Altitude Acclimatization Research Articles

Marching to the Beet: The effect of dietary nitrate supplementation on high altitude exercise performance and adaptation during a military trekking expedition

PurposeThe aim was to investigate the effect of dietary nitrate supplementation (in the form of beetroot juice, BRJ) for 20 days on salivary nitrite (a potential precursor of bioactive nitric oxide), exercise performance and high altitude (HA) acclimatisation in field conditions (hypobaric hypoxia). MethodsThis was a single-blinded randomised control study of 22 healthy adult participants (12 men, 10 women, mean age 28 ± 12 years) across a HA military expedition. Participants were randomised pre-ascent to receive two 70 ml dose per day of either BRJ (~12.5 mmol nitrate per day; n = 11) or non-nitrate calorie matched control (n = 11). Participants ingested supplement doses daily, beginning 3 days prior to departure and continued until the highest sleeping altitude (4800 m) reached on day 17 of the expedition. Data were collected at baseline (44 m altitude), at 2350 m (day 9), 3400 m (day 12) and 4800 m (day 17). ResultsBRJ enhanced the salivary levels of nitrite (p = 0.007). There was a significant decrease in peripheral oxygen saturation and there were increases in heart rate, diastolic blood pressure, and rating of perceived exertion with increasing altitude (p=<0.001). Harvard Step Test fitness scores significantly declined at 4800 m in the control group (p = 0.003) compared with baseline. In contrast, there was no decline in fitness scores at 4800 m compared with baseline (p = 0.26) in the BRJ group. Heart rate recovery speed following exercise at 4800 m was significantly prolonged in the control group (p=<0.01) but was unchanged in the BRJ group (p = 0.61). BRJ did not affect the burden of HA illness (p = 1.00). ConclusionsBRJ increases salivary nitrite levels and ameliorates the decline in fitness at altitude but does not affect the occurrence of HA illness.

Cardiorespiratory Coordination in Hypercapnic Test Before and After High-Altitude Expedition.

Coordination of cardiovascular and respiratory systems enables a wide range of human adaptation and depends upon the functional state of an individual organism. Hypoxia is known to elicit changes in oxygen and carbon dioxide sensitivity, while training alters cardiorespiratory coordination (CRC). The delayed effect of high altitude (HA) acclimatization on CRC in mountaineers remains unknown. The objective of this study was to compare CRC in acute hypercapnia in mountaineers before and after a HA expedition. Nine trained male mountaineers were investigated at sea level before (Pre-HA) and after a 20-day sojourn at altitudes of 4,000–7,000 m (Post-HA) in three states (Baseline, Hypercapnic Rebreathing, and Recovery). A principal component (PC) analysis was performed to evaluate the CRC. The number of mountaineers with one PC increased Post-HA (nine out of nine), compared to Pre-HA (five out of nine) [Chi-square (df = 1) = 5.14, P = 0.023]; the percentage of total variance explained by PC1 increased [Pre-HA median 65.6 (Q1 64.9/Q3 74.9), Post-HA 75.6 (73.3/77.9), P = 0.028]. Post-HA, the loadings of the expired fraction of O2, CO2, and ventilation onto PC1 did not change, and the loading of heart rate increased [Pre-HA 0.64 (0.45/0.68) and Post-HA 0.76 (0.65/0.82), P = 0.038]. During the Recovery, the percentage of total variance explained by PC1 was higher than during the Baseline. Post-HA, there was a high correlation between the Exercise addiction scores and the eigenvalues of PC1 (r = 0.9, P = 0.001). Thus, acute hypercapnic exposure reveals the Post-HA increase in cardiorespiratory coordination, which is highly related to the level of exercise addiction.

Effects of chronic intermittent hypobaric hypoxia on prostate-specific antigen (PSA) in Chilean miners

ObjectiveThe aim was to determine the effects of chronic intermittent hypobaric hypoxia (CIHH) on prostate-specific antigen (PSA) levels in Chilean miners who work at different altitudes.MethodsA cross-sectional study was conducted...

