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Introduction: Special Operations Forces (SOF) often conduct operations in physiologically stressful environments such as severe heat, cold, or hypoxia, which can induce decreases in a variety of cognitive abilities. Given the promising empirical demonstration of the efficacy of exogenous ketone monoester (KME) supplementation in attenuating cognitive performance decrease during hypoxia at rest in a laboratory setting, we conducted a real-world, field experiment examining KME's efficacy during high-altitude mountaineering, an austere environment in which US SOF have conducted increasing numbers of operations over the past two decades. Methods: Specifically, 34 students and cadre at the US Army 10th Special Forces Group Special Operations Advanced Mountaineering School (SOAMS) participated in a randomized, double-blind, placebo (PLA)-controlled crossover trial (KME vs. PLA) over 2 days of tactical mountain operations training. The participants ascended from 7,500 ft in altitude (basecamp) to 12,460 ft on 1 day and 13,627 ft the other day (in randomized order), while performing various training activities inducing high physical and cognitive loads over 8-12 h, and consumed six doses of KME or PLA 2-3 h apart throughout each training day. Results and Discussion: While KME increased blood ketone levels and decreased glucose levels, there were no clear indications that the elevated ketone level enhanced physical or cognitive performance. KME also produced a greater incidence of heartburn, nausea, and vomiting. In these elite operators, highaltitude mountaineering had a limited impact on cognitive performance, and KME supplementation did not demonstrate any benefit. [ABSTRACT FROM AUTHOR]

IntroductionSpecial Operations Forces (SOF) often conduct operations in physiologically stressful environments such as severe heat, cold, or hypoxia, which can induce decreases in a variety of cognitive abilities. Given the promising empirical demonstration of the efficacy of exogenous ketone monoester (KME) supplementation in attenuating cognitive performance decrease during hypoxia at rest in a laboratory setting, we conducted a real-world, field experiment examining KME’s efficacy during high-altitude mountaineering, an austere environment in which US SOF have conducted increasing numbers of operations over the past two decades.MethodsSpecifically, 34 students and cadre at the US Army 10th Special Forces Group Special Operations Advanced Mountaineering School (SOAMS) participated in a randomized, double-blind, placebo (PLA)–controlled crossover trial (KME vs. PLA) over 2 days of tactical mountain operations training. The participants ascended from 7,500 ft in altitude (basecamp) to 12,460 ft on 1 day and 13,627 ft the other day (in randomized order), while performing various training activities inducing high physical and cognitive loads over 8–12 h, and consumed six doses of KME or PLA 2–3 h apart throughout each training day.Results and DiscussionWhile KME increased blood ketone levels and decreased glucose levels, there were no clear indications that the elevated ketone level enhanced physical or cognitive performance. KME also produced a greater incidence of heartburn, nausea, and vomiting. In these elite operators, high-altitude mountaineering had a limited impact on cognitive performance, and KME supplementation did not demonstrate any benefit.

Previous studies on the cardiac data of healthy permanent residents living in highaltitude regions such as Tibet and the Andes have yielded inconsistent findings and significant disparities. These discrepancies can be mainly attributed to the invasive methods conventionally used for parameter evaluation. However, with the introduction of cutting-edge ultrasound technology, there is now an innovative approach to addressing and reconciling these variations. In this pilot study, we employed an ultrasound-based cardiac output monitoring (USCOM) device to evaluate cardiac output and related hemodynamic variables in a group of 20 healthy high-altitude Andean residents (comprising 10 men and 10 women) aged between 26 and 35 years old. The monocentric study was carried out in La Paz, Bolivia, located between at an altitude of 3,600-4,000 m. A total of 60 hemodynamic measurements were evaluated, accounting for three technical replicates per subject. Our results showed strong intrasubject reproducibility and revealed important differences related to both sex and hemodynamic parameters in highlanders compared to individuals residing at sea level. We conclude that USCOM represents a highly reliable technology for performing hemodynamic measurements in high-altitude residents. Our preliminary findings underscore the need for larger studies, encompassing larger sample sizes, specifically tailored to gender considerations, and extendable to broader highland populations. These findings have special significant implications for the management of hemodynamics in intensive care and postoperative settings, warranting further comprehensive research efforts. [ABSTRACT FROM AUTHOR]

Introduction: This prospective cohort study assessed the effects of chronic hypoxaemia due to high-altitude residency on the cerebral tissue oxygenation (CTO) and cerebrovascular reactivity. Methods: Highlanders, born, raised, and currently living above 2,500 m, without cardiopulmonary disease, participated in a prospective cohort study from 2012 until 2017. The measurements were performed at 3,250 m. After 20 min of rest in supine position while breathing ambient air (FiO2 0.21) or oxygen (FiO2 1.0) in random order, guided hyperventilation followed under the corresponding gas mixture. Finger pulse oximetry (SpO2) and cerebral near-infrared spectroscopy assessing CTO and change in cerebral haemoglobin concentration (cHb), a surrogate of cerebral blood volume changes and cerebrovascular reactivity, were applied. Arterial blood gases were obtained during ambient air breathing.Results: Fifty three highlanders, aged 50 ± 2 years, participated in 2017 and 2012. While breathing air in 2017 vs. 2012, PaO2 was reduced, mean ± SE, 7.40 ± 0.13 vs. 7.84 ± 0.13 kPa; heart rate was increased 77 ± 1 vs. 70 ± 1 bpm (p < 0.05) but CTO remained unchanged, 67.2% ± 0.7% vs. 67.4% ± 0.7%. With oxygen, SpO2 and CTO increased similarly in 2017 and 2012, by a mean (95% CI) of 8.3% (7.5–9.1) vs. 8.5% (7.7–9.3) in SpO2, and 5.5% (4.1–7.0) vs. 4.5% (3.0–6.0) in CTO, respectively. Hyperventilation resulted in less reduction of cHb in 2017 vs. 2012, mean difference (95% CI) in change with air 2.0 U/L (0.3–3.6); with oxygen, 2.1 U/L (0.5–3.7). Conclusion: Within 5 years, CTO in highlanders was preserved despite a decreased PaO2. As this was associated with a reduced response of cerebral blood volume to hypocapnia, adaptation of cerebrovascular reactivity might have occurred. [ABSTRACT FROM AUTHOR]

Previous studies on the cardiac data of healthy permanent residents living in high-altitude regions such as Tibet and the Andes have yielded inconsistent findings and significant disparities. These discrepancies can be mainly attributed to the invasive methods conventionally used for parameter evaluation. However, with the introduction of cutting-edge ultrasound technology, there is now an innovative approach to addressing and reconciling these variations. In this pilot study, we employed an ultrasound-based cardiac output monitoring (USCOM) device to evaluate cardiac output and related hemodynamic variables in a group of 20 healthy high-altitude Andean residents (comprising 10 men and 10 women) aged between 26 and 35 years old. The monocentric study was carried out in La Paz, Bolivia, located between at an altitude of 3,600–4,000 m. A total of 60 hemodynamic measurements were evaluated, accounting for three technical replicates per subject. Our results showed strong intrasubject reproducibility and revealed important differences related to both sex and hemodynamic parameters in highlanders compared to individuals residing at sea level. We conclude that USCOM represents a highly reliable technology for performing hemodynamic measurements in high-altitude residents. Our preliminary findings underscore the need for larger studies, encompassing larger sample sizes, specifically tailored to gender considerations, and extendable to broader highland populations. These findings have special significant implications for the management of hemodynamics in intensive care and postoperative settings, warranting further comprehensive research efforts.

