Ventilatory responses to independent and combined hypoxia, hypercapnia and hypobaria in healthy pre-term-born adults.

Pre-term birth is associated with physiological sequelae that persist into adulthood. In particular, modulated ventilatory responsiveness to hypoxia and hypercapnia has been observed in this population. Whether pre-term birth per se causes these effects remains unclear. Therefore, we aimed to assess pulmonary ventilation and blood gases under various environmental conditions, comparing 17 healthy prematurely born individuals (mean ± SD; gestational age, 28 ± 2 weeks; age, 21 ± 4 years; peak oxygen uptake, 48.1 ± 11.2 ml kg-1  min-1 ) with 16 well-matched adults born at term (gestational age, 40 ± 1 weeks; age, 22 ± 2 years; peak oxygen uptake, 51.2 ± 7.7 ml kg-1  min-1 ). Participants were exposed to seven combinations of hypoxia/hypobaria (equivalent to ∼3375 m) and/or hypercapnia (3% CO2 ), at rest for 6 min. Pulmonary ventilation, pulse oxygen saturation and the arterial partial pressures of O2 and CO2 were similar in pre-term and full-term individuals under all conditions. Higher ventilation in hypoxia compared to normoxia was only observed at terrestrial altitude, despite an equivalent (normobaric) hypoxic stimulus administered at sea level (0.138 F i O 2 ${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ). Assessment of oscillations in key variables revealed that combined hypoxic hypercapnia induced greater underlying fluctuations in ventilation in pre-term individuals only. In general, higher pulse oxygen saturation fluctuations were observed with hypoxia, and lower fluctuations in end-tidal CO2 with hypercapnia, despite similar ventilatory oscillations observed between conditions. These findings suggest that healthy prematurely born adults display similar overall ventilation to their term-born counterparts under various environmental stressors, but that combined ventilatory stimuli could induce an irregular underlying ventilatory pattern. Moreover, barometric pressure may be an important factor when assessing ventilatory responsiveness to moderate hypoxic stimuli. KEY POINTS: Evidence exists for unique pulmonary and respiratory function under hypoxic conditions in adult survivors of pre-term birth. Whether pre-term birth per se causes these differences requires a comparison of conventionally healthy prematurely born adults with an appropriately matched sample of term-born individuals. According to the present data, there is no difference between healthy pre-term and well-matched term-born individuals in the magnitude of pulmonary ventilation or arterial blood gases during independent and combined hypobaria, hypoxia and hypercapnia. Terrestrial altitude (hypobaria) was necessary to induce differences in ventilation between normoxia and a hypoxic stimulus equivalent to ∼3375 m of altitude. Furthermore, peak power in pulse oxygen saturation was similar between hypobaric normoxia and normobaric hypoxia. The observed similarities between groups suggest that ventilatory regulation under various environmental stimuli is not impaired by pre-term birth per se. Instead, an integrated combination of neonatal treatment strategies and cardiorespiratory fitness/disease status might underlie previously observed chemosensitivity impairments.

'White Mars' - nearly two decades of biomedical research at the Antarctic Concordia station.

NEW FINDINGS: What is the topic of this review? Biomedical research at the Antarctic Concordia Station. What advances does it highlight? Overview of findings in psychology, neuroscience, sleep, cardiovascular physiology and immune system, relevant in isolated, confined and extreme environments and spaceflight. ABSTRACT: Extended stays in isolated, confined and extreme (ICE) environments like Antarctica are associated with a whole set of psychological and physiological challenges for the crew. As such, winter-over stays at Antarctica provide an important opportunity to acquire knowledge into the physiological and psychological changes that ICE environments inevitably bring. The European Space Agency (ESA) is particularly interested in conducting research in such an environment, as it is a unique opportunity to translate these results to space crews experiencing very similar issues. In the past two decades, the ESA has supported a total of 36 biomedical research projects at the Concordia station in collaboration with the French and Italian polar institutes. More specifically, studies in the areas of psychology, neuroscience, sleep physiology, cardiovascular physiology and immunology were performed. The outcomes of these studies are directly relevant for people working in ICE environments, but also help to better understand the biomedical challenges of those environments. Consequently, they can help to better prepare for human space exploration and to identify countermeasures to minimize the adverse effects of space environments on astronaut health. The aim of this review is to provide an overview of the biomedical studies that have taken place in the past two decades at the Antarctic Concordia station and to summarize the results and their implication for human spaceflight.

Respiratory muscle training and exercise ventilation while diving at altitude.