Testing Ventilatory Acclimatization to High Altitude using the Hyperoxic Ventilatory Withdrawal Test

Testing the transient hypoxic ventilatory response (HVR) is the most common method utilized for assessing ventilatory acclimatization in the setting of high altitude ascent, as the peripheral chemoreceptors become sensitized to hypoxia with chronic exposure. However, this test requires sophisticated equipment (e.g., gas tanks, feedback controllers) that lacks portability, and may lead to participant discomfort while already hypoxic while at altitude. The transient hyperoxic withdrawal (HVW) test is simple, portable and safe, using a small 100% O2 tank available on most expeditions, and may better assess ventilatory acclimatization when participants are chronically hypoxic in high altitude fieldwork studies. We hypothesized that the HVW would be larger following 7-days of ascent to 4240m while taking acetazolamide (Diamox; i.e., ventilatory stimulant) than an acute hypoxic control group at low altitude, thus having utility in detecting ventilatory acclimatization during ascent to high altitude. Using two separate recruitments, we tested two groups in two contexts. In Part A, we recruited 14 participants to assess the HVW in the context of acute, steady-state hypoxia (~30-min; FIO2 13.5-14%) in a laboratory context (1045m, PATM ~665 mmHg). In Part B, 12 participants were recruited from a large research expedition to high altitude in the Nepal Himalaya, following 7 days of incremental ascent to high altitude (4240m, PATM ~460 mmHg), while taking prophylactic Diamox (125 mg, BID). Participants were instrumented with a mouthpiece and bacteriological filter attached to a calibrated pneumotachometer (to measure inspired ventilation; VI; L/min) and a peripheral pulse oximeter to measure oxygen saturation (SpO2;%). First, while breathing roughly equivalent PIO2 of ~85 mmHg at baseline (BL), both groups were exposed a single tidal breath of 100% O2 from a 50L Douglas bag by switching a three-way valve from room air to hyperoxia. The HVW was quantified as the change (delta) in VI from BL to the smallest instantaneous breath within 20-sec of the hyperoxic stimulus indexed to the change in SpO2 from BL to the peak following the hyperoxic breath, wherever it occurred (i.e., ventilatory response/oxygen change). We found that the HVW values from acute hypoxic participants had a mean of 0.34±0.23 L/min/%, while those who underwent acclimatization to high altitude hypoxia had a significantly larger HVW of 0.53±0.24 L/min/% (P=0.03). Our results suggest that the transient HVW test is a feasible method to detect peripheral chemoreceptor sensitization and ventilatory acclimatization in the context of high altitude ascent.

Difference in Steady‐state Chemoreflex Drive Between Groups With and Without a Patent Foramen Ovale

Ventilatory acclimatization is a hallmark physiological response to high altitude. In ~30% of the population, a shunt located between the right and left atrium called patent foramen ovale (PFO) is present. People with a PFO have a reduced degree of ventilatory acclimatization which may contribute to their increased risk for high altitude illnesses. Recently, the development of a steady-state chemoreflex drive (SS-CD) index has provided a novel approach to assessing the overall ventilatory drive at altitude. Using data from a previous high-altitude expedition (AltitudeOmics), the SS-CD index (SS-CD = Minute ventilation (VE), / (arterial partial pressure of carbon dioxide (PaCO2) / arterial oxygen saturation (SaO2)) was utilized to quantify differences in the degree of ventilatory acclimatization between groups with a PFO, ­­­­­(PFO+) and without a PFO, (PFO-). We aimed to test two hypotheses: 1) PFO- subjects would have a higher SS-CD than PFO+ subjects 2) PFO+ subjects would have no significant change in their SS-CD from ALT1 to ALT16. Twenty-one participants (n=11 PFO+, n=10 PFO-) participated in a high-altitude study during which they spent 16 days at 5260 meters in Bolivia. VE, PaCO2, and SaO2 data were collected at sea level (SL), day 1 at 5260m (ALT1), and day 16 at 5260m (ALT16). VE was obtained using a pneumotach. PaCO2 and SaO2 were obtained from a radial artery catheter. A mixed-model 2 way repeat measure ANOVA was performed for statistical analysis with Tukey's multiple comparisons test. There was a main effect of time on the SS-CD (p<0.0001), but no significant difference between PFO+ and PFO- subjects (p=0.2). Within PFO+ and PFO- subject groups the SS-CD significantly increased from SL to ALT16 (PFO+ : 33.5 ± 5.9 vs 80.9 ± 47.8, p=0.0006; PFO- : 37.7 ± 10.3 vs 103.1 ± 44.2, p<0.0001) and from ALT1 and ALT16 (PFO+ : 43.16 ± 9.2 vs 80.9 ± 47.8, p=0.0077; PFO- : 52.08 ± 14.3 vs 103.1 ± 44.2, p=0.0052). Using the SS-CD to quantify chemoreceptor drive between groups, our findings suggest the overall chemoreflex drive from ALT1 to ALT16 in both groups reflects significant changes in ventilation. Additionally, PFO+ subjects exhibit no differences in their overall chemoreflex response to altitude from PFO- subjects, despite significant differences in a more classical index of drive (i.e., change in VE/change in SaO2). Future research should aim to investigate this inconsistency in chemoreflex responses in PFO+ and PFO- subjects at altitude.