Hypobaric hypoxia (HH) characteristics induce impaired cognitive function, reduced concentration, and memory. In recent years, an increasing number of people have migrated to high-altitude areas for work and study. Headache, sleep disturbance, and cognitive impairment from HH, severely challenges the physical and mental health and affects their quality of life and work efficiency. This review summarizes the manifestations, mechanisms, and preventive and therapeutic methods of HH environment affecting cognitive function and provides theoretical references for exploring and treating high altitude-induced cognitive impairment. [ABSTRACT FROM AUTHOR]

Introduction: This prospective cohort study assessed the effects of chronic hypoxaemia due to high-altitude residency on the cerebral tissue oxygenation (CTO) and cerebrovascular reactivity.Methods: Highlanders, born, raised, and currently living above 2,500 m, without cardiopulmonary disease, participated in a prospective cohort study from 2012 until 2017. The measurements were performed at 3,250 m. After 20 min of rest in supine position while breathing ambient air (FiO2 0.21) or oxygen (FiO2 1.0) in random order, guided hyperventilation followed under the corresponding gas mixture. Finger pulse oximetry (SpO2) and cerebral near-infrared spectroscopy assessing CTO and change in cerebral haemoglobin concentration (cHb), a surrogate of cerebral blood volume changes and cerebrovascular reactivity, were applied. Arterial blood gases were obtained during ambient air breathing.Results: Fifty three highlanders, aged 50 ± 2 years, participated in 2017 and 2012. While breathing air in 2017 vs. 2012, PaO2 was reduced, mean ± SE, 7.40 ± 0.13 vs. 7.84 ± 0.13 kPa; heart rate was increased 77 ± 1 vs. 70 ± 1 bpm (p < 0.05) but CTO remained unchanged, 67.2% ± 0.7% vs. 67.4% ± 0.7%. With oxygen, SpO2 and CTO increased similarly in 2017 and 2012, by a mean (95% CI) of 8.3% (7.5–9.1) vs. 8.5% (7.7–9.3) in SpO2, and 5.5% (4.1–7.0) vs. 4.5% (3.0–6.0) in CTO, respectively. Hyperventilation resulted in less reduction of cHb in 2017 vs. 2012, mean difference (95% CI) in change with air 2.0 U/L (0.3–3.6); with oxygen, 2.1 U/L (0.5–3.7).Conclusion: Within 5 years, CTO in highlanders was preserved despite a decreased PaO2. As this was associated with a reduced response of cerebral blood volume to hypocapnia, adaptation of cerebrovascular reactivity might have occurred.

Background: Acute mountain sickness (AMS) is the most common disease caused by hypobaric hypoxia (HH) in high-altitude (HA) associated with high mortality when progressing to high-altitude pulmonary edema (HAPE) and/or high-altitude cerebral edema (HACE). There is evidence for a role of pro- and anti-inflammatory cytokines in development of AMS, but biological pathways and molecular mechanisms underlying AMS remain elusive. We aimed to measure changes in blood cytokine levels and their possible association with the development of AMS. Method: 15 healthy mountaineers were included into this prospective clinical trial. All participants underwent baseline normoxic testing with venous EDTA blood sampling at the Bangor University in United Kingdom (69 m). The participants started from Beni at an altitude of 869 m and trekked same routes in four groups the Dhaulagiri circuit in the Nepali Himalaya. Trekking a 14-day route, the mountaineers reached the final HA of 5,050 m at the Hidden Valley Base Camp (HVBC). Venous EDTA blood sampling was performed after active ascent to HA the following morning after arrival at 5,050 m (HVBC). A panel of 21 cytokines, chemokines and growth factors were assessed using Luminex system (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-1ra, sIL-2Rα, IFN-γ, TNF-α, MCP-1, MIP-1α, MIP-1β, IP-10, G-CSF, GM-CSF, EGF, FGF-2, VEGF, and TGF-β1). Results: There was a significant main effect for the gradual ascent from sea-level (SL) to HA on nearly all cytokines. Serum levels for TNF-α, sIL-2Rα, G-CSF, VEGF, EGF, TGF-β1, IL-8, MCP-1, MIP-1β, and IP-10 were significantly increased at HA compared to SL, whereas levels for IFN-γ and MIP-1α were significantly decreased. Serum VEGF was higher in AMS susceptible versus AMS resistant subjects (p < 0.027, main effect of AMS) and increased after ascent to HA in both AMS groups (p < 0.011, main effect of HA). Serum VEGF increased more from SL values in the AMS susceptible group than in the AMS resistant group (p < 0.049, interaction effect). Conclusion: Cytokine concentrations are significantly altered in HA. Within short interval after ascent, cytokine concentrations in HH normalize to values at SL. VEGF is significantly increased in mountaineers suffering from AMS, indicating its potential role as a biomarker for AMS. [ABSTRACT FROM AUTHOR]

Background: The two main symptoms at high altitude, sleep abnormalities and cognitive impairments, interact with each other. These two dysfunctions are also closely related to systemic multisystem diseases, including cerebrovascular diseases, psychiatric disorders, and immune regulatory diseases. Purpose: To systematically analyze and visualize research on sleep disturbances and cognitive impairment at high altitudes using a bibliometrics method, and to determine future research directions by analyzing research trends and the latest hotspots. Methods: Publications from 1990 to 2022 on sleep disturbances and cognitive impairment at high altitudes were retrieved from the Web of Science. Using the R Bibliometrix software and Microsoft Excel, all data were examined statistically and qualitatively. For network visualization, the data were later exported into VOSviewer 1.6.17 and CiteSpace 6.1.R6. Results: A total of 487 articles in this area were published from 1990 to 2022. In this period, there was an overall increase in the number of publications. The United States has shown considerable importance in this sector. Bloch Konrad E was the most prolific and valuable author. The most prolific journal was High Altitude Medicine & Biology, and it has been the first choice for publishing in this field in recent years. Analysis of keyword co-occurrences suggested that research interest in the clinical manifestations of sleep disturbances and cognitive impairment caused by altitude hypoxia was mainly focused on “acute mountain-sickness,” “insomnia,” “apnea syndrome,” “depression,” “anxiety,” “Cheyne-strokes respiration,” and “pulmonary hypertension.” The mechanisms of disease development related to “oxidative stress,” “inflammation,” “hippocampus,” “prefrontal cortex,” “neurodegeneration,” and “spatial memory” in the brain have been the focus of recent research. According to burst detection analysis, “mood” and “memory impairment,” as terms with high strength, are expected to remain hot topics in the coming years. High-altitude-induced pulmonary hypertension is also in the emerging stage of research, and the treatments will continue to receive attention in the future. Conclusion: More attention is being focused on sleep disturbances and cognitive impairment at high altitudes. This work will serve as a useful reference for the clinical development of treatments for sleep disturbances and cognitive impairment induced by hypobaric hypoxia at high altitudes. [ABSTRACT FROM AUTHOR]

Background: Acute mountain sickness (AMS) is the most common disease caused by hypobaric hypoxia (HH) in high-altitude (HA) associated with high mortality when progressing to high-altitude pulmonary edema (HAPE) and/or high-altitude cerebral edema (HACE). There is evidence for a role of pro- and anti-inflammatory cytokines in development of AMS, but biological pathways and molecular mechanisms underlying AMS remain elusive. We aimed to measure changes in blood cytokine levels and their possible association with the development of AMS.Method: 15 healthy mountaineers were included into this prospective clinical trial. All participants underwent baseline normoxic testing with venous EDTA blood sampling at the Bangor University in United Kingdom (69 m). The participants started from Beni at an altitude of 869 m and trekked same routes in four groups the Dhaulagiri circuit in the Nepali Himalaya. Trekking a 14-day route, the mountaineers reached the final HA of 5,050 m at the Hidden Valley Base Camp (HVBC). Venous EDTA blood sampling was performed after active ascent to HA the following morning after arrival at 5,050 m (HVBC). A panel of 21 cytokines, chemokines and growth factors were assessed using Luminex system (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-1ra, sIL-2Rα, IFN-γ, TNF-α, MCP-1, MIP-1α, MIP-1β, IP-10, G-CSF, GM-CSF, EGF, FGF-2, VEGF, and TGF-β1).Results: There was a significant main effect for the gradual ascent from sea-level (SL) to HA on nearly all cytokines. Serum levels for TNF-α, sIL-2Rα, G-CSF, VEGF, EGF, TGF-β1, IL-8, MCP-1, MIP-1β, and IP-10 were significantly increased at HA compared to SL, whereas levels for IFN-γ and MIP-1α were significantly decreased. Serum VEGF was higher in AMS susceptible versus AMS resistant subjects (p < 0.027, main effect of AMS) and increased after ascent to HA in both AMS groups (p < 0.011, main effect of HA). Serum VEGF increased more from SL values in the AMS susceptible group than in the AMS resistant group (p < 0.049, interaction effect).Conclusion: Cytokine concentrations are significantly altered in HA. Within short interval after ascent, cytokine concentrations in HH normalize to values at SL. VEGF is significantly increased in mountaineers suffering from AMS, indicating its potential role as a biomarker for AMS.