Introduction: Pre-dive altitude exposure may increase respiratory fatigue and subsequently augment exercise ventilation at depth. This study examined pre-dive altitude exposure and the efficacy of resistance respiratory muscle training (RMT) on respiratory fatigue while diving at altitude. Methods: Ten men (26±5 years; VO2peak: 39.8±3.3 mL• kg-1•min-1) performed three dives; one control (ground level) and two simulated altitude dives (3,658 m) to 17 msw, relative to ground level, before and after four weeks of resistance RMT. Subjects performed pulmonary function testing (e.g., inspiratory [PI] and expiratory [PE] pressure testing) pre- and post-RMT and during dive visits. During each dive, subjects exercised for 18 minutes at 55% VO2peak, and ventilation (VE), breathing frequency (ƒb,), tidal volume (VT) and rating of perceived exertion (RPE) were measured. Results: Pre-dive altitude exposure reduced PI before diving (p=0.03), but had no effect on exercise VE, ƒb, or VT at depth. At the end of the dive in the pre-RMT condition, RPE was lower (p=0.01) compared to control. RMT increased PI and PE (p<0.01). PE was reduced from baseline after diving at altitude (p<0.03) and this was abated after RMT. RMT did not improve VE or VT at depth, but decreased ƒb (p=0.01) and RPE (p=0.048) during the final minutes of exercise. Conclusion: Acute altitude exposure pre- and post-dive induces decrements in PI and PE before and after diving, but does not seem to influence ventilation at depth. RMT reduced ƒb and RPE during exercise at depth, and may be useful to reduce work of breathing and respiratory fatigue during dives at altitude.

Cell cycle inhibition reduces inflammatory responses, neuronal loss, and cognitive deficits induced by hypobaria exposure following traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) patients in military settings can be exposed to prolonged periods of hypobaria (HB) during aeromedical evacuation. Hypobaric exposure, even with supplemental oxygen to prevent hypoxia, worsens outcome after experimental TBI, in part by increasing neuroinflammation. Cell cycle activation (CCA) after TBI has been implicated as a mechanism contributing to both post-traumatic cell death and neuroinflammation. Here, we examined whether hypobaric exposure in rats subjected to TBI increases CCA and microglial activation in the brain, as compared to TBI alone, and to evaluate the ability of a cyclin-dependent kinase (CDK) inhibitor (CR8) to reduce such changes and improve behavioral outcomes. METHODS: Adult male Sprague Dawley rats were subjected to fluid percussion-induced injury, and HB exposure was performed at 6 h after TBI. Western blot and immunohistochemistry (IHC) were used to assess cell cycle-related protein expression and inflammation at 1 and 30 days after injury. CR8 was administered intraperitoneally at 3 h post-injury; chronic functional recovery and histological changes were assessed. RESULTS: Post-traumatic hypobaric exposure increased upregulation of cell cycle-related proteins (cyclin D1, proliferating cell nuclear antigen, and CDK4) and microglial/macrophage activation in the ipsilateral cortex at day 1 post-injury as compared to TBI alone. Increased immunoreactivity of cell cycle proteins, as well as numbers of Iba-1+ and GFAP+ cells in both the ipsilateral cortex and hippocampus were found at day 30 post-injury. TBI/HB significantly increased the numbers of NADPH oxidase 2 (gp91phox) enzyme-expressing cells that were co-localized with Iba-1+. Each of these changes was significantly reduced by the administration of CR8. Unbiased stereological assessment showed significantly decreased numbers of microglia displaying the highly activated phenotype in the ipsilateral cortex of TBI/HB/CR8 rats compared with TBI/HB/Veh rats. Moreover, treatment with this CDK inhibitor also significantly improved spatial and retention memory and reduced lesion volume and hippocampal neuronal cell loss. CONCLUSIONS: HB exposure following TBI increases CCA, neuroinflammation, and associated neuronal cell loss. These changes and post-traumatic cognitive deficits are reduced by CDK inhibition; such drugs may therefore serve to protect TBI patients requiring aeromedical evacuation.

Surpassing Mt. Everest: extreme flight performance of alpine bumble-bees.

Animal flight at altitude involves substantial aerodynamic and physiological challenges. Hovering at high elevations is particularly demanding from the dual perspectives of lift and power output; nevertheless, some volant insects reside and fly at elevations in excess of 4000 m. Here, we demonstrate that alpine bumble-bees possess substantial aerodynamic reserves, and can sustain hovering flight under hypobaria at effective elevations in excess of 9000 m, i.e. higher than Mt. Everest. Modulation of stroke amplitude and not wingbeat frequency is the primary means of compensation for overcoming the aerodynamic challenge. The presence of such excess capacity in a high-altitude bumble-bee is surprising and suggests intermittent behavioural demands for extreme flight performance supplemental to routine foraging.