Heterogeneity in Hematological Parameters of High and Low Altitude Tibetan Populations.

IntroductionHigh altitude hypoxia is believed to be experienced at elevations of more than 2500 meters above sea level. Several studies have shed light on the biochemical aspects of high altitude acclimatization, where participants were sojourners to the high altitude from low altitude areas. However, information regarding the difference between the high altitude adapted Tibetans living at high altitude and their counterparts who reside at low altitude are lacking. To understand this, we have measured various hematological parameters in the Tibetan populations, who are residing in both high and low altitudes in India.MethodsA total of 168 individuals (79 from high altitude (≥4500 meters) and 89 from low altitude (~850 meters) were recruited for this study. Hematological parameters such as red blood cells (RBC) count, hematocrit (HCT), hemoglobin concentration (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were measured from the individuals from high and low altitudes. Serum erythropoietin (EPO) was measured by ELISA. Statistical analyses were performed to compare data from both of the altitudes. Gender-wise comparison of data was reported. Correlation analysis was performed within relevant parameters.ResultsHighly significant differences (p <0.0001) between high and low altitude Tibetans were detected in RBC count, HCT, Hb, MCHC in both males and females and in MCV in females. In the case of MCHC, however, age and BMI were potential confounders. Nominally significant differences (p <0.05) were detected in MCV and MCH within males. No significant difference in serum EPO level was found between altitude groups, in any gender. No significant correlation was found between serum EPO with Hb as well as serum EPO with HCT.DiscussionOur study explores significantly lower RBC count, HCT, Hb, MCH, MCHC and higher MCV in long-term Tibetan residents living at low altitude compared to their high altitude counterparts, which is likely due to the outcome of hematological adaptation to a relatively hyperoxic environment in low altitude areas.

A structural analysis of the hypoxia response network.

BackgroundThe hypoxia-inducible factor-1 (HIF-1) signaling pathway is an important topic in high-altitude medicine. Network analysis is a novel method for integrating information on different aspects and levels of biological networks. However, this method has not been used in research on the HIF-1 signaling pathway network. To introduce this method into HIF-1-related research fields and verify its feasibility and effectiveness, we used a network analytical method to explore the structural attributes of the HIF-1 signaling pathway network.MethodsFirst, we analyzed the overall network of the HIF-1 signaling pathway using information retrieved from the Kyoto Encyclopedia of Genes and Genomes (KEGG). We performed topology analysis, centrality analysis, and subgroup analysis of the network. Then, we analyzed the core network based on the overall network analysis. We analyzed the properties of the topology, the bow-tie structure, and the structural complexity of the core network.ResultsWe obtained topological structure diagrams and quantitative indicators of the overall and core networks of the HIF-1 signaling pathway. For the structure diagrams, we generated topology diagrams of the network and the bow-tie structure of the core network. As quantitative indicators, we identified topology, centrality, subgroups, the bow-tie structure, and structural complexity. The topology indicators were the number of nodes, the number of lines, the network diameter, and the network density. The centrality indicators were the degree, closeness, and betweenness. The cohesive subgroup indicator was the components of the network. The bow-tie structure indicators included the core, input, and tendril-like structures. The structural complexity indicators included a power-law fitting model and its scale parameter.ConclusionsThe core network could be extracted based on the subgroup analysis of the overall network of the HIF-1 signaling pathway. The critical elements of the network could be identified in the centrality analysis. The results of the study show the feasibility and effectiveness of the network analytical method used to explore the network properties of the HIF-1 signaling pathway and provide support for further research.

Time course and magnitude of ventilatory and renal acid-base acclimatization following rapid ascent to and residence at 3,800 m over nine days.