High altitudes or exposure to hypoxia leads to female reproductive disorders. Circadian clocks are intrinsic time-tracking systems that enable organisms to adapt to the Earth's 24-h light/dark cycle, which can be entrained by other environmental stimuli to regulate physiological and pathological responses. In this study, we focused on whether ovarian circadian clock proteins were involved in regulating female reproductive dysfunction under hypoxic conditions. Hypobaric hypoxia was found to induce a significantly prolonged estrous cycle in female mice, accompanied by follicular atresia, pituitary/ovarian hormone synthesis disorder, and decreased LHCGR expression in the ovaries. Under the same conditions, the levels of the ovarian circadian clock proteins, CLOCK and BMAL1, were suppressed, whereas E4BP4 levels were upregulated. Results from granulosa cells (GCs) further demonstrated that CLOCK: BMAL1 and E4BP4 function as transcriptional activators and repressors of LHCGR in ovarian GCs, respectively, whose responses were mediated by HIF1ɑ-dependent (E4BP4 upregulation) and ɑ-independent (CLOCK and BMAL1 downregulation) manners. The LHCGR agonist was shown to efficiently recover the impairment of ovulation-related gene (EREG and PGR) expression in GCs induced by hypoxia. We conclude that hypoxia exposure causes dysregulation of ovarian circadian clock protein (CLOCK, BMAL1, and E4BP4) expression, which mediates female reproductive dysfunction by impairing LHCGR-dependent signaling events. Adjusting the timing system or recovering the LHCGR level in the ovaries may be helpful in overcoming female reproductive disorders occurring in the highlands. [ABSTRACT FROM AUTHOR]

Remote ischemic preconditioning (RIPC) may improve exercise performance. However, the influence of RIPC on aerobic performance and underlying physiological mechanisms during hypobaric hypoxia (HH) exposure remains relatively uncertain. Here, we systematically evaluated the potential performance benefits and underlying mechanisms of RIPC during HH exposure. Seventy-nine healthy participants were randomly assigned to receive sham intervention or RIPC (4 × 5 min occlusion 180 mm Hg/ reperfusion 0 mm Hg, bilaterally on the upper arms) for 8 consecutive days in phases 1 (24 participants) and phase 2 (55 participants). In the phases 1, we measured the change in maximal oxygen uptake capacity (VO2max) and muscle oxygenation (SmO2) on the leg during a graded exercise test. We also measured regional cerebral oxygenation (rSO2) on the forehead. These measures and physiological variables, such as cardiovascular hemodynamic parameters and heart rate variability index, were used to evaluate the intervention effect of RIPC on the changes in bodily functions caused by HH exposure. In the phase 2, plasma protein mass spectrometry was then performed after RIPC intervention, and the results were further evaluated using ELISA tests to assess possible mechanisms. The results suggested that RIPC intervention improved VO2max (11.29%) and accelerated both the maximum (18.13%) and minimum (53%) values of SmO2 and rSO2 (6.88%) compared to sham intervention in hypobaric hypoxia exposure. Cardiovascular hemodynamic parameters (SV, SVRI, PPV% and SpMet%) and the heart rate variability index (Mean RR, Mean HR, RMSSD, pNN50, Lfnu, Hfnu, SD1, SD2/SD1, ApEn, SampEn, DFA1and DFA2) were evaluated. Protein sequence analysis showed 42 unregulated and six downregulated proteins in the plasma of the RIPC group compared to the sham group after HH exposure. Three proteins, thymosin β4 (Tβ4), heat shock protein-70 (HSP70), and heat shock protein-90 (HSP90), were significantly altered in the plasma of the RIPC group before and after HH exposure. Our data demonstrated that in acute HH exposure, RIPC mitigates the decline in VO2max and regional oxygenation, as well as physiological variables, such as cardiovascular hemodynamic parameters and the heart rate variability index, by influencing plasma Tβ4, HSP70, and HSP90. These data suggest that RIPC may be beneficial for acute HH exposure. [ABSTRACT FROM AUTHOR]

Acute exposure to high altitude perturbs physiological parameters and induces an array of molecular changes in healthy lowlanders. However, activation of compensatory mechanisms and biological processes facilitates high altitude acclimatization. A large number of lowlanders stay at high altitude regions from weeks to months for work and professional commitments, and thus are vulnerable to altitude-associated disorders. Despite this, there is a scarcity of information for molecular changes associated with long-term stay at high altitudes. In the present study, we evaluated oxygen saturation (SpO2), heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) of lowlanders after short- (7 days, HA-D7) and long-term (3 months, HA-D150) stay at high altitudes, and used TMT-based proteomics studies to decipher plasma proteome alterations. We observed improvements in SpO2 levels after prolonged stay, while HR, SBP, and DBP remained elevated as compared with short-term stay. Plasma proteomics studies revealed higher levels of apolipoproteins APOB, APOCI, APOCIII, APOE, and APOL, and carbonic anhydrases (CA1 and CA2) during hypoxia exposure. Biological network analysis also identified profound alterations in lipoprotein-associated pathways like plasma lipoprotein assembly, VLDL clearance, chylomicron assembly, chylomicron remodeling, plasma lipoprotein clearance, and chylomicron clearance. In corroboration, lipid profiling revealed higher levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) for HA-D150 whereas high density lipoproteins (HDL) levels were lower as compared with HA-D7 and sea-level indicating dyslipidemia. We also observed higher levels of proinflammatory cytokines IL-6, TNFα, and CRP for HA-D150 along with oxidized LDL (oxLDL), suggesting vascular inflammation and proartherogenic propensity. These results demonstrate that long-term stay at high altitudes exacerbates dyslipidemia and associated disorders. [ABSTRACT FROM AUTHOR]

High-altitude exposure results in hypobaric hypoxia, which affects organisms by activating several mechanisms at the physiological, cellular, and molecular levels and triggering the development of several pathologies. One such pathology is high-altitude pulmonary hypertension (HAPH), which is initiated through hypoxic pulmonary vasoconstriction to distribute blood to more adequately ventilated areas of the lungs. Importantly, all layers of the pulmonary artery (adventitia, smooth muscle, and endothelium) contribute to or are involved in the development of HAPH. However, the principal action sites of HAPH are pulmonary artery smooth muscle cells (PASMCs), which interact with several extracellular and intracellular molecules and participate in mechanisms leading to proliferation, apoptosis, and fibrosis. This review summarizes the alterations in molecular pathways related to oxidative stress, inflammation, kinase activation, and other processes that occur in PASMCs during pulmonary hypertension under hypobaric hypoxia and proposes updates to pharmacological treatments to mitigate the pathological changes in PASMCs under such conditions. In general, PASMCs exposed to hypobaric hypoxia undergo oxidative stress mediated by Nox4, inflammation mediated by increases in interleukin-6 levels and inflammatory cell infiltration, and activation of the protein kinase ERK1/2, which lead to the proliferation of PASMCs and contribute to the development of hypobaric hypoxia-induced pulmonary hypertension. [ABSTRACT FROM AUTHOR]

High-altitude exposure results in hypobaric hypoxia, which affects organisms by activating several mechanisms at the physiological, cellular, and molecular levels and triggering the development of several pathologies. One such pathology is high-altitude pulmonary hypertension (HAPH), which is initiated through hypoxic pulmonary vasoconstriction to distribute blood to more adequately ventilated areas of the lungs. Importantly, all layers of the pulmonary artery (adventitia, smooth muscle, and endothelium) contribute to or are involved in the development of HAPH. However, the principal action sites of HAPH are pulmonary artery smooth muscle cells (PASMCs), which interact with several extracellular and intracellular molecules and participate in mechanisms leading to proliferation, apoptosis, and fibrosis. This review summarizes the alterations in molecular pathways related to oxidative stress, inflammation, kinase activation, and other processes that occur in PASMCs during pulmonary hypertension under hypobaric hypoxia and proposes updates to pharmacological treatments to mitigate the pathological changes in PASMCs under such conditions. In general, PASMCs exposed to hypobaric hypoxia undergo oxidative stress mediated by Nox4, inflammation mediated by increases in interleukin-6 levels and inflammatory cell infiltration, and activation of the protein kinase ERK1/2, which lead to the proliferation of PASMCs and contribute to the development of hypobaric hypoxia-induced pulmonary hypertension.