Baroreflex sensitivity is blunted in hypoxia independently of changes in inspired carbon dioxide pressure in prematurely born male adults.

Premature birth may result in specific cardiovascular responses to hypoxia and hypercapnia, that might hamper high-altitude acclimatization. This study investigated the consequences of premature birth on baroreflex sensitivity (BRS) under hypoxic, hypobaric and hypercapnic conditions. Seventeen preterm born males (gestational age, 29 ± 1 weeks), and 17 age-matched term born adults (40 ± 0 weeks) underwent consecutive 6-min stages breathing different oxygen and carbon dioxide concentrations at both sea-level and high-altitude (3375 m). Continuous blood pressure and ventilatory parameters were recorded in normobaric normoxia (NNx), normobaric normoxic hypercapnia (NNx + CO2 ), hypobaric hypoxia (HHx), hypobaric normoxia (HNx), hypobaric normoxia hypercapnia (HNx + CO2 ), and hypobaric hypoxia with end-tidal CO2 clamped at NNx value (HHx + clamp). BRS was assessed using the sequence method. Across all conditions, BRS was lower in term born compared to preterm (13.0 ± 7.5 vs. 21.2 ± 8.8 ms⋅mmHg-1 , main group effect: p < 0.01) participants. BRS was lower in HHx compared to NNx in term born (10.5 ± 4.9 vs. 16.0 ± 6.0 ms⋅mmHg-1 , p = 0.05), but not in preterm (27.3 ± 15.7 vs. 17.6 ± 8.3 ms⋅mmHg-1 , p = 0.43) participants, leading to a lower BRS in HHx in term born compared to preterm (p < 0.01). In conclusion, this study reports a blunted response of BRS during acute high-altitude exposure without any influence of changes in inspired CO2 in healthy prematurely born adults.

Effects of hypobaria, hyperoxia, and nitrogen form on the growth and nutritional quality of lettuce.

The objectives of this research were to investigate the impact of hypobaria, hyperoxia, and nitrogen form on the growth and nutritional quality of plants. Pre-culture 20-day-old lettuce (Lactuca sativa L. var. Rome) seedlings grew for 25 days under three levels of total atmospheric pressure (101, 54, and 30 kPa), two levels of oxygen partial pressure (21 and 28 kPa), and two forms of nitrogen (NO3N and NH4N). The ratios of NO3N to NH4N included 3: 1, 4: 0, 2: 2, and 0: 4. The nitrogen quantity included two levels, i.e. N1, 0.1 g N kg-1 dry matrix and N2, 0.2 g N kg-1 dry matrix. The growth status of lettuce plants in different treatments differentiated markedly. Regardless of the nitrogen factor, the growth status of lettuce plants treated with total atmospheric pressure/oxygen partial pressure at 54/21 was equivalent to the treatment of 101/21. Under the hypobaric condition (54 kPa), compared with 21 kPa oxygen partial pressure, hyperoxia (28 kPa) significantly inhibited the growth of lettuce plants and the biomass (fresh weight) decreased by 60.9%-69.9% compared with that under 101/21 treatment. At the N1 level, the sequence of the biomass of lettuce plants supplied with different ratios of NO3N to NH4N was 3: 1 > 4: 0 > 2: 2 > 0: 4, and there were higher concentrations of chlorophyll and carotenoid of lettuce plants supplied with the higher ratio of NO3 to NH4. At the N2 level, the effects of different ratios of NO3N to NH4N on lettuce plants were similar to those at the N1 level. The high nitrogen (N2) promoted the growth of lettuce plants such as 54/21/N2 treatments. Both form and nitrogen level did not affect the stress resistance of lettuce plants. Hypobaria (54 kPa) increased the contents of N, P, and K and hyperoxia (28 kPa) decreased the content of organic carbon in lettuce plants. The high nitrogen (N2) improved the content of total N and the N uptake. The ratios of NO3N to NH4N were 4: 0 and 3: 1, lettuce could absorb and utilize N effectively. This study demonstrated that hyperoxia (28 kPa) inhibited the growth of lettuce plants under the hypobaric condition (54 kPa), and high level of nitrogen (0.2 g N kg-1 dry matrix) and NO3N: NH4N at 3: 1 markedly enhanced the growth, the contents of mineral elements and the nutritional quality of lettuce plants.

Brain Magnetic Resonance Imaging Responses to Nonhypoxic Hypobaric Decompression.

