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Background: Repeated exposure to heat (ie, plasma volume expansion) or altitude (ie, increase in total hemoglobin mass), in conjunction with exercise, induces hematological adaptations that enhance endurance performance in each respective environment. Recently, combining heat and altitude training has become increasingly common for athletes preparing to compete in temperate, sea-level conditions. Purpose: To review the physiological adaptations to training interventions combining thermal and hypoxic stimuli and summarize the implications for temperate, sea-level performance. Current Evidence: To date, research on combining heat and hypoxia has employed 2 main approaches: simultaneously combining the stressors during training or concurrently training in the heat and sleeping at altitude, sometimes with additional training in hypoxia. When environmental stimuli are combined in a training session, improvements in aerobic fitness and time-trial performance in temperate, sea-level conditions are generally similar in magnitude to those observed with heat, or altitude, training alone. Similarly, training in the heat and sleeping at altitude does not appear to provide any additional hematological or nonhematological benefits for temperate; sea-level performance relative to training in hot, hypoxic, or control conditions. Conclusions: Current research regarding combined heat and altitude interventions does not seem to indicate that it enhances temperate, sea-level performance to a greater extent than "traditional" (heat or hypoxia alone) training approaches. A major challenge in implementing combined-stressor approaches lies in the uncertainty surrounding the prescription of dosing regimens (ie, exercise and environmental stress). The potential benefits of conducting heat and altitude exposure sequentially (ie, one after the other) warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: Total hemoglobin mass (tHbmass) and blood volume (BV) are important determinants of maximal oxygen uptake and endurance capacity. Higher-caliber endurance athletes usually possess higher tHbmass and BV values. This study aimed to compare tHbmass and BV among swimmers of diverse competitive calibers and distances. Methods: Thirty swimmers (16 female and 14 male) participated in the study: 3 were tier 5, world class (869 [59] FINA points); 15 were tier 4, elite/international (853 [38] points); and 12 were tier 3, highly trained/national (808 [35] points). They specialized in competition distances ranging from 200 m to open-water 10 km. Between February 2019 and February 2020, all swimmers had their tHbmass and BV measured by carbon monoxide rebreathing 1 to 6 times and participated in multiple competitions and race events. Results: Relative tHbmass and BV were not different (P >.05) between tiers among women or among men (pooled tHbmass values 14.5 [0.5], 12.5 [1.5], 12.6 [2.3] g/kg for tier 5, tier 4, and tier 3, respectively). No differences were observed in relative tHbmass (P =.215) and BV (P =.458) between pool and open-water swimmers or between 200-, 400-, and 1500-m specialists (P >.05). No significant correlations were found between the highest measured absolute or relative tHbmass and BV and the highest FINA points scored over the follow-up period (R = −.42–.17, P =.256–.833), irrespective of competition distance. Conclusion: tHbmass and BV values did not differ between swimmers of different calibers or among competition distances. Furthermore, these values did not correlate with FINA points, either in males or in females. The present results indicate that hematological characteristics may have a lesser impact on swimming performance than on land-based endurance sports. [ABSTRACT FROM AUTHOR]

Aim: Greater quantification and characterisation of training load (TL) throughout Live-high, train-high (LHTH) altitude (ALT) training is required to identify periodisation strategies that may lead to physiological and performance improvements in swimmers. Purpose: This study aimed to examine the physiological responses and performance outcomes of 14 high-performance swimmers (FINA points: 836.0 ± 35.1) following 3 weeks of LHTH at 2320 m, while characterising the training load periodisation strategy adopted during the intervention. Methods: Haemoglobin (Hb) mass was measured pre-, 7 and 14 days post-ALT via CO rebreathing. Performance in each athlete's primary event at national standard meets were converted to FINA points and compared from pre-to-post-ALT. TL was quantified at sea level (SL) and ALT through session rating of perceived exertion (RPE), where duration of each session was multiplied by its RPE for each athlete, with all sessions totalled to give a weekly TL. Pre-to-post-ALT changes were evaluated using repeated-measures ANOVA. Results: Hb mass increased significantly from 798 ± 182 g pre-ALT to 828 ± 187 g at 7 days post (p = 0.013) and 833 ± 205 g 14 days post-ALT (p = 0.026). Weekly TL increased from SL (3179 ± 638 au) during week one (4797 ± 1349 au, p < 0.001) and week two (4373 ± 967 au, p < 0.001), but not week three (3511 ± 730 au, p = 0.149). No evidence of improved SL swimming performance was identified. Conclusion: A periodisation strategy characterised by a sharp spike in TL followed by a slight de-load towards the end of a LHTH intervention led to improved physiological characteristics but no change in the competitive performance of high-performance swimmers. [ABSTRACT FROM AUTHOR]

Ventilatory responses to hypoxia and hypercapnia play a vital role in maintaining gas exchange homeostasis and in adaptation to high-altitude environments. This study investigates the mechanisms underlying sensitization of hypoxic and hypercapnic ventilatory response (HVR and HCVR, respectively) in individuals acclimatized to moderate high altitude (3,800 m). Thirty-one participants underwent chemoreflex testing using the Duffin-modified rebreathing technique. Measures were taken at sea level and after 2 days of acclimatization to high altitude. Ventilatory recruitment threshold (VRT), HCVR-Hyperoxia, HCVR-Hypoxia, and HVR were quantified. Acclimatization to high altitude resulted in increased HVR (P < 0.001) and HCVR-Hyperoxia (P < 0.001), as expected. We also observed that the decrease in VRT under hypoxic test conditions significantly contributed to the elevated HVR at high altitude since the change in VRT across hyperoxic and hypoxic test conditions was greater at high altitudes compared to baseline sea-level tests (P = 0.043). Pre-VRT, or basal, ventilation also increased at high altitudes (P < 0.001), but the change did not differ between oxygen conditions. Taken together, these data suggest that the increase in HVR at high altitude is at least partially driven by a larger decrease in the VRT in hypoxia versus hyperoxia at high altitude compared to sea level. This study highlights the intricacies of respiratory adaptations during acclimatization to moderate high altitude, shedding light on the roles of the VRT, baseline respiratory drive, and two-slope HCVR in this process. These findings contribute to our understanding of how human respiratory control responds to hypoxic and hypercapnic challenges at high altitude. NEW & NOTEWORTHY: We report the first measurements of the hypoxic ventilatory response (HVR) after 2 days at high altitude using a CO2 rebreathing technique. We evaluated mechanisms by which the HVR becomes elevated with acclimatization (increased hypercapnic ventilatory response sensitivity in hypoxia, increased baseline respiratory drive in hypoxia, or lower ventilatory recruitment thresholds in hypoxia). For the first time, we report that decreases in the ventilatory recruitment threshold in hypoxia contribute to elevated HVR at high altitude. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate changes in dynamic cerebral autoregulation (CA) during short‐term and long‐term exposure to high altitude with ultrasonography, and also study the sex differences in the response of CA to altitude. Methods: We assessed the differences in dynamic CA and measured with Doppler ultrasound of the bilateral internal carotid artery (ICA), vertebral artery (VA), and middle cerebral artery (MCA) and the values of basic information within 48 hours and at 2 years after arrival at Tibet in 65 healthy Han young Chinese volunteers, meanwhile, we compared the resistance index (RI) and pulsatility index (PI) of the right MCA at inhale oxygen 8 minutes when a newcomer with 2 years after arrival at Tibet. Results: With 2 years of altitude exposure, the SaO2 of all subjects was above 90%, the mean PEF, DAP, and HR values decreased, HGB increased compared within 48 hours in same‐gender groups. Comparisons of cerebral hemodynamics between before 2 years and after 2 years within male and female groups, the mean RI and PI values of bilateral MCA after 2 years were significantly higher than before 2 years, at the same time, the mean RI and PI values of bilateral ICA were significant differences (P <.05) between male groups, with regard to female groups, showed that the mean RI and PI values of bilateral VA were significant differences (P <.05). Comparisons of Right MCA hemodynamics between after oxygen uptake 8 minutes and 2 years, the mean RI and PI values were no significant difference within male and female groups (P >.05). Conclusions: Acute mountain sickness could result from an alteration of dynamic autoregulation of cerebral blood flow, but the impaired autoregulation may be corrected with the extension of time, furthermore, the response of CA to altitude in males and females are different. [ABSTRACT FROM AUTHOR]

Background: To quantify the changes in dynamic visual acuity (DVA) and explain the hidden reasons after acute exposure to hypobaric hypoxia status. Methods: The study group comprised 18 healthy male and 15 healthy female participants aged 20-24 years old. DVA was measured with the self-developed software of Meidixin (Tianjin) Co., Ltd. Measurements were taken at eight altitudes. Data analysis was performed using the Kolmogorov-Smirnov test, paired sample T-test, and two-way repeated measures analysis of variance (ANOVA) for repeated measurements. Results: At constant altitude, DVA showed an overall decreasing trend with increasing angular velocity and a fluctuating decrease at the vast majority of altitudes. At constant angular velocities, DVA gradually increased with altitude, with the most pronounced increase in DVA at altitude 5, and thereafter a gradual decrease in DVA as altitude increased. Finally, as altitude decreased, DVA increased again and reached a higher level at the end of the experiment, which was superior to the DVA in the initial state. Conclusion: Under a hypobaric hypoxic environment at high altitude, DVA was affected by the angular velocity and the degree of hypoxia, manifesting as an increase or decrease in DVA, which affects the pilot's observation of the display and control interfaces during the driving process, acquisition of information, and decision-making ability, which in turn may potentially jeopardize the safety of the flight. [ABSTRACT FROM AUTHOR]