This study investigates the changes in soldiers' brain executive function at different altitude environments and their relationship with blood oxygen saturation. Stratified sampling was conducted in different altitude 133 active-duty soldiers who were stationed in Weinan (347 m, n = 34), Nyingchi (2,950 m, n = 32), Lhasa (3,860 m, n = 33), and Nagqu (4,890 m, n = 34) for 2 years. The Go/NoGo paradigm with event-related potentials (ERPs) and event-related oscillations (EROs) was used to explore the time and neural oscillation courses of response inhibition. Behavioral results revealed that at the 4,890-m altitude area, the soldiers had the highest false alarm rate, the longest reaction time, and the slowest information transmission rate. The electrophysiological results revealed that NoGo-N2 and N2d decreased with increasing altitude, with significant changes at 3,860 m; the amplitudes of NoGo-P3 and P3d in plateau groups were significantly more negative than the plain and changed significantly at 2,950 m. The results of correlation analysis showed that NoGo-P3 was negatively correlated with altitude (r = −0.358, p = 0.000), positively correlated with SpO2 (r = 0.197, p = 0.041) and information translation rate (ITR) (r = 0.202, p = 0.036). P3d was negatively correlated with altitude (r = −0.276, p = 0.004) and positively correlated with ITR (r = 0.228, p = 0.018). N2d was negatively correlated with ITR (r = 0.204, p = 0.034). The power spectrum analysis of NoGo-N2 and NoGo-P3 showed that the power of δ and θ bands at the plateau area was significantly lower than the plain area and showed a significant step-by-step decrease; the α-band power increases significantly only in the area of 4,890 m. The effect of chronic hypoxia exposure at different altitudes of the plateau on the response inhibition of soldiers was manifested: 3,860 m was the altitude at which the brain response inhibition function decreased during the conflict monitoring stage, and 2,950 m was the altitude at which it dropped during the response inhibition stage. In addition, the soldier's brain's executive function was closely related to SpO2, and a reduction in SpO2 may lead to a decline in response inhibition.

This study investigates the changes in soldiers' brain executive function at different altitude environments and their relationship with blood oxygen saturation. Stratified sampling was conducted in different altitude 133 active-duty soldiers who were stationed in Weinan (347 m, n = 34), Nyingchi (2,950 m, n = 32), Lhasa (3,860 m, n = 33), and Nagqu (4,890 m, n = 34) for 2 years. The Go/NoGo paradigm with event-related potentials (ERPs) and event-related oscillations (EROs) was used to explore the time and neural oscillation courses of response inhibition. Behavioral results revealed that at the 4,890-m altitude area, the soldiers had the highest false alarm rate, the longest reaction time, and the slowest information transmission rate. The electrophysiological results revealed that NoGo-N2 and N2d decreased with increasing altitude, with significant changes at 3,860 m; the amplitudes of NoGo-P3 and P3d in plateau groups were significantly more negative than the plain and changed significantly at 2,950 m. The results of correlation analysis showed that NoGo-P3 was negatively correlated with altitude (r = −0.358, p = 0.000), positively correlated with SpO2 (r = 0.197, p = 0.041) and information translation rate (ITR) (r = 0.202, p = 0.036). P3d was negatively correlated with altitude (r = −0.276, p = 0.004) and positively correlated with ITR (r = 0.228, p = 0.018). N2d was negatively correlated with ITR (r = 0.204, p = 0.034). The power spectrum analysis of NoGo-N2 and NoGo-P3 showed that the power of δ and θ bands at the plateau area was significantly lower than the plain area and showed a significant step-by-step decrease; the α-band power increases significantly only in the area of 4,890 m. The effect of chronic hypoxia exposure at different altitudes of the plateau on the response inhibition of soldiers was manifested: 3,860 m was the altitude at which the brain response inhibition function decreased during the conflict monitoring stage, and 2,950 m was the altitude at which it dropped during the response inhibition stage. In addition, the soldier's brain's executive function was closely related to SpO2, and a reduction in SpO2 may lead to a decline in response inhibition. [ABSTRACT FROM AUTHOR]

Altitude ascending represents an intriguing experimental model reproducing physiological and pathophysiological conditions sharing hypoxemia as the denominator. The aim of the present study was to investigate fractional oxygen extraction and blood dynamics in response to hypobaric hypoxia and to acute resistance exercises, taking into account several factors including different ethnic origin and muscle groups. As part of the “Kanchenjunga Exploration & Physiology” project, six Italian trekkers and six Nepalese porters took part in a high altitude trek in the Himalayas. The measurements were carried out at low (1,450 m) and high altitude (HA; 4,780 m). Near-infrared spectroscopy (NIRS)-derived parameters, i.e., Tot-Hb and tissue saturation index (TSI), were gathered at rest and after bouts of 3-min resistive exercise, both in the quadriceps and in the forearm muscles. TSI decreased with altitude, particularly in forearm muscles (from 66.9 to 57.3%), whereas the decrement was less in the quadriceps (from 62.5 to 57.2%); Nepalese porters were characterized by greater values in thigh TSI than Italian trekkers. Tot-Hb was increased after exercise. At altitude, such increase appeared to be higher in the quadriceps. This effect might be a consequence of the long-term adaptive memory due to the frequent exposures to altitude. Although speculative, we suggest a long-term adaptation of the Nepalese porters due to improved oxygenation of muscles frequently undergoing hypoxic exercise. Muscle structure, individual factors, and altitude exposure time should be taken into account to move on the knowledge of oxygen delivery and utilization at altitude.

Altitude ascending represents an intriguing experimental model reproducing physiological and pathophysiological conditions sharing hypoxemia as the denominator. The aim of the present study was to investigate fractional oxygen extraction and blood dynamics in response to hypobaric hypoxia and to acute resistance exercises, taking into account several factors including different ethnic origin and muscle groups. As part of the "Kanchenjunga Exploration & Physiology" project, six Italian trekkers and six Nepalese porters took part in a high altitude trek in the Himalayas. The measurements were carried out at low (1,450 m) and high altitude (HA; 4,780 m). Near-infrared spectroscopy (NIRS)-derived parameters, i.e., Tot-Hb and tissue saturation index (TSI), were gathered at rest and after bouts of 3-min resistive exercise, both in the quadriceps and in the forearm muscles. TSI decreased with altitude, particularly in forearm muscles (from 66.9 to 57.3%), whereas the decrement was less in the quadriceps (from 62.5 to 57.2%); Nepalese porters were characterized by greater values in thigh TSI than Italian trekkers. Tot-Hb was increased after exercise. At altitude, such increase appeared to be higher in the quadriceps. This effect might be a consequence of the long-term adaptive memory due to the frequent exposures to altitude. Although speculative, we suggest a long-term adaptation of the Nepalese porters due to improved oxygenation of muscles frequently undergoing hypoxic exercise. Muscle structure, individual factors, and altitude exposure time should be taken into account to move on the knowledge of oxygen delivery and utilization at altitude. [ABSTRACT FROM AUTHOR]

IntroductionThe present study evaluated the putative effect of hypobaria on resting HRV in normoxia and hypoxia.MethodsFifteen young pilot trainees were exposed to five different conditions in a randomized order: normobaric normoxia (NN, PB = 726 ± 5 mmHg, FIO2 = 20.9%), hypobaric normoxia (HN, PB = 380 ± 6 mmHg, FIO2≅40%), normobaric hypoxia (NH, PB = 725 ± 4 mmHg, FIO2≅11%); and hypobaric hypoxia (HH at 3000 and 5500 m, HH3000 and HH5500, PB = 525 ± 6 and 380 ± 8 mmHg, respectively, FIO2 = 20.9%). HRV and pulse arterial oxygen saturation (SpO2) were measured at rest seated during a 6 min period in each condition. HRV parameters were analyzed (Kubios HVR Standard, V 3.0) for time (RMSSD) and frequency (LF, HF, LF/HF ratio, and total power). Gas exchanges were collected at rest for 10 min following HRV recording.ResultsSpO2 decreased in HH3000 (95 ± 3) and HH5500 (81 ± 5), when compared to NN (99 ± 0). SpO2 was higher in NH (86 ± 4) than HH5500 but similar between HN (98 ± 2) and NN. Participants showed lower RMSSD and total power values in NH and HH5500 when compared to NN. In hypoxia, LF/HF ratio was greater in HH5500 than NH, whereas in normoxia, LF/HF ratio was lower in HN than NN. Minute ventilation was higher in HH5500 than in all other conditions.DiscussionThe present study reports a slight hypobaric effect either in normoxia or in hypoxia on some HRV parameters. In hypoxia, with a more prominent sympathetic activation, the hypobaric effect is likely due to the greater ventilation stimulus and larger desaturation. In normoxia, the HRV differences may come from the hyperoxic breathing and slight breathing pattern change due to hypobaria in HN.

