Simulated Altitude Research Articles

Exposure to 16\u2009h of normobaric hypoxia induces ionic edema in the healthy brain

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI. This dual approach allowed us to directly measure key factors in the development of hypoxia-induced brain edema: (1) Sodium signals as a surrogate of the distribution of electrolytes within the cerebral tissue and (2) Ktrans as a marker of blood–brain–barrier integrity. The measurements point toward an accumulation of sodium ions in extra- but not in intracellular space in combination with an intact endothelium. Both findings in combination are indicative of ionic extracellular edema, a subtype of cerebral edema that was only recently specified as an intermittent, yet distinct stage between cytotoxic and vasogenic edemas. In sum, here a combination of imaging techniques demonstrates the development of ionic edemas following prolonged normobaric hypoxia in agreement with cascadic models of edema formation.

Protective effects of active compounds from on heart and brain of mice at simulated high altitude.

To investigate the active compounds from on the heart and brain of mice at simulated high altitude.Fifty healthy male adult BALB/c mice were randomly divided into normal control group, hypoxic model group, acetazolamide group, petroleum ether extract of (PESI) group and octacosan group with 10 mice in each group. Acetazolamide group, PESI group and octacosan group were treated with acetazolamide PESI (200 mg/kg) or octacosan by single tail vein injection, respectively. Except normal control group, the mice were exposed to a simulated high altitude of for in an animal decompression chamber. After the mice were sacrificed by cervical dislocation, the heart and brain were histologically observed by HE staining; superoxide dismutase (SOD) activity, total anti-oxidant capacity (T-AOC) and the content of malondialdehyde (MDA) in plasma, heart and brain tissues were detected by WST-1 method, ABTS method and TBA method, respectively; lactic acid and lactate dehydrogenase (LDH) activity in plasma, heart and brain tissues were detected by colorimetric method and microwell plate method, respectively; ATP content and ATPase activity in heart and brain tissues were detected by colorimetric method. PESI and octacosane significantly attenuated the pathological damages of heart and brain tissue at simulated high altitude; increased SOD activity, T-AOC and LDH activity, and decreased the contents of MDA and lactic acid in plasma, heart and brain tissues; increased the content of ATP in heart and brain tissues; increased the activities of Na-K ATPase, Mg ATPase, Ca ATPase and Ca-Mg ATPase in myocardial tissue; and increased the activities of Mg ATPase, Ca-Mg ATPase in brain tissue. PESI and octacosan exert anti-hypoxic activity by improving the antioxidant capacity, reducing the free radical levels, promoting the anaerobic fermentation, and alleviating the energy deficiency and metabolic disorders caused by hypoxia in mice.

ITRAQ-based quantitative proteomic analysis of the improved effects of total flavones of Dracocephalum Moldavica L. in chronic mountain sickness

To use isobaric tags for relative and absolute quantification (iTRAQ) technology to study the pathogenesis of chronic mountain sickness (CMS), identify biomarkers for CMS, and investigate the effect of total flavones of Dracocephalum moldavica L. (TFDM) on a rat model of CMS. We simulated high altitude hypobaric hypoxia conditions and generated a rat model of CMS. Following the administration of TFDM, we measured the pulmonary artery pressure and serum levels of hemoglobin (Hb), the hematocrit (Hct), and observed the structure of the pulmonary artery in experimental rats. Furthermore, we applied iTRAQ-labeled quantitative proteomics technology to identify differentially expressed proteins (DEPs) in the serum, performed bioinformatics analysis, and verified the DEPs by immunohistochemistry. Analysis showed that the pulmonary artery pressure, serum levels of Hb, and the Hct, were significantly increased in a rat model of CMS (P < 0.05). Pathological analysis of lung tissue and pulmonary artery tissue showed that the alveolar compartment had obvious hyperplasia and the pulmonary artery degree of muscularization was enhanced. Both pulmonary artery pressure and tissue morphology were improved following the administration of TFDM. We identified 532 DEPs by quantitative proteomics; gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis further revealed that metabolic pathways associated with coagulation and complement play crucial roles in the occurrence of CMS. Immunohistochemistry verified that several DEPs (α-1-acid glycoprotein, collagen, fibulin, haptoglobin, PLTP, and TAGLN2) are important biological markers for CMS. Our analyses demonstrated that TFDM can improve CMS and exert action by influencing the metabolic pathways associated with coagulation and complement. This process relieves pulmonary artery pressure and improves lung function. We also identified that α-1-acid glycoprotein, collagen, fibulin, haptoglobin, PLTP, and TAGLN2 may represent potential biomarkers for CMS.