Background: Altitude training is often regarded as an indispensable tool for the success of elite endurance athletes. Historically, altitude training emerged as a key strategy to prepare for the 1968 Olympics, held at 2300 m in Mexico City, and was limited to the "Live High-Train High" method for endurance athletes aiming for performance gains through improved oxygen transport. This "classical" intervention was modified in 1997 by the "Live High-Train Low" (LHTL) model wherein athletes supplemented acclimatization to chronic hypoxia with high-intensity training at low altitude. Purpose: This review discusses important considerations for successful implementation of LHTL camps in elite athletes based on experiences, both published and unpublished, of the authors. Approach: The originality of our approach is to discuss 10 key "lessons learned," since the seminal work by Levine and Stray-Gundersen was published in 1997, and focusing on (1) optimal dose, (2) individual responses, (3) iron status, (4) training-load monitoring, (5) wellness and well-being monitoring, (6) timing of the intervention, (7) use of natural versus simulated hypoxia, (8) robustness of adaptative mechanisms versus performance benefits, (9) application for a broad range of athletes, and (10) combination of methods. Successful LHTL strategies implemented by Team USA athletes for podium performance at Olympic Games and/or World Championships are presented. Conclusions: The evolution of the LHTL model represents an essential framework for sport science, in which field-driven questions about performance led to critical scientific investigation and subsequent practical implementation of a unique approach to altitude training. [ABSTRACT FROM AUTHOR]

Exposure to high altitude might cause the body to adapt with negative energy and fluid balance that compromise body composition and physical performance. In this field study involving 12 healthy adults, sex-balanced, and aged 29 ± 4 years with a body mass index of 21.6 ± 1.8 kg/m2, we investigated the effects of a 4-day trekking up to 4556 m a.s.l. on Monte Rosa (Alps, Italy). The food intake was recorded using food diaries and nutrient averages were calculated. The bio-impedance analysis was performed at low and high altitudes, and a wearable biosensor (Swemax) was used to track hydro-saline losses in two participants. Daily total energy intake was 3348 ± 386 kcal for males and 2804 ± 415 kcal for females (13%–14% protein, 35% fat, 44%–46% carbohydrates). Although there was a significant body weight loss (65.0 ± 9.3 vs. 64.2 ± 9.10 kg, p < 0.001, d = 1.398), no significant changes in body composition parameter were found but a trend in the increase of the bioelectrical phase angle in males (p = 0.059, d = −0.991). Body water percentage significantly changed (p = 0.026, η2p = 0.440), but the absolute water did not, suggesting that the weight loss was not due to water loss. Salivary and urinary osmolality did not change. A reduction in sweat rate at higher altitudes was observed in both participants. Interestingly, salivary leptin increased (p = 0.014, η2p = 0.510), and salivary ghrelin decreased (p = 0.036, η2p = 0.403). Therefore, the 4-day trekking at altitude of hypoxia exposure induced changes in satiety and appetite hormones. High altitude expeditions require more specific nutritional guidance, and using multiplex analysis could help in monitoring fluid balance and body composition. [ABSTRACT FROM AUTHOR]

Gardner, Laurel, Linda E. Keyes, Caleb Phillips, Elan Small, Tejaswi Adhikari, Nathan Barott, Ken Zafren, Rony Maharjan, and James Marvel. Women at altitude: Menstrual-cycle phase, menopause, and exogenous progesterone are not associated with acute mountain sickness. High Alt Med Biol. 00:000–000, 2024. Background: Elevated progesterone levels in women may protect against acute mountain sickness (AMS). The impact of hormonal contraception (HC) on AMS is unknown. We examined the effect of natural and exogenous progesterone on the occurrence of AMS. Methods: We conducted a prospective observational convenience study of female trekkers in Lobuche (4,940 m) and Manang (3,519 m). We collected data on last menstrual period, use of exogenous hormones, and development of AMS. Results: There were 1,161 trekkers who met inclusion criteria, of whom 307 (26%) had AMS. There was no significant difference in occurrence of AMS between women in the follicular (28%) and the luteal (25%) phases of menstruation (p = 0.48). The proportion of premenopausal (25%) versus postmenopausal women (30%) with AMS did not differ (p = 0.33). The use of HC did not influence the occurrence of AMS (HC 23% vs. no HC 26%, p = 0.47), nor did hormonal replacement therapy (HRT) (HRT 11% vs. no HRT 31%, p = 0.13). Conclusion: We found no relationship between menstrual-cycle phase, menopausal status, or use of exogenous progesterone and the occurrence of AMS in trekkers and conclude that hormonal status is not a risk factor for AMS. Furthermore, women should not be excluded from future AMS studies based on hormonal status. [ABSTRACT FROM AUTHOR]

Basketball involves frequent high-intensity movements requiring optimal aerobic power. Altitude training can enhance physiological adaptations, but research examining its effects in basketball is limited. This study aimed to characterize the internal/external workload of professional basketball players during preseason and evaluate the effects of altitude and playing position. Twelve top-tier professional male basketball players (Liga Endesa, ACB; guards: n = 3, forwards: n = 5, and centers: n = 4) participated in a crossover study design composed of two training camps with nine sessions over 6 days under two different conditions: high altitude (2320 m) and sea level (10 m). Internal loads (heart rate, %HRMAX) and external loads (total distances covered across speed thresholds, accelerations/decelerations, impacts, and jumps) were quantified via wearable tracking and heart rate telemetry. Repeated-measures MANOVA tested the altitude x playing position effects. Altitude increased the total distance (+10%), lower-speed running distances (+10–39%), accelerations/decelerations (+25–30%), average heart rate (+6%), time in higher-intensity HR zones (+23–63%), and jumps (+13%) across all positions (p < 0.05). Positional differences existed, with guards accruing more high-speed running and centers exhibiting greater cardiovascular demands (p < 0.05). In conclusion, a 6-day altitude block effectively overloads training, providing a stimulus to enhance fitness capacities when structured appropriately. Monitoring workloads and individualizing training by playing position are important when implementing altitude training, given the varied responses. [ABSTRACT FROM AUTHOR]

Adaptation of humans to challenging environmental conditions, such as extreme temperature, malnutrition, or hypoxia, is an interesting phenomenon for both basic and applied research. Identification of the genetic factors contributing to human adaptation to these conditions enhances our understanding of the underlying molecular and physiological mechanisms. In our study, we analyzed the exomes of 22 high altitude mountaineers to uncover genetic variants contributing to hypoxic adaptation. To our surprise, we identified two putative loss‐of‐function variants, rs1385101139 in RTEL1 and rs1002726737 in COL6A1 in two extremely high altitude (personal record of more than 8500 m) professional climbers. Both variants can be interpreted as pathogenic according to medical geneticists' guidelines, and are linked to inherited conditions involving respiratory failure (late‐onset pulmonary fibrosis and severe Ullrich muscular dystrophy for rs1385101139 and rs1002726737, respectively). Our results suggest that a loss of gene function may act as an important factor of human adaptation, which is corroborated by previous reports in other human subjects. [ABSTRACT FROM AUTHOR]

This study investigated the reliability of the Affinity Altitude hypoxic generator within-day, between-day and between-generator under acute and chronic hypoxic conditions. An additional objective was to assess the validity of the fraction of inspired oxygen (FiO2) values in relation to the claimed manufacture's reference values to ensure the accuracy and safety of the product. Three altitude generators (Affinity Altitude Ltd., Sussex, UK) were assessed across all available settings during a test–retest design for equivalent FiO2 and output volume. This consisted of two phases: 1) acute exposure (10 min per setting) and 2) chronic exposure (8 h per setting). FiO2 and volume data were calculated from 1 min collection samples using the Douglas bag method for acute and chronic exposures. There were low variations in FiO2 data across all settings within the acute exposure for within-day (coefficient of variation [CV] range: 0.0–2.6%), between-day (0.2–1.3%), and between-generator analysis (0.7–1.4%). This was similarly found for volume data within-day (0.1–3.7%), between-day (0.7–5.4%), and between-generator (1.2–3.0%). Equally, for chronic exposure trials, CV for FiO2 (< 4.0%) and volume (< 5.0%) across each of the generators presented low variations. The FiO2 values were similar to reference values, however, significant differences were found for settings 4 (−0.3% [17.6% vs. 17.9% reference value]) and 5 (−0.1% [15.8% vs. 15.9% reference value], both p < 0.05). A 'good' level of reliability (CV < 5%) and validity were found within and between the Affinity Altitude's generators. However, a review of the reference values is warranted, and long-term experimental studies are required to determine the efficacy of this device for the purpose of physiological adaptations. [ABSTRACT FROM AUTHOR]

Background: Gut microbiota is significantly influenced by altitude. However, the dynamics of gut microbiota in relation to altitude remains undisclosed. Methods: In this study, we investigated the microbiome profile of 610 healthy young men from three different places in China, grouped by altitude, duration of residence, and ethnicity. We conducted widely targeted metabolomic profiling and clinical testing to explore metabolic characteristics. Results: Our findings revealed that as the Han individuals migrated from low altitude to high latitude, the gut microbiota gradually converged towards that of the Tibetan populations but reversed upon returning to lower altitude. Across different cohorts, we identified 51 species specifically enriched during acclimatization and 57 species enriched during deacclimatization to high altitude. Notably, Prevotella copri was found to be the most enriched taxon in both Tibetan and Han populations after ascending to high altitude. Furthermore, significant variations in host plasma metabolome and clinical indices at high altitude could be largely explained by changes in gut microbiota composition. Similar to Tibetans, 41 plasma metabolites, such as lactic acid, sphingosine-1-phosphate, taurine, and inositol, were significantly elevated in Han populations after ascending to high altitude. Germ-free animal experiments demonstrated that certain species, such as Escherichia coli and Klebsiella pneumoniae, which exhibited altitude-dependent variations in human populations, might play crucial roles in host purine metabolism. Conclusions: This study provides insights into the dynamics of gut microbiota and host plasma metabolome with respect to altitude changes, indicating that their dynamics may have implications for host health at high altitude and contribute to host adaptation. 88DwbBo5LkUszxYCpXiUg_ Video Abstract [ABSTRACT FROM AUTHOR]