High-altitude (HA) natives have evolved some beneficial responses leading to superior work capacity at HA compared to native lowlanders. Our aim was to study two responses potentially protective against hypoxia: the spleen contraction elevating hemoglobin concentration (Hb) and the cardiovascular diving response in Sherpa highlanders, compared to lowlanders. Male participants were recruited from three groups: (1) 21 Sherpa living at HA (SH); (2) seven Sherpa living at low altitude (SL); and (3) ten native Nepalese lowlanders (NL). They performed three apneas spaced by a two-min rest at low altitude (1370 m). Their peripheral oxygen saturation (SpO2), heart rate (HR), and spleen volume were measured across the apnea protocol. Spleen volume at rest was 198 ± 56 mL in SH and 159 ± 35 mL in SL (p = 0.047). The spleen was larger in Sherpa groups compared to the 129 ± 22 mL in NL (p < 0.001 compared to SH; p = 0.046 compared to SL). Spleen contraction occurred in all groups during apnea, but it was greater in Sherpa groups compared to NL (p < 0.001). HR was lower in Sherpa groups compared to NL both during rest (SL: p < 0.001; SH: p = 0.003) and during maximal apneas (SL: p < 0.001; SH: p = 0.06). The apnea-induced HR reduction was 8 ± 8% in SH, 10 ± 4% in SL (NS), and 18 ± 6% in NL (SH: p = 0.005; SL: p = 0.021 compared to NL). Resting SpO2 was similar in all groups. The progressively decreasing baseline spleen size across SH, SL, and NL suggests a role of the spleen at HA and further that both genetic predisposition and environmental exposure determine human spleen size. The similar HR responses of SH and SL suggest that a genetic component is involved in determining the cardiovascular diving response.

BackgroundBoth chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypoxic conditions.MethodsSixty male adult rats were separated into two groups (n = 30 per group) according to their previous diet: a caloric restriction (CR) group and an ad libitum (AL) group. Rats in both groups were randomly assigned to 3 groups: a normoxic group (NX, n = 10), a CIH group (2 days hypoxia/2 days normoxia; n = 10) and a CH group (n = 10). The CR group was previously fed 10 g daily, and the other was fed ad libitum. Rats were exposed to simulated hypobaric hypoxia in a hypobaric chamber set to 428 Torr (the equivalent pressure to that at an altitude of 4,600 m above sea level) for 30 days. Measurements included body weight; hematocrit; serum insulin; glycemia; the degree of RVH (Fulton’s index and histology); and AMPK, mTOR, and PP2C expression levels in the right ventricle determined by western blotting.ResultsA lower degree of RVH, higher AMPK activation, and no activation of mTOR were found in the CR groups exposed to hypobaric hypoxia compared to the AL groups (p < 0.05). Additionally, decreased glycemia and serum insulin levels were observed. Interestingly, PP2C expression showed an increase in the AL groups but not in the CR groups (p < 0.05).ConclusionMaintaining a low weight before and during exposure to high-altitude hypoxia, during either CH or CIH, could prevent a major degree of RVH. This cardioprotection would likely be due to the activation of AMPK. Thus, body weight is a factor that might contribute to RVH at high altitudes.

Introduction: The present study evaluated the putative effect of hypobaria on resting HRV in normoxia and hypoxia. Methods: Fifteen young pilot trainees were exposed to five different conditions in a randomized order: normobaric normoxia (NN, PB = 726 ± 5 mmHg, FIO2 = 20.9%), hypobaric normoxia (HN, PB = 380 ± 6 mmHg, FIO2≅40%), normobaric hypoxia (NH, PB = 725 ± 4 mmHg, FIO2≅11%); and hypobaric hypoxia (HH at 3000 and 5500 m, HH3000 and HH5500, PB = 525 ± 6 and 380 ± 8 mmHg, respectively, FIO2 = 20.9%). HRV and pulse arterial oxygen saturation (SpO2) were measured at rest seated during a 6 min period in each condition. HRV parameters were analyzed (Kubios HVR Standard, V 3.0) for time (RMSSD) and frequency (LF, HF, LF/HF ratio, and total power). Gas exchanges were collected at rest for 10 min following HRV recording. Results: SpO2 decreased in HH3000 (95 ± 3) and HH5500 (81 ± 5), when compared to NN (99 ± 0). SpO2 was higher in NH (86 ± 4) than HH5500 but similar between HN (98 ± 2) and NN. Participants showed lower RMSSD and total power values in NH and HH5500 when compared to NN. In hypoxia, LF/HF ratio was greater in HH5500 than NH, whereas in normoxia, LF/HF ratio was lower in HN than NN. Minute ventilation was higher in HH5500 than in all other conditions. Discussion: The present study reports a slight hypobaric effect either in normoxia or in hypoxia on some HRV parameters. In hypoxia, with a more prominent sympathetic activation, the hypobaric effect is likely due to the greater ventilation stimulus and larger desaturation. In normoxia, the HRV differences may come from the hyperoxic breathing and slight breathing pattern change due to hypobaria in HN. [ABSTRACT FROM AUTHOR]

High-altitude (HA) natives have evolved some beneficial responses leading to superior work capacity at HA compared to native lowlanders. Our aim was to study two responses potentially protective against hypoxia: the spleen contraction elevating hemoglobin concentration (Hb) and the cardiovascular diving response in Sherpa highlanders, compared to lowlanders. Male participants were recruited from three groups: (1) 21 Sherpa living at HA (SH); (2) seven Sherpa living at low altitude (SL); and (3) ten native Nepalese lowlanders (NL). They performed three apneas spaced by a two-min rest at low altitude (1370 m). Their peripheral oxygen saturation (SpO2), heart rate (HR), and spleen volume were measured across the apnea protocol. Spleen volume at rest was 198 ± 56 mL in SH and 159 ± 35 mL in SL (p = 0.047). The spleen was larger in Sherpa groups compared to the 129 ± 22 mL in NL (p < 0.001 compared to SH; p = 0.046 compared to SL). Spleen contraction occurred in all groups during apnea, but it was greater in Sherpa groups compared to NL (p < 0.001). HR was lower in Sherpa groups compared to NL both during rest (SL: p < 0.001; SH: p = 0.003) and during maximal apneas (SL: p < 0.001; SH: p = 0.06). The apnea-induced HR reduction was 8 ± 8% in SH, 10 ± 4% in SL (NS), and 18 ± 6% in NL (SH: p = 0.005; SL: p = 0.021 compared to NL). Resting SpO2 was similar in all groups. The progressively decreasing baseline spleen size across SH, SL, and NL suggests a role of the spleen at HA and further that both genetic predisposition and environmental exposure determine human spleen size. The similar HR responses of SH and SL suggest that a genetic component is involved in determining the cardiovascular diving response. [ABSTRACT FROM AUTHOR]

Background: Both chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypoxic conditions. Methods: Sixty male adult rats were separated into two groups (n = 30 per group) according to their previous diet: a caloric restriction (CR) group and an ad libitum (AL) group. Rats in both groups were randomly assigned to 3 groups: a normoxic group (NX, n = 10), a CIH group (2 days hypoxia/2 days normoxia; n = 10) and a CH group (n = 10). The CR group was previously fed 10 g daily, and the other was fed ad libitum. Rats were exposed to simulated hypobaric hypoxia in a hypobaric chamber set to 428 Torr (the equivalent pressure to that at an altitude of 4,600 m above sea level) for 30 days. Measurements included body weight; hematocrit; serum insulin; glycemia; the degree of RVH (Fulton's index and histology); and AMPK, mTOR, and PP2C expression levels in the right ventricle determined by western blotting. Results: A lower degree of RVH, higher AMPK activation, and no activation of mTOR were found in the CR groups exposed to hypobaric hypoxia compared to the AL groups (p < 0.05). Additionally, decreased glycemia and serum insulin levels were observed. Interestingly, PP2C expression showed an increase in the AL groups but not in the CR groups (p < 0.05). Conclusion: Maintaining a low weight before and during exposure to high-altitude hypoxia, during either CH or CIH, could prevent a major degree of RVH. This cardioprotection would likely be due to the activation of AMPK. Thus, body weight is a factor that might contribute to RVH at high altitudes. [ABSTRACT FROM AUTHOR]

