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Accentuated hypoxemia at high altitude in subjects susceptible to high-altitude pulmonary edema.

To investigate the hypotheses that activated coagulation, catecholamine release, or arginine vasopressin release are involved in the pathogenesis of high-altitude pulmonary edema (HAPE), we measured these variables in seven subjects susceptible to HAPE and in nine control subjects at an altitude of 1,600 m, and after 6 and 12 h at a simulated altitude of 4,150 m. Each subject was studied twice, once after 3 days of placebo medication and once after 3 days of premedication with aspirin and dipyridamole. At high altitude, HAPE-susceptible subjects showed significantly exaggerated hypoxemia and a slightly higher end-tidal carbon dioxide partial pressure that did not account fully for the hypoxemia. Fibrinolytic activity was significantly accelerated in both groups at high altitude, whereas other coagulation measurements, catecholamines and arginine vasopressin levels, and pulmonary function tests were not significantly changed. Similar findings were obtained after both placebo and platelet-inhibitor premedication. The results indicate that none of the three hypothesized mechanisms, i.e., activated coagulation, excessive catecholamine release, or antidiuresis, would account for HAPE susceptibility. Instead, HAPE-susceptible subjects exhibited exaggerated hypoxemia associated with relative hypoventilation and a widened alveolar-arterial gas pressure difference.

Adolescent

Pulmonary gas exchange, diffusing capacity in natives and newcomers at high altitude.

At high altitude, in resting conditions, no differences have been observed between High Altitude Natives (HAN) and acclimatized Sea Level Natives (SLN) in AaDO2, aADCO2 or venous admixture. In acclimatized SLN, AaDO2 is smaller than at sea level because of: (1) The minor effect on arterial oxygenation of the probably constant venous admixture. (2) The reduction of VA/Q inequality as shown by a smaller aADCO2. In HAN, DLCO is greater than in SLN; the contribution of DM or VC in this difference remains unsettled, mainly because of the difficulties of measurement of DM and VC in HAN suddenly exposed to acute hyperoxia. In SLN, in acute hypoxia, DLCO increased transitorily. Asynchronous mechanisms of adaptation to high altitude are evoked.

Acclimatization

Further studies on pulmonary oedema of high altitude. Abnormal responses to hypoxia of men who had developed pulmonary oedema at high altitude.

101 Indian soldiers, 57 of whom had developed pulmonary oedema of high altitude (POHA) and 44 who had not developed this condition in spite of being at high altitudes for over 2 years, were investigated for observing the differences, if any, in their reaction to acute hypoxic stress. Each subject was made to breathe a 10% hypoxic mixture for 5 min. Haemodynamic parameters like pulmonary artery pressure (systolic, diastolic and mean), brachial artery pressure, wedge pressure, cardiac output, minute ventilation, arterial oxygen saturation and oxygen uptake before and at the end of hypoxic breathing were estimated. In addition, results of the cold pressor test were recorded and the Vd/Vt ratio was estimated. The results obtained in the present study confirmed those obtained in our previous studies. In addition, it was observed that oxygen uptake was significantly higher and oxygen saturation lower after hypoxia in the POHA subjects than in the controls. Certain parameters for screening of subjects possibly susceptible to POHA have been suggested.

Adult

Integrated Cytokine and Immune Cell Profiling Reveals a Distinct Immune Signature Associated with High-Altitude Pulmonary Edema.

High-altitude pulmonary edema (HAPE) is a rapidly progressive, life-threatening disorder arising in otherwise healthy individuals upon ascent to high altitude, yet the mechanisms underlying maladaptive vascular leak remain poorly defined. Although elevated pulmonary arterial pressure and capillary stress failure are recognized as central hemodynamic drivers, accumulating evidence indicates that innate immune dysregulation is an equally critical, largely unexplored determinant of HAPE. To systematically delineate the immune and molecular programs that distinguish pathological responses to hypobaric hypoxia from acclimatization, peripheral blood along with clinical details was collected from low-altitude controls (LA-Cntrl, number of participants, (n = 19), healthy high-altitude sojourners (HA-Cntrl, n = 47), and HAPE patients (n = 90). Plasma proteomic markers were quantified using a targeted panel, while monocyte and dendritic cell subsets in peripheral blood mononuclear cells were immunophenotyped by multicolor flow cytometry. HA-Cntrl subjects displayed an anti-inflammatory profile, marked by the suppression of CXC chemokine receptor 3 axis chemokines. HAPE patients, in contrast, exhibited a pro-inflammatory, vascular injury signature, with elevated levels of inflammatory interleukins and myeloid and chemotactic factors. This inflammatory signature was accompanied by the expansion of classical monocytes, implicating a myeloid vascular program associated with HAPE.