INTRODUCTION: The pathophysiological basis of neurological decompression sickness and the association between cerebral subcortical white matter (WM) change and nonhypoxic hypobaria remain poorly understood. Recent study of altitude decompression sickness risk evaluated acute WM responses to intensive hypobaric exposure using brain magnetic resonance imaging. METHODS: Six healthy men (20 to 50 yr) completed 6 h of hyperoxic hypobaria during three same-day altitude chamber decompressions to pressure altitudes ≥ 22,000 ft (6706 m). Research magnetic resonance imaging sequences, conducted on the days preceding and following decompression, evaluated subcortical WM integrity, cerebral blood flow, neuronal integrity (fractional anisotropy), and neurometabolite concentrations. RESULTS: No subcortical lesions were evident on diffusion weighted imaging and WM fractional anisotropy was unaffected. Mean WM blood flow was upregulated by 20% to over 25 mL · 100 g-1 · min-1. Gray matter flow was unchanged. There were no changes in gray matter or cerebellar neurometabolites. In parietal subcortical WM, levels of γ-aminobutyric acid (GABA) fell from (mean ± SD) 1.68 ± 0.2 to 1.35 ± 0.3 institutional units while glutathione (GSH) fell from 1.71 ± 0.4 to 1.25 ± 0.3 institutional units. Lactate increased postexposure in five subjects. CONCLUSIONS: Postexposure decrements in GABA and GSH imply WM insult with loss of neuroprotection and oxidative stress. An association between decrements in GABA and GSH support a common origin, while GSH decrements also correlate with WM blood flow responses. WM lactate increments are prone to error but suggest dysregulation of subcortical microvascular flow. WM neurometabolite and blood flow indices did not normalize by 24 h postexposure. Connolly D, Davagnanam I, Wylezinska-Arridge M, Mallon D, Wastling S, Lee VM. Brain magnetic resonance imaging responses to nonhypoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(10):733-740.

Lung diffusing capacity for nitric oxide in space: microgravity gas density interactions.

Introduction: During manned space exploration lung health is threatened by toxic planetary dust and radiation. Thus, tests such as lung diffusing capacity (DL) are likely be used in planetary habitats to monitor lung health. During a DL maneuver the rate of uptake of an inspired blood-soluble gas such as nitric oxide (NO) is determined (DLNO). The aim of this study was to investigate the influence of altered gravity and reduced atmospheric pressure on the test results, since the atmospheric pressure in a habitat on the moon or on Mars is planned to be lower than on Earth. Changes of gravity are known to alter the blood filling of the lungs which in turn may modify the rate of gas uptake into the blood, and changes of atmospheric pressure may alter the speed of gas transport in the gas phase. Methods: DLNO was determined in 11 subjects on the ground and in microgravity on the International Space Station. Experiments were performed at both normal (1.0 atm absolute, ata) and reduced (0.7 ata) atmospheric pressures. Results: On the ground, DLNO did not differ between pressures, but in microgravity DLNO was increased by 9.8% (9.5) (mean [SD]) and 18.3% (15.8) at 1.0 and 0.7 ata respectively, compared to normal gravity, 1.0 ata. There was a significant interaction between pressure and gravity (p = 0.0135). Discussion: Estimates of the membrane (DmNO) and gas phase (DgNO) components of DLNO suggested that at normal gravity a reduced pressure led to opposing effects in convective and diffusive transport in the gas phase, with no net effect of pressure. In contrast, a DLNO increase with reduced pressure at microgravity is compatible with a substantial increase of DmNO partially offset by reduced DgNO, the latter being compatible with interstitial edema. In microgravity therefore, DmNO would be proportionally underestimated from DLNO. We also conclude that normal values for DL in anticipation of planetary exploration should be determined not only on the ground but also at the gravity and pressure conditions of a future planetary habitat.

Effect of reduced atmospheric pressure on growth and quality of two lettuce cultivars.