Rapid ascent to high altitude imposes an acute hypoxic and acid-base challenge, with ventilatory and renal acclimatization countering these perturbations. Specifically, ventilatory acclimatization improves oxygenation, but with concomitant hypocapnia and respiratory alkalosis. A compensatory, renally mediated relative metabolic acidosis follows via bicarbonate elimination, normalizing arterial pH(a). The time course and magnitude of these integrated acclimatization processes are highly variable between individuals. Using a previously developed metric of renal reactivity (RR), indexing the change in arterial bicarbonate concentration (Δ[HCO3-]a; renal response) over the change in arterial pressure of CO2 (Δ[Formula: see text]; renal stimulus), we aimed to characterize changes in RR magnitude following rapid ascent and residence at altitude. Resident lowlanders (n = 16) were tested at 1,045 m (day [D]0) prior to ascent, on D2 within 24 h of arrival, and D9 during residence at 3,800 m. Radial artery blood draws were obtained to measure acid-base variables: [Formula: see text], [HCO3-]a, and pHa. Compared with D0, [Formula: see text] and [HCO3-]a were lower on D2 (P < 0.01) and D9 (P < 0.01), whereas significant changes in pHa (P = 0.072) and RR (P = 0.056) were not detected. As pHa appeared fully compensated on D2 and RR did not increase significantly from D2 to D9, these data demonstrate renal acid-base compensation within 24 h at moderate steady-state altitude. Moreover, RR was strongly and inversely correlated with ΔpHa on D2 and D9 (r≤ -0.95; P < 0.0001), suggesting that a high-gain renal response better protects pHa. Our study highlights the differential time course, magnitude, and variability of integrated ventilatory and renal acid-base acclimatization following rapid ascent and residence at high altitude.NEW & NOTEWORTHY We assessed the time course, magnitude, and variability of integrated ventilatory and renal acid-base acclimatization with rapid ascent and residence at 3,800 m. Despite reductions in [Formula: see text] upon ascent, pHa was normalized within 24 h of arrival at 3,800 m through renal compensation (i.e., bicarbonate elimination). Renal reactivity (RR) was unchanged between days 2 and 9, suggesting a lack of plasticity at moderate steady-state altitude. RR was strongly correlated with ΔpHa, suggesting that a high-gain renal response better protects pHa.

Pro-Oxidant/Antioxidant Balance during a Prolonged Exposure to Moderate Altitude in Athletes Exhibiting Exercise-Induced Hypoxemia at Sea-Level.

This study examined to what extent athletes exhibiting exercise-induced hypoxemia (EIH) possess an altered redox status at rest, in response to exercise at sea level (SL) and during moderate altitude exposure. EIH was defined as a fall in arterial O2 saturation of at least 4% during exercise. Nine endurance athletes with EIH and ten without (NEIH) performed a maximal incremental test under three conditions: SL, one (H1) and five (H2) days after arrival to 2400 m. Gas exchange and peripheral capillary oxygen saturation (SpO2) were continuously monitored. Blood was sampled before exercise and after exercise cessation. Advanced oxidation protein products (AOPP), catalase, ferric-reducing antioxidant power, glutathione peroxidase, superoxide dismutase (SOD) and nitric oxide metabolites (NOx) were measured in plasma by spectrophotometry. EIH athletes had higher AOPP and NOx concentrations at pre- and post-exercise stages compared to NEIH at SL, H2 but not at H1. Only the EIH group experienced increased SOD activity between pre- and post-exercise exercise at SL and H2 but not at H1. EIH athletes had exacerbated oxidative stress compared to the NEIH athletes at SL and H2. These differences were blunted at H1. Oxidative stress did not alter the EIH groups’ aerobic performance and could lead to higher minute ventilation at H2. These results suggest that higher oxidative stress response EIH athletes could be involved in improved aerobic muscle functionality and a greater ventilatory acclimatization during prolonged hypoxia.