Humans

Plasma Proteomic Profiling Reveals ITGA2B as A Key Regulator of Heart Health in High-altitude Settlers.

Myocardial injury is a common disease in the plateau, especially in the lowlanders who have migrated to the plateau, in which the pathogenesis is not well understood. Here, we established a cohort of lowlanders comprising individuals from both low-altitude and high-altitude areas and conducted plasma proteomic profiling. Proteomic data showed that there was a significant shift in energy metabolism and inflammatory response in individuals with myocardial abnormalities at high altitude. Notably, integrin alpha-Ⅱb (ITGA2B) emerged as a potential key player in this context. Functional studies demonstrated that ITGA2B upregulated the transcription and secretion of interleukin-6 (IL-6) through the integrin-linked kinase (ILK)/nuclear factor-κB (NF-κB) signaling axis under hypoxic conditions. Moreover, ITGA2B disrupted mitochondrial structure and function, increased glycolytic capacity, and aggravated energy reprogramming from oxidative phosphorylation to glycolysis. Leveraging the therapeutic potential of traditional Chinese medicine in cardiac diseases, we discovered that tanshinone ⅡA (TanⅡA) effectively alleviated the myocardial injury caused by the abnormally elevated expression of ITGA2B and hypobaric hypoxia exposure in mice, thus providing a novel candidate therapeutic strategy for the prevention and treatment of high-altitude myocardial injury.

Animals

[Hormonal variation during physical exertion at high altitude].

The influence of the physical exercise at high altitude on the endocrine function was studied in 8 normal native men of sea level and in 8 natives men of high altitude. The sea level dwellers were studied both, at sea level, during an acute exposure to low barometric pressure and after 3 months of acclimatization to altitudes over 3,500 meters above the sea level. The experiments at high altitude were conducted at an altitude of 4,500 meters above the sea level. Two types of exercise were carried out, sub-maximal and maximal, at fasting state, between 8 and 10 a.m. During an acute exposure to altitude the physical exercise produced a marked rise of glucose, cortisol and growth hormone and a fall in the insulin content of plasma. In the sea level dwellers, acclimatized to altitude during 3 months, an elevation of growth hormone was observed only during maximal physical effort. Marked variation in glucose and cortisol were observed during both types of exercise. This shows that in these subjects some adaptative changes have ocurred but of lesser extent as those observed in altitude natives. In the high altitude native higher basal concentrations of growth hormone and glucagón as well as a lower glucose concentration in blood, were found. During exercise the high altitude dweller showed no significant changes in somatotropin, meanwhile an important elevation of cortisol occurred. These findings indicate that the high altitude native has metabolic and endocrine responses to exercise similar to those found in well fitted atletes of sea level. The exposure to altitude provoked a rise in glucagon concentration directly proportional to the time of exposition ot altitude. The physical exercise did not elucidate any change in the glucagon content of blood.

Adult

High altitude medical problems.

Increased travel to high altitude areas by mountaineers and nonclimbing tourists has emphasized the clinical problems associated with rapid ascent. Acute mountain sickness affects most sojourners at elevations above 10,000 feet. Symptoms are usually worse on the second or third day after arrival. Gradual ascent, spending one to three days at an intermediate altitude, and the use of acetazolamide (Diamox) will prevent or ameliorate symptoms in most instances. Serious and potentially fatal problems, such as high altitude pulmonary edema or cerebral edema, occur in approximately 0.5 percent to 1.0 percent of visitors to elevations above 10,000 feet-especially with heavy physical exertion on arrival, such as climbing or skiing. Early recognition, high flow oxygen therapy and prompt descent are crucially important in management. Our knowledge of the causes of these and other high altitude problems, such as retinal hemorrhage, systemic edema and pulmonary hypertension, is still incomplete. Even less is known of the effect of high altitudes on medical conditions common at sea level or on the action of commonly used drugs.