Future space missions will likely include plants to provide fresh foods and bioregenerative life support capabilities. Current spacecraft such as the International Space Station (ISS) operate at 1 atm (101 kPa) pressure, but future missions will likely use reduced pressures to minimize gas leakage and facilitate rapid egress (space walks). Plants for these missions must be able to tolerate and grow reliably at these reduced pressures. We grew two lettuce cultivars, 'Flandria' a green bibb-type and 'Outredgeous,' a red, loose-leaf type, under three pressures: 96 kPa (ambient control), 67 kPa (2/3 atm), and 33 kPa (1/3 atm) for 21 days in rockwool using recirculating nutrient film technique hydroponics. Each treatment was repeated three times using a different hypobaric chamber each time. A daily light integral of 17.2 Moles Photosynthetically Active Radiation per day was provided with metal halide lamps set to deliver 300 µmol m-2s -1 photosynthetic photon flux (PPF) for a 16 h photoperiod at 22 °C. Oxygen was maintained at 21 kPa (equal to 21% at 1 atm) and CO2 at 0.12 kPa (equal to 1200 ppm at 1 atm). Leaf area for 'Outredgeous' was reduced 20% and 38% at 67 kPa and 33 kPa respectively; shoot fresh mass was reduced 22% and 41% at 67 kPa and 33 kPa respectively when compared to control plants at 96 kPa. These trends were not statistically significant at P ≥ 0.05. Leaf area for 'Flandria' showed no difference between 96 and 67 kPa but was reduced 31% at 33 kPa; shoot fresh mass was reduced 6% and 27% at 66 kPa and 33 kPa respectively compared to 96 kPa. There were 10% and 25% increases in anthocyanin concentration at 66 kPa and 33 kPa compared to 96 kPa, potentially increasing the bioprotective capacity of the plant. Previous studies with other cultivars of lettuce showed slight change in growth across this range of pressures, suggesting responses may vary among genotypes, hypobaric exposure treatments, and / or environmental conditions. Collectively, the findings suggest further testing is needed to understand the effects of atmospheric pressure on plant growth.

Effects of sequential aeromedical evacuations following traumatic brain injury in swine.

INTRODUCTION: Traumatic brain injuries (TBI) represent a significant percentage of critical injuries in military conflicts. Following injury, wounded warfighters are often subjected to multiple aeromedical evacuations (AE) and associated hypobaria, yet the impact in TBI patients remains to be characterized. This study evaluated the impact of two consecutive simulated AEs in a fluid-percussion TBI model in swine to characterize these effects. METHODS: Following instrumentation, anesthetized Yorkshire swine underwent a frontal TBI via fluid-percussion. A hypobaric chamber was then used to simulate AE at simulated cabin pressure equivalent to 8000ft (hypobaria) in a 6 h initial flight on day 3, followed by a 9 h flight on day 6, and were monitored for 14 days. Animals in the normobaria group were subjected to the same steps at sea level while Sham animals in both groups were instrumented but not injured. Parameters measured included physiologic response, intracranial pressure (ICP), hematology, chemistry, and serum cytokines. Histopathology of brain, lung, intestine, and kidney was performed, as well as fluorojade staining to evaluate neurodegeneration. All animals were divided into sub-groups by block randomization utilizing a 2-way ANOVA to analyze independent variables. RESULTS: Survival was 100% in all groups. Physiologic parameters were largely similar across groups as well during both 6 and 9 h AE. Animals exposed to hypobaria in both the TBI and Sham groups had elevated heart rate (HR) during the 6 h flight (p<0.05). Three animals in the TBI hypo group demonstrated leukocytosis with histologic evidence of meningeal inflammatory response. Expression of serum cytokines was low across all groups. No significant neuronal degeneration was identified in areas away from the site of injury. CONCLUSION: Aeromedical evacuation in swine was not associated with significant differences in physiologic measures, cytokine expression or levels of neuronal degeneration. Histological examination revealed higher risk of meningeal inflammatory response and leucocytosis in swine exposed to hypobaria.

Expiratory Peak Flow and Minute Ventilation Are Significantly Increased at High Altitude versus Simulated Altitude in Normobaria.

Simulated altitude (normobaric hypoxia, NH) is used to study physiologic hypoxia responses of altitude. However, several publications show differences in physiological responses between NH and hypobaric conditions at altitude (hypobaric hypoxia, HH). The causality for these differences is controversially discussed. One theory is that the lower air density and environmental pressure in HH compared to NH lead to lower alveolar pressure and therefore lower oxygen diffusion in the lung. We hypothesized that, if this theory is correct, due to physical laws (Hagen-Poiseuille, Boyle), resistance respectively air compression (Boyle) at expiration should be lower, expiratory flow higher, and therefore peak flow and maximum expiratory flow (MEF) 75-50 increased in hypobaric hypoxia (HH) vs. normobaric hypoxia (NH). To prove the hypothesis of differences in respiratory flow as a result of lower alveolar pressure between HH and NH, we performed spirography in NH at different simulated altitudes and the corresponding altitudes in HH. In a cross over study, 6 healthy subjects (2 f/4 m, 28.3 ± 8.2 years, BMI: 23.2 ± 1.9) performed spirography as part of spiroergometry in a normobaric hypoxic room at a simulated altitude of 2800 m and after a seven-hour hike on a treadmill (average incline 14%, average walking speed 1.6 km/h) to the simulated summit of Mauna Kea at 4200 m. After a two-month washout, we repeated the spirometry in HH on the start and top of the Mauna Kea hiking trail, HI/USA. Comparison of NH (simulated 4200 m) and HH at 4200 m resulted in increased pulmonary ventilation during exercise (VE) (11.5%, p < 0.01), breathing-frequency (7.8%, p < 0.01), peak expiratory flow PEF (13.4%, p = 0.028), and MEF50 (15.9%, p = 0.028) in HH compared to NH, whereas VO2max decreased by 2%. At 2800 m, differences were only trendy, and at no altitude were differences in volume parameters. Spirography expresses higher mid expiratory flows and peak flows in HH vs. NH. This supports the theory of lower alveolar and small airway pressure due to a lower air density resulting in a lower resistance.