Effect of intermittent hypoxic conditioning on inflammatory biomarkers in older adults.

Ageing is associated with chronic low-grade inflammation and with a decrease in muscle mass and strength. The aim of the study was to evaluate the effect of a resistance training programme in conditions of intermittent hypoxia on inflammatory biomarkers in older people. A total of 54 older adults (aged 65-75years), who voluntarily participated in the study, were randomly divided into three groups: the control (CON) group, the resistance training normoxia (RTN) group that performed resistance training in normoxia and resistance training hypoxia (RTH) group that trained under hypoxic conditions at a simulated altitude of 2500m above sea level. The training programme that was carried out during 24weeks was similar in both experimental groups and consisted of a full-body workout with elastic bands and kettlebells (three sets x 12-15 reps). Blood inflammatory parameters (CRP, VCAM-1, IL-6, IL-8 and IL-10) were analysed before and after the intervention. After the resistance training programme, a significant decrease in CRP and IL-8 levels was observed, as well as an increase in IL-10 levels, both in normoxia and hypoxia. These results show that resistance training, either in conditions of normoxia or hypoxia, is useful to deal with the chronic inflammation associated with ageing.

Hearing Aids Performance in Hypobaric Environments.

OBJECTIVE: High altitudes imply exposure to a decreased ambient air pressure. Such a situation may also alter the performance of acoustic transducers using vibrating diaphragms due to air rarefaction. This study aimed at analyzing the performance at high altitude of hearing aids (HAs) where mechano-electric and electro-mechanic transducers are used. METHODS: A hypobaric chamber was used to perform two separated experimental sessions. In the first one two commercial models of HAs were exposed to a simulated altitude of 25,000 ft (7620 m) and to a subsequent rapid decompression profile, with a rapid climb (< 3 s) from 8000 (2438 m) to 25,000 ft. The second session separately analyzed the performance of microphone and receiver at an altitude of 9000 and 15,000 ft (2743 and 4572 m). Before and after the first session, the HAs were tested with an electronic ear while a dedicated recording system was used in the second session. RESULTS: No HA damage or dysfunction was detected during the first session. In the second one, the microphone showed a mild decrease of its output, while the receiver exhibited a much higher reduction of its output. CONCLUSION: Our findings highlight the safe use of HAs even under extreme environmental pressure changes. For altitudes exceeding 10,000 ft (3048 m), a recalibration of the HAs output via a dedicated program may be suggested. Lucertini M, Sanjust F, Manca R, Cerini L, Lucertini L, Sisto R. Hearing aids performance in hypobaric environments. Aerosp Med Hum Perform. 2021; 92(9):738743.

English

Introduction: The possibility of performing intense workouts without falling into states of chronic fatigue stimulates the use of devices that improve muscular and hormonal functionality in athletes. The Elevation Training Mask (Training Mask LLC) (ETM) allows the application of hypoxia during exercise. The ETM is integrated into training routines increasing the physical stimulus to improve performance. Objective: We evaluated the impact of ETM on Workouts of the Day (WODs), muscular and hormonal behavior in Crossfit® athletes. Material and method: Prospective cohort study. During 12 weeks 20 Crossfit® athletes trained 60 minutes 3 days a week were randomly divided into 2 groups, control group (CG) (n=10) and ETM group (EG) (n=10) applying an additional progressive simulated altitude between 914 and 2743 meters. WODs (press, squat, deadlift, total CF and grace), macular markers: lactate dehydrogenase (LDH); creatine kinase (CK); myoglobin (Mb) and hormones: testosterone (T); cortisol (C), were evaluated at 2 time points of the study: day 1 (T1) and day 84 (T2). Results: All WODs and parameters LDH, CK, Mb, T and C showed no significant difference (p&gt;0.05) in the time group interaction. In EG, a substantially lower percentage change (Δ) between T1 and T2 was observed in Mb (-16.01±25.82%), CK (6.16±26.05%) and C (-0.18±4.01%) than in CG (Mb: -094±4.39%; CK: 17.98±27.19%; C: 4.56±3.44%). The Δ T1-T2 in the WODs were similar. Conclusion: After 12 weeks of training under simulated hypoxia conditions with ETM there are no improvements in athletic performance assessed by WODs. However, the greater tendency to decrease Mb, CK and C, after using ETM, could stimulate recovery and indicate a lower muscle catabolism of the Crossfit® athlete in the long term.