Background: Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high-altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) regulates pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, we investigated whether ADMA concentration at sea level predicts HAPH among Chilean frontiers personnel exposed to 6 months of CIH.Methods: In this prospective study, 123 healthy army draftees were subjected to CIH (5 days at 3,550 m, 2 days at sea level) for 6 months. In 100 study participants with complete data, ADMA, symmetric dimethylarginine (SDMA), L-arginine, arterial oxygen saturation (SaO2), systemic blood pressure, and hematocrit were assessed at months 0 (sea level), 1, 4, and 6. Acclimatization to altitude was determined using the Lake Louise Score (LLS) and the presence of acute mountain sickness (AMS). Echocardiography was performed after 6 months of CIH in 43 individuals with either good (n = 23) or poor (n = 20) acclimatization.Results: SaO2 acutely decreased at altitude and plateaued at 90% thereafter. ADMA increased and SDMA decreased during the study course. The incidence of AMS and the LLS was high after the first ascent (53 and 3.1 ± 2.4) and at 1 month of CIH (47 and 3.0 ± 2.6), but decreased to 20 and 1.4 ± 2.0 at month 6 (both p 25 mm Hg, out of which 9 (21%) were classified as HAPH (mPAP ≥ 30 mm Hg). ADMA at sea level was significantly associated with mPAP at high altitude in month 6 (R = 0.413; p = 0.007). In ROC analysis, a cutoff for baseline ADMA of 0.665 μmol/L was determined to predict HAPH (mPAP > 30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%.Conclusions: ADMA concentration increases during CIH. ADMA at sea level is an independent predictive biomarker of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of HAPH.

Objective: To determine whether the acute cerebral hemodynamic responses to oxygen inhalation are impacted by race or acclimation to high altitude.Methods: Three groups of young healthy males, who were Tibetans (highlanders, n = 15) with lifelong exposure to high altitude, and Han Chinese (lowlanders) with five-year (Han-5 yr, n = 15) and three-day (Han-3 d, n = 16) exposures, participated in the study at an altitude of 3658 m. Cerebral blood flow velocity (CBFV) was recorded for three minutes prior to and during pure oxygen inhalation (2 L/min), respectively, using a transcranial color-coded duplex (TCCD) sonography at the middle cerebral artery (MCA). The blood draw and simultaneous monitoring of blood pressure (BP), heart rate (HR), and finger arterial oxygen saturation (SaO2) were also performed.Results: Values are Mean ± SEM. The three groups had similar demographic characteristics and HR responses, with the group differences (P < 0.05) found in hemoglobin concentration (16.9 ± 0.9, 18.4 ± 1.3, and 15.5 ± 1.0 gm/dL), baseline BPs and HR as expected. Both the Tibetans and Han-5yr groups presented blunted BP responses to O2-inhalation when compared to the Han-3d group; more interestingly, the Tibetans showed significantly reduced responses compared with Han-5yr and Han-3d in CBFV, cerebral oxygen delivery (COD), and pulsatility index (PI) as assessed by Δ%CBFV/ΔSaO2 (-1.50 ± 0.25 vs. -2.24 ± 0.25 and -2.23 ± 0.27, P = 0.049 and 0.048), Δ%COD/ΔSaO2 (-0.52 ± 0.27 vs. -1.33 ± 0.26 and -1.38 ± 0.28, P = 0.044 and 0.031), and Δ%PI (7 ± 2 vs. 16 ± 3 and 16 ± 3 %, P = 0.036 and 0.023), respectively.Conclusion: These findings provide evidence on the Tibetans trait of a distinct cerebral hemodynamic regulatory pattern to keep more stable cerebral blood flow (CBF), oxygen delivery, and pulsatility in response to oxygen inhalation as compared with Han Chinese, which is likely due to a genetic adaptation to altitude.

The Antarctic continent is an environment of extreme conditions. Only few research stations exist that are occupied throughout the year. The German station Neumayer III and the French-Italian Concordia station are such research platforms and human outposts. The seasonal shifts of complete daylight (summer) to complete darkness (winter) as well as massive changes in outside temperatures (down to -80°C at Concordia) during winter result in complete confinement of the crews from the outside world. In addition, the crew at Concordia is subjected to hypobaric hypoxia of ∼650 hPa as the station is situated at high altitude (3,233 m). We studied three expedition crews at Neumayer III (sea level) (n = 16) and two at Concordia (high altitude) (n = 15) to determine the effects of hypobaric hypoxia on hormonal/metabolic stress parameters [endocannabinoids (ECs), catecholamines, and glucocorticoids] and evaluated the psychological stress over a period of 11 months including winter confinement. In the Neumayer III (sea level) crew, EC and n-acylethanolamide (NAE) concentrations increased significantly already at the beginning of the deployment (p < 0.001) whereas catecholamines and cortisol remained unaffected. Over the year, ECs and NAEs stayed elevated and fluctuated before slowly decreasing till the end of the deployment. The classical stress hormones showed small increases in the last third of deployment. By contrast, at Concordia (high altitude), norepinephrine concentrations increased significantly at the beginning (p < 0.001) which was paralleled by low EC levels. Prior to the second half of deployment, norepinephrine declined constantly to end on a low plateau level, whereas then the EC concentrations increased significantly in this second period during the overwintering (p < 0.001). Psychometric data showed no significant changes in the crews at either station. These findings demonstrate that exposition of healthy humans to the physically challenging extreme environment of Antarctica (i) has a distinct modulating effect on stress responses. Additionally, (ii) acute high altitude/hypobaric hypoxia at the beginning seem to trigger catecholamine release that downregulates the EC response. These results (iii) are not associated with psychological stress.

Background: Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high-altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) regulates pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, we investigated whether ADMA concentration at sea level predicts HAPH among Chilean frontiers personnel exposed to 6 months of CIH. Methods: In this prospective study, 123 healthy army draftees were subjected to CIH (5 days at 3,550 m, 2 days at sea level) for 6 months. In 100 study participants with complete data, ADMA, symmetric dimethylarginine (SDMA), L-arginine, arterial oxygen saturation (SaO2), systemic blood pressure, and hematocrit were assessed at months 0 (sea level), 1, 4, and 6. Acclimatization to altitude was determined using the Lake Louise Score (LLS) and the presence of acute mountain sickness (AMS). Echocardiography was performed after 6 months of CIH in 43 individuals with either good (n = 23) or poor (n = 20) acclimatization. Results: SaO2 acutely decreased at altitude and plateaued at 90% thereafter. ADMA increased and SDMA decreased during the study course. The incidence of AMS and the LLS was high after the first ascent (53 and 3.1 ± 2.4) and at 1 month of CIH (47 and 3.0 ± 2.6), but decreased to 20 and 1.4 ± 2.0 at month 6 (both p < 0.001). Eighteen participants (42%) showed a mean pulmonary arterial pressure (mPAP) >25 mm Hg, out of which 9 (21%) were classified as HAPH (mPAP ≥ 30 mm Hg). ADMA at sea level was significantly associated with mPAP at high altitude in month 6 (R = 0.413; p = 0.007). In ROC analysis, a cutoff for baseline ADMA of 0.665 μmol/L was determined to predict HAPH (mPAP > 30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. Conclusions: ADMA concentration increases during CIH. ADMA at sea level is an independent predictive biomarker of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of HAPH. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the acute cerebral hemodynamic responses to oxygen inhalation are impacted by race or acclimation to high altitude. Methods: Three groups of young healthy males, who were Tibetans (highlanders, n = 15) with lifelong exposure to high altitude, and Han Chinese (lowlanders) with five-year (Han-5 yr, n = 15) and three-day (Han-3 d, n = 16) exposures, participated in the study at an altitude of 3658 m. Cerebral blood flow velocity (CBFV) was recorded for three minutes prior to and during pure oxygen inhalation (2 L/min), respectively, using a transcranial color-coded duplex (TCCD) sonography at the middle cerebral artery (MCA). The blood draw and simultaneous monitoring of blood pressure (BP), heart rate (HR), and finger arterial oxygen saturation (SaO2) were also performed. Results: Values are Mean ± SEM. The three groups had similar demographic characteristics and HR responses, with the group differences (P < 0.05) found in hemoglobin concentration (16.9 ± 0.9, 18.4 ± 1.3, and 15.5 ± 1.0 gm/dL), baseline BPs and HR as expected. Both the Tibetans and Han-5yr groups presented blunted BP responses to O2-inhalation when compared to the Han-3d group; more interestingly, the Tibetans showed significantly reduced responses compared with Han-5yr and Han-3d in CBFV, cerebral oxygen delivery (COD), and pulsatility index (PI) as assessed by Δ%CBFV/ΔSaO2 (-1.50 ± 0.25 vs. -2.24 ± 0.25 and -2.23 ± 0.27, P = 0.049 and 0.048), Δ%COD/ΔSaO2 (-0.52 ± 0.27 vs. -1.33 ± 0.26 and -1.38 ± 0.28, P = 0.044 and 0.031), and Δ%PI (7 ± 2 vs. 16 ± 3 and 16 ± 3 %, P = 0.036 and 0.023), respectively. Conclusion: These findings provide evidence on the Tibetans trait of a distinct cerebral hemodynamic regulatory pattern to keep more stable cerebral blood flow (CBF), oxygen delivery, and pulsatility in response to oxygen inhalation as compared with Han Chinese, which is likely due to a genetic adaptation to altitude. [ABSTRACT FROM AUTHOR]