Adolescent

Changes in transthoracic electrical impedance at high altitude.

Mean transthoracic electrical impedance (impedance) which is inversely related to intrathoracic extravascular fluid volume was measured in 121 normal healthy volunteers at sea-level and at 3658 metres altitude. Fifty (group A) reached the high altitude location after an hour's journey in a pressurised aircraft. Twenty-five (group D) underwent slow road ascent including acclimatisation en route. Thirty permanent residents (group B) and 16 temporary residents at high altitude (group C) were also studied. Serial studies in the 30 subjects of group A who developed symptoms of high altidue sickness showed a significant decrease of impedance up to the fourth day of exposure to high altitude which later returned to normal. The 4 volunteers who developed severe symptoms showed the largest drop in impedance. A case of acute pulmonary oedema developing at 4300 metres showed an impedance value of 24-1 ohms on admission. After effective treatment the impedance increased by 11-9 to 36-0 ohms. Twenty asymptomatic subjects of group A and 25 of group D showed a small average increase in impedance values at high altitude. These obstructions suggest that measurement of transthoracic electrical impedance may be a valuable means of detecting incipient high altitude pulmonary oedema.

Acclimatization

Evidence for increased intrathoracic fluid volume in man at high altitude.

To determine if subclinical pulmonary edema occurs commonly at high altitude, 25 soldiers participated in two consecutive 72-h field exercises, the first at low altitude (200-875 m) and the second at high altitude (3,000-4,300 m). Various aspects of ventilatory function and pulmonary mechanics were measured at 0, 36, and 72 h of each exercise. Based on physical examination and chest radiographs there was no evidence of pulmonary edema at high altitude. There was, however, an immediate and sustained decrease in vital capacity and transthoracic electrical impedance as well as a clockwise rotation of the transpulmonary pressure-volume curve. In contrast, closing capacity and residual volume did not change immediately upon arrival at high altitude but did increase later during the exposure. These observations are consistent with an abrupt increase in thoracic intravascular fluid volume upon arrival at high altitude followed by a more gradual increase in extravascular fluid volume in the peribronchial spaces of dependent lung regions.

Adolescent

High altitude pulmonary edema. Epidemiologic observations in Peru.

The incidence of high altitude pulmonary edema was examined by a survey (via questionnaire) of residents living at 3,750 meters (12,303 feet) in the mining community of La Oroya, Peru. Ninety-seven subjects made a total of 1,157 ascents to high altitude after a stay at sea level of longer than 14 days. Sixty-four subjects experienced at least one episode of high-altitude pulmonary edema. The incidence was higher in subjects aged 13 to 20 years, where 17 percent (15) of 90 ascents resulted in episodes of high-altitude pulmonary edema, than in subjects 21 years or older (3 percent; 18/686 ascents). Young subjects (2 to 12 years old) had more severe episodes of high-altitude pulmonary edema (81 percent; 30/37 episodes) than adults (22 percent; 4/18 episodes). No episodes were observed in children under two years old. Five subjects under 21 years of age experienced recurrent episodes. Our estimated incidence of severe episodes of high altitude pulmonary edema per ascent in adults (0.6 percent; 4/686) is similar to that reported by other workers (incidence of 0.15 to 0.57 percent) in various parts of the world.

Adolescent

High-altitude hypoxia alters the visual control of standing balance in lowlanders and Tibetan highlanders.