The human spleen contracts in response to stress‐induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non‐Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = ∼430 torr; PO2${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ = ∼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation (SpO2${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non‐Sherpa (165 ± 34 mL; P < 0.001; effect size (ES) = 0.95, 95% CI: 0.3–1.6). In response to hyperoxia, non‐Sherpa demonstrated 22 ± 12% increase in spleen size (35 ± 17 mL, 95% CI: 20.7–48.9; P < 0.001; ES = 1.8, 95% CI: 0.93–2.66), while spleen size remained unchanged in Sherpa (−2 ± 13 mL, 95% CI: −2.4 to 7.3; P = 0.640; ES = 0.18, 95% CI: −0.10 to 0.47). Our findings suggest that Sherpa and non‐Sherpas of lowland ancestry exhibit distinct variations in spleen volume during hyperoxia at high altitude, potentially indicating two distinct splenic functions. In Sherpa, this phenomenon may signify a diminished splenic response to altitude‐related hypoxia at rest, potentially contributing to enhanced splenic contractions during physical stress. Conversely, non‐Sherpa experienced a transient increase in spleen size during hyperoxia, indicating an active tonic contraction, which may influence early altitude acclimatization in lowlanders by raising [Hb]. What is the central question of this study?Indigenous Sherpa exhibit greater spleen size and enhanced exercise‐induced contraction at high altitude compared to lowlanders: how does spleen size of Sherpa and lowlanders respond to hyperoxic breathing at high altitude?What is the main finding and its importance?Sherpa do not experience any changes in spleen size when subjected to hyperoxic breathing at high altitude, whereas lowlanders show a 20% increase in spleen size under similar conditions. This may represent adaptive traits in Sherpa, potentially enhancing the spleen's capacity for contractions during increased metabolic demands. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the altitude of birth/childhood influences the values in peak power output (PPO) and estimated maximum oxygen uptake (estVO2max) in male Colombian road cyclists of different performance levels. This study also aimed to determine whether cyclists born at high altitudes tend to be more successful. Methods: Eighty riders aged between 17 and 22 years of 3 performance levels (U23 world-class level, WC, n = 8; U23 national level, N23, n = 41; junior national level, J, n = 31) and 3 altitude levels (<800 m, low; 800–2000 m, moderate; >2000 m, high) performed an ergocycle maximal incremental test to exhaustion at an altitude of 2570 m. Results: Altogether, while cyclists born at an altitude >2000 m represented ∼50% of the analyzed sample, there was a significantly higher proportion (84%) of these cyclists who had participated as professionals in a Grand Tour (χ2[1, N = 80] = 4.58, P <.05). Riders of the low group had lower values of PPO and estVO2max than cyclists of moderate and high altitudes, while no differences were noted between moderate- and high-altitude groups. In N23, PPO and estVO2max were lower in the low- than in the moderate-altitude group, while in the J cyclists, PPO and estVO2max were lower in the low-altitude compared with both moderate- and high-altitude groups. Discussion: Among the cyclists tested at altitude in junior and U23, there is an overrepresentation of individuals who reached an elite level and were born at a high altitude (>2000 m). As no clear differences were observed between moderate- and high-altitude cyclists, the higher prevalence of elite cyclists in the latter group may originate from various—still unclear—mechanisms. [ABSTRACT FROM AUTHOR]

Hypoxic exercise, which can induce arterial and tissue deoxygenation, promotes physiological adaptations. However, reduced oxygen availability can lower the absolute training intensity (i.e., mechanical stress). Adding normoxic recovery to sprint interval exercise (SIE) is one potential approach to strike a balance between providing a hypoxic stimulus and maintaining the absolute training intensity. However, the effects of adding normoxic recovery to SIE on performance and physiological responses are uncertain. We tested the hypothesis that hypoxic SIE with normoxic recovery enhances arterial deoxygenation and muscle deoxygenation levels without impeding performance compared to an entirely normoxic condition. On separate days, seven male sprinters performed 4 × 30‐s 'all‐out' cycle sprints with 4.5‐min recovery with hypoxic exposure (FiO2: 12.7%O2) applied continuously (hypoxia, HYP), intermittently during sprint periods only (intermittent, INT), or not at all (normoxia, NOR). Power output, oxygen saturation, muscle oxygenation, surface electromyography (EMG) activity, heart rate, blood lactate concentration, and ratings of perceived exertion were measured. The total work significantly decreased in HYP than NOR (p < 0.05) and INT (p < 0.01). The aTrterial oxygen saturation was lower during HYP than NOR (∼86% vs. ∼97%; p < 0.001), while lower values were also obtained for INT than NOR during sprint periods (∼85% vs. ∼97%; p < 0.001) but not during recovery periods (∼96% vs. ∼97%). The heart rate differed (p < 0.05) between conditions (NOR: ∼164 bpm; INT: ∼160 bpm; HYP: ∼156 bpm). No other variables demonstrated significant differences between conditions. Adding hypoxia during exercise while recovering in normoxia did not compromise exercise capacity during SIE, despite inducing larger arterial deoxygenation levels compared to normoxia. Highlights: Utilizing severe hypoxia during exercise and normoxia during recovery induces a substantial hypoxic stimulus while safeguarding mechanical performance in sprinters.This approach maintains neuromuscular, metabolic, and perceptual parameters without any detrimental effects, ensuring athletes can perform at their best.Alternating hypoxia and normoxia during active and passive phases shows potential for optimizing hypoxic training, striking an ideal balance between the hypoxic stimulus and training intensity and load. [ABSTRACT FROM AUTHOR]

Poudel, Sangeeta, Sandesh Gautam, Purushottam Adhikari, and Ken Zafren. Physiological effects of sildenafil versus placebo at high altitude: a systematic review. High Alt Med Biol. 25:16–25, 2024. Introduction: High altitude pulmonary edema (HAPE), a life-threatening condition that affects individuals ascending to high altitude, requires the development of pulmonary hypertension. Sildenafil can be used to prevent and treat HAPE, presumably by decreasing pulmonary artery pressure (PaP). We compared the physiological effects of sildenafil versus placebo at high altitude (above 2,500 m), including the effects on PaP. Methods: We performed a systematic search of PubMed, EMBASE, and Cochrane CENTRAL for randomized controlled studies of the physiological effects of sildenafil in hypoxia in healthy individuals. We conducted a systematic review of all studies meeting our criteria. Results: Of the 14 studies that met the inclusion criteria, 8 were hypobaric hypoxia studies. Six studies reported data at rest at altitudes from 3,650 to 5,245 m. Two were simulations reporting exercise data at equivalent altitudes of 2,750–5,000 m. Nine studies used normobaric hypoxia corresponding to altitudes between 2,500 and 6,400 m. One reported only rest data, two reported rest and exercise data, and the others reported only exercise data. Sildenafil significantly reduced PaP at rest and exercise in hypobaric or normobaric hypoxia. There were no significant differences between arterial oxygen saturation (SpO2) with sildenafil in hypobaric or normobaric hypoxia at rest or exercise. There were no significant differences in heart rate or mean arterial pressure (MAP) at rest or exercise and cardiac output during exercise in hypobaric or normobaric hypoxia. Conclusions: Sildenafil significantly reduces PaP at rest and exercise in normobaric or hypobaric hypoxia. Sildenafil has no significant effects on SpO2, heart rate, cardiac output (during exercise), or MAP at rest or exercise in hypobaric or normobaric hypoxia. [ABSTRACT FROM AUTHOR]

BACKGROUND: The impact of gravity on the existence of all living things has long been of interest to scientists. The force of the Earth's gravity combined with hypoxia significantly affects blood circulation and blood accumulation in various parts of the human and animal body. To date, the relationship between body position and blood circulation in pulmonary circulation under hypobaric hypoxia has not been sufficiently studied. OBJECTIVES: Therefore, the research aims to determine the possibility of changing the body position in space on the reactions in the pulmonary circulation in the plains and highlands. METHODS: For this purpose, research was conducted on male Wistar rats, 44 of whom spent 150 days at an altitude of 3200 m above sea level, and 25 representatives of the control group - at an altitude of 164 m. RESULTS: The study revealed that gravitational redistribution of blood in mountainous conditions is less pronounced compared to the control group. This is explained by the remodeling of the vascular wall and an increase in its stiffness. It was found that a change in pulmonary artery pressure at the time of a change in body position was recorded both on the plains and in the highlands. On the plains, when the body position of rats was changed to passive orthostatic, a decrease in systolic and diastolic pulmonary artery pressure was noted, and when the body position was changed to passive anti-orthostatic, an increase in pulmonary artery pressure was observed. The increase in pulmonary artery pressure was a compensatory mechanism due to the increased stiffness of the pulmonary vasculature. CONCLUSIONS: The practical significance of this research is to expand the understanding of the pathogenesis of pulmonary hypertension in high-altitude hypoxia. [ABSTRACT FROM AUTHOR]

