In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and ...genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.
High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, ...suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.
High‐altitude physiology can be said to have begun in 1644 when Torricelli described the first mercury barometer and wrote the immortal words “We live submerged at the bottom of an ocean of the ...element air.” Interestingly, the notion of atmospheric pressure had eluded his teacher, the great Galileo. Blaise Pascal was responsible for describing the fall in pressure with increasing altitude, and Otto von Guericke gave a dramatic demonstration of the enormous force that could be developed by atmospheric pressure. Robert Boyle learned of Guericke's experiment and, with Robert Hooke, constructed the first air pump that allowed small animals to be exposed to a low pressure. Hooke also constructed a small low‐pressure chamber and exposed himself to a simulated altitude of about 2400 meters. With the advent of ballooning, humans were rapidly exposed to very low pressures, sometimes with tragic results. For example, the French balloon, Zénith, rose to over 8000 m, and two of the three aeronauts succumbed to the hypoxia. Paul Bert was the first person to clearly state that the deleterious effects of high altitude were caused by the low partial pressure of oxygen (PO2), and later research was accelerated by high‐altitude stations and expeditions to high altitude.
High-altitude environments present strong stresses for living organisms, which have driven striking phenotypic and genetic adaptations. While previous studies have revealed multiple genetic ...adaptations in high-altitude species, how evolutionary history (i.e., phylogenetic background) contributes to similarity in genetic adaptations to high-altitude environments is largely unknown, in particular in a group of birds. We explored this in 3 high-altitude passerine birds from the Qinghai-Tibet Plateau and their low-altitude relatives in lowland eastern China. We generated transcriptomic data for 5 tissues across these species and compared sequence changes and expression shifts between high- and low-altitude pairs. Sequence comparison revealed that similarity in all 3 high-altitude species was high for genes under positive selection (218 genes) but low in amino acid substitutions (only 4 genes sharing identical amino acid substitutions). Expression profiles for all genes identified a tissue-specific expression pattern (i.e., all species clustered by tissue). By contrast, an altitude-related pattern was observed in genes differentially expressed between all 3 species pairs and genes associated with altitude, suggesting that the high-altitude environment may drive similar expression shifts in the 3 high-altitude species. Gene expression level, gene connectivity, and the interactions of these 2 factors with altitude were correlated with evolutionary rates. Our results provide evidence for how gene sequence changes and expression shifts work in a concerted way in a group of high-altitude birds, leading to similar evolution routes in response to high-altitude environmental stresses.
High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal ...model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.
Acute high-altitude sickness Luks, Andrew M; Swenson, Erik R; Bärtsch, Peter
European respiratory review,
01/2017, Letnik:
26, Številka:
143
Journal Article
Recenzirano
Odprti dostop
At any point 1-5 days following ascent to altitudes ≥2500 m, individuals are at risk of developing one of three forms of acute altitude illness: acute mountain sickness, a syndrome of nonspecific ...symptoms including headache, lassitude, dizziness and nausea; high-altitude cerebral oedema, a potentially fatal illness characterised by ataxia, decreased consciousness and characteristic changes on magnetic resonance imaging; and high-altitude pulmonary oedema, a noncardiogenic form of pulmonary oedema resulting from excessive hypoxic pulmonary vasoconstriction which can be fatal if not recognised and treated promptly. This review provides detailed information about each of these important clinical entities. After reviewing the clinical features, epidemiology and current understanding of the pathophysiology of each disorder, we describe the current pharmacological and nonpharmacological approaches to the prevention and treatment of these diseases.