High-altitude hypoxia affects both visual function and postural control, yet the influence of optic-flow perturbations on standing balance under hypoxic stress remains unclear. Tibetan highlanders (TH) exhibit adaptations to chronic hypoxia, but whether their visually driven postural responses differ from those of lowlanders (LL) has not been investigated. We examined how high-altitude exposure and acclimatization influence static and dynamic visual contributions to balance by delivering sinusoidal optic-flow perturbations in virtual reality at low altitude (1,400 m) and after incremental ascent to high altitude (4,300 m) in acclimatizing LL (n = 15) and TH (n = 14). Anteroposterior center of pressure (AP CoP) velocity and mean power frequency (MPF) were measured during three visual-field conditions (full-, central-, and peripheral-vision) and two optic-flow velocities (peak 1 m/s and 8 m/s at 0.25 Hz). At high altitude, both groups showed attenuated responses to optic flow compared with 1,400 m, reflected by reduced AP CoP velocity and lower MPF across visual-field conditions, consistent with reduced responsiveness to dynamic visual-motion cues under high altitude hypoxia. In contrast, during eyes-open quiet stance [no virtual reality (VR)], TH but not LL exhibited increased AP CoP velocity and MPF at 4,300 m, and no altitude effect was observed with eyes-closed in either group. This finding indicates that TH adopt a visually dependent postural strategy at altitude, whereas LL show minimal changes in static visual balance control but reduced responsiveness to fast dynamic motion. Together, these findings demonstrate that high-altitude hypoxia disrupts dynamic visual processing for balance control in both groups, while revealing group differences in the use of static visual cues during quiet stance.NEW & NOTEWORTHY This is the first study to investigate how high-altitude hypoxia alters visually driven postural control using virtual reality (VR) optic-flow perturbations. We show that hypoxia attenuates sway responses to optic-flow in both lowlanders and Tibetan highlanders, and that visual weighting differs between these groups. These findings reveal altitude- and population-related changes in sensory weighting during standing balance, advancing sensorimotor understanding of postural control in hypoxia.

Humans

Sex modifies the association of high-altitude hypoxia with poor sleep quality and depression in school-age children and adolescents.

BACKGROUND: While chronic exposure to high-altitude hypoxia is known to impair sleep and mental health, whether these effects are sex-dependent remains unclear. This study addresses a critical gap by investigating how sex modifies the association between high-altitude hypoxia and risks of poor sleep quality, depressive symptoms, and their co-occurrence in children and adolescents. METHODS: In this cross-sectional study (March-May 2024), we enrolled 1,345 long-term residents of the Shannan Tibet Autonomous Prefecture (altitude: 3,650-4,800&#xa0;m) and 2,909 age-matched controls from low-altitude plains (Anhui Province, China). Sleep quality and depression were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Montgomery-Asberg Depression Rating Scale (MADRS), respectively. Sex-stratified analyses and interaction metrics (RERI/AP/SI) were employed to evaluate additive and multiplicative effects. RESULTS: High-altitude residents exhibited significantly higher prevalence of poor sleep (24.2% vs. 18.7%, P&#x2009;<&#x2009;0.001), depression (23.6% vs. 15.3%, P&#x2009;<&#x2009;0.001), and their co-occurrence (12.6% vs. 8.6%, P&#x2009;<&#x2009;0.001) compared to low-altitude controls. A significant negative additive interaction (RERI&#x2009;=&#x2009;-&#x2009;0.78, 95% CI: -1.35 to -&#x2009;0.3; P&#x2009;<&#x2009;0.001) indicated that sex modifies the altitude-outcome association. Specifically: (1) high-altitude residence significantly increased poor sleep risk in males (OR&#x2009;=&#x2009;1.60, 95% CI: 1.26-2.03) but not in females (OR&#x2009;=&#x2009;1.39, 95% CI: 1.07-1.79); and (2) the expected female predominance in poor sleep observed in the plain region (OR&#x2009;=&#x2009;1.452, 95% CI: 1.191-1.769) disappeared in the plateau region (OR&#x2009;=&#x2009;0.865, 95% CI: 0.667-1.121). Similar patterns were independently replicated for depressive symptoms. These findings confirm that high-altitude exposure differentially increases risk in males rather than protecting females. CONCLUSION: Males show marked vulnerability to high-altitude-associated sleep and mood impairments, while females demonstrate resilience. Sex-tailored interventions for high-altitude populations, particularly targeting male adolescents, are urgently needed.