Background: Hypoxia and old age impair postural control and may therefore enhance the risk of accidents. We investigated whether acetazolamide, the recommended drug for prevention of acute mountain sickness, may prevent altitude-induced deterioration of postural control in older persons. Methods: In this parallel-design trial, 95 healthy volunteers, 40 years of age or older, living <1,000 m, were randomized to preventive therapy with acetazolamide (375 mg/d) or placebo starting 24 h before and during a 2-day sojourn at 3,100 m. Instability of postural control was quantified by a balance platform with the center of pressure path length (COPL) as primary outcome while pulse oximetry (SpO2) was monitored. Effects of altitude and treatment on COPL were evaluated by ordered logistic regression. www.ClinicalTrials.gov NCT03536429. Results: In participants taking placebo, ascent from 760 m to 3,100 m increased median COPL from 25.8 cm to 27.6 cm (odds ratio 3.80, 95%CI 2.53-5.70) and decreased SpO2 from 96% to 91% (odds ratio 0.0003, 95%CI 0.0002-0.0007); in participants taking acetazolamide, altitude ascent increased COPL from 24.6 cm to 27.3 cm (odds ratio 2.22, 95%CI 1.57-3.13), while SpO2 decreased from 96% to 93% (odds ratio 0.007, 95%CI 0.004-0.012). Altitude-induced increases in COPL were smaller with acetazolamide vs. placebo (odds ratio 0.58, 95%CI 0.34-0.99) while drops in SpO2 were mitigated (odds ratio 19.2, 95%CI 9.9-37.6). Conclusion: In healthy individuals, 40 years of age or older, postural control was impaired after spending a night at 3,100 m. The altitude-induced deterioration of postural control was mitigated by acetazolamide, most likely due to the associated improvement in oxygenation. [ABSTRACT FROM AUTHOR]

The intensification of the stress response during resistance training (RT) under hypoxia conditions could trigger unwanted effects that compromise muscle health and, therefore, the ability of the muscle to adapt to longer training periods. We examined the effect of acute moderate terrestrial hypoxia on metabolic, inflammation, antioxidant capacity and muscle atrophy biomarkers after a single RT session in a young male population. Twenty healthy volunteers allocated to the normoxia (N < 700 m asl) or moderate altitude (HH = 2320 m asl) group participated in this study. Before and throughout the 30 min following the RT session (3 × 10 reps, 90 s rest, 70% 1RM), venous blood samples were taken and analysed for circulating calcium, inorganic phosphate, cytokines (IL-6, IL-10 and TNF-α), total antioxidant capacity (TAC) and myostatin. Main results displayed a marked metabolic stress response after the RT in both conditions. A large to very large proportional increase in the adjusted to pre-exercise change of inflammatory and anti-inflammatory markers favoured HH (serum TNF-α [ES = 1.10; p = 0.024] and IL-10 [ES = 1.31; p = 0.009]). The exercise produced a similar moderate increment of myostatin in both groups, followed by a moderate non-significant reduction in HH throughout the recovery (ES = − 0.72; p = 0.21). The RT slightly increased the antioxidant response regardless of the environmental condition. These results revealed no clear impact of RT under acute hypoxia on the metabolic, TAC and muscle atrophy biomarkers. However, a coordinated pro/anti-inflammatory response balances the potentiated effect of RT on systemic inflammation. [ABSTRACT FROM AUTHOR]

Introduction: Peak oxygen uptake (V̇O2peak) declines by ~7% per 1000 m of increasing altitude, whereas exercise performance seems reduced to a lesser extent. For example, 800–10 000 m track and field performances are decreased by 0.4%–2.4% above 1000 m as compared to below and some studies show similar drops in cycling performance. A greater decline in V̇O2peak than in endurance performance with altitude suggests a higher fractional utilization of V̇O2peak (%V̇O2peak). Therefore, we hypothesized that the %V̇O2peak is higher with acute hypoxic exposure than near sea level. Methods: Sixteen lowlanders (8 women, age: 31 ± 7 years [mean ± SD], body mass: 68 ± 8 kg, V̇O2peak: 60 ± 8 mL min−1 kg−1) underwent cycling testing in a hypobaric hypoxic chamber on 6 test days, three conducted at 300 m and three at 2800 m of acute altitude. At both altitudes, V̇O2peak was determined, and during a 40‐min all out maximal effort time trial (TT), mean power output (MPO) and mean V̇O2 (%V̇O2peak) were assessed. Results: V̇O2peak decreased by 11.2 ± 3.0% (p < 0.001), while MPO during the TT declined by 10.7 ± 3.1% (p < 0.001) at 2800 m as compared to 300 m. During the TT, %V̇O2peak was higher at altitude, corresponding to 75.9 ± 4.5% at 300 m and 78.8 ± 4.2% at 2800 m (p = 0.011), and cycling economy (mL O2 kJ−1) was poorer (+3.4 ± 2.7%, p < 0.001). Conclusion: The %V̇O2peak was higher during a cycling TT at 2800 m of altitude than near sea level, while cycling economy was poorer. This resulted in a similar reduction in performance and V̇O2peak. Future studies should address the physiological mechanisms underlying the elevated %V̇O2peak. [ABSTRACT FROM AUTHOR]

Introduction: High altitude exposure may lead to high altitude pulmonary hypertension (HAPH) and high altitude pulmonary edema (HAPE). The pathophysiologic processes of both entities have been linked to decreased nitric oxide (NO) availability. Methods: We studied the effect of acute high altitude exposure on the plasma concentrations of asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-arginine, L-ornithine, and L-citrulline in two independent studies. We further investigated whether these biomarkers involved inNOmetabolism were related to HAPH and HAPE, respectively. Fifty (study A) and thirteen (study B) nonacclimatized lowlanders were exposed to 4,559 m for 44 and 67 h, respectively. In contrast to study A, the participants in study B were characterized by a history of at least one episode of HAPE. Arterial blood gases and biomarker concentrations in venous plasma were assessed at low altitude (baseline) and repeatedly at high altitude. HAPE was diagnosed by chest radiography, and HAPH by measuring right ventricular to atrial pressure gradient (RVPG) with transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and the AMS-C score. Results: In both studies SDMA concentration significantly increased at high altitude. ADMA baseline concentrations were higher in individuals with HAPE susceptibility (study B) compared to those without (study A). However, upon high altitude exposure ADMA only increased in individuals without HAPE susceptibility, while there was no further increase in those with HAPE susceptibility. We observed an acute and transient decrease of L-ornithine and a more delayed but prolonged reduction of L-citrulline during high altitude exposure. In both studies SDMA positively correlated and L-ornithine negatively correlated with RVPG. ADMA was significantly associated with the occurrence of HAPE (study B). ADMA and SDMA were inversely correlated with alveolar PO2, while L-ornithine was inversely correlated with blood oxygenation and haemoglobin levels, respectively. Discussion: In non-acclimatized individuals ADMA and SDMA, two biomarkers decreasing endothelial NO production, increased after acute exposure to 4,559 m. The observed biomarker changes suggest that both NO synthesis and arginase pathways are involved in the pathophysiology of HAPH and HAPE. [ABSTRACT FROM AUTHOR]

Objectives: Hypoxia is a physiological state characterized by reduced oxygen levels in organs and tissues. It is a common clinicopathological process and a major cause of health problems in highland areas. Heart rate variability (HRV) is a measure of the balance in autonomic innervation to the heart. It provides valuable information on the regulation of the cardiovascular system by neurohumoral factors, and changes in HRV reflect the complex interactions between multiple systems. In this review, we provide a comprehensive overview of the relationship between high-altitude hypoxia and HRV. We summarize the different mechanisms of diseases caused by hypoxia and explore the changes in HRV across various systems. Additionally, we discuss relevant pharmaceutical interventions. Overall, this review aims to provide research ideas and assistance for in-depth studies on HRV. By understanding the intricate relationship between high-altitude hypoxia and HRV, we can gain insights into the underlying mechanisms and potential therapeutic approaches to mitigate the effects of hypoxia on cardiovascular and other systems. Methods: The relevant literature was collected systematically from scientific database, including PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Baidu Scholar, as well as other literature sources, such as classic books of hypoxia. Results: There is a close relationship between heart rate variability and high-altitude hypoxia. Heart rate variability is an indicator that evaluates the impact of hypoxia on the cardiovascular system and other related systems. By improving the observation of HRV, we can estimate the progress of cardiovascular diseases and predict the impact on other systems related to cardiovascular health. At the same time, changes in heart rate variability can be used to observe the efficacy of preventive drugs for altitude related diseases. Conclusions: HRV can be used to assess autonomic nervous function under various systemic conditions, and can be used to predict and monitor diseases caused by hypoxia at high altitude. Investigating the correlation between high altitude hypoxia and heart rate variability can help make HRV more rapid, accurate, and effective for the diagnosis of plateau-related diseases. [ABSTRACT FROM AUTHOR]

Using phylogenetic analysis of the nucleotide sequences of whole mitochondrial genomes (mtDNA), the spectra of germline nucleotide substitutions (on the L-chain of mtDNA) were reconstructed in highland populations of the Pamirs and Tibet in comparison with regional indigenous groups of Western Asia, Northeastern Siberia, and Southern Siberia. No differences were found in the distribution of nucleotide substitution frequencies in the mtDNA spectra depending on the population distribution by altitude. Pyrimidine transitions dominate in all mtDNA spectra, and T → C substitutions are the most frequent among them. Next in frequency in most regional groups are A → G substitutions, but in the Pamir and northeast Asian groups, G → A substitutions are prevalent. Of the transversions in all populations studied, C → A substitutions are found to be predominant, except for the Tibetan one, where A → C substitutions are more frequent. The lack of differences in the distribution of mtDNA mutations in high-altitude and non-highland populations indicates that the structure of mtDNA spectra in human populations is independent of the oxidative stress intensity in mitochondria. [ABSTRACT FROM AUTHOR]