Impairments in cognitive function, mood, and sleep quality occur following ascent to high altitude. Low oxygen (hypoxia) and poor sleep quality are both linked to impaired cognitive performance, but ...their independent contributions at high altitude remain unknown. Adaptive servoventilation (ASV) improves sleep quality by stabilizing breathing and preventing central apneas without supplemental oxygen. We compared the efficacy of ASV and supplemental oxygen sleep treatments for improving daytime cognitive function and mood in high-altitude visitors (N = 18) during acclimatization to 3,800 m. Each night, subjects were randomly provided with ASV, supplemental oxygen (SpO2 > 95%), or no treatment. Each morning subjects completed a series of cognitive function tests and questionnaires to assess mood and multiple aspects of cognitive performance. We found that both ASV and supplemental oxygen (O2) improved daytime feelings of confusion (ASV: p < 0.01; O2: p < 0.05) and fatigue (ASV: p < 0.01; O2: p < 0.01) but did not improve other measures of cognitive performance at high altitude. However, performance improved on the trail making tests (TMT) A and B (p < 0.001), the balloon analog risk test (p < 0.0001), and the psychomotor vigilance test (p < 0.01) over the course of three days at altitude after controlling for effects of sleep treatments. Compared to sea level, subjects reported higher levels of confusion (p < 0.01) and performed worse on the TMT A (p < 0.05) and the emotion recognition test (p < 0.05) on nights when they received no treatment at high altitude. These results suggest that stabilizing breathing (ASV) or increasing oxygenation (supplemental oxygen) during sleep can reduce feelings of fatigue and confusion, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high altitude. Furthermore, this study provides evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve with acclimatization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-altitude cerebral edema (HACE) and acute mountain sickness (AMS) are neuro-pathologies associated with rapid exposure to hypoxia. However, speculation remains regarding the exact etiology of ...both HACE and AMS and whether or not they share a common mechanistic pathology. This mini-review outlines the basic principles of HACE development, highlighting how edema could develop from 1) a progression from cytotoxic swelling to ionic edema, or 2) permeation of the blood brain barrier (BBB) with or without ionic edema. Thereafter, discussion turns to the available neuroimaging literature in the context of cytotoxic, ionic or vasogenic edema in both HACE and AMS. While HACE is clearly caused by an increase in brain water of ionic and/or vasogenic origin, there is very little evidence that this type of edema is present when AMS develops. However, cerebral vasodilation, increased intracranial blood volume and concomitant intracranial fluid shifts from the extracellular to the intracellular space, as interpreted from changes in diffusion indices within white matter, are observed consistently in persons acutely exposed to hypoxia and with AMS. Therefore, herein we explore the idea that intracellular swelling occurs alongside AMS, and is a critical pre-cursor to extracellular ionic edema formation. We propose that this process produces a subtle modulation of the BBB, which either together with or independent of vasogenic edema provides a transvascular segue from the end-stage of AMS to HACE. Ultimately, this mini-review seeks to shed light on the possible processes underlying HACE pathophysiology, and thus highlight potential avenues for future prevention and treatment.
This study aimed to explore the neural mechanisms underlying high‐altitude (HA) adaptation and deadaptation in perceptual processes in lowlanders. Eighteen healthy lowlanders were administered a ...facial S1‐S2 matching task that included incomplete face (S1) and complete face (S2) photographs combined with ERP technology. Participants were tested at four time points: shortly before they departed the HA (Test 1), twenty‐five days after entering the HA (Test 2), and one week (Test 3) and one month (Test 4) after returning to the lowlands. Compared with those at sea level (SL), shorter reaction times (RTs), shorter latencies of P1 and N170, and larger amplitudes of complete face N170 were found in HAs. After returning to SL, compared with that of HA, the amplitude of the incomplete face P1 was smaller after one week, and the complete face was smaller after one month. The right hemisphere N170 amplitude was greater after entering HA and one week after returning to SL than at baseline, but it returned to baseline after one month. Taken together, the current findings suggest that HA adaptation increases visual cortex excitation to accelerate perceptual processing. More mental resources are recruited during the configural encoding stage of complete faces after HA exposure. The perceptual processes affected by HA exposure are reversible after returning to SL, but the low‐level processing stage differs between incomplete and complete faces due to neural compensation mechanisms. The configural encoding stage in the right hemisphere is affected by HA exposure and requires more than one week but less than one month to recover to baseline.
We demonstrated that high‐altitude adaptation accompanies increased occipital lobe excitation, and more neural resources are recruited during the configural encoding stage. Moreover, this change is reversible after returning to the lowlands, and the neural compensation mechanism exists. It provided new insights for understanding how hypoxia affects nonprefrontal lobe functions.
Abstract
Background
Altitude sojourns increasingly attract individuals of all ages and different health statuses due to the appeal of high-altitude destinations worldwide and easy access to air ...travel. The risk of acute mountain sickness (AMS) when flying to high-altitude destinations remains underemphasized. Thus, this review aims to evaluate the altitude-dependent AMS incidence depending on the mode of ascending, e.g. by air vs terrestrial travel.
Methods
A literature search was performed to identify the observational studies assessing AMS incidence after acute ascent of primarily healthy adults to real high altitude. In addition, placebo arms of interventional trials evaluating the prophylactic efficacy of various drugs have been separately analysed to confirm or refute the findings from the observational studies. Linear regression analyses were used to evaluate the altitude-dependent AMS incidence.
Results
Findings of 12 observational studies, in which the AMS incidence in 11 021 individuals ascending to 19 different altitudes (2200–4559 m) was evaluated, revealed an impressive 4.5-fold steeper increase in the AMS incidence for air travel as compared with slower ascent modes, i.e. hiking or combined car and/or air travel and hiking. The higher AMS incidence following transportation by flight vs slower means was also confirmed in placebo-treated participants in 10 studies of drug prophylaxis against AMS.
Conclusions
Due to the short time span in going from low to high altitude, reduced acclimatization likely is the main reason for a higher AMS risk when travelling to high-altitude destinations by flight. To avoid frustrating travel experiences and health risks, appropriate and timely medical advice on how to prepare for air travel to high altitude is of vital importance. Effective preparation options include the use of modern pre-acclimatization strategies and pharmacological prophylaxis by acetazolamide or dexamethasone, or even considering alternate itineraries with more gradual ascent.
Graphical Abstract
Graphical Abstract
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