Humans

Whole methylomes reveal high-altitude-associated methylation at hypoxia and pigmentation genes in South American Indigenous populations.

High-altitude adaptation in Andean populations has traditionally been studied through the lens of genetic variation, with limited exploration of epigenetic mechanisms such as DNA methylation. Here, we present the first whole-methylome data comparing Indigenous populations residing in high-altitude regions of the Ecuadorian Andes to those in low-altitude Peruvian Amazon regions bordering the Andes. By leveraging whole-methylome sequencing rather than methylation arrays, we achieved an unprecedented resolution of epigenetic variation, revealing novel insights into altitude-associated adaptations. We identified significant differentially methylated regions in genes involved in hypoxia response and skin pigmentation that differ from patterns previously observed in high-altitude Tibetan individuals [Lin et al. (Genome-wide DNA methylation landscape of four Chinese populations and epigenetic variation linked to Tibetan high-altitude adaptation. Science China Life Sciences 2023;66:2354-69. https://doi.org/10.1007/s11427-022-2284-8.)]. Our findings highlight the influence that altitude-specific environmental pressures, such as hypoxia and ultraviolet radiation, can have on the epigenetic landscapes observed between human populations. Importantly, we uncovered unique regulatory methylation signatures in the hypoxia response pathways of Andean populations, underscoring a distinct epigenetic trajectory compared to other high-altitude groups. This study represents a step forward in understanding Indigenous American genomic plasticity and demonstrates the value of whole-methylome data over methylation arrays in capturing the complex interplay between epigenetics and the environment. These results support a new approach to studying altitude plasticity and underscore the critical role of epigenetics in shaping population-specific cellular responses in Indigenous communities.

UV response

Immunological survey in high altitude: effect on antibody production and the complement system.

In order to asses the effect of acute exposure to natural high altitude on some immunological mechanisms of mice, the primary response to SRBC was studied by the direct Hemolytic Plaque and Hemagglutination Tests. A control group was studied in Lima, Peru, 150 m. At high altitude (Ticlio, Peru, 4843 m), we found fewer spleen plaque-forming cells (PFC) and the maximal peak of PFC was delayed 1 day, as compared with the response at a lower altitude. Conversely, there was a higher serum concentration of 2-ME sensitive and resistant hemagglutinin antibodies at high altitude and the 19-S (2-ME sensitive) response was predominant during the first days at high altitude while the 7-S response was retarded. These results are interpreted as a stimulating effect of hypoxia on the 19-S antibody production rather than a cellular proliferation as far as the SRBC system is concerned. Serum concentrations of Igs G, M, A and the fraction C'3 of the Complement (B1C/B1A globulin) were determined in normal natives from three cities at different altitude levels: Morococha-Ticlio, 4680 m; La Oroya, 3700 m; and Tarma, 3051 m by the Radial Immunodiffusion Test. The serum concentration of C'3 was correlated with the total hemolytic activity of Complement (C'H50 method) in a group of natives from Morococha. The control group was of normal natives from Lima. No significant differences were found between resum concentration of Igs G, M and A in both groups, but there was a tendency for higher values of IgA at higher altitudes, and most sera in the high altitude group were above the normal IgG values for adults. The resum concentration of C'3 and the hemolytic activity of Complement were wound to be diminished in the high altitude group. These results are interpreted as an inhibitory effect of the altitude on the sequential activation and/or lysing capability rather than a reduction in the C'3 concentration.

Adult

Impaired oxygenation during sleep in excessive polycythemia of high altitude: improvement with respiratory stimulation.