Combined Traumatic Brain Injury and Hemorrhagic Shock in Ferrets Leads to Structural, Neurochemical, and Functional Impairments.

Aeromedical evacuation-relevant hypobaria after traumatic brain injury (TBI) leads to increased neurological injury and death in rats relative to those maintained under normobaria. Applicability of rodent brain injury research to humans may be limited, however, by differences in neuroanatomy. Therefore, we developed a model in which ferrets are exposed to polytrauma consisting of controlled cortical impact TBI and hemorrhagic shock subjected 24 h later to 6 h of hypobaria or normobaria. Our objective was to determine whether the deleterious effects of hypobaria observed in rats, with lissencephalic brains, are also present in a species with a human-like gyrencephalic brain. While no deaths were observed, magnetic resonance spectroscopy (MRS) results obtained two days post-injury indicated reduced cortical creatine, N-acetylaspartate, gamma-aminobutyric acid, myo-inositol, and glutamate that were not affected by hypobaria. T2-weighted magnetic resonance imaging quantification revealed increased hyperintensity volume representing cortical edema at the site of impact after polytrauma. Hypobaria did not exacerbate this focal edema but did lead to overall reductions in total cortical volume. Both normobaric and hypobaric ferrets exhibited impaired spatial memory six days post-injury on the Object Location Test, but no differences were noted between groups. Finally, cortical lesion volume was not exacerbated by hypobaria exposure on day 7 post-injury. Results suggest that air travel 24 h after polytrauma is associated with structural changes in the ferret brain. Future studies should investigate secondary injury from hypobaria after polytrauma in greater detail including alternative outcome measures, time points, and exposure to multiple flights.

Impact of High Altitude on Cardiovascular Health: Current Perspectives.

Globally, about 400 million people reside at terrestrial altitudes above 1500 m, and more than 100 million lowlanders visit mountainous areas above 2500 m annually. The interactions between the low barometric pressure and partial pressure of O2, climate, individual genetic, lifestyle and socio-economic factors, as well as adaptation and acclimatization processes at high elevations are extremely complex. It is challenging to decipher the effects of these myriad factors on the cardiovascular health in high altitude residents, and even more so in those ascending to high altitudes with or without preexisting diseases. This review aims to interpret epidemiological observations in high-altitude populations; present and discuss cardiovascular responses to acute and subacute high-altitude exposure in general and more specifically in people with preexisting cardiovascular diseases; the relations between cardiovascular pathologies and neurodegenerative diseases at altitude; the effects of high-altitude exercise; and the putative cardioprotective mechanisms of hypobaric hypoxia.

Hypobaria-Induced Oxidative Stress Facilitates Homocysteine Transsulfuration and Promotes Glutathione Oxidation in Rats with Mild Traumatic Brain Injury.

BACKGROUND: United States service members injured in combat theatre are often aeromedically evacuated within a few days to regional military hospitals. Animal and epidemiological research indicates that early exposure to flight hypobaria may worsen brain and other injuries. The mechanisms by which secondary exposure to hypobaria worsen trauma outcomes are not well elucidated. This study tested the hypothesis that hypobaria-induced oxidative stress and associated changes in homocysteine levels play a role in traumatic brain injury (TBI) pathological progression caused by hypobaria. METHODS: Male Sprague Dawley rats were exposed to a 6 h hypobaria 24 h after mild TBI by the controlled cortical impact. Plasma and brain tissues were assessed for homocysteine levels, oxidative stress markers or glutathione metabolism, and behavioral deficits post-injury in the absence and presence of hypobaria exposure. RESULTS: We found that hypobaria after TBI increased oxidative stress markers, altered homocysteine metabolism, and promoted glutathione oxidation. Increased glutathione metabolism was driven by differential upregulation of glutathione metabolizing genes. These changes correlated with increased anxiety-like behavior. CONCLUSION: These data provide evidence that hypobaria exposure after TBI increases oxidative stress and alters homocysteine elimination likely through enhanced glutathione metabolism. This pathway may represent a compensatory mechanism to attenuate free radical formation. Thus, hypobaria-induced enhancement of glutathione metabolism represents a potential therapeutic target for TBI management.