Background: Chronic Obstructive Pulmonary Disease (COPD) is a chronic, noncommunicable disease characterized by hypoxemia, with altered lung function, dyspnea on mild exertion, limited tolerance to physical exertion, and functional impairment. Physical exercise has been recommended worldwide as an efficient strategy to improve the autonomy and quality of life of patients affected by COPD. However, the adaptive molecular mechanisms occurring in these patients after the exposure to the hypoxic stimulus triggered by physical exercise have currently not been described in populations living at high altitude. Methods: The clinical trial we are presenting here consists of a quasi-experimental design with longitudinal analysis of repeated measures, with intra- and inter-group comparisons, measuring primary and secondary variables in 4 temporal points. Participants will be people with a diagnosis of COPD residing at high altitudes (> 2600 m), without oncological, renal, cardiac, or musculoskeletal comorbidities with a low level of physical activity. The intervention will be an 8-week program of physical exercise of resistance and muscular strength (8-WVP) which will be carried out at home. Primary outcome variables will be the expression of HIF-1α, VEGF, and EPO. As secondary outcome variables, we will consider lung function (measured by spirometry), physical performance (measured by ergospirometry and dynamometry), and hematological parameters. Discussion: The results obtained after the clinical trial proposed here will promote knowledge on the expression of signaling proteins as an adaptive response to hypoxia in people with COPD living at high altitude, which will be relevant because there are not data on this population group. The knowledge generated from the application of this protocol will increase the pathophysiological understanding of the disease and future medical and therapeutic decision-making based on physical exercise prescription. Trial registration {2a}: NCT04955977 [ClinicalTrials.gov]—NCT04955977 [WHO ICRTP]. First Posted: July 9, 2021. [ABSTRACT FROM AUTHOR]

Objective: To determine changes in protein expression related to brain aging and imaging features in mice after chronic hypoxia exposure at high altitude. Method: A total of 24 healthy 4-week-old mice were randomly divided into high altitude hypoxia (HH) and plain control (PC) groups (n = 8 per group). HH mice were transported from Xi’an (450 m above sea level) to Maduo (4,300 m above sea level) while PC mice were raised in Xi’an. After 6 months, 7.0T magnetic resonance imaging (MRI) was performed. All mice completed T2-weighted imaging (T2WI), diffusion tensor imaging (DTI), resting-state functional MRI (rs-fMRI), arterial spin labeling (ASL), and magnetic resonance angiography (MRA) examinations. Next, brain slices were prepared and Nissl staining was used to observe morphological changes in neurons. Ultrastructural changes in neurons were observed by transmission electron microscopy. Expression changes of Caspase-3, klotho, P16, P21, and P53 at the gene and protein levels were detected by real-time PCR (RT- PCR) and Western blot. Results: The number of neuronal Nissl bodies in the hippocampus and frontal cortex was significantly decreased in the HH group compared to the PC group. Some hippocampal and frontal cortical neurons were apoptotic, the nuclei were wrinkled, chromatin was aggregated, and most mitochondria were mildly swollen (crista lysis, fracture). Compared with the PC group, the HH group showed elevated expression of caspase-3 mRNA, P16 mRNA, P21 mRNA, and P53 mRNA in the hippocampus and frontal cortex. Expression of Klotho mRNA in the frontal cortex was also significantly decreased. Western blot results showed that caspase-3 protein expression in the hippocampus and frontal cortex of the HH group was increased compared with the PC group. Moreover, there was decreased Klotho protein expression and significantly increased P-P53 protein expression. Compared with the PC group, expression of P16 protein in the frontal cortex of the HH group was increased and the gray matter (GM) volume in the left visceral area, left caudate nucleus, and left piriform cortex was decreased. Furthermore, the amplitude of low frequency fluctuation was decreased in the left posterior nongranular insular lobe, right small cell reticular nucleus, left flocculus, left accessory flocculus, and left primary auditory area, but increased in the GM layer of the left superior colliculus. Regional homogeneity was decreased in the left and right olfactory regions, but increased in the left bed nucleus. After exposure to high altitude, functional connectivity (FC) between the bilateral caudate nucleus and thalamus, corpus callosum, cingulate gyrus, anterior limbic cortex, globus pallidus, and hippocampus was weakened. FC between the right caudate nucleus and hypothalamus and entorhinal cortex was also weakened. The fractional anisotropy value of the left hippocampus was decreased in the HH group. Compared with the PC group, the HH group showed significantly increased inner diameters of the bilateral common carotid artery and left internal carotid artery. The cerebral blood flow values of the bilateral cortex and bilateral hippocampus in the HH group did not change significantly. Conclusion: Taken together, our findings show that chronic hypoxia exposure at high altitude may promote neuronal apoptosis and abnormal expression of related proteins, changing the structure and function of brain. These changes may contribute to brain aging. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the changes in blood viscosity, pulmonary hemodynamics, nitric oxide (NO) production, and maximal oxygen uptake ( V ˙ O 2 max) during a maximal incremental test conducted in normoxia and during exposure to moderate altitude (2,400 m) in athletes exhibiting exercise-induced hypoxemia at sea level (EIH). Nine endurance athletes with EIH and eight without EIH (NEIH) performed a maximal incremental test under three conditions: sea level, 1 day after arrival in hypoxia, and 5 days after arrival in hypoxia (H5) at 2,400 m. Gas exchange and oxygen peripheral saturation (SpO2) were continuously monitored. Cardiac output, pulmonary arterial pressure, and total pulmonary vascular resistance were assessed by echocardiography. Venous blood was sampled before and 3 min after exercise cessation to analyze blood viscosity and NO end-products. At sea level, athletes with EIH exhibited an increase in blood viscosity and NO levels during exercise while NEIH athletes showed no change. Pulmonary hemodynamics and aerobic performance were not different between the two groups. No between-group differences in blood viscosity, pulmonary hemodynamics, and V ˙ O 2 max were found at 1 day after arrival in hypoxia. At H5, lower total pulmonary vascular resistance and greater NO concentration were reported in response to exercise in EIH compared with NEIH athletes. EIH athletes had greater cardiac output and lower SpO2 at maximal exercise in H5, but no between-group differences occurred regarding blood viscosity and V ˙ O 2 max. The pulmonary vascular response observed at H5 in EIH athletes may be involved in the greater cardiac output of EIH group and counterbalanced the drop in SpO2 in order to achieve similar V ˙ O 2 max than NEIH athletes. [ABSTRACT FROM AUTHOR]

This article discusses the adverse events and the effect of oxygen therapy on stable-treated patients with pulmonary vascular disease (PVD) who are exposed to high altitude. The study involved investigating PVD patients at low altitude and high altitude during a 30-hour overnight stay. The main outcomes measured were severe hypoxemia, acute mountain sickness, and the therapeutic effect of supplemental oxygen therapy. The results showed that some patients experienced adverse events at high altitude, primarily severe hypoxemia, which was effectively treated with supplemental oxygen therapy. The study suggests that stable, low-risk PVD patients can tolerate short-term stays at high altitude but may require supplemental oxygen therapy in certain cases. [Extracted from the article]

Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and subacute cardiopulmonary acclimatization to high altitude in middle-aged asthmatics without other comorbidities. Methods: In this prospective study in lowlander subjects with mostly mild asthma who revealed an asthma control questionnaire score >0.75 and participated in a three-week rehabilitation program, we assessed systolic pulmonary artery pressure (sPAP), cardiac function, and extravascular lung water (EVLW) at 760 m (baseline) by Doppler-echocardiography and on the second (acute) and last day (subacute) at a high altitude clinic in Kyrgyzstan (3100 m). Results: The study included 22 patients (eight male) with a mean age of 44.3 ± 12.4 years, body mass index of 25.8 ± 4.7 kg/m², a forced expiratory volume in 1 s of 92% ± 19% predicted (post-bronchodilator), and partially uncontrolled asthma. sPAP increased from 21.8 mmHg by mean difference by 7.5 [95% confidence interval 3.9 to 10.5] mmHg (p < 0.001) during acute exposure and by 4.8 [1.0 to 8.6] mmHg (p = 0.014) during subacute exposure. The right-ventricular-to-pulmonary-artery coupling expressed by TAPSE/sPAP decreased from 1.1 by -0.2 [-0.3 to -0.1] mm/mmHg (p < 0.001) during acute exposure and by -0.2 [-0.3 to -0.1] mm/mmHg (p = 0.002) during subacute exposure, accordingly. EVLW significantly increased from baseline (1.3 ± 1.8) to acute hypoxia (5.5 ± 3.5, p < 0.001) but showed no difference after 3 weeks (2.0 ± 1.8). Conclusion: In otherwise healthy asthmatics, acute exposure to hypoxia at high altitude increases pulmonary artery pressure (PAP) and EVLW. During subacute exposure, PAP remains increased, but EVLW returns to baseline values, suggesting compensatory mechanisms that contribute to EVLW homeostasis during acclimatization. [ABSTRACT FROM AUTHOR]

Background: Asthma rehabilitation at high altitude is common. Little is known about the acute and subacute cardiopulmonary acclimatization to high altitude in middle-aged asthmatics without other comorbidities. Methods: In this prospective study in lowlander subjects with mostly mild asthma who revealed an asthma control questionnaire score >0.75 and participated in a three-week rehabilitation program, we assessed systolic pulmonary artery pressure (sPAP), cardiac function, and extravascular lung water (EVLW) at 760 m (baseline) by Doppler-echocardiography and on the second (acute) and last day (subacute) at a high altitude clinic in Kyrgyzstan (3100 m). Results: The study included 22 patients (eight male) with a mean age of 44.3 ± 12.4 years, body mass index of 25.8 ± 4.7 kg/m2, a forced expiratory volume in 1 s of 92% ± 19% predicted (post-bronchodilator), and partially uncontrolled asthma. sPAP increased from 21.8 mmHg by mean difference by 7.5 [95% confidence interval 3.9 to 10.5] mmHg (p < 0.001) during acute exposure and by 4.8 [1.0 to 8.6] mmHg (p = 0.014) during subacute exposure. The right-ventricular-topulmonary-artery coupling expressed by TAPSE/sPAP decreased from 1.1 by −0.2 [−0.3 to −0.1] mm/mmHg (p < 0.001) during acute exposure and by −0.2 [−0.3 to −0.1] mm/mmHg (p = 0.002) during subacute exposure, accordingly. EVLW significantly increased from baseline (1.3 ± 1.8) to acute hypoxia (5.5 ± 3.5, p < 0.001) but showed no difference after 3 weeks (2.0 ± 1.8). Conclusion: In otherwise healthy asthmatics, acute exposure to hypoxia at high altitude increases pulmonary artery pressure (PAP) and EVLW. During subacute exposure, PAP remains increased, but EVLW returns to baseline values, suggesting compensatory mechanisms that contribute to EVLW homeostasis during acclimatization. [ABSTRACT FROM AUTHOR]

