Chronic High-altitude Exposure Research Articles

Using modified Fenn diagrams to assess ventilatory acclimatization during ascent to high altitude: Effect of acetazolamide.

High altitude (HA) ascent imposes systemic hypoxia and associated risk of acute mountain sickness. Acute hypoxia elicits a hypoxic ventilatory response (HVR), which is augmented with chronic HA exposure (i.e., ventilatory acclimatization; VA). However, laboratory-based HVR tests lack portability and feasibility in field studies. As an alternative, we aimed to characterize area under the curve (AUC) calculations on Fenn diagrams, modified by plotting portable measurements of end-tidal carbon dioxide ( ) against peripheral oxygen saturation ( ) to characterize and quantify VA during incremental ascent to HA (n=46). Secondarily, these participants were compared with a separate group following the identical ascent profile whilst self-administering a prophylactic oral dose of acetazolamide (Az; 125mg BID; n=20) during ascent. First, morning and measurements were collected on 46 acetazolamide-free (NAz) lowland participants during an incremental ascent over 10days to 5160m in the Nepal Himalaya. AUC was calculated from individually constructed Fenn diagrams, with a trichotomized split on ranked values characterizing the smallest, medium, and largest magnitudes of AUC, representing high (n=15), moderate (n=16), and low (n=15) degrees of acclimatization. After characterizing the range of response magnitudes, we further demonstrated that AUC magnitudes were significantly smaller in the Az group compared to the NAz group (P=0.0021), suggesting improved VA. These results suggest that calculating AUC on modified Fenn diagrams has utility in assessing VA in large groups of trekkers during incremental ascent to HA, due to the associated portability and congruency with known physiology, although this novel analytical method requires further validation in controlled experiments. HIGHLIGHTS: What is the central question of this study? What are the characteristics of a novel methodological approach to assess ventilatory acclimatization (VA) with incremental ascent to high altitude (HA)? What is the main finding and its importance? Area under the curve (AUC) magnitudes calculated from modified Fenn diagrams were significantly smaller in trekkers taking an oral prophylactic dose of acetazolamide compared to an acetazolamide-free group, suggesting improved VA. During incremental HA ascent, quantifying AUC using modified Fenn diagrams is feasible to assess VA in large groups of trekkers with ascent, although this novel analytical method requires further validation in controlled experiments.

The Effect of Chronic Altitude Exposure on COPD Outcomes in the SPIROMICS Cohort.

Individuals with COPD have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Does residence at higher-altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, or mortality? From the SPIROMICS cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n= 1,367) versus above 4,000 ft (1,219 m) elevation (n= 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Living at higher altitude was associated with reduced functional exercise capacity as defined by 6MWD (-32.3 m, (-55.7 to -28.6)). There were no differences in patient-reported outcomes as defined by symptoms (CAT, mMRC), or health status (SGRQ). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (IRR 0.65, (0.46 to 0.90)). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (HR 1.25, (1.0 to 1.55)); however, this association was no longer significant when accounting for air pollution. Chronic altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. Additionally, chronic high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry.

A Pilot Study Investigating the Impact of High Altitude on Myostatin and Irisin Levels

Many people visit and stay at high altitude due to adventure or occupation. The high-altitude environment comprises many factors alien to sea residents and detrimental to physical and mental health. Myokines are peptides and cytokines secreted from muscles and have a prime role in regulating skeletal muscle growth and myo-degradation. Therefore, the present study investigated the function of myokines in regulating muscle mass during acute and chronic high-altitude exposure. The study was conducted on Indian healthy subjects (n=29) who were distributed into three groups: Control (sea level (SL; n=15), acute high altitude stayed subjects (stayed at high altitude for less than ten days (AHA; n=7); chronic high altitude stayed subjects (stayed at high altitude for 15 days to 3 months (CHA; n=7). Acute exposure to high altitude leads to an increase in myostatin levels, indicating enhanced myo-degradation. Irisin levels were also increased in AHA group compared to SL group, depicting inclined myogenesis. However, CHA group showed an increase in myostatin levels but a non-significant change in irisin content in relation to SL group, suggesting enhanced myo-degradation. These findings generated a unique role of myokines, including myostatin and irisin, in managing skeletal muscle health with reference to high altitude.

