minutes of oxygen supplementation (O2) on brachial artery hemodynamics, reactive hyperemia (RH; microvascular function), and flow-mediated dilation (FMD; endothelial function). Participants (aged 21-42 years) were examined before and with O2 at 3,440 m (n = 7), 4,371 m (n = 7), and 5,050 m (n = 12) using Duplex ultrasound (days 4, 7, and 10 respectively). At 3,440 m, O2 decreased brachial artery diameter (-5% ± 5%; p = 0.04), baseline blood flow (-44% ± 15%; p < 0.001), oxygen delivery (-39 ± 16; p < 0.001), and peak RH (-8% ± 8%; p = 0.02), but not RH normalized for baseline blood flow. Elevated FMD (p = 0.04) with O2 at 3,440 m was attributed to the reduction in baseline diameter. At 5,050 m, a reduction in brachial artery blood flow (-17% ± 22%; p = 0.03), but not oxygen delivery, diameter, RH, or FMD occurred with O2. These findings suggest that during early trekking at high altitude, O2 causes vasoconstriction in the upper limb along the arterial tree (conduit and resistance arteries). With incremental high-altitude exposure, O2 reduces blood flow without compromising oxygen delivery, RH, or FMD, suggesting a differential impact on vascular function modulated by the duration and severity of high-altitude exposure.

Emotion-driven problem behaviour: The predictive utility of positive and negative urgency.

Impulsive urgency describes the tendency to act rashly when experiencing extreme emotions. This Australian study aimed to investigate the predictive utility of impulsivity, including impulsive urgency (positive and negative), across a range of problem behaviours. Data from two community samples, one retrospective (n = 281) and one current (n = 604), were analysed using hierarchical regression to determine which facets of impulsivity, as assessed with a comprehensive scale (i.e. negative urgency, positive urgency, lack or premeditation, lack of perseverance, and sensation seeking), best predicted a series of problem behaviours (i.e. problem gambling, disorderly alcohol use, online gambling disorder, obsessive-compulsive disorder behaviours, and social media addiction). The impulsive urgency facets were shown to be significant predictors across the behaviours examined. More specifically, negative urgency was the strongest predictor of disorderly alcohol use, obsessive-compulsive disorder behaviours, and social media addiction. Positive urgency was associated with problem gambling and online gambling disorder behaviours. These findings suggest that impulsive urgency is a key contributing factor in many behavioural problems and that the valence of the urgency is an important consideration when addressing a broad range of psychopathologies.

Acid-base balance at high altitude in lowlanders and indigenous highlanders.

High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (∼3,800, ∼4,300, and ∼5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1) at 3,800 m, Andeans (n = 7) had elevated pHa compared with Sherpas (n = 12; P < 0.01), but not to lowlanders (n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders (n = 16; 21 days acclimatized) had elevated pHa compared with Andeans (n = 32) and Sherpas (n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas (P = 0.01); and 3) at 5,000 m, lowlanders (n = 16; 14 days acclimatized) had higher pHa compared with both Andeans (n = 66) and Sherpas (n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa (P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders.NEW & NOTEWORTHY Lowlander, Andean, and Sherpa arterial blood data were combined across five independent high-altitude expeditions in the United States, Nepal, and Peru to assess acid-base status at ∼3,800, ∼4,300, and ∼5,000 m. The main finding was that Andean and Sherpa highlander populations have more acidic arterial blood, due to elevated arterial carbon dioxide and similar arterial bicarbonate compared with acclimatizing lowlanders at altitudes ≥4,300 m.

Regulation of cerebral blood flow by arterial PCO2 independent of metabolic acidosis at 5050 m.