High-altitude decompression strain can be reduced by an early excursion to moderate altitude while breathing oxygen

Recent observations suggest that development of venous gas emboli (VGE) during high-altitude flying whilst breathing hyperoxic gas will be reduced by intermittent excursions to moderate altitude. The present study aimed to investigate if an early, single excursion from high to moderate altitude can be used as an in-flight means to reduce high-altitude decompression strain. Ten healthy men were investigated whilst breathing oxygen in a hypobaric chamber under two conditions, once during a 90-min continuous exposure to a simulated cabin altitude of 24,000 ft (High; H) and once during 10 min at 24,000 ft, followed by 30 min at 15,000 ft and by 80 min at 24,000 ft (high–low–high; H–L–H). VGE scores were assessed by cardiac ultrasound, using a 6-graded scale. In H, VGE increased throughout the course of the sojourn at 24,000 ft to attain peak value [median (range)] of 3 (2–4) at min 90, just prior to descent. In H–L–H, median VGE scores were 0 throughout the trial, except for at min 10, just prior to the excursion to 15,000 ft, whence the VGE score was 1.5 (0–3). Thus, an early, single excursion from high to moderate cabin altitude holds promise as an in-flight means to reduce the risk of altitude decompression sickness during long-duration high-altitude flying in aircraft with limited cabin pressurization. Presumably, such excursion acts by facilitating the gas exchange in decompression bubbles from a predomination of nitrogen to that of oxygen.

Oxygen Enrichment Mitigates High-Altitude Hypoxia-Induced Hippocampal Neurodegeneration and Memory Dysfunction Associated with Attenuated Tau Phosphorylation.

Cai, Jing, Junyong Ruan, Xi Shao, Yuanjun Ding, Kangning Xie, Chi Tang, Zedong Yan, Erping Luo, and Da Jing. Oxygen enrichment mitigates high-altitude hypoxia-induced hippocampal neurodegeneration and memory dysfunction associated with attenuated tau phosphorylation. High Alt Med Biol. 22:274-284, 2021. Background: Brain is predominantly vulnerable to high-altitude hypoxia (HAH), resulting in neurodegeneration and cognitive impairment. The technology of oxygen enrichment has proven effective to decrease the heart rate and improve the arterial oxygen saturation by reducing the equivalent altitude. However, the efficacy of oxygen enrichment on HAH-induced cognitive impairments remains controversial based on the results of neuropsychological tests, and its role in HAH-induced hippocampal morphological and molecular changes remains unknown. Therefore, this study aims to systematically investigate the effects of oxygen enrichment on the memory dysfunction and hippocampal neurodegeneration caused by HAH. Materials and Methods: Fifty-one male Sprague-Dawley rats were equally assigned to three groups: normal control, HAH, and HAH with oxygen enrichment (HAHO). Rats in the HAH and HAHO groups were exposed to hypoxia for 3 days in a hypobaric hypoxia chamber at a simulated altitude of 6,000 m. Rats in the HAHO group were supplemented with oxygen-enriched air, with 12 hours/day in the hypobaric hypoxia chamber. Results: Our results showed that oxygen enrichment improved the locomotor activity of HAH-exposed rats. The Morris water maze test revealed that oxygen enrichment significantly ameliorated HAH-induced spatial memory deficits. Oxygen enrichment also improved morphological alterations of pyramidal cells and the ultrastructure of neurons in the hippocampal CA1 region in rats exposed to acute HAH. Tau hyperphosphorylation at Ser396, Ser262, Thr231, and Thr181 was also significantly attenuated by oxygen enrichment in HAH-exposed rats. Conclusions: Together, our study reveals that oxygen enrichment can ameliorate HAH-induced cognitive impairments associated with improved hippocampal morphology and molecular expression, and highlights that oxygen enrichment may become a promising alternative treatment against neurodegeneration for humans ascending to the plateau.