Adrenergic control of skeletal muscle blood flow during chronic hypoxia in healthy males.

Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signaling, the primary mechanism mediating sympathetic vasoconstriction at sea level (SL), has not been examined at HA. In nine male lowlanders, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (ΔFVC) during 1) incremental intra-arterial infusion of phenylephrine to assess α1-adrenergic receptor responsiveness and 2) combined intra-arterial infusion of β-adrenergic and α-adrenergic antagonists propranolol and phentolamine (α-β-blockade) to assess adrenergic vascular restraint at rest and during exercise-induced sympathoexcitation (cycling; 60% peak power). Experiments were performed near SL (344 m) and after 3 wk at HA (4,383 m). HA abolished the vasoconstrictor response to low-dose phenylephrine (ΔFVC: SL: -34 ± 15%, vs. HA; +3 ± 18%; P < 0.0001) and markedly attenuated the response to medium (ΔFVC: SL: -45 ± 18% vs. HA: -28 ± 11%; P = 0.009) and high (ΔFVC: SL: -47 ± 20%, vs. HA: -35 ± 20%; P = 0.041) doses. Blockade of β-adrenergic receptors alone had no effect on resting FVC (P = 0.500) and combined α-β-blockade induced a similar vasodilatory response at SL and HA (P = 0.580). Forearm vasoconstriction during cycling was not different at SL and HA (P = 0.999). Interestingly, cycling-induced forearm vasoconstriction was attenuated by α-β-blockade at SL (ΔFVC: Control: -27 ± 128 vs. α-β-blockade: +19 ± 23%; P = 0.0004), but unaffected at HA (ΔFVC: Control: -20 ± 22 vs. α-β-blockade: -23 ± 11%; P = 0.999). Our results indicate that in healthy males, altitude acclimatization attenuates α1-adrenergic receptor responsiveness; however, resting α-adrenergic restraint remains intact, due to concurrent resting sympathoexcitation. Furthermore, forearm vasoconstrictor responses to cycling are preserved, although the contribution of adrenergic receptors is diminished, indicating a reliance on alternative vasoconstrictor mechanisms.

Machine Learning Based on Event-Related EEG of Sustained Attention Differentiates Adults with Chronic High-Altitude Exposure from Healthy Controls.

(1) Objective: The aim of this study was to examine the effect of high altitude on inhibitory control processes that underlie sustained attention in the neural correlates of EEG data, and explore whether the EEG data reflecting inhibitory control contain valuable information to classify high-altitude chronic hypoxia and plain controls. (2) Methods: 35 chronic high-altitude hypoxic adults and 32 matched controls were recruited. They were required to perform the go/no-go sustained attention task (GSAT) using event-related potentials. Three machine learning algorithms, namely a support vector machine (SVM), logistic regression (LR), and a decision tree (DT), were trained based on the related ERP components and neural oscillations to build a dichotomous classification model. (3) Results: Behaviorally, we found that the high altitude (HA) group had lower omission error rates during all observation periods than the low altitude (LA) group. Meanwhile, the ERP results showed that the HA participants had significantly shorter latency than the LAs for sustained potential (SP), indicating vigilance to response-related conflict. Meanwhile, event-related spectral perturbation (ERSP) analysis suggested that lowlander immigrants exposed to high altitudes may have compensatory activated prefrontal cortexes (PFC), as reflected by slow alpha, beta, and theta frequency-band neural oscillations. Finally, the machine learning results showed that the SVM achieved the optimal classification F1 score in the later stage of sustained attention, with an F1 score of 0.93, accuracy of 92.54%, sensitivity of 91.43%, specificity of 93.75%, and area under ROC curve (AUC) of 0.97. The results proved that SVM classification algorithms could be applied to identify chronic high-altitude hypoxia. (4) Conclusions: Compared with other methods, the SVM leads to a good overall performance that increases with the time spent on task, illustrating that the ERPs and neural oscillations may provide neuroelectrophysiological markers for identifying chronic plateau hypoxia.