KEY POINTS: We investigated the influence of arterial PCO2 (PaCO2 ) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m. At sea level and high altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO3- ). Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO3- ] (i.e. buffering capacity) were effectively altered. The cerebrovascular responses to changes in arterial [H+ ]/pH were consistent with the altered relationship between PaCO2 and [H+ ]/pH following ACZ at high altitude (i.e. leftward x-intercept shifts). Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. ABSTRACT: Alterations in acid-base balance with progressive acclimatization to high altitude have been well-established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050 m; involving: (1) resting acid-base balance (control); (2) following metabolic acidosis via 2 days of oral acetazolamide at 250 mg every 8 h (ACZ; pH: Δ -0.07 ± 0.04 and base excess: Δ -5.7 ± 1.9 mEq⋅l-1 , trial effects: P < 0.001 and P < 0.001, respectively); and (3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ + HCO3- ; pH: Δ -0.01 ± 0.04 and base excess: Δ -1.5 ± 2.1 mEq⋅l-1 , trial effects: P = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO2 (PaCO2 ), i.e. cerebrovascular CO2 reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e. Δ -3.4 ± 2.3 mmHg PaCO2 , trial effect: P < 0.001) was sufficient to offset any elevations in CBF induced via the ACZ-mediated metabolic acidosis. Between trials at high altitude, we observed consistent leftward shifts in both the PaCO2 -pH and CBV-pH responses across the CO2 reactivity tests with experimentally reduced arterial pH via ACZ. When indexed against PaCO2 - rather than pH - the absolute CBV and sensitivity of CBV-PaCO2 was unchanged between trials at high altitude. Taken together, following acclimatization, CO2 -mediated changes in cerebrovascular tone rather than arterial [H+ ]/pH is integral to CBF regulation at high altitude.

Influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050 m.

KEY POINTS: Iron acts as a cofactor in the stabilization of the hypoxic-inducible factor family, and plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either (1) ascent to high altitude, or (2) following partial acclimatization, when compared to high-altitude adapted Sherpa. During ascent to 5050 m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050 m, PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders compared to Sherpa. Following partial acclimatization to 5050 m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature. ABSTRACT: To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the haematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: (1) a 9-day ascent to 5050 m (20 lowlanders; 12 Sherpa), and (2) following partial acclimatization (11 ± 4 days) to 5050 m (18 lowlanders; 20 Sherpa), where both groups received an i.v. infusion of either iron (iron (iii)-hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a Δhepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400-5050 m (P = 0.016 and P = 0.029, respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050 m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxaemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron-infusion attenuated PASP in both groups at rest (P = 0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxaemia ( PIO2  = 67 mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude.

An Investigation of Alternative Factor Models of Impulsivity using the UPPS-P.

The UPPS-P measures impulsivity as a five-factor construct (lack of premeditation, lack of perseverance, positive urgency, negative urgency and sensation seeking). Drawing on a number of theoretical considerations and alternative conceptions of impulsivity, the current study used confirmatory factor analysis (N = 1635) and multiple regression to evaluate and test alternative models comprising three, five, and a hierarchical model containing latent factors. The five factor and hierarchical models were shown to be valid and of near identical fit, whereas the three-factor model fit the data poorly. The current findings suggest that both the five factor and hierarchical models are useful applications of the UPPS-P. Depending on the purpose of future research, both models demonstrate utility in both risk assessment and treatment development. Multiple regression analysis revealed that positive urgency predicted problem gambling, which supports the predictive utility of impulsivity as a five-factor construct. While the latent factors of the hierarchical model are consistent with emerging theory, those using the UPPS-P should not overlook the unique contributions of the five factors. As the current study found meaningful predictive distinctions between positive and negative urgency, utilizing all five factors may increase measurement sensitivity and predictive utility.

Highs and lows of sympathetic neurocardiovascular transduction: influence of altitude acclimatization and adaptation.