Reliability and validity of the Hypoxico Everest Summit II altitude generator

The Hypoxico Everest Summit II Altitude Generator produces normobaric hypoxic conditions, which are commonly used in altitude acclimation. Despite being used routinely within applied sport science, this system is yet to be independently validated. Thus, the aim of this study was to explore within- and between-day inter- and intra-machine reliability and validity. Two Hypoxico Everest Summit II Altitude Generators were investigated for six altitude settings in a randomised order (0.5, 3.0, 5.5, 8.0, 10.5, 12.0). Following institutional ethics approval, Hypoxico generated air was sequentially pumped into three Douglas bags, each with a 1-min collection period. Samples were collected on eight occasions, measuring inter- and intra-machine reliability, both within-day (9 AM–2 PM) and between-day (48-h) with samples analysed to determine FiO2 (%) and volume (L·min−1). Coefficient of variation (CV) was calculated for FiO2 and volume for each altitude setting. Mean CV for FiO2 did not exceed 0.42% within-day, 0.49% between-day and 0.81% inter-machine. Volume mean CV did not exceed 0.85% within-day, 0.91% between-day and 1.17% inter-machine. One-sampled t-tests were conducted comparing Hypoxico reference values with collected samples using equivalent FiO2 for each altitude setting with a Bonferroni corrected significance set at p &lt; 0.004. Settings 3.0, 5.5, 8.0, 10.5 and 12.0 all produced significantly different ( p &lt; 0.001) FiO2 concentrations than the reference values stated (−0.51, −0.97, −0.72, +0.41 and +0.40%, respectively). Altitude setting and 1-min volume had an inverse relationship. All settings produced a significantly lower ( p &lt; 0.001) volume by 21.80 to 35.40 L·min−1 as compared to the company’s claim of 126.6 L·min−1. The Hypoxico Everest Summit II produced a reliable and consistent air feed; however, the manufacturer’s reference values demonstrated poor agreement with machine produced FiO2 and volume. Therefore, it is recommended that athletes, practitioners and researchers self-validate the altitude generator post-warm-up using an accurate oxygen sensor for accuracy and safety purposes.

Using Composite Phenotypes to Reveal Hidden Physiological Heterogeneity in High-Altitude Acclimatization in a Chinese Han Longitudinal Cohort

Altitude acclimatization is a human physiological process of adjusting to the decreased oxygen availability. Since several physiological processes are involved and their correlations are complicated, the analyses of single traits are insufficient in revealing the complex mechanism of high-altitude acclimatization. In this study, we examined these physiological responses as the composite phenotypes that are represented by a linear combination of physiological traits. We developed a strategy that combines both spectral clustering and partial least squares path modeling (PLSPM) to define composite phenotypes based on a cohort study of 883 Chinese Han males. In addition, we captured 14 composite phenotypes from 28 physiological traits of high-altitude acclimatization. Using these composite phenotypes, we applied k-means clustering to reveal hidden population physiological heterogeneity in high-altitude acclimatization. Furthermore, we employed multivariate linear regression to systematically model (Models 1 and 2) oxygen saturation (SpO2) changes in high-altitude acclimatization and evaluated model fitness performance. Composite phenotypes based on Model 2 fit better than single trait-based Model 1 in all measurement indices. This new strategy of using composite phenotypes may be potentially employed as a general strategy for complex traits research such as genetic loci discovery and analyses of phenomics.

Recommendations for traveling to altitude with neurological disorders.

BackgroundSeveral neurological conditions might worsen with the exposure to high altitude (HA). The aim of this review was to summarize the available knowledge on the neurological HA illnesses and the risk for people with neurological disorders to attend HA locations.MethodsA search of literature was conducted for several neurological disorders in PubMed and other databases since 1970. The neurological conditions searched were migraine, different cerebrovascular disease, intracranial space occupying mass, multiple sclerosis, peripheral neuropathies, neuromuscular disorders, epileptic seizures, delirium, dementia, and Parkinson’s disease (PD).ResultsAttempts were made to classify the risk posed by each condition and to provide recommendations regarding medical evaluation and advice for or against traveling to altitude. Individual cases should be advised after careful examination and risk evaluation performed either in an outpatient mountain medicine service or by a physician with knowledge of HA risks. Preliminary diagnostic methods and anticipation of neurological complications are needed.ConclusionsOur recommendations suggest absolute contraindications to HA exposure for the following neurological conditions: (1) Unstable conditions–such as recent strokes, (2) Diabetic neuropathy, (3) Transient ischemic attack in the last month, (4) Brain tumors, and 5. Neuromuscular disorders with a decrease of forced vital capacity >60%. We consider the following relative contraindications where decision has to be made case by case: (1) Epilepsy based on recurrence of seizure and stabilization with the therapy, (2) PD (± obstructive sleep apnea syndrome-OSAS), (3) Mild Cognitive Impairment (± OSAS), and (4) Patent foramen ovale and migraine have to be considered risk factors for acute mountain sickness.