Proteomic analysis reveals proteins and pathways associated with declined testosterone production in male obese mice after chronic high-altitude exposure.

Obesity is common in highland areas owing to lifestyle alterations. There are pieces of evidence to suggest that both obesity and hypoxia may promote oxidative stress, leading to hypogonadism in males. These findings indicate an increased risk of hypogonadism in obese males following hypoxia exposure. However, the mechanisms underlying the disease process remain unclear. The current study aims to explore the mechanism of testosterone production dysfunction in obese male mice exposed to a chronic high-altitude hypoxia environment. An obese male mouse model was generated by inducing obesity in mice via a high-fat diet for 14 weeks, and the obese mice were then exposed to a high-altitude hypoxia environment for 24 days. Sera and testicular tissues were collected to detect serum lipids, sex hormone level, and testicular oxidative stress indicators. Morphological examination was performed to assess pathological alterations in testicular tissues and suborganelles in leydig cells. Proteomic alterations in testicular tissues were investigated using quantitative proteomics in Obese/Control and Obese-Hypoxia/Obese groups. The results showed that chronic high-altitude hypoxia exposure aggravated low testosterone production in obese male mice accompanied by increased testicular oxidative stress and histological damages. In total, 363 and 242 differentially expressed proteins (DEPs) were identified in the two comparison groups, Obese/Control and Obese-Hypoxia/Obese, respectively. Functional enrichment analysis demonstrated that several significant functional terms and pathways related to testosterone production were altered in the two comparison groups. These included cholesterol metabolism, steroid hormone biosynthesis, peroxisome proliferator-activated receptor (PPAR) signaling pathway, oxidative stress responses, as well as retinol metabolism. Finally, 10 representative DEPs were selected for parallel reaction monitoring verification. Among them, StAR, DHCR7, NSDHL, CYP51A1, FDPS, FDX1, CYP11A1, ALDH1A1, and GPX3 were confirmed to be downregulated in the two groups. Chronic hypoxia exposure could exacerbate low testosterone production in obese male mice by influencing the expression of key proteins involved in steroid hormone biosynthesis, cholesterol biosynthesis, oxidative stress responses and retinol metabolism.

Evaluation of macular and choroidal thickness in healthy residents living at high altitude.

Purpose:Assessment of long-term effects of high altitude on choroidal thickness.Methods:This prospective cross-sectional study included 88 and 79 age- and sex-matched healthy individuals who were living at sea-level (SL group) and high-altitude (HA group), respectively. Participants were required to have resided in the same place for at least 10 years. Spectral-domain optical coherence tomography (SD-OCT) scans were conducted in two different and were performed within the same time (08:00 am to 10:00 am). Central macular thickness (CMT) and choroidal thickness were measured at five different points (i.e., at the central fovea and 1 mm and 2 mm temporal and nasal of the fovea). Blood hemoglobin (Hb), red blood cell (RBC), hematocrit (Htc) levels, blood oxygen saturation, heart rate, and body mass index (BMI) were compared between groups statistically.Results:The HA group had a mean age of 47.5 ± 13.3 years, whereas the SL group was 48.7 ± 13.4 years (P = 0.57). There was no significant difference between the groups in terms of CMT. Subfoveal choroidal thickness (SCFT) was 282.73 ± 87.82 mm in the HA group and 310.49 ± 74.73 in the SL group (P = 0.02). The choroid was found to be thinner at all the measured locations in the HA group except the 2 mm nasal point of the fovea. However, only the difference at an SFCT was statistically significant. Furthermore compared with the SL group statistically significant higher Hb, RBC, Htc levels were determined in the HA group. In the multiple linear regression model analysis, age was found an only effective confounder factor for SCFT (P = 0.001, 95% CI 4.132–2.476).Conclusion:The systemic adaptive changes due to chronic high altitude exposure may cause structural changes in the choroidal vascular network. The current study results revealed significant thinning only at SFCT. Large-scale longitudinal studies are needed to obtain more definitive data on this subject.