The primary objective of this investigation was to study the effect of altitude on fish swimming ability. Different species were tested to ensure that the differences observed are not associated with a single species. Fish critical swimming speed and burst speed were determined using stepped-velocity tests in a Brett-type swimming respirometer. Based on the effects of water temperature and dissolved oxygen, it is clear that the swimming ability of fish decreases as altitude increases. Further, because the effects of high altitude on fish physiology go beyond the effects of lower temperature and dissolved oxygen, we recommend that fish swimming ability be tested at an altitude similar to the target fishway site to ensure the validity of fish data used for fishway design. [ABSTRACT FROM AUTHOR]

Determining which traits allow species to live at higher elevations is essential to understanding the forces that shape montane biodiversity.For the many animals that rely on flight for locomotion, a long‐standing hypothesis is that species with relatively large wings should better persist in high‐elevation environments because wings that are large relative to the body generate more lift and decrease the aerobic costs of remaining aloft. Although these biomechanical and physiological predictions have received some support in birds, other flying taxa often possess smaller wings at high elevations or no wings at all.To test if predictions about the requirements for relative wing size at high elevations are generalizable beyond birds, we conducted macroecological analyses on the altitudinal characteristics of 302 Nearctic dragonfly species.Consistent with the biomechanical and aerobic hypotheses, species with relatively larger wings live at higher elevations and have wider elevation breadths—even after controlling for a species' body size, mean thermal conditions, and range size. Moreover, a species' relative wing size had nearly as large of an impact on its maximum elevation as being adapted to the cold.Relatively large wings may be essential to high‐elevation life in species that completely depend on flight for locomotion, like dragonflies or birds. With climate change forcing taxa to disperse upslope, our findings further suggest that relatively large wings could be a requirement for completely volant taxa to persist in montane habitats. [ABSTRACT FROM AUTHOR]

It is popular for high-performance athletes to attend training camps at natural moderate altitude (1800–2500m), which may have direct and indirect effects on the quantity and quality of sleep athletes obtain. This can potentially influence the ability to maximise training responses and optimise recovery from exercise. This study aimed to compare objective and subjective markers of sleep quality between sea level (SL) and moderate altitude (ALT) in a sample of 14 (male n = 5, female n = 9) high-performance collegiate swimmers. Sleep was objectively (wristwatch actigraphy) and subjectively (Athlete Sleep Screening Questionnaire; ASSQ) assessed at SL and an ALT of 2,320m. A significant increase (p = 0.028, d = 0.76) in the 'sleep difficulty score' calculated from the ASSQ was identified from SL (4.9 ± 1.7 au) to ALT (6.6 ± 2.3 au), with a greater number of the swimmers judged to have a more severe clinical sleep problem at ALT. Of the seven sleep characteristics assessed objectively, there were no significant differences identified between the two environments. Sleep disruption was found to substantially improve following rest/recovery days while at ALT. Although this study highlights possible inconsistencies between objective and subjective measures of sleep quality while at ALT, any suggestion of reduced sleep quality should be considered seriously. Practically, the present study demonstrates the importance of, at altitude, using both objective and subjective measures to monitor athlete sleep quality, and ensuring training schedules are carefully periodised, incorporating rest or recovery days within intense training blocks for optimal sleep quality to be achieved. [ABSTRACT FROM AUTHOR]

This study investigated the effects of a 3-week power-oriented resistance training programme performed at moderate altitude on the lower-limb maximal theoretical power and force-velocity (F-V) imbalance of elite judokas. Twenty-two elite male judokas were randomly assigned to either a hypobaric hypoxia or normoxia group. Mechanical outputs from an incremental loaded countermovement jump test were assessed at sea level, before and after training, and 1 week later. Results indicated an increase in the maximal theoretical force and a reduction in the F-V imbalance both at moderate altitude and sea level. Altitude training induced additional benefits when compared to sea level for F-V imbalance (8.4%; CI: 0.3, 17.3%), maximal theoretical power (2.09 W·kg−1; CI: 0.13, 4.52 W·kg−1) and force (1.32 N·kg−1; CI: −0.12, 2.96 N·kg−1), jump height (3.24 cm; CI: 2.02, 4.80 cm) and optimal maximal theoretical force (1.61 N·kg−1; CI: 0.06, 3.60 N·kg−1) and velocity (0.08 m·s−1; CI: 0.00, 0.17 m·s−1) after the training period. The hypoxia group achieved their best results immediately after the training period, while the normoxia group achieved them one week later. These results suggest that a power-oriented resistance training programme carried out at moderate altitude accelerates and improves the gains in lower-limb muscle power, while minimizing lower-limb imbalances. Therefore, it seems appropriate to compete immediately after the return to sea level and/or use altitude training as a tool to improve muscle power levels of athletes without tapering goals, especially in highly trained power athletes, since their window of adaptation for further power enhancement is smaller. Highlights A 3-week power-oriented resistance training programme improved lower-limb mechanical outputs of elite judokas both at moderate altitude and sea level; training at moderate altitude increases and accelerates these improvements, reducing athletes' imbalances. It may be optimal for judokas to compete immediately after the return to sea level and/or use altitude training as a tool to improve muscle power levels of athletes without tapering goals, especially in highly trained power athletes, since their window of adaptation for further power enhancement is attenuated. Athletes should ensure they possess adequate strength levels before employing a power-oriented training programme to potentiate further improvements in muscle power. [ABSTRACT FROM AUTHOR]

Purpose: Ingestion of sildenafil citrate has performance-enhancing effects at high altitudes above 3800 m in able-bodied individuals. It is unknown whether it can improve the performance of athletes with spinal cord injury (SCI) at moderate altitudes (<2200 m), relevant to Paralympic competitions. As most men with SCI suffer from erectile dysfunction of neurologic origin and use sildenafil on a regular basis, it seems important to study the impact of sildenafil on exercise capacity. The outcome of this study is also relevant to the antidoping community. Methods: Twenty-seven healthy male wheelchair athletes with a motor-complete SCI participated in this prospective double-blind, randomized, placebo-controlled study. The participants performed arm cranking exercise to exhaustion at sea level and moderate altitude (2200 m) after ingestion of 50 mg sildenafil citrate or a placebo. Peak power output, peak oxygen uptake, peak heart rate, rating of perceived exertion, oxygen saturation, and lactate concentrations at exhaustion were measured. Results: Friedman analysis showed that peak power output at sea level was significantly higher (P =.004) under placebo treatment (median [minimum; maximum]: 120 W [35; 170]) compared with sildenafil (115 W [40; 165]). Blood oxygen saturation under sildenafil treatment at sea level (98% [81; 100]) was significantly higher (P =.006) compared with sildenafil treatment at moderate altitude (94% [85; 100]). All other parameters revealed no impact of sildenafil or altitude. Conclusions: In this study, the ingestion of sildenafil citrate in athletes with SCI demonstrated no positive effects on peak arm-cranking-exercise capacity compared with placebo either at sea level or at moderate altitude. [ABSTRACT FROM AUTHOR]

Purpose: There is debate as to which environmental intervention produces the most benefit for team sport athletes, particularly comparing heat and altitude. This quasi-experimental study aimed to compare blood volume (BV) responses with heat and altitude training camps in Australian footballers. Methods: The BV of 7 professional Australian footballers (91.8 [10.5] kg, 191.8 [10.1] cm) was measured throughout 3 consecutive spring/summer preseasons. During each preseason, players participated in altitude (year 1 and year 2) and heat (year 3) environmental training camps. Year 1 and year 2 altitude camps were in November/December in the United States, whereas the year 3 heat camp was in February/March in Australia after a full exposure to summer heat. BV, red cell volume, and plasma volume (PV) were measured at least 3 times during each preseason. Results: Red cell volume increased substantially following altitude in both year 1 (d = 0.67) and year 2 (d = 1.03), before returning to baseline 4 weeks postaltitude. Immediately following altitude, concurrent decreases in PV were observed during year 1 (d = −0.40) and year 2 (d = −0.98). With spring/summer training in year 3, BV and PV were substantially higher in January than temporally matched postaltitude measurements during year 1 (BV: d = −0.93, PV: d = −1.07) and year 2 (BV: d = −1.99, PV: d = −2.25), with year 3 total BV, red cell volume, and PV not changing further despite the 6-day heat intervention. Conclusions: We found greater BV after training throughout spring/summer conditions, compared with interrupting spring/summer exposure to train at altitude in the cold, with no additional benefits observed from a heat camp following spring/summer training. [ABSTRACT FROM AUTHOR]

The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has affected the world in multiple ways and has been a challenge for the health systems of each country. From the beginning, risk factors for the severity and mortality of the disease were considered, as the spread of the virus was related to the living conditions of each population. Methods: In this ecological study we have evaluated the role of geography, precisely the altitude above sea level in the incidence and mortality of COVID-19 in Peru. Incidence and mortality data were taken from the open-access database of the government of Peru until March 2021. COVID-19 cases and COVID-19 mortality were treated as cases/density population and 1000 x cases/inhabitants while altitude was treated as continuous and as a categorical variable divided in 7 categories. The relationship between COVID-19 cases or deaths for COVID-19 and altitude as continuous variable was determined using Spearman correlation test. Meanwhile when altitude was considered as a categorical variable, Poisson regression or negative binomial analyses were applied. Results: A significant inverse correlation was found between COVID-19 cases by population density and altitude (r=-0.37 p < 0.001). By altitude categories, the lowest risk for infection was observed between 3,000 and 3,500 m (IRR 0.08; 95% CI 0.05,0.12). Moreover, we found an inverse correlation between altitude and COVID-19 mortality (r=-0.39 p < 0.001). Also, the lowest risk for mortality was observed between 3,000 and 3,500 m (IRR 0.12; 95%CI 0.08; 0.18). Similar results were found when analyses were adjusted for inhabitants and stratified by sex. Conclusion: This study reports an inverse relationship between COVID-19 incidence and mortality with respect to the altitude of residence, particularly, a u-shaped protection is shown, with a highest benefit between 3000 and 3500 m. The possibility of using hypoxia as an alternative treatment requires more complex studies that should allow knowing the physiological and environmental mechanisms of the protective role. [ABSTRACT FROM AUTHOR]