The Antarctic continent is an environment of extreme conditions. Only few research stations exist that are occupied throughout the year. The German station Neumayer III and the French-Italian Concordia station are such research platforms and human outposts. The seasonal shifts of complete daylight (summer) to complete darkness (winter) as well as massive changes in outside temperatures (down to -80°C at Concordia) during winter result in complete confinement of the crews from the outside world. In addition, the crew at Concordia is subjected to hypobaric hypoxia of ∼650 hPa as the station is situated at high altitude (3,233 m). We studied three expedition crews at Neumayer III (sea level) (n = 16) and two at Concordia (high altitude) (n = 15) to determine the effects of hypobaric hypoxia on hormonal/metabolic stress parameters [endocannabinoids (ECs), catecholamines, and glucocorticoids] and evaluated the psychological stress over a period of 11 months including winter confinement. In the Neumayer III (sea level) crew, EC and n -acylethanolamide (NAE) concentrations increased significantly already at the beginning of the deployment (p < 0.001) whereas catecholamines and cortisol remained unaffected. Over the year, ECs and NAEs stayed elevated and fluctuated before slowly decreasing till the end of the deployment. The classical stress hormones showed small increases in the last third of deployment. By contrast, at Concordia (high altitude), norepinephrine concentrations increased significantly at the beginning (p < 0.001) which was paralleled by low EC levels. Prior to the second half of deployment, norepinephrine declined constantly to end on a low plateau level, whereas then the EC concentrations increased significantly in this second period during the overwintering (p < 0.001). Psychometric data showed no significant changes in the crews at either station. These findings demonstrate that exposition of healthy humans to the physically challenging extreme environment of Antarctica (i) has a distinct modulating effect on stress responses. Additionally, (ii) acute high altitude/hypobaric hypoxia at the beginning seem to trigger catecholamine release that downregulates the EC response. These results (iii) are not associated with psychological stress. [ABSTRACT FROM AUTHOR]

An increasing number of people are living or working at high altitudes (hypobaric hypoxia) and therefore suffering several physiological, biochemical, and molecular changes. Pulmonary vasculature is one of the main and first responses to hypoxia. These responses imply hypoxic pulmonary vasoconstriction (HPV), remodeling, and eventually pulmonary hypertension (PH). These events occur according to the type and extension of the exposure. There is also increasing evidence that these changes in the pulmonary vascular bed could be mainly attributed to a homeostatic imbalance as a result of increased levels of reactive oxygen species (ROS). The increase in ROS production during hypobaric hypoxia has been attributed to an enhanced activity and expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), though there is some dispute about which subunit is involved. This enzymatic complex may be directly induced by hypoxia-inducible factor-1α (HIF-1α). ROS has been found to be related to several pathways, cells, enzymes, and molecules in hypoxic pulmonary vasculature responses, from HPV to inflammation, and structural changes, such as remodeling and, ultimately, PH. Therefore, we performed a comprehensive review of the current evidence on the role of ROS in the development of pulmonary vasculature changes under hypoxic conditions, with a focus on hypobaric hypoxia. This review provides information supporting the role of oxidative stress (mainly ROS) in the pulmonary vasculature’s responses under hypobaric hypoxia and depicting possible future therapeutics or research targets. NADPH oxidase-produced oxidative stress is highlighted as a major source of ROS. Moreover, new molecules, such as asymmetric dimethylarginine, and critical inflammatory cells as fibroblasts, could be also involved. Several controversies remain regarding the role of ROS and the mechanisms involved in hypoxic responses that need to be elucidated.

Hypobaric hypoxia (HH) characteristics induce impaired cognitive function, reduced concentration, and memory. In recent years, an increasing number of people have migrated to high-altitude areas for work and study. Headache, sleep disturbance, and cognitive impairment from HH, severely challenges the physical and mental health and affects their quality of life and work efficiency. This review summarizes the manifestations, mechanisms, and preventive and therapeutic methods of HH environment affecting cognitive function and provides theoretical references for exploring and treating high altitude-induced cognitive impairment., Competing Interests: Author YuL was employed by Sichuan Xincheng Biological Co., LTD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Zhang, Lin, Li, Wang, Wang, Liu, Hu and Liu.)

An increasing number of people are living or working at high altitudes (hypobaric hypoxia) and therefore suffering several physiological, biochemical, and molecular changes. Pulmonary vasculature is one of the main and first responses to hypoxia. These responses imply hypoxic pulmonary vasoconstriction (HPV), remodeling, and eventually pulmonary hypertension (PH). These events occur according to the type and extension of the exposure. There is also increasing evidence that these changes in the pulmonary vascular bed could be mainly attributed to a homeostatic imbalance as a result of increased levels of reactive oxygen species (ROS). The increase in ROS production during hypobaric hypoxia has been attributed to an enhanced activity and expression of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase), though there is some dispute about which subunit is involved. This enzymatic complex may be directly induced by hypoxia-inducible factor-1α (HIF-1α). ROS has been found to be related to several pathways, cells, enzymes, and molecules in hypoxic pulmonary vasculature responses, from HPV to inflammation, and structural changes, such as remodeling and, ultimately, PH. Therefore, we performed a comprehensive review of the current evidence on the role of ROS in the development of pulmonary vasculature changes under hypoxic conditions, with a focus on hypobaric hypoxia. This review provides information supporting the role of oxidative stress (mainly ROS) in the pulmonary vasculature’s responses under hypobaric hypoxia and depicting possible future therapeutics or research targets. NADPH oxidase-produced oxidative stress is highlighted as a major source of ROS. Moreover, new molecules, such as asymmetric dimethylarginine, and critical inflammatory cells as fibroblasts, could be also involved. Several controversies remain regarding the role of ROS and the mechanisms involved in hypoxic responses that need to be elucidated. [ABSTRACT FROM AUTHOR]

Rationale: Exposures to simulated altitude (normobaric hypoxia, NH) are frequently used in preparation for mountaineering activities at real altitude (hypobaric hypoxia, HH). However, physiological responses to exercise in NH and HH may differ. Unfortunately clinically useful information on such differences is largely lacking. This study therefore compared exercise responses between a simulated hike on a treadmill in NH and a similar field hike in HH. Methods: Six subjects (four men) participated in two trials, one in a NH chamber and a second in HH at an altitude of 4,205 m on the mountain Mauna Kea. Subjects hiked in each setting for 7 h including breaks. In NH, hiking was simulated by walking on a treadmill. To achieve maximal similarity between hikes, subjects used the same nutrition, clothes, and gear weight. Measurements of peripheral oxygen saturation (SpO2), heart rate (HR) and barometrical pressure (PB)/inspired oxygen fraction (FiO2) were taken every 15 min. Acute mountain sickness (AMS) symptoms were assessed using the Lake-Louise-Score at altitudes of 2,800, 3,500, and 4,200 m. Results: Mean SpO2 values of 85.8% in NH were significantly higher compared to those of 80.2% in HH (p = 0.027). Mean HR values of 103 bpm in NH were significantly lower than those of 121 bpm in HH (p = 0.029). AMS scores did not differ significantly between the two conditions. Conclusion: Physiological responses to exercise recorded in NH are different from those provoked by HH. These findings are of clinical importance for subjects using simulated altitude to prepare for activity at real altitude. [ABSTRACT FROM AUTHOR]