A Low-Pressure, N2/CO2 Atmosphere Is Suitable for Cyanobacterium-Based Life-Support Systems on Mars.

The leading space agencies aim for crewed missions to Mars in the coming decades. Among the associated challenges is the need to provide astronauts with life-support consumables and, for a Mars exploration program to be sustainable, most of those consumables should be generated on site. Research is being done to achieve this using cyanobacteria: fed from Mars's regolith and atmosphere, they would serve as a basis for biological life-support systems that rely on local materials. Efficiency will largely depend on cyanobacteria's behavior under artificial atmospheres: a compromise is needed between conditions that would be desirable from a purely engineering and logistical standpoint (by being close to conditions found on the Martian surface) and conditions that optimize cyanobacterial productivity. To help identify this compromise, we developed a low-pressure photobioreactor, dubbed Atmos, that can provide tightly regulated atmospheric conditions to nine cultivation chambers. We used it to study the effects of a 96% N2, 4% CO2 gas mixture at a total pressure of 100 hPa on Anabaena sp. PCC 7938. We showed that those atmospheric conditions (referred to as MDA-1) can support the vigorous autotrophic, diazotrophic growth of cyanobacteria. We found that MDA-1 did not prevent Anabaena sp. from using an analog of Martian regolith (MGS-1) as a nutrient source. Finally, we demonstrated that cyanobacterial biomass grown under MDA-1 could be used for feeding secondary consumers (here, the heterotrophic bacterium E. coli W). Taken as a whole, our results suggest that a mixture of gases extracted from the Martian atmosphere, brought to approximately one tenth of Earth's pressure at sea level, would be suitable for photobioreactor modules of cyanobacterium-based life-support systems. This finding could greatly enhance the viability of such systems on Mars.

Physiological Effects of Intermittent Passive Exposure to Hypobaric Hypoxia and Cold in Rats.

The benefits of intermittent hypobaric hypoxia (IHH) exposure for health and its potential use as a training tool are well-documented. However, since hypobaric hypoxia and cold are environmental factors always strongly associated in the biosphere, additive or synergistic adaptations could have evolved in animals' genomes. For that reason, the aim of the present study was to investigate body composition and hematological and muscle morphofunctional responses to simultaneous intermittent exposure to hypoxia and cold. Adult male rats were randomly divided into four groups: (1) control, maintained in normoxia at 25°C (CTRL); (2) IHH exposed 4 h/day at 4,500 m (HYPO); (3) intermittent cold exposed 4 h/day at 4°C (COLD); and (4) simultaneously cold and hypoxia exposed (COHY). At the end of 9 and 21 days of exposure, blood was withdrawn and gastrocnemius (GAS) and tibialis anterior muscles, perigonadal and brown adipose tissue, diaphragm, and heart were excised. GAS transversal sections were stained for myofibrillar ATPase and succinate dehydrogenase for fiber typing and for endothelial ATPase to assess capillarization. Hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and glucose transporter 1 (GLUT1) from GAS samples were semi-quantified by Western blotting. COLD and HYPO underwent physiological adjustments such as higher brown adipose tissue weight and increase in blood-related oxygen transport parameters, while avoiding some negative effects of chronic exposure to cold and hypoxia, such as body weight and muscle mass loss. COHY presented an additive erythropoietic response and was prevented from right ventricle hypertrophy. Intermittent cold exposure induced muscle angiogenesis, and IHH seems to indicate better muscle oxygenation through fiber area reduction.

High Altitude Pregnancies and Vascular Dysfunction: Observations From Latin American Studies.