Organisms often acquire physiological and morphological modifications to conquer ecological challenges when colonizing new environments which lead to their adaptive evolution. However, deciphering the genomic mechanism of ecological adaptation is difficult because ecological environments are often too complex for straightforward interpretation. Thus, we examined the adaptation of a widespread songbird—the rufous‐capped babbler (Cyanoderma ruficeps)—to a relatively simple system: distinct environments across elevational gradients on the mountainous island of Taiwan. We focused on the genomic sequences of 43 birds from five populations to show that the Taiwan group split from its sister group in mainland China around 1–2 million years ago (Ma) and colonized the montane habitats of Taiwan at least twice around 0.03–0.22 Ma. The montane and lowland Taiwan populations diverged with gene flow between them, suggesting strong selection associated with different elevations. We found that the montane babblers had smaller beaks than the lowland ones, consistent with Allen's rule, and identified candidate genes—COL9A1 and SOX11—underlying the beak size changes. We also found that altitudinally divergent mutations were mostly located in noncoding regions and tended to accumulate in chromosomal inversions and autosomes. The altitudinally divergent mutations might regulate genes related to haematopoietic, metabolic, immune, auditory and vision functions, as well as cerebrum morphology and plumage development. The results reveal the genomic bases of morphological and physiological adaptation in this species to the low temperature, hypoxia and high UV light environment at high elevation. These findings improve our understanding of how ecological adaptation drives population divergence from the perspective of genomic architecture. [ABSTRACT FROM AUTHOR]

The main objective of this study was to compare the physical response of para-footballers with cerebral palsy (CP) in official international football matches played at moderate altitude and sea level locations. Eighty-seven international CP footballers participated in this study. We divided participants according to the place of the international competition [sea level group (SLG) and moderate altitude group (MAG)], sport classes (i.e., FT1, FT2, and FT3), and match playing time (i.e., <20 min, 20‒40 min, and >40 min). We recorded the physical response using global position system devices during matches. This study showed that MAG described a lower physical response than SLG on total distance, distance covered at different intensities, and the number of accelerations and decelerations. FT2 and FT3 presented a similar pattern, where we found significant differences for total distance, distance covered at lower and high intensities and moderate accelerations, and decelerations. Considering the playing time during altitude matches, the 20‒40 min and >40 min groups obtained more marked differences in the physical response variables. Para-footballers with CP who competed under altitude conditions showed a lower physical response during football matches, suggesting the implementation of specific preparation and training strategies to face the demanding environmental conditions. [ABSTRACT FROM AUTHOR]

Purpose: Chronic exposure to hypoxia can induce muscle wasting in unaccustomed individuals. Detailed assessment of the effects of hypoxia on muscle tissue adaptation in elite mountaineers has not been performed. This study aims to assess muscle volume after exposure to normobaric hypoxia. Methods: Two professional mountaineers (A and B) participated in a 35-d intervention of graded normobaric hypoxia with the aim of 14 d exposure to 8% oxygen corresponding to 7112-m altitude. Volume of the shank, thigh, and hip muscles was assessed by magnetic resonance imaging pre- and postintervention. Dietary intake and physical activity were monitored throughout the study from food images and accelerometry analysis, together with blood analysis and anthropometric measurements. Results: Hypoxia reduced total leg muscle volume by 3.3% ± 6.0% in A and by 9.4% ± 7.3% in B. A lost 288 g and B 642 g of muscle mass, whereas dietary intake only declined by ~23% in the last intervention week. Arterial oxygen saturation declined from 95% and 86% to 77% and 72% in A and B, respectively. In hypoxia, participants could not maintain their physical activity levels. Notably, muscle loss varied substantially across muscle groups amounting to 5.4% ± 3.0%, 8.3% ± 5.2%, and 4.1% ± 8.6% for hip, thigh, and shank muscles, respectively. Conclusions: Our results indicate that hypoxia and resultant reductions in physical activity and caloric intake lead to substantial loss of muscle mass that was accentuated in proximal muscle as opposed to distal muscles. Surprisingly, thigh muscle wasting during this intervention is comparable with that observed during strict 56-d bed rest. [ABSTRACT FROM AUTHOR]

Trait genetic architecture plays an important role in the probability that variation in that trait leads to divergence and speciation. In some cases, speciation may be driven by the generation of novel phenotypes through the recombination of genes associated with traits that are important for local adaptation or sexual selection. Here, we investigate the genetic basis of three plumage color traits, and one ecological trait, breeding elevation, in a recent avian radiation, the North American rosy-finches (Leucosticte spp.). We identify unique genomic regions associated with each trait and highlight 11 candidate genes. Among these are well-characterized melanogenesis genes, including Mitf and Tyrp1, and previously reported hypoxia-related genes including Egln1. Additionally, we use mitochondrial data to date the divergence of rosy-finch clades which appear to have diverged within the past 250 ky. Given the low levels of genome-wide differentiation among rosy-finch taxa, and evidence for extensive introgression in North America, plumage coloration and adaptation to high elevations have likely played large roles in generating the observed patterns of lineage divergence. The relative independence of these candidate regions across the genome suggests that recombination might have led to multiple phenotypes, and subsequent rosy-finch speciation, over short periods of time. [ABSTRACT FROM AUTHOR]

INTRODUCTION: A study was performed to evaluate a cockpit flight simulation suite for measuring moderate altitude effects in a limited subject group. Objectives were to determine whether the apparatus can detect subtle deterioration, record physiological processes throughout hypobaric exposure, and assess recovery. METHODS: Eight subjects trained to perform precision instrument control (PICT) flight and unusual attitude recovery (UAR) and completed chamber flights dedicated to the PICT and UAR, respectively. Each flight comprised five epochs, including ground level pressure (GLP), ascent through altitude plateaus at 10,000, 14,000, and 17,500 ft (3050, 4270, and 5338 m), then postexposure recovery. PICT performance was assessed using control error (FSE) and time-out-of-bounds (TOO B) when pilots exited the flight corridor. UAR s were assessed using response times needed to initiate correction and to achieve wings-level attitude. Physiological indices included Spo2, heart rate (HR), end tidal O2 and CO2 pressures, and respiration metrics. RESULTS: Seven subjects completed both flights. PICT performance deteriorated at altitude: FSE increased 33% at 17,513 ft and 21% in Recovery vs. GLP. Mean TOO B increased from 11 s at GLP to 60 s in Recovery. UAR effects were less clear, with some evidence of accelerated responses during and after ascent. CONCLUSIONS: The test paradigm was shown to be effective; piloting impairment was detected during and after exposure. Physiological channels recorded a combination of hypoxia, elevated ventilation, and hypocapnia during ascent, followed by respiratory slowing in recovery. Findings indicate precision piloting and respiration are subject to changes during moderate altitude exposure and may remain altered after Spo2 recovers, and changes may be linked to hypocapnia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is highly prevalent and often associated with chronic hypoxia. Previous studies have shown alterations of cerebral oxygenation and cardiac repolarization in COPD patients (GOLD stage II-IV). Airplane travel is common in patients with COPD; however, the clinical effects of a diminished oxygen partial pressure in aircraft cabin environments at cruising altitude remain elusive. The aim of this study was to assess changes of cerebral oxygenation as well as parameters of cardiac repolarization during a hypoxia altitude simulation combined with mild physical activity in these patients. METHODS: Patients with COPD and healthy subjects (10 per group) randomly selected from the Charité outpatient clinic conducted a hypoxia altitude simulation test which consisted of three phases. The regional cerebral oxygen saturation (rSO2) of the frontal cortex was measured at rest using near-infrared spectroscopy (NIRS). Furthermore, oxygen saturation (SpO2), blood pressure, and heart rate values, as well as a 12-lead-ECG, were recorded. Subsequently, a mild treadmill exercise program (25 W) was divided into 10 min of normoxia (pre-hypoxia), 30 min of mild hypoxia (FIO2 = 0.15), followed by a second 10-min period of normoxia (post-hypoxia). Meanwhile, mentioned parameters were recorded in 2-min intervals. P, PQ, QRS, QT, QTc, QTd, T-peak-T-end interval (TpTe), and corrected TpTe (TpTec) were measured on three ECG complexes, each at baseline, at the end of the normoxic phase, and at the end of the hypoxic phase. RESULTS: A total of 10 patients with COPD and 10 control subjects were included in this study. SpO2 was significantly lower in COPD patients throughout the whole test. Frontal cerebral rSO2 was significantly lower in the left hemisphere during hypoxia altitude simulation in COPD patients (59.5 ± 8.5 vs. 67.5 ± 5.7). CONCLUSIONS: We show reduced left frontal cerebral oxygenation during hypoxia and mild exercise in patients with COPD, suggesting diminished altitude resilience and altitude capabilities. Preflight hypoxia assessment might be recommended to patients with severe COPD. [ABSTRACT FROM AUTHOR]