Beet on Alps: Time-course changes of plasma nitrate and nitrite concentrations during acclimatization to high-altitude

Nitric oxide seems to be involved in the altitude acclimatization process due to its ability to regulate pulmonary, cardiovascular and muscular responses to hypoxia. In this study, we investigated the plasma nitrate (NO3−) and nitrite (NO2−) response to hypobaric hypoxia in two groups of lowlanders exposed at different altitudes.For seven days, fourteen subjects were evaluated at Casati Hut (3269 m a.s.l. M.CEVEDALE) and eleven individuals were studied at Capanna Regina Margherita (4554 m a.s.l. M.ROSA). Before expeditions and at different time points during high-altitude sojourn, plasma NO3− and NO2− concentrations were measured by chemiluminescence. Resting peripheral arterial oxygen saturation (SpO2), heart rate (HR) and mean arterial blood pressure (MAP) were monitored during the experimental period. Possible confounding factors such as dietary NO3− intake, physical activity and altitude changes were controlled.Sea level plasma NO3− and NO2− concentrations significantly increased at altitude in both M.CEVEDALE group (+26.2 μM, p ≤ 0.0001, 95% CI [+17.6, +34.8] and +559.2 nM, p ≤ 0.0001, [+332.8, +785.6]) and M.ROSA group (+18.7 μM, p ≤ 0.0001, [+10.8, +26.5] and +463.7 nM, p ≤ 0.0001, [+314.3, +613.0]). Average peak value in NO metabolites concentration occurred earlier in M.CEVEDALE group vs M.ROSA group (NO3−, day 3 vs day 5, p = 0.007; NO2−, day 3 vs day 5, p = 0.019). In both groups, resting SpO2, HR and MAP values changed according to altitude levels.This study shows that exposure to hypobaric hypoxia affects nitric oxide metabolites, resulting in a significant increase in plasma NO3− and NO2− concentrations from sea level values. Interestingly, the higher the altitude reached, the longer the time taken to reach a peak in plasma concentrations of nitric oxide metabolites.

Abstract 14359: Single Nucleotide Polymorphisms in Genes Involved in L-arginine / Dimethylarginine Metabolism Predispose for Pulmonary Hypertension and Acute Mountain Sickness at High Altitude

Introduction: Chronic (CH) and chronic-intermittent (CIH) exposure to hypoxia at high altitude causes acute or chronic mountain sickness and elevation of mean pulmonary arterial pressure (mPAP). This is paralleled by increased plasma levels of ADMA, an endogenous inhibitor of NO synthesis. ADMA is cleaved by dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), whilst symmetric dimethylarginine (SDMA) is cleaved by AGXT2. Arginase (ARG1 and ARG2) competes with endothelial NO synthase (NOS3) for L-arginine as substrate. We have shown previously that baseline ADMA (at sea level) determines mPAP after six months of CIH; cut-off values of 25 mm Hg and 30 mm Hg are being used to diagnose high altitude pulmonary hypertension. Hypothesis: We hypothesized that genetic variability in genes coding for core enzymes of ADMA, SDMA, and L-arginine metabolism may predispose individuals for high altitude disease and pulmonary hypertension. Methods: We genotyped 16 common single nucleotide polymorphisms in the NOS3, DDAH1, DDAH2, AGXT2, ARG1 and ARG2 genes of 69 healthy male Chilean subjects. Study participants adhered to a CIH regimen (5d at 3,550m, 2d at sea level) for six months. Metabolites were measured by LC-MS/MS; mPAP was estimated by echocardiography at six months, and altitude acclimatization was assessed by Lake Louise Score and arterial oxygen saturation. Results: Carriers of the minor allele of DDAH1 rs233112 had a higher mean baseline ADMA level (0.76±0.03 vs. 0.67±0.02 μmol/l; p&lt;0.05), whilst the major allele of DDAH2 rs805304 was linked to an exacerbated increase of ADMA in hypoxia (0.10±0.03 vs. 0.04±0.04 μmol/l; p&lt;0.02). Study participants carrying the minor allele of ARG1 rs2781667 had a relative risk of elevated mPAP (&gt;25 mm Hg) of 1.70 (1.56-1.85; p&lt;0.0001), and carriers of the minor allele of NOS3 rs2070744 had a relative risk of elevated mPAP (&gt;30 mm Hg) of 1.58 (1.47-1.69; p&lt;0.0001). The NOS3 and DDAH2 genes were associated with the incidence of acute mountain sickness. Conclusions: We conclude that genetic variability in the L-arginine / ADMA / NO pathway is an important determinant of high altitude pulmonary hypertension and acute mountain sickness. DDAH1 is linked to baseline ADMA, whilst DDAH2 determines the response of ADMA to hypoxia.