Association of Peripheral Plasma Neurotransmitters with Cognitive Performance in Chronic High-altitude Exposure

Long-term living at high altitude causes significant impairment of cognitive function. Central neurotransmitters are potential mediators of cognitive performance. We aimed to determine whether there were significant associations between select peripheral plasma neurotransmitters and cognitive performance in humans with chronic high-altitude (HA) exposure and to determine the association between peripheral plasma neurotransmitters and brain neurotransmitters in rats after chronic hypobaric hypoxia (HH) exposure. We demonstrated that 3,4-dihydroxy-L-phenylalanine (DOPA), dopamine, serotonin, 5-hydroxyindole-3-acetic acid (5-HIAA) and GABA in the peripheral plasma were associated with cognitive performance in humans with HA exposure. Consistent with this result, peripheral plasma DOPA, dopamine, serotonin, 5-HIAA and glutamate were associated with brain neurotransmitter levels after chronic HH exposure in rats. These results provide experimental data indicating that neurotransmitter levels and cognitive performance are modified in chronic high-altitude exposure, with a possible causal effect.

Oxidative and Endoplasmic Reticulum Stress Responses to Chronic High-Altitude Exposure During the Development of High-Altitude Pulmonary Hypertension.

Pu, Xiaoyan, Xue Lin, Xianglan Duan, Junjie Wang, Jun Shang, Haixia Yun, and Zhi Chen. Oxidative and endoplasmic reticulum stress responses to chronic high-altitude exposure during the development of high-altitude pulmonary hypertension. High Alt Med Biol. 21:378-387, 2020. Objectives: To investigate the effect of endoplasmic reticulum (ER) stress during the development of high-altitude pulmonary hypertension (HAPH) after chronic high-altitude exposure, as well as the association between oxidative stress and ER stress. Methods: Forty male Sprague-Dawley rats were placed in a low-pressure chamber with a simulated altitude of 4,200 m for 0-28 days. Rats were chosen at random on days 0, 7, 14, and 28 of chronic high-altitude exposure and were examined for pulmonary arterial pressure, oxidative stress, apoptosis, and ER stress. Results: Chronic high-altitude exposure caused a continuous deterioration of pulmonary hypertension, which was accompanied by obvious apoptosis of alveolar epithelial cells and remodeling of pulmonary vessels. From day 7 of high-altitude exposure, although the activities of glutathione peroxidase and superoxide dismutase were gradually decreased, the generation of both malondialdehyde and reactive oxygen species was increased in a time-dependent manner. The protein expression of ER stress-related GRP78, PERK, IRE1α, ATF6, ATF4, CHOP, and caspase-12 in lung tissue was significantly upregulated from day 14 of high-altitude exposure. Further, the expression of caspase-12 in alveolar epithelial cells and vascular smooth muscle cells was also increased from day 14 of high-altitude exposure. Conclusions: Early high-altitude exposure first activates oxidative stress; then, it gradually activates ER stress. The activation of ER stress might promote the apoptosis of alveolar epithelial cells and the remodeling of pulmonary vessels by exacerbating the oxidative stress response during the development of HAPH after chronic high-altitude exposure.

Transcriptomic modifications in developmental cardiopulmonary adaptations to chronic hypoxia using a murine model of simulated high-altitude exposure.

Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 ft elevation). Mating, pregnancy, and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNA-Seq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, and RV systolic pressure, as well as increased pulmonary artery remodeling. RNA-Seq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. Although there was considerable similarity between hypoxic lungs and RVs compared with RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune downregulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.

Changes in energy system contributions to the Wingate anaerobic test in climbers after a high altitude expedition.