High-altitude (>2,500 m) exposure results in increased muscle sympathetic nervous activity (MSNA) in acclimatizing lowlanders. However, little is known about how altitude affects MSNA in indigenous high-altitude populations. Additionally, the relationship between MSNA and blood pressure regulation (i.e., neurovascular transduction) at high-altitude is unclear. We sought to determine 1) how high-altitude effects neurocardiovascular transduction and 2) whether differences exist in neurocardiovascular transduction between low- and high-altitude populations. Measurements of MSNA (microneurography), mean arterial blood pressure (MAP; finger photoplethysmography), and heart rate (electrocardiogram) were collected in 1) lowlanders (n = 14) at low (344 m) and high altitude (5,050 m), 2) Sherpa highlanders (n = 8; 5,050 m), and 3) Andean (with and without excessive erythrocytosis) highlanders (n = 15; 4,300 m). Cardiovascular responses to MSNA burst sequences (i.e., singlet, couplet, triplet, and quadruplet) were quantified using custom software (coded in MATLAB, v.2015b). Slopes were generated for each individual based on peak responses and normalized total MSNA. High altitude reduced neurocardiovascular transduction in lowlanders (MAP slope: high altitude, 0.0075 ± 0.0060 vs. low altitude, 0.0134 ± 0.080; P = 0.03). Transduction was elevated in Sherpa (MAP slope, 0.012 ± 0.007) compared with Andeans (0.003 ± 0.002, P = 0.001). MAP transduction was not statistically different between acclimatizing lowlanders and Sherpa (MAP slope, P = 0.08) or Andeans (MAP slope, P = 0.07). When resting MSNA is accounted for (ANCOVA), transduction was inversely related to basal MSNA (bursts/minute) independent of population (RRI, r = 0.578 P < 0.001; MAP, r = -0.627, P < 0.0001). Our results demonstrate that transduction is blunted in individuals with higher basal MSNA, suggesting that blunted neurocardiovascular transduction is a physiological adaptation to elevated MSNA rather than an effect or adaptation specific to chronic hypoxic exposure.NEW & NOTEWORTHY This study has identified that sympathetically mediated blood pressure regulation is reduced following ascent to high-altitude. Additionally, we show that high altitude Andean natives have reduced blood pressure responsiveness to sympathetic nervous activity (SNA) compared with Nepalese Sherpa. However, basal sympathetic activity is inversely related to the magnitude of SNA-mediated fluctuations in blood pressure regardless of population or condition. These data set a foundation to explore more precise mechanisms of blood pressure control under conditions of persistent sympathetic activation and hypoxia.

The independent effects of hypovolaemia and pulmonary vasoconstriction on ventricular function and exercise capacity during acclimatisation to 3800 m.

KEY POINTS: We sought to determine the isolated and combined influence of hypovolaemia and hypoxic pulmonary vasoconstriction on the decrease in left ventricular (LV) function and maximal exercise capacity observed under hypobaric hypoxia. We performed echocardiography and maximal exercise tests at sea level (344 m), and following 5-10 days at the Barcroft Laboratory (3800 m; White Mountain, California) with and without (i) plasma volume expansion to sea level values and (ii) administration of the pulmonary vasodilatator sildenafil in a double-blinded and placebo-controlled trial. The high altitude-induced reduction in LV filling and ejection was abolished by plasma volume expansion but to a lesser extent by sildenafil administration; however, neither intervention had a positive effect on maximal exercise capacity. Both hypovolaemia and hypoxic pulmonary vasoconstriction play a role in the reduction of LV filling at 3800 m, but the increase in LV filling does not influence exercise capacity at this moderate altitude. ABSTRACT: We aimed to determine the isolated and combined contribution of hypovolaemia and hypoxic pulmonary vasoconstriction in limiting left ventricular (LV) function and exercise capacity under chronic hypoxaemia at high altitude. In a double-blinded, randomised and placebo-controlled design, 12 healthy participants underwent echocardiography at rest and during submaximal exercise before completing a maximal test to exhaustion at sea level (SL; 344 m) and after 5-10 days at 3800 m. Plasma volume was normalised to SL values, and hypoxic pulmonary vasoconstriction was reversed by administration of sildenafil (50 mg) to create four unique experimental conditions that were compared with SL values: high altitude (HA), Plasma Volume Expansion (HA-PVX), Sildenafil (HA-SIL) and Plasma Volume Expansion with Sildenafil (HA-PVX-SIL). High altitude exposure reduced plasma volume by 11% (P < 0.01) and increased pulmonary artery systolic pressure (19.6 ± 4.3 vs. 26.0 ± 5.4, P < 0.001); these differences were abolished by PVX and SIL respectively. LV end-diastolic volume (EDV) and stroke volume (SV) were decreased upon ascent to high altitude, but were comparable to sea level in the HA-PVX trial. LV EDV and SV were also elevated in the HA-SIL and HA-PVX-SIL trials compared to HA, but to a lesser extent. Neither PVX nor SIL had a significant effect on the LV EDV and SV response to exercise, or the maximal oxygen consumption or peak power output. In summary, at 3800 m both hypovolaemia and hypoxic pulmonary vasoconstriction contribute to the decrease in LV filling, but restoring LV filling does not confer an improvement in maximal exercise performance.