Acute Altitude Acclimatization in Young Healthy Volunteers: Nocturnal Oxygenation Increases Over Time, Whereas Periodic Breathing Persists.

Ju, Jia-Der, Cristian Zhang, Francis P. Sgambati, Lidia M. Lopez, Luu V. Pham, Alan R. Schwartz, and Roberto A. Accinelli. Acute altitude acclimatization in young healthy volunteers: nocturnal oxygenation increases over time whereas periodic breathing persists. High Alt Med Biol. 22:14-23, 2021. Study Objectives: This study aimed to examine the acute effects of high altitude (HA) on sleep disordered breathing (sleep apnea and nocturnal hypoxemia) and acute mountain sickness and to characterize acclimatization over time. Methods: Ten native lowlanders residing at sea level (SL) completed the Lake Louise Score (LLS) and underwent nocturnal polygraphy (ApneaLink Plus) for nine consecutive nights (N1-N9) at HA (2,761 m) and two nights before and after HA. Nocturnal oxygen profiles were assessed by measuring the mean nocturnal oxyhemoglobin saturation (SpO2) during sleep, and sleep apnea severity as assessed by measuring the Apnea-Hypopnea Index (AHI). Mixed-effects linear regression was used to model responses in outcomes (mean nocturnal SpO2, logAHI, and LLS) between HA and SL. Changes in SpO2 and AHI were examined in subgroups with mild versus marked nocturnal SpO2 and low versus high AHI during exposure to HA and compared between subgroups. Results: Compared with SL, the mean nocturnal SpO2 was lower (p < 0.0001) and AHI was higher (p < 0.0001) at HA. The mean nocturnal SpO2 increased progressively (p < 0.001), whereas AHI remained high (p < 0.978) and relatively unchanged over nine successive nights at HA. Those with markedly reduced SpO2 upon arrival at HA exhibited progressive increases in the mean nocturnal SpO2 over time at HA compared with those with mild nocturnal desaturation. LLS rose at HA, but no differences were observed between subgroups. Conclusions: In healthy HA sojourners, the mean nocturnal SpO2 increased progressively over time, whereas AHI remained elevated, suggesting distinctive phenotypes and acclimatization responses to HA.

Mountain and Alpine Medicine

Mountain and Alpine Medicine

Altitude Variation Aids Rapid Altitude Acclimatization: A Proof-of –Concept from Rats to Humans

Altitude Variation Aids Rapid Altitude Acclimatization: A Proof-of –Concept from Rats to Humans

Global REACH 2018: renal oxygen delivery is maintained during early acclimatization to 4,330 m

Early acclimatization to high altitude is characterized by various respiratory, hematological, and cardiovascular adaptations that serve to restore oxygen delivery to tissue. However, less is understood about renal function and the role of renal oxygen delivery (RDO2) during high altitude acclimatization. We hypothesized that 1) RDO2 would be reduced after 12 h of high altitude exposure (high altitude day 1) but restored to sea level values after 1 wk (high altitude day 7) and 2) RDO2 would be associated with renal reactivity, an index of acid-base compensation at high altitude. Twenty-four healthy lowlander participants were tested at sea level (344 m, Kelowna, BC, Canada) and on day 1 and day 7 at high altitude (4,330 m, Cerro de Pasco, Peru). Cardiac output, renal blood flow, and arterial and venous blood sampling for renin-angiotensin-aldosterone system hormones and NH2-terminal pro-B-type natriuretic peptides were collected at each time point. Renal reactivity was calculated as follows: (Δarterial bicarbonate)/(Δarterial Pco2) between sea level and high altitude day 1 and sea level and high altitude day 7. The main findings were that 1) RDO2 was initially decreased at high altitude compared with sea level (ΔRDO2: -22 ± 17%, P < 0.001) but was restored to sea level values on high altitude day 7 (ΔRDO2: -6 ± 14%, P = 0.36). The observed improvements in RDO2 resulted from both changes in renal blood flow (Δ from high altitude day 1: +12 ± 11%, P = 0.008) and arterial oxygen content (Δ from high altitude day 1: +44.8 ± 17.7%, P = 0.006) and 2) renal reactivity was positively correlated with RDO2 on high altitude day 7 (r = 0.70, P < 0.001) but not high altitude day 1 (r = 0.26, P = 0.29). These findings characterize the temporal responses of renal function during early high altitude acclimatization and the influence of RDO2 in the regulation of acid-base balance.