The Wingate anaerobic test measures the maximum anaerobic capacity of the lower limbs. The energy sources of Wingate test are dominated by anaerobic metabolism (~ 80%). Chronic high altitude exposure induces adaptations on skeletal muscle function and metabolism. Therefore, the study aim was to investigate possible changes in the energy system contribution to Wingate test before and after a high-altitude sojourn. Seven male climbers performed a Wingate test before and after a 43-day expedition in the Himalaya (23days above 5.000m). Mechanical parameters included: peak power (PP), average power (AP), minimum power (MP) and fatigue index (FI). The metabolic equivalents were calculated as aerobic contribution from O2 uptake during the 30-s exercise phase (WVO2), lactic and alactic anaerobic energy sources were determined from net lactate production (WLa) and the fast component of the kinetics of post-exercise oxygen uptake (WPCr), respectively. The total metabolic work (WTOT) was calculated as the sum of the three energy sources. PP and AP decreased from 7.3 ± 1.1 to 6.7 ± 1.1W/kg and from 5.9 ± 0.7 to 5.4 ± 0.8W/kg, respectively, while FI was unchanged. WTOT declined from 103.9 ± 28.7 to 83.8 ± 17.8kJ. Relative aerobic contribution remained unchanged (19.9 ± 4.8% vs 18.3 ± 2.3%), while anaerobic lactic and alactic contributions decreased from 48.3 ± 11.7 to 43.1 ± 8.9% and increased from 31.8 ± 14.5 to 38.6 ± 7.4%, respectively. Chronic high altitude exposure induced a reduction in both mechanical and metabolic parameters of Wingate test. The anaerobic alactic relative contribution increased while the anaerobic lactic decreased, leaving unaffected the overall relative anaerobic contribution to Wingate test.

Altered resting-state networks may explain the executive impairment in young health immigrants into high-altitude area.

Executive function is a complex involving multiple advanced brain functions like planning, working memory, mental flexibility and psychomotor. Previous researches indicated that executive function may be impaired after acute or chronic high-altitude exposure, while the underlying neurobiological mechanism has not been totally clarified. In the present study, based on 69 young healthy volunteers immigrating to high-altitude, Stroop test was utilized to identify the potential impairment of executive function after two-year high-altitude exposure while resting-state functional MRI (rs-fMRI) technology was employed to observe the alteration of resting-state networks. Stroop test indicated that the subjects experienced significantly lower accuracies and prolonged responding time after two-year exposure. Resting-state network analysis displayed a significantly decreased degree of co-activation within the left/right frontoparietal network, sensorimotor network, and auditory network after exposure. In the frontoparietal network, decreased co-activation intensity was found in left angular gyrus, while in the right frontoparietal network, decreased co-activation intensity was found in left precentral gyrus and postcentral gyrus. Similarly, as for sensorimotor and auditory network, left middle frontal gyrus and left superior temporal gyrus was identified to have decreased co-activation, respectively. Moreover, the responding delays in ST (part II) were negatively correlated with the signal intensity alteration of the right frontoparietal network. All these evidences indicated that the high-altitude exposure induced alteration in above resting state networks may be the functional basis of executive control impairment.

High-Altitude Is Associated with Better Short-Term Survival in Critically Ill COVID-19 Patients Admitted to the ICU