UBC-Nepal Expedition: An experimental overview of the 2016 University of British Columbia Scientific Expedition to Nepal Himalaya.

The University of British Columbia Nepal Expedition took place over several months in the fall of 2016 and was comprised of an international team of 37 researchers. This paper describes the objectives, study characteristics, organization and management of this expedition, and presents novel blood gas data during acclimatization in both lowlanders and Sherpa. An overview and framework for the forthcoming publications is provided. The expedition conducted 17 major studies with two principal goals-to identify physiological differences in: 1) acclimatization; and 2) responses to sustained high-altitude exposure between lowland natives and people of Tibetan descent. We performed observational cohort studies of human responses to progressive hypobaric hypoxia (during ascent), and to sustained exposure to 5050 m over 3 weeks comparing lowlander adults (n = 30) with Sherpa adults (n = 24). Sherpa were tested both with (n = 12) and without (n = 12) descent to Kathmandu. Data collected from lowlander children (n = 30) in Canada were compared with those collected from Sherpa children (n = 57; 3400-3900m). Studies were conducted in Canada (344m) and the following locations in Nepal: Kathmandu (1400m), Namche Bazaar (3440m), Kunde Hospital (3480m), Pheriche (4371m) and the Ev-K2-CNR Research Pyramid Laboratory (5050m). The core studies focused on the mechanisms of cerebral blood flow regulation, the role of iron in cardiopulmonary regulation, pulmonary pressures, intra-ocular pressures, cardiac function, neuromuscular fatigue and function, blood volume regulation, autonomic control, and micro and macro vascular function. A total of 335 study sessions were conducted over three weeks at 5050m. In addition to an overview of this expedition and arterial blood gas data from Sherpa, suggestions for scientists aiming to perform field-based altitude research are also presented. Together, these findings will contribute to our understanding of human acclimatization and adaptation to the stress of residence at high-altitude.

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.

Oxygen therapy improves cerebral oxygen delivery and neurovascular function in hypoxaemic chronic obstructive pulmonary disease patients.