Although polycythemia of high altitude is usually due to excessive hypoxemia, in some patients the hematocrit is elevated out of proportion to the degree of hypoxemia measured awake. One possible explanation is that severe hypoxemia occurs during sleep in these subjects. We therefore monitored oxygen saturation (SaO2), breathing pattern, and electroencephalogram (EEG) during sleep in five normal high-altitude residents and in five patients with excessive polycythemia. The polycythemic patients were studied as part of a placebo--drug double-blind crossover trial of the respiratory stimulant drug medroxyprogesterone acetate (MPA). The polycythemic patients while taking placebo were much more hypoxemic during sleep than the normals (all-night mean SaO2: 79.4 +/- 1.7% versus 87.8 +/- 1.7%, p less than 0.01). Abnormalities in breathing patterns were observed in all the subjects, especially during REM stage sleep. In polycythemic subjects, this resulted in precipitous hypoxemia with SaO2 as low as 50%--70%. Severe hypoxemia was not observed in control subjects despite similar abnormalities in breathing. Significant improvement in nocturnal SaO2 occurred when the polycythemic patients were taking MPA, mean SaO2 rising from 79.4 +/- 1.7% to 83.7 +/- 0.7%, p less than 0.05. Of probably greater importance, MPA largely prevented the precipitous drops in SaO2, mean lowest SaO2 rising from 64.6 +/- 4.7% to 76.0 +/- 2.1% p less than 0.05. The severe decreases in SaO2 during sleep may explain elevations in hematocrit that are out of proportion to the awake SaO2 in man at high altitude. The therapeutic effect of MPA in this condition may be due to amelioration of sleep hypoxemia.

Adult

Integrative Genomic, Transcriptomic and Epigenomic Analysis Reveals cis-regulatory Contributions to High-altitude Adaptation in Tibetan Pigs.

The Qinghai-Tibet Plateau, characterized by its extreme environmental conditions, presents significant challenges to life, making it an ideal region for studying adaptation and evolution. Tibetan pigs, known for their high genetic diversity and exceptional adaptability to high altitudes, serve as excellent models for investigating high-altitude adaptation. While previous studies have extensively identified genetic determinants associated with high-altitude adaptation, the molecular mechanisms, particularly cis-regulatory patterns, remain poorly understood. Here, we conducted a selective sweep analysis using 484 genomes from Chinese and Western pig breeds across various altitudes, revealing 38.56 Mb of genomic regions under selection in Tibetan pigs. Enrichment analysis identified the lung as the primary functional tissue involved in high-altitude adaptation, supported by tissue-specific transcriptional and regulatory patterns observed between Tibetan and Meishan pigs (low altitude). By integrating genomic, RNA-seq, ATAC-seq, and H3K27ac HiChIP data, we constructed comprehensive enhancer-promoter regulatory maps of candidate genes and pinpointed promising genetic determinants associated with high-altitude adaptation, including SNPs in EPAS1, KLF13, SPRED1, and CFD. These loci were predicted to influence chromatin accessibility and the interactions of regulatory elements, with altered binding strength of relevant transcription factors. Further in vitro experiments confirmed that these loci function as allele-specific enhancers, modulating the expression of target genes. Our findings elucidate the regulatory basis of high-altitude adaptation in Tibetan pigs and provide valuable insights for exploring hypoxia-related diseases in livestock and humans.

Animals

Sleep physiology at high altitude.

All night sleep EEG, EKG, and respiration were recorded from six young men during 2 nights at sea level and 4 nonconsecutive nights at high altitude (14.110 ft., 4301 m). Sleep at high altitude was chraacterized initially by a significant decrease in Stages 3 and 4, a significant increase in the number of arousals, and a trend towards more time spent awake. In terms of actual time spent sleep, however, a relatively good night's sleep was obtained, which suggests that the objective sleep disturbance was not commensurate with the marked subjective complaints of sleeplessness. Periodic respiration during sleep was frequent at high altitude, was quickly terminated by oxygen administration, was not clearly related to the increased number of arousals, and usually was not seen during REM periods. Heart rate was increased during sleep at high altitude. All measures tended to return towards sea level means during 12 days at altitude. We suggest that the marked increase in the number of arousals may account for the disparity between the subjective reports and objective measures of sleep disturbance at high altitude. Although the objective sleep disruption is probably related in some fashion to hypoxemia, it is unclear whether hypoxemia itself or the alkalosis commonly present shortly after arrival at altitude is the major factor.

Adult