Background: The novel human coronavirus, SARS-CoV-2, has affected at least 218 countries worldwide. Some geographical and environmental factors are positively associated with a better or worse prognosis concerning COVID-19 disease and with lower or higher SARS-CoV-2 transmission. High altitude exposure has been associated with lower SARS-CoV-2 attack rates; nevertheless, the role of chronic high-altitude exposure on the clinical outcome of critically ill COVID-19 patients has not been studied.Objective: To compare the clinical course and outcomes of critically ill patients with COVID-19 hospitalized in two intensive care units (ICU) located at low and high altitude.Exposure and Outcome: To explore the effect of two different elevations (10 m vs 2,850 m above sea level) on COVID-19 clinical outcome and survival.Methods: A prospective cohort, two-center study in confirmed COVID-19 adult patients admitted to a low altitude (Sea level) and high altitude (2,850 m) ICU units in Ecuador was conducted. Two hundred and thirty confirmed COVID-19 patients were enrolled from March 15th to July 15th, 2020. Sociodemographic, clinical, laboratory and imaging parameters including supportive therapies, pharmacological treatments and medical complications were reported and compared between the low and high-altitude groups.Results: The median age of all the patients was 60 years, 64.8% were men and 35.2% were women. A total of 105 (45.7%) patients had at least one underlying comorbidity, the most frequent being chronic diseases, such as hypertension (33.5%), diabetes (16.5%), and chronic kidney failure (5.7%). The APACHE II scale at 72 hours was especially higher in the low-altitude group with a median of 18 points (IQR: 9.5-24.0), compared to 9 points (IQR: 5.0-22.0) obtained in the group of high altitude. There is evidence of a difference in survival in favor of the high-altitude group (p = 0.006), the median survival being 39 days, compared to 21 days in the low altitude group. Conclusion: There has been a substantial improvement in survival amongst people admitted to the high-altitude critical care unit. Low altitude living was associated with improved survival, especially among patients with no comorbidities. COVID-19 patients admitted to the high-altitude ICU unit have improved severity-of-disease classification system scores at 72 hours and reported better respiratory and ventilatory profiles than the low altitude group.Funding Statement: This work did not receive a formal grant: however, it received financial support associated with the publication fee from the University of the Americas in Quito, Ecuador.Declaration of Interests: The authors have no conflict of interest to declare.Ethics Approval Statement: This work was approved by the hospital's internal bioethical review committee (ID: IESS-HG-SQ-CIE-2020-2656-M).

Combined fractional anisotropy and subcortical volumetric abnormalities in healthy immigrants to high altitude: A longitudinal study.

The study of individuals at high-altitude (HA) exposure provides an important opportunity for unraveling physiological and psychological mechanism of brain underlying hypoxia condition. However, this has rarely been assessed longitudinally. We aim to explore the cognitive and cerebral microstructural alterations after chronic HA exposure. We recruited 49 college freshmen who immigrated to Tibet and followed up for 2 years. Control group consisted of 49 gender and age-matched subjects from sea level. Neuropsychological tests were also conducted to determine whether the subjects' cognitive function had changed in response to chronic HA exposure. Surface-based cortical and subcortical volumes were calculated from structural magnetic resonance imaging data, and tract-based spatial statistics (TBSS) analysis of white matter (WM) fractional anisotropy (FA) based on diffusion weighted images were performed. Compared to healthy controls, the high-altitude exposed individuals showed significantly lower accuracy and longer reaction times in memory tests. Significantly decreased gray matter volume in the caudate region and significant FA changes in multiple WM tracts were observed for HA immigrants. Furthermore, differences in subcortical volume and WM integration were found to be significantly correlated with the cognitive changes after 2 years' HA exposure. Cognitive functions such as working memory and psychomotor function were found to be impaired during chronic HA. Differences of brain subcortical volumes and WM integration between HA and sea-level participants indicated potential impairments in the brain structural modifications and microstructural integrity of WM tracts after HA exposure.

Anabolic signaling responses to exercise and recovery whey protein are suppressed at high altitude