NEW FINDINGS: What is the central question of this study? How does oxygen therapy influence cerebral blood flow, cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients? What is the main finding and its importance? Oxygen therapy improves cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients. This improvement in cerebral oxygen delivery and neurovascular function might provide a physiological link between oxygen therapy and a reduced risk of cerebrovascular disease (e.g. stroke, mild cognitive impairment and dementia) in chronic obstructive pulmonary disease. ABSTRACT: We investigated the role of hypoxaemia in cerebral blood flow (CBF), oxygen delivery (CDO2 ) and neurovascular coupling (coupling of CBF to neural activity; NVC) in hypoxaemic chronic obstructive pulmonary disease (COPD) patients (n = 14). Resting CBF (duplex ultrasound), peripheral oxyhaemoglobin saturation (SpO2; pulse-oximetry) and NVC (transcranial Doppler) were assessed before and after a 20 min wash-in of supplemental oxygen (∼3 l min-1 ). The peripheral oxyhaemoglobin saturation increased from 91.0 ± 3.3 to 97.4 ± 3.0% (P < 0.01), whereas CBF was unaltered (593.0 ± 162.8 versus 590.1 ± 138.5 ml min-1 ; P = 0.91) with supplemental O2 . In contrast, both CDO2 (98.1 ± 25.7 versus 108.7 ± 28.4 ml dl-1 ; P = 0.02) and NVC were improved. Specifically, the posterior cerebral artery cerebrovascular conductance was increased to a greater extent after O2 normalization (+40%, from 20.4 ± 9.9 to 28.0 ± 10.4% increase in conductance; P = 0.04), whereas the posterior cerebral artery cerebrovascular resistance decreased to a greater extent during O2 normalization (+22%, from -16.7 ± 7.3 to -21.4 ± 6.6% decrease in resistance; P = 0.04). The cerebral vasculature of COPD patients appears insensitive to oxygen, because CBF was unaltered in response to O2 supplementation leading to improved CDO2 . In patients, the improvements in CDO2 and neurovascular function with supplemental O2 may underlie the cognitive benefits associated with O2 therapy.

Chemoreflex mediated arrhythmia during apnea at 5,050 m in low- but not high-altitude natives.

Peripheral chemoreflex mediated increases in both parasympathetic and sympathetic drive under chronic hypoxia may evoke bradyarrhythmias during apneic periods. We determined whether 1) voluntary apnea unmasks arrhythmia at low (344 m) and high (5,050 m) altitude, 2) high-altitude natives (Nepalese Sherpa) exhibit similar cardiovagal responses at altitude, and 3) bradyarrhythmias at altitude are partially chemoreflex mediated. Participants were grouped as Lowlanders ( n = 14; age = 27 ± 6 yr) and Nepalese Sherpa ( n = 8; age = 32 ± 11 yr). Lowlanders were assessed at 344 and 5,050 m, whereas Sherpa were assessed at 5,050 m. Heart rate (HR) and rhythm (lead II ECG) were recorded during rest and voluntary end-expiratory apnea. Peripheral chemoreflex contributions were assessed in Lowlanders ( n = 7) at altitude after 100% oxygen. Lowlanders had higher resting HR at altitude (70 ± 15 vs. 61 ± 15 beats/min; P < 0.01) that was similar to Sherpa (71 ± 5 beats/min; P = 0.94). High-altitude apnea caused arrhythmias in 11 of 14 Lowlanders [junctional rhythm ( n = 4), 3° atrioventricular block ( n = 3), sinus pause ( n = 4)] not present at low altitude and larger marked bradycardia (nadir -39 ± 18 beats/min; P < 0.001). Sherpa exhibited a reduced bradycardia response during apnea compared with Lowlanders ( P < 0.001) and did not develop arrhythmias. Hyperoxia blunted bradycardia (nadir -10 ± 14 beats/min; P < 0.001 compared with hypoxic state) and reduced arrhythmia incidence (3 of 7 Lowlanders). Degree of bradycardia was significantly related to hypoxic ventilatory response (HVR) at altitude and predictive of arrhythmias ( P < 0.05). Our data demonstrate apnea-induced bradyarrhythmias in Lowlanders at altitude but not in Sherpa (potentially through cardioprotective phenotypes). The chemoreflex is an important mechanism in genesis of bradyarrhythmias, and the HVR may be predictive for identifying individual susceptibility to events at altitude. NEW & NOTEWORTHY The peripheral chemoreflex increases both parasympathetic and sympathetic drive under chronic hypoxia. We found that this evoked bradyarrhythmias when combined with apneic periods in Lowlanders at altitude, which become relieved through supplemental oxygen. In contrast, high-altitude residents (Nepalese Sherpa) do not exhibit bradyarrhythmias during apnea at altitude through potential cardioprotective adaptations. The degree of bradycardia and bradyarrhythmias was related to the hypoxic ventilatory response, demonstrating that the chemoreflex plays an important role in these findings.