An estimated human population of 170 million inhabit at high-altitude (HA, above 2,500 m). The potential pathological effects of HA hypobaric hypoxia during gestation have been the focus of several researchers around the world. The studies based on the Himalayan and Central/South American mountains are particularly interesting as these areas account for nearly 70% of the HA world population. At present, studies in human and animal models revealed important alterations in fetal development and growth at HA. Moreover, vascular responses to chronic hypobaria in the pregnant mother and her fetus may induce marked cardiovascular impairments during pregnancy or in the neonatal period. In addition, recent studies have shown potential long-lasting postnatal effects that may increase cardiovascular risk in individuals gestated under chronic hypobaria. Hence, the maternal and fetal adaptive responses to hypoxia, influenced by HA ancestry, are vital for a better developmental and cardiovascular outcome of the offspring. This mini-review exposes and discusses the main determinants of vascular dysfunction due to developmental hypoxia at HA, such as the Andean Mountains, at the maternal and fetal/neonatal levels. Although significant advances have been made from Latin American studies, this area still needs further investigations to reveal the mechanisms involved in vascular dysfunction, to estimate complications of pregnancy and postnatal life adequately, and most importantly, to determine potential treatments to prevent or treat the pathological effects of being developed under chronic hypobaric hypoxia.

Cardiorespiratory Response and Power Output During Submaximal Exercise in Normobaric Versus Hypobaric Hypoxia: A Pilot Study Using a Specific Chamber that Controls Environmental Factors.

Takezawa, Toshihiro, Shohei Dobashi, and Katsuhiro Koyama. Cardiorespiratory response and power output during submaximal exercise in normobaric versus hypobaric hypoxia: a pilot study using a specific chamber that controls environmental factors. High Alt Med Biol. 22: 201-208, 2021. Background: Many previous studies have examined hypoxia-induced physiological responses using various conditions, e.g., artificially reduced atmospheric oxygen concentration [normobaric hypoxia (NH) condition] or low barometric pressure at a mountain [hypobaric hypoxia (HH) condition]. However, when comparing the results from these previous studies conducted in artificial NH and HH including real high altitude, we must consider the possibility that environmental factors, such as temperature, humidity, and fraction of inspired carbon dioxide, might affect the physiological responses. Therefore, we examined cardiorespiratory responses and exercise performances during low- to high-intensity exercise at a fixed heart rate (HR) in both NH and HH using a specific chamber where atmospheric oxygen concentration and barometric pressure as well as the abovementioned environmental factors were precisely controlled. Methods: Ten well-trained university students (eight males and two females) performed the exercise test consisting of two 20-minute submaximal pedaling at the intensity corresponding to 50% (low) and 70% (high) of their HR reserve, under three conditions [NH (fraction of inspired oxygen, 0.135; barometric pressure, 754 mmHg), HH (fraction of inspired oxygen, 0.209; barometric pressure, 504 mmHg), and normobaric normoxia (NN; fraction of inspired oxygen, 0.209; barometric pressure, 754 mmHg)]. Peripheral oxygen saturation (SpO2) to estimate arterial oxygen saturation and partial pressure of end-tidal carbon dioxide (PETCO2) were monitored throughout the experiment. Results: SpO2, PETCO2, and power output at fixed HRs (i.e., pedaling efficiency) in NH and HH were all significantly lower than those in NN. Moreover, high-intensity exercise in HH induced greater decreases in SpO2 and power output than did high-intensity exercise in NH (NH vs. HH; SpO2, 78.2% ± 5.0% vs. 75.1% ± 7.1%; power output, 120.7 ± 24.9 W vs. 112.4 ± 23.2 W, both p < 0.05). However, high-intensity exercise in HH induced greater increases in PETCO2 than did high-intensity exercise in NH (NH vs. HH; 54.2 ± 5.9 mmHg vs. 57.2 ± 3.4 mmHg, p < 0.01). Conclusions: These results suggest that physiological responses and power output at a fixed HR during hypoxic exposure might depend on the method used to generate the hypoxic condition.

The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude.

Chronic hypoxia during gestation induces greater occurrence of perinatal complications such as intrauterine growth restriction, fetal hypoxia, newborn asphyxia, and respiratory distress, among others. This condition may also cause a failure in the transition of the fetal to neonatal circulation, inducing pulmonary arterial hypertension of the neonate (PAHN), a syndrome that involves pulmonary vascular dysfunction, increased vasoconstrictor tone and pathological remodeling. As this syndrome has a relatively low prevalence in lowlands (~7 per 1000 live births) and very little is known about its prevalence and clinical evolution in highlands (above 2500 meters), our understanding is very limited. Therefore, studies on appropriate animal models have been crucial to comprehend the mechanisms underlying this pathology. Considering the strengths and weaknesses of any animal model of human disease is fundamental to achieve an effective and meaningful translation to clinical practice. The sheep model has been used to study the normal and abnormal cardiovascular development of the fetus and the neonate for almost a century. The aim of this review is to highlight the advances in our knowledge on the programming of cardiopulmonary function with the use of high-altitude newborn sheep as a translational model of PAHN.