Background: The two main symptoms at high altitude, sleep abnormalities and cognitive impairments, interact with each other. These two dysfunctions are also closely related to systemic multisystem diseases, including cerebrovascular diseases, psychiatric disorders, and immune regulatory diseases. Purpose: To systematically analyze and visualize research on sleep disturbances and cognitive impairment at high altitudes using a bibliometrics method, and to determine future research directions by analyzing research trends and the latest hotspots. Methods: Publications from 1990 to 2022 on sleep disturbances and cognitive impairment at high altitudes were retrieved from the Web of Science. Using the R Bibliometrix software and Microsoft Excel, all data were examined statistically and qualitatively. For network visualization, the data were later exported into VOSviewer 1.6.17 and CiteSpace 6.1.R6. Results: A total of 487 articles in this area were published from 1990 to 2022. In this period, there was an overall increase in the number of publications. The United States has shown considerable importance in this sector. Bloch Konrad E was the most prolific and valuable author. The most prolific journal was High Altitude Medicine & Biology, and it has been the first choice for publishing in this field in recent years. Analysis of keyword co-occurrences suggested that research interest in the clinical manifestations of sleep disturbances and cognitive impairment caused by altitude hypoxia was mainly focused on "acute mountain-sickness," "insomnia," "apnea syndrome," "depression," "anxiety," "Cheyne-strokes respiration," and "pulmonary hypertension." The mechanisms of disease development related to "oxidative stress," "inflammation," "hippocampus," "prefrontal cortex," "neurodegeneration," and "spatial memory" in the brain have been the focus of recent research. According to burst detection analysis, "mood" and "memory impairment," as terms with high strength, are expected to remain hot topics in the coming years. High-altitude-induced pulmonary hypertension is also in the emerging stage of research, and the treatments will continue to receive attention in the future. Conclusion: More attention is being focused on sleep disturbances and cognitive impairment at high altitudes. This work will serve as a useful reference for the clinical development of treatments for sleep disturbances and cognitive impairment induced by hypobaric hypoxia at high altitudes., Competing Interests: Author LW is employed by Sichuan Baicheng Chinese Medicine Technology Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Tang, Chen, Jiang, Liao, Liu, Wang and Chen.)

High altitudes or exposure to hypoxia leads to female reproductive disorders. Circadian clocks are intrinsic time-tracking systems that enable organisms to adapt to the Earth's 24-h light/dark cycle, which can be entrained by other environmental stimuli to regulate physiological and pathological responses. In this study, we focused on whether ovarian circadian clock proteins were involved in regulating female reproductive dysfunction under hypoxic conditions. Hypobaric hypoxia was found to induce a significantly prolonged estrous cycle in female mice, accompanied by follicular atresia, pituitary/ovarian hormone synthesis disorder, and decreased LHCGR expression in the ovaries. Under the same conditions, the levels of the ovarian circadian clock proteins, CLOCK and BMAL1, were suppressed, whereas E4BP4 levels were upregulated. Results from granulosa cells (GCs) further demonstrated that CLOCK: BMAL1 and E4BP4 function as transcriptional activators and repressors of LHCGR in ovarian GCs, respectively, whose responses were mediated by HIF1ɑ-dependent (E4BP4 upregulation) and ɑ-independent (CLOCK and BMAL1 downregulation) manners. The LHCGR agonist was shown to efficiently recover the impairment of ovulation-related gene ( EREG and PGR ) expression in GCs induced by hypoxia. We conclude that hypoxia exposure causes dysregulation of ovarian circadian clock protein (CLOCK, BMAL1, and E4BP4) expression, which mediates female reproductive dysfunction by impairing LHCGR-dependent signaling events. Adjusting the timing system or recovering the LHCGR level in the ovaries may be helpful in overcoming female reproductive disorders occurring in the highlands., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ding, Lu, Huang, Xing, Hou, Wang, Zhang, Wang, Zhang, Zhang, Meng, Liu, Liu, Zhao and Song.)

Remote ischemic preconditioning (RIPC) may improve exercise performance. However, the influence of RIPC on aerobic performance and underlying physiological mechanisms during hypobaric hypoxia (HH) exposure remains relatively uncertain. Here, we systematically evaluated the potential performance benefits and underlying mechanisms of RIPC during HH exposure. Seventy-nine healthy participants were randomly assigned to receive sham intervention or RIPC (4 × 5 min occlusion 180 mm Hg/reperfusion 0 mm Hg, bilaterally on the upper arms) for 8 consecutive days in phases 1 (24 participants) and phase 2 (55 participants). In the phases 1, we measured the change in maximal oxygen uptake capacity (VO 2 max) and muscle oxygenation (SmO 2 ) on the leg during a graded exercise test. We also measured regional cerebral oxygenation (rSO 2 ) on the forehead. These measures and physiological variables, such as cardiovascular hemodynamic parameters and heart rate variability index, were used to evaluate the intervention effect of RIPC on the changes in bodily functions caused by HH exposure. In the phase 2, plasma protein mass spectrometry was then performed after RIPC intervention, and the results were further evaluated using ELISA tests to assess possible mechanisms. The results suggested that RIPC intervention improved VO 2 max (11.29%) and accelerated both the maximum (18.13%) and minimum (53%) values of SmO 2 and rSO 2 (6.88%) compared to sham intervention in hypobaric hypoxia exposure. Cardiovascular hemodynamic parameters (SV, SVRI, PPV% and SpMet%) and the heart rate variability index (Mean RR, Mean HR, RMSSD, pNN50, Lfnu, Hfnu, SD1, SD2/SD1, ApEn, SampEn, DFA1and DFA2) were evaluated. Protein sequence analysis showed 42 unregulated and six downregulated proteins in the plasma of the RIPC group compared to the sham group after HH exposure. Three proteins, thymosin β4 (Tβ4), heat shock protein-70 (HSP70), and heat shock protein-90 (HSP90), were significantly altered in the plasma of the RIPC group before and after HH exposure. Our data demonstrated that in acute HH exposure, RIPC mitigates the decline in VO 2 max and regional oxygenation, as well as physiological variables, such as cardiovascular hemodynamic parameters and the heart rate variability index, by influencing plasma Tβ4, HSP70, and HSP90. These data suggest that RIPC may be beneficial for acute HH exposure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhong, Dong, Wu, Zhou, Li, Huang, Tian, Li, Xiao, Yang, Xiong, Zhang, Tang, Li, Fan, Yuan, Ning, Li, Xie and Li.)

Rationale: Exposures to simulated altitude (normobaric hypoxia, NH) are frequently used in preparation for mountaineering activities at real altitude (hypobaric hypoxia, HH). However, physiological responses to exercise in NH and HH may differ. Unfortunately clinically useful information on such differences is largely lacking. This study therefore compared exercise responses between a simulated hike on a treadmill in NH and a similar field hike in HH. Methods: Six subjects (four men) participated in two trials, one in a NH chamber and a second in HH at an altitude of 4,205 m on the mountain Mauna Kea. Subjects hiked in each setting for 7 h including breaks. In NH, hiking was simulated by walking on a treadmill. To achieve maximal similarity between hikes, subjects used the same nutrition, clothes, and gear weight. Measurements of peripheral oxygen saturation (SpO 2 ), heart rate (HR) and barometrical pressure (P B )/inspired oxygen fraction (F i O 2 ) were taken every 15 min. Acute mountain sickness (AMS) symptoms were assessed using the Lake-Louise-Score at altitudes of 2,800, 3,500, and 4,200 m. Results: Mean SpO 2 values of 85.8% in NH were significantly higher compared to those of 80.2% in HH ( p = 0.027). Mean HR values of 103 bpm in NH were significantly lower than those of 121 bpm in HH ( p = 0.029). AMS scores did not differ significantly between the two conditions. Conclusion: Physiological responses to exercise recorded in NH are different from those provoked by HH. These findings are of clinical importance for subjects using simulated altitude to prepare for activity at real altitude. Trial registration: Registration at DRKS. (Approval No. 359/12, Trial No. DRKS00005241).