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.

Surviving Without Oxygen: How Low Can the Human Brain Go?

Bailey, Damian M., Christopher K. Willie, Ryan L. Hoiland, Anthony R. Bain, David B. MacLeod, Maria A. Santoro, Daniel K. DeMasi, Andrea Andrijanic, Tanja Mijacika, Otto F. Barak, Zeljko Dujic, and Philip N. Ainslie. Surviving without oxygen: how low can the human brain go? High Alt Med Biol 18:73-79, 2017.-Hypoxic cerebral vasodilation is a highly conserved physiological response coupling cerebral O2 delivery (CDO2) to metabolic demand with increasingly important roles identified for the red blood cell (sensor) and nitric oxide (effector). In the current article, we reexamine previously published cerebral blood flow (CBF) and arterial blood gas data obtained in freedivers and mountaineers, extreme athletes in whom the lowest arterial partial pressures of O2 (19-23 mmHg) and greatest extremes of carbon dioxide (16-61 mmHg) were recorded during (acute) maximal static dry apnea or (chronic) exposure to terrestrial high altitude. Data highlight compensatory increases in CBF (+96% in freedivers to +209% in mountaineers relative to normoxic baseline controls) that were sufficient to sustain CDO2 (+24% in freedivers to +183% in mountaineers) even in the face of the most severe reductions in arterial O2 content (-61% in freedivers to -9% in mountaineers) reported in the literature, consistent with the conservation of mass principle. These unique findings highlight to what extent cerebral vasodilation likely contributes toward these athletes' extraordinary abilities to survive in such harsh environments characterized by physiological extremes of hypoxemia, alkalosis, and acidosis helping define the human brain's remarkable limits of tolerance.

The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude.

The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO2 would affect cerebral metabolism more than hypoxia. PaO2 and PaCO2 were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial-jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO2-H(+) relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO2 reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia.

Regulation of brain blood flow and oxygen delivery in elite breath-hold divers.

The roles of involuntary breathing movements (IBMs) and cerebral oxygen delivery in the tolerance to extreme hypoxemia displayed by elite breath-hold divers are unknown. Cerebral blood flow (CBF), arterial blood gases (ABGs), and cardiorespiratory metrics were measured during maximum dry apneas in elite breath-hold divers (n=17). To isolate the effects of apnea and IBM from the concurrent changes on ABG, end-tidal forcing ('clamp') was then used to replicate an identical temporal pattern of decreasing arterial PO2 (PaO2) and increasing arterial PCO2 (PaCO2) while breathing. End-apnea PaO2 ranged from 23 to 37 mm Hg (30 ± 7 mm Hg). Elevation in mean arterial pressure was greater during apnea than during clamp reaching +54 ± 24% versus 34 ± 26%, respectively; however, CBF increased similarly between apnea and clamp (93.6 ± 28% and 83.4 ± 38%, respectively). This latter observation indicates that during the overall apnea period IBM per se do not augment CBF and that the brain remains sufficiently protected against hypertension. Termination of apnea was not determined by reduced cerebral oxygen delivery; despite 40% to 50% reductions in arterial oxygen content, oxygen delivery was maintained by commensurately increased CBF.

Impact of hypocapnia and cerebral perfusion on orthostatic tolerance.