Lowlanders sojourning to high‐altitude (HA) often experience muscle mass losses that are attributable to negative energy balance and potential dysregulation of intramuscular anabolic signaling. The combined effects of exercise and high‐quality protein ingestion can ameliorate the effects of short‐term, moderate negative energy balance (10‐d, ≤ 40 % total energy requirements) on intramuscular anabolic signaling at sea level (SL); however, the ability to sustain this effect at HA is unknown. This study examined the combined effects of HA (4300 m) and severe negative energy balance (21‐d, 70% of SL total energy requirements) on mTORC1 signaling responses after aerobic exercise and recovery whey protein (WP) ingestion in recreationally active, native lowlanders (n = 8 males). Total body mass and fat‐free mass were assessed using dual energy x‐ray absorptiometry before and after the 21‐d energy deficit at HA. Muscle biopsies of the vastus lateralis were obtained at SL, acute HA (3‐h HA exposure, day 0), and chronic HA (day 21), before (BASE) and after completing 80‐min of steady‐state aerobic exercise followed by a 2 mile time trial (POST), and 3 h into recovery (REC). In each trial, 25 g WP was consumed as a drink immediately after the POST biopsy. Intramuscular anabolic signaling was determined using Western blot and RT‐qPCR. Participants lost 7.5 ± 0.8 kg of total body mass (4.3 ± 1.0 kg of fat‐free mass, P &lt; 0.05). POST and REC p‐mTORSer2448, p‐70S6KSer424/421 and p‐rpS6Ser235/236 were 2‐, 23‐, and 7‐fold higher (P &lt; 0.05) than BASE at SL. At acute HA, POST p‐mTORSer2448, and POST and REC p‐70S6KSer424/421 were not different (P &gt; 0.05) from BASE and were 1‐ and 20‐fold lower than SL (P &lt; 0.05). However, POST and REC p‐rpS6Ser235/236 at acute HA was 4‐fold higher (P &lt; 0.05) than BASE and not different from SL. At chronic HA, POST and REC p‐mTORSer2448 and p‐70S6KSer424/421 were not different from BASE and were 1‐ and 19‐fold lower (P &lt; 0.05) than SL. POST and REC p‐rpS6Ser235/236 at chronic HA was 2‐fold higher (P &lt; 0.05) than BASE, but overall phosphorylation was 4‐fold lower (P &lt; 0.05) than SL. BASE HIF‐1α mRNA expression tended to be higher (P = 0.07) at acute HA than SL, whereas REC HIF‐1α mRNA expression at acute and chronic HA were lower (P &lt; 0.05) than SL. REDD1 mRNA expression and REDD1/14‐3‐3 coupling were not affected by study phase. These findings indicate that acute HA exposure induces intramuscular anabolic resistance that is further impaired with chronic HA exposure concomitant with severe negative energy balance, suggesting a mechanism for muscle loss at HA.Support or Funding InformationThis material is based on the work supported by US Army Medical Research and Material Command and the US Army Natick Soldier Research Development and Engineering Center. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the US Army.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Role of G protein‐coupled estrogen receptors in pulmonary hypertension

Chronic hypoxia (CH) resulting from chronic obstructive pulmonary disease, sleep apnea, and high altitude exposure leads to oxidative stress and increased pulmonary vascular resistance. The resultant pulmonary hypertension (PH) contributes to right ventricular hypertrophy and may culminate in right heart failure, peripheral edema, and dyspnea. Because the G protein‐coupled estrogen receptor (GPER) has been implicated in oxidative stress in systemic hypertension, we hypothesized that GPER contributes to the development of CH‐induced PH. To test this hypothesis, we assessed indices of PH in female wild type (WT) and GPER knockout (KO) mice exposed to normoxia or CH (4 wk, PB= 0.5 atm) (n= 4–6/group). Right ventricular systolic pressure (RVSP) was measured by direct cardiac puncture during isoflurane anesthesia. In addition, right ventricular hypertrophy and polycythemic responses to CH were determined from Fulton's index (right ventricle/(left ventricle + septum weight)) and hematocrit, respectively. CH resulted in greater RVSP in WT mice (p&lt;0.05), indicative of PH. Although CH also tended to increase Fulton's index and hematocrit in WT mice, these responses did not reach statistical significance. GPER KO mice unexpectedly showed significantly (p &lt; 0.05) elevated RVSP, right ventricular hypertrophy and hematocrit compared to WT controls under normoxic conditions. Furthermore, these responses to GPER knockdown were not potentiated by CH. We conclude that GPER deficiency results in PH under normoxic conditions, supporting a role for GPER in the maintenance of the pulmonary circulation as a low‐pressure circuit.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Central Corneal Thickness of Healthy Lowlanders at High Altitude: A Systematic Review and Meta-Analysis