Introduction: Technological advances have made high-altitude ski slopes easily accessible to skiers of all ages. However, research on the effects of hypoxia experienced during excursions to such altitudes on physiological systems, including the ocular system, in children is scarce. Retinal vessels are embryologically of the same origin as vessels in the brain, and have similar anatomical and physiological characteristics. Thus, any hypoxia-related changes in the morphology of the former may reflect the status of the latter. Objective: To compare the effect of one-day hypoxic exposure, equivalent to the elevation of high-altitude ski resorts in North America and Europe (~3,000 m), on retinal vessel diameter between adults and children. Methods: 11 adults (age: 40.1 ± 4.1 years) and 8 children (age: 9.3 ± 1.3 years) took part in the study. They spent 3 days at the Olympic Sports Centre Planica (Slovenia; altitude: 940 m). During days 1 and 2 they were exposed to normoxia (Fi O2 = 0.209), and day 3 to normobaric hypoxia (Fi O2 = 0.162 ± 0.03). Digital highresolution retinal fundus photographs were obtained in normoxia (Day 2) and hypoxia (Day 3). Central retinal arteriolar equivalent (CRAE) and venular equivalents (CRVE) were determined using an Automated Retinal Image Analyser. Results: Central retinal arteriolar and venular equivalents increased with hypoxia in children (central retinal arteriolar equivalent: 105.32 ± 7.72 µm, hypoxia: 110.13 ± 7.16 µm, central retinal venular equivalent: normoxia: 123.39 ± 8.34 µm, hypoxia: 130.11 ± 8.54 µm) and adults (central retinal arteriolar equivalent: normoxia: 105.35 ± 10.67 µm, hypoxia: 110.77 ± 8.36 µm; central retinal venular equivalent: normoxia: 126.89 ± 7.24 µm, hypoxia: 132.03 ± 9.72 µm), with no main effect of group or group*condition interaction. A main effect of condition on central retinal arteriolar and venular equivalents was observed (central retinal arteriolar equivalent: normoxia: 105.34 ± 9.30 µm, hypoxia: 110.50 ± 7.67 µm, p < 0.001; central retinal venular equivalent: normoxia: 125.41 ± 7.70 µm, hypoxia: 131.22 ± 9.05 µm, p < 0.001). Conclusion: A 20-hour hypoxic exposure significantly increased central retinal arteriolar and venular equivalents in adults and children. These hypoxia-induced increases were not significantly different between the age groups, confirming that vasomotor sensitivity of the retinal vessels to acute hypoxia is comparable between adults and prepubertal children. [ABSTRACT FROM AUTHOR]

High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the modulation of circulating exosome-like extracellular vesicles (ELVs) after 6 wk of sprint interval training (SIT) at sea level and at 2000, 3000, and 4000 m. Methods: Thirty trained endurance male athletes (18–35 yr) participated in a 6-wk SIT program (30-s all-out sprint, 4-min 30-s recovery; 4–9 repetitions, 2 sessions per week) at sea level (n = 8), 2000 m (fraction of inspired oxygen (F io 2) 0.167, n = 8), 3000 m (F io 2 0.145, n = 7), or 4000 m (F io 2 0.13, n = 7). Venous blood samples were taken before and after the training period. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis, and characterized according to international standards. Candidate ELV microRNAs (miRNAs) were quantified by real-time polymerase chain reaction. Results: When the three hypoxic groups were analyzed separately, only very minor differences could be detected in the levels of circulating particles, ELV markers, or miRNA. However, the levels of circulating particles increased (+262%) after training when the three hypoxic groups were pooled, and tended to increase at sea level (+65%), with no difference between these two groups. A trend to an increase was observed for the two ELV markers, TSG101 (+65%) and HSP60 (+441%), at sea level, but not in hypoxia. Training also seemed to decrease the abundance of miR-23a-3p and to increase the abundance of miR-21-5p in hypoxia but not at sea level. Conclusions: A 6-wk SIT program tended to increase the basal levels of circulating ELVs when performed at sea level but not in hypoxia. In contrast, ELV miRNA cargo seemed to be modulated in hypoxic conditions only. Further research should explore the potential differences in the origin of ELVs between normoxic and local and systemic hypoxic conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Cyclooxygenase 2 (COX2) inhibitors have been demonstrated to protect against hypoxia pathogenesis in several investigations. In several studies, it has been shown that COX2 inhibitors guard against the pathogenesis of hypoxia. However, there are conflicting findings on COX inhibitors' potency in treating COVID-19, and they have drawbacks. As a result, therapeutic COX2 inhibition may not always be beneficial, and further research into potential downstream mediators for hypoxic environment adaptability is required. According to research, those who are used to the lower oxygen levels at altitude may be more resistant to the negative effects of COVID-19. It indicates that COVID-19 poses a greater risk to people who live at lower elevations. It has been demonstrated that the COX2 pathway's downstream molecules adapt in people who live at high altitudes, which may help to explain why these people have a decreased prevalence of COVID-19 infection. Intermittent hypoxia training can be used to imitate the gene-environment interactions found in people who live at higher altitudes (IHT). It appears that COX-2 adaptation brought on by hypoxia exposure at altitude or IHT serves a significant therapeutic purpose. In this article, we highlight some of the most significant common genes associated with the pathophysiology of COVID-19 and hypoxia. We propose a common pathway between COVID-19 pathogenesis and hypoxia that influences apoptosis, proliferation, the immune system, and metabolism. We also emphasize the importance of researching people who reside at higher elevations to mimic their gene-environment interactions and contrast the results with IHT. Finally, we suggest COX2 as an upstream target for evaluating IHT's efficacy in preventing or mitigating the consequences of COVID-19 and other oxygen-related pathological conditions in the future. Cyclooxygenase 2 (COX2) inhibitors have been demonstrated to protect against hypoxia pathogenesis in several investigations. It has also been utilized as an adjuvant therapy in the treatment of COVID-19. COX inhibitors, which have previously been shown to be effective in treating previous viral and malarial infections are strong candidates for improving the COVID-19 therapeutic doctrine. However, another COX inhibitor, ibuprofen, is linked to an increase in the angiotensin-converting enzyme 2 (ACE2), which could increase virus susceptibility. Hence, inhibiting COX2 via therapeutics might not always be protective and we need to investigate the downstream molecules that may be involved in hypoxia environment adaptation. Research has discovered that people who are accustomed to reduced oxygen levels at altitude may be protected against the harmful effects of COVID-19. It is important to highlight that the study's conclusions only applied to those who regularly lived at high altitudes; they did not apply to those who occasionally moved to higher altitudes but still lived at lower altitudes. COVID-19 appears to be more dangerous to individuals residing at lower altitudes. The downstream molecules in the (COX2) pathway have been shown to adapt in high-altitude dwellers, which may partially explain why these individuals have a lower prevalence of COVID-19 infection. More research is needed, however, to directly address COX2 expression in people living at higher altitudes. It is possible to mimic the gene–environment interaction of higher altitude people by intermittent hypoxia training. COX-2 adaptation resulting from hypoxic exposure at altitude or intermittent hypoxia exercise training (IHT) seems to have an important therapeutic function. Swimming, a type of IHT, was found to lower COX-2 protein production, a pro-inflammatory milieu transcription factor, while increasing the anti-inflammatory microenvironment. Furthermore, Intermittent Hypoxia Preconditioning (IHP) has been demonstrated in numerous clinical investigations to enhance patients' cardiopulmonary function, raise cardiorespiratory fitness, and increase tissues' and organs' tolerance to ischemia. Biochemical activities of IHP have also been reported as a feasible application strategy for IHP for the rehabilitation of COVID-19 patients. In this paper, we aim to highlight some of the most relevant shared genes implicated with COVID-19 pathogenesis and hypoxia. We hypothesize that COVID-19 pathogenesis and hypoxia share a similar mechanism that affects apoptosis, proliferation, the immune system, and metabolism. We also highlight the necessity of studying individuals who live at higher altitudes to emulate their gene–environment interactions and compare the findings with IHT. Finally, we propose COX2 as an upstream target for testing the effectiveness of IHT in preventing or minimizing the effects of COVID-19 and other oxygen-related pathological conditions in the future. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?How does hypoxic pulmonary vasoconstriction and the response to supplemental oxygen change over time at high altitude?What is the main finding and its importance?Lowlanders and partially de‐acclimatized Sherpa both demonstrated pulmonary vascular responsiveness to supplemental oxygen that was maintained for 12 days' exposure to progressively increasing altitude. An additional 2 weeks' acclimatization at 5050 m altitude rendered the pulmonary vasculature minimally responsive to oxygen similar to the fully acclimatized non‐ascent Sherpa. Additional hypoxic exposure at that time point did not augment hypoxic pulmonary vasoconstriction. Prolonged alveolar hypoxia leads to pulmonary vascular remodelling. We examined the time course at altitude, over which hypoxic pulmonary vasoconstriction goes from being acutely reversible to potentially irreversible. Study subjects were lowlanders (n = 20) and two Sherpa groups. All Sherpa were born and raised at altitude. One group (ascent Sherpa, n = 11) left altitude and after de‐acclimatization in Kathmandu for ∼7 days re‐ascended with the lowlanders over 8–10 days to 5050 m. The second Sherpa group (non‐ascent Sherpa, n = 12) remained continuously at altitude. Pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) were measured while breathing ambient air and following supplemental oxygen. During ascent PASP and PVR increased in lowlanders and ascent Sherpa; however, with supplemental oxygen, lowlanders had significantly greater decrease in PASP (P = 0.02) and PVR (P = 0.02). After ∼14 days at 5050 m, PASP decreased with supplemental oxygen (mean decrease: 3.9 mmHg, 95% CI 2.1–5.7 mmHg, P < 0.001); however, PVR was unchanged (P = 0.49). In conclusion, PASP and PVR increased with gradual ascent to altitude and decreased via oxygen supplementation in both lowlanders and ascent Sherpa. Following ∼14 days at 5050 m altitude, there was no change in PVR to hypoxia or O2 supplementation in lowlanders or either Sherpa group. These data show that both duration of exposure and residential altitude influence the pulmonary vascular responses to hypoxia. [ABSTRACT FROM AUTHOR]