We examined two novel hypotheses: (1) that orthostatic tolerance (OT) would be prolonged when hyperventilatory-induced hypocapnia (and hence cerebral hypoperfusion) was prevented; and (2) that pharmacological reductions in cerebral blood flow (CBF) at baseline would lower the 'CBF reserve', and ultimately reduce OT. In study 1 (n = 24; aged 25 ± 4 years) participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope; end-tidal carbon dioxide (P ET , CO 2) was clamped at baseline levels (isocapnic trial) or uncontrolled. In study 2 (n = 10; aged 25 ± 4 years), CBF was pharmacologically reduced by administration of indomethacin (INDO; 1.2 mg kg(-1)) or unaltered (placebo) followed by LBNP to pre-syncope. Beat-by-beat measurements of middle cerebral artery blood flow velocity (MCAv; transcranial Doppler), heart rate (ECG), blood pressure (BP; Finometer) and end-tidal gases were obtained continuously. In a subset of subjects' arterial-to-jugular venous differences were obtained to examine the independent impact of hypocapnia or cerebral hypoperfusion (following INDO) on cerebral oxygen delivery and extraction. In study 1, during the isocapnic trial, P ET , CO 2 was successfully clamped at baseline levels at pre-syncope (38.3 ± 2.7 vs. 38.5 ± 2.5 mmHg respectively; P = 0.50). In the uncontrolled trial, P ET , CO 2 at pre-syncope was reduced by 10.9 ± 3.9 mmHg (P ≤ 0.001). Compared to the isocapnic trial, the decline in mean MCAv was 15 ± 4 cm s(-1) (35%; P ≤ 0.001) greater in the uncontrolled trial, yet the time to pre-syncope was comparable between trials (544 ± 130 vs. 572 ± 180 s; P = 0.30). In study 2, compared to placebo, INDO reduced resting MCAv by 19 ± 4 cm s(-1) (31%; P ≤ 0.001), but time to pre-syncope remained similar between trials (placebo: 1123 ± 138 s vs. INDO: 1175 ± 212 s; P = 0.53). The brain extracted more oxygen in face of hypocapnia (34% to 53%) or cerebral hypoperfusion (34% to 57%) to compensate for reductions in delivery. In summary, cerebral hypoperfusion either at rest or induced by hypocapnia at pre-syncope does not impact OT, probably due to a compensatory increase in oxygen extraction.

Integrative regulation of human brain blood flow.

Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation. With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60-150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure. Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research.

Stability of cerebral metabolism and substrate availability in humans during hypoxia and hyperoxia.

Characterization of the influence of oxygen availability on brain metabolism is an essential step toward a better understanding of brain energy homoeostasis and has obvious clinical implications. However, how brain metabolism depends on oxygen availability has not been clearly examined in humans. We therefore assessed the influence of oxygen on CBF (cerebral blood flow) and CMRO2 (cerebral metabolic rates for oxygen) and carbohydrates. PaO2 (arterial partial pressure of oxygen) was decreased for 15 min to ~60, ~44 and ~35 mmHg [to target a SaO2 (arterial oxygen saturation) of 90, 80 and 70% respectively], and elevated to ~320 and ~430 mmHg. Isocapnia was maintained during each trial. At the end of each stage, arterial-jugular venous differences and volumetric CBF were measured to directly calculate cerebral metabolic rates. During progressive hypoxaemia, elevations in CBF were correlated with the reductions in both SaO2 (R2=0.54, P<0.05) and CaO2 (arterial oxygen content) (R2=0.57, P<0.05). Despite markedly reduced CaO2, cerebral oxygen delivery was maintained by increased CBF. Cerebral metabolic rates for oxygen, glucose and lactate remained unaltered during progressive hypoxia. Consequently, cerebral glucose delivery was in excess of that required, and net lactate efflux increased slightly in severe hypoxia, as reflected by a small increase in jugular venous lactate. Progressive hyperoxia did not alter CBF, CaO2, substrate delivery or cerebral metabolism. In conclusion, marked elevations in CBF with progressive hypoxaemia and related reductions in CaO2 resulted in a well-maintained cerebral oxygen delivery. As such, cerebral metabolism is still supported almost exclusively by carbohydrate oxidation during severe levels of hypoxaemia.