ABSTRACTPurpose: Central corneal thickness, a marker of corneal hydration and metabolism, was reported to increase at high elevations. This study aimed to assess the effect of chronic high-altitude exposure on the central corneal thickness of healthy lowlanders with unoperated corneas, and determine if a relationship exists between exposure time and corneal edema formation.Materials and Methods: The PubMed, Embase, Scopus, Cochrane Library, and Airiti Library databases were searched up to 2017 January 31 for prospective cohort studies performed above 2500 m in healthy lowlanders with measurements of the central corneal thickness. Subjects with prior eye surgery, contact lens, and non-hypobaric hypoxic exposure were excluded.Results: Seven studies of 207 adults were included. The pooled effect of high-altitude exposure on the central corneal thickness for < 12 hours, 3–5 days, 6–7 days, and > 10 days was a mean difference of 13.4 (95% confidence interval: 5.1–21.6) μm with moderate heterogeneity (p < 0.05, I2 = 59%), 19.3 (95% confidence interval: 9.7–29) μm with low heterogeneity (p = 0.88, I2 = 0%), 20.4 (95% confidence interval: 10.3–30.5) μm with low heterogeneity (p = 0.73, I2 = 0%), and 30.8 (95% confidence interval: 20.4–41.2) μm with low heterogeneity (p = 0.69, I2 = 0%), respectively. Baseline differences between pre-exposure and post-exposure were not statistically significant. Regression analysis revealed a significant linear relation between high-altitude exposure time and corneal edema formation that exceeded 5% after 10 days.Conclusions: High-altitude exposure induces central corneal thickening with significant linear progression over time, whereas it takes over 10 days to reach clinical significance in healthy lowlanders with unoperated corneas, and changes in central corneal thickness are reversible after descent to lower elevations.

The Impact of Altitude on Sleep-Disordered Breathing in Children Dwelling at High Altitude: A Crossover Study.

Sleep-disordered breathing (SDB) is prevalent among children and is associated with adverse health outcomes. Worldwide, approximately 250 million individuals reside at altitudes higher than 2000 meters above sea level (masl). The effect of chronic high-altitude exposure on children with SDB is unknown. This study aims to determine the impact of altitude on sleep study outcomes in children with SDB dwelling at high altitude. A single-center crossover study was performed to compare results of high-altitude home polysomnography (H-PSG) with lower altitude laboratory polysomnography (L-PSG) in school-age children dwelling at high altitude with symptoms consistent with SDB. The primary outcome was apnea-hypopnea index (AHI), with secondary outcomes including obstructive AHI; central AHI; and measures of oxygenation, sleep quality, and pulse rate. Twelve participants were enrolled, with 10 included in the final analysis. Median altitude was 1644 masl on L-PSG and 2531 masl on H-PSG. Median AHI was 2.40 on L-PSG and 10.95 on H-PSG. Both obstructive and central respiratory events accounted for the difference in AHI. Oxygenation and sleep fragmentation were worse and pulse rate higher on H-PSG compared to L-PSG. These findings reveal a clinically substantial impact of altitude on respiratory, sleep, and cardiovascular outcomes in children with SDB who dwell at high altitude. Within this population, L-PSG underestimates obstructive sleep apnea and central sleep apnea compared to H-PSG. Given the shortage of high-altitude pediatric sleep laboratories, these results suggest a role for home sleep apnea testing for children residing at high altitude.

"Direct" and "Indirect" Methods to Detect Oxidative Stress During Acute or Chronic High-Altitude Exposure.

"Direct" and "Indirect" Methods to Detect Oxidative Stress During Acute or Chronic High-Altitude Exposure.

UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level.

Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 ± 1.0 yr old, 129 ± 9 cm, 27 ± 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 ± 0.7 yr old, 143 ± 7 cm, 34 ± 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 ± 2 vs. 99 ± 1%, P < 0.01) and end-tidal Pco2 (24 ± 3 vs. 36 ± 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ∼30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 ± 108 vs. 333 ± 56 ml/min, P = 0.05), VA flow (78 ± 26 vs. 118 ± 35 ml/min, P < 0.05), and MCA velocity (72 ± 14 vs. 88 ± 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 ± 92 vs. 441 ± 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia.NEW & NOTEWORTHY Cerebral blood flow is lower in Sherpa children compared with children residing at sea level; this may reflect a cerebral hemodynamic pattern, potentially due to adaptation to a hypoxic environment.