Physiological and oxidative stress responses to intermittent hypoxia training in Sprague Dawley rats

Aim Rapid ascent to high altitude and inability to acclimatize lead to high-altitude illnesses. Intermittent hypoxia (IH) conditioning has been hypothesized as a non-pharmacological strategy aiming to improve adaptive responses during high altitude ascent. In the recent years, IH training (IHT) has become increasingly popular among recreational and professional athletes owing to its ability to mitigate high altitude related problems. This study aimed at exploring the role of IHT in altitude acclimatization. Methods Male Sprague Dawley rats were subjected to IHT for 4 h consecutively for 5 days at 12% FiO2 under normobaric conditions. To assess the effect of IHT in hypoxic acclimatization, animals were further exposed to extreme hypoxia (EH) at 8% FiO2. Oxygen saturation (SpO2), respiratory rate and heart rate were recorded during the exposure. Oxidative stress (ROS, MDA, and 4-HNE) and histopathological examinations were studied in the lung tissue sections. Hypoxia biomarkers, HIF-1α, EPO, VEGF, and BPGM were evaluated through western blotting in the lung tissue. Results Assessment of the IHT showed that SpO2 levels were found to be higher in the IH trained rats with a statistical difference of p < 0.01 in the first hour of hypoxia exposure as compared to the untrained rats. There was a significantly higher (p < 0.001) generation of ROS and MDA in the untrained rats as compared to the trained rats. Lipid peroxidation markers and systemic inflammatory marker were found to be expressed at much higher level in the untrained rats. There was a higher expression of HIF-1α (1.24-fold ↑), VEGF (1.14-fold ↑) and decrease in EPO (1.43-fold ↓) in the untrained rats as compared to trained rats. Conclusions Preconditioning with IHT resulted in the reduction in hypoxia induced oxidative stress during extreme hypoxia exposure and thus, maintaining redox balance as well as adjustment in the physiological changes in rats.

Transcriptomic Changes in Young Japanese Males After Exposure to Acute Hypobaric Hypoxia.

After the genomic era, the development of high-throughput sequencing technologies has allowed us to advance our understanding of genetic variants responsible for adaptation to high altitude in humans. However, transcriptomic characteristics associated with phenotypic plasticity conferring tolerance to acute hypobaric hypoxic stress remain unclear. To elucidate the effects of hypobaric hypoxic stress on transcriptional variability, we aimed to describe transcriptomic profiles in response to acute hypobaric hypoxia in humans. In a hypobaric hypoxic chamber, young Japanese males were exposed to a barometric pressure of 493 mmHg (hypobaric hypoxia) for 75 min after resting for 30 min at the pressure of 760 mmHg (normobaric normoxia) at 28°C. Saliva samples of the subjects were collected before and after hypobaric hypoxia exposure, to be used for RNA sequencing. Differential gene expression analysis identified 30 significantly upregulated genes and some of these genes may be involved in biological processes influencing hematological or immunological responses to hypobaric hypoxic stress. We also confirmed the absence of any significant transcriptional fluctuations in the analysis of basal transcriptomic profiles under no-stimulus conditions, suggesting that the 30 genes were actually upregulated by hypobaric hypoxia exposure. In conclusion, our findings showed that the transcriptional profiles of Japanese individuals can be rapidly changed as a result of acute hypobaric hypoxia, and this change may influence the phenotypic plasticity of lowland individuals for acclimatization to a hypobaric hypoxic environment. Therefore, the results obtained in this study shed light on the transcriptional mechanisms underlying high-altitude acclimatization in humans.