Aeroengine High-Attitude/Low Mach Number Oscillations: Mechanism and Prevention Design

The issue of aeroengine oscillations over high-attitude and low-speed flight envelope has been an unsolved problem due to their classified nature and hard reproduction in simulated altitude test stand. Efforts have been sought for either structural integrity or component damage. However, it is rarely realized that the oscillations can be an inherent property of the engine itself. Consequently, a dynamical system approach is proposed in this paper to demonstrate that engine oscillations are recurring over high-attitude and low-speed flight envelope, yet they can be suppressed through appropriate control designs. However, the resulting design can be compromised with the conventional high-gain control where the transient and steady-state performance must be balanced with disturbance attenuation performance. Examples are given to illustrate and validate the claims made through the en route analysis.

Effects of Acute Hypoxia on Lactate Thresholds and High-Intensity Endurance Performance-A Pilot Study.

The present project compared acute hypoxia-induced changes in lactate thresholds (methods according to Mader, Dickhuth and Cheng) with changes in high-intensity endurance performance. Six healthy and well-trained volunteers conducted graded cycle ergometer tests in normoxia and in acute normobaric hypoxia (simulated altitude 3000 m) to determine power output at three lactate thresholds (PMader, PDickhuth, PCheng). Subsequently, participants performed two maximal 30-min cycling time trials in normoxia (test 1 for habituation) and one in normobaric hypoxia to determine mean power output (Pmean). PMader, PDickhuth and PCheng decreased significantly from normoxia to hypoxia by 18.9 ± 9.6%, 18.4 ± 7.3%, and 11.5 ± 6.0%, whereas Pmean decreased by only 8.3 ± 1.6%. Correlation analyses revealed strong and significant correlations between Pmean and PMader (r = 0.935), PDickhuth (r = 0.931) and PCheng (r = 0.977) in normoxia and partly weaker significant correlations between Pmean and PMader (r = 0.941), PDickhuth (r = 0.869) and PCheng (r = 0.887) in hypoxia. PMader and PCheng did not significantly differ from Pmean (p = 0.867 and p = 0.784) in normoxia, whereas this was only the case for PCheng (p = 0.284) in hypoxia. Although investigated in a small and select sample, the results suggest a cautious application of lactate thresholds for exercise intensity prescription in hypoxia.

Heat acclimation enhances the cold-induced vasodilation response

PurposeIt has been reported that the cold-induced vasodilation (CIVD) response can be trained using either regular local cold stimulation or exercise training. The present study investigated whether repeated exposure to environmental stressors, known to improve aerobic performance (heat and/or hypoxia), could also provide benefit to the CIVD response.MethodsForty male participants undertook three 10-day acclimation protocols including daily exercise training: heat acclimation (HeA; daily exercise training at an ambient temperature, Ta = 35 °C), combined heat and hypoxic acclimation (HeA/HypA; daily exercise training at Ta = 35 °C, while confined to a simulated altitude of ~ 4000 m) and exercise training in normoxic thermoneutral conditions (NorEx; no environmental stressors). To observe potential effects of the local acclimation on the CIVD response, participants additionally immersed their hand in warm water (35 °C) daily during the HeA/HypA and NorEx. Before and after the acclimation protocols, participants completed hand immersions in cold water (8 °C) for 30 min, followed by 15-min recovery phases. The temperature was measured in each finger.ResultsFollowing the HeA protocol, the average temperature of all five fingers was higher during immersion (from 13.9 ± 2.4 to 15.5 ± 2.5 °C; p = 0.04) and recovery (from 22.2 ± 4.0 to 25.9 ± 4.9 °C; p = 0.02). The HeA/HypA and NorEx protocols did not enhance the CIVD response.ConclusionWhole-body heat acclimation increased the finger vasodilatory response during cold-water immersion, and enhanced the rewarming rate of the hand, thus potentially contributing to improved local cold tolerance. Daily hand immersion in warm water for 10 days during HeA/Hyp and NorEx, did not contribute to any changes in the CIVD response.

Fasting improves tolerance to acute hypoxia in rats

Acute high-altitude illness seriously threatens the health and lives of people who rapidly ascend to high altitudes, but there is currently no particularly effective method for the prevention or treatment of acute high-altitude illness. In the present study, we found that fasting preconditioning effectively improved the survival rate of rats exposed to a simulated altitude of 7620 m for 24 h, and a novel animal model of rapid adaptation to acute hypoxia was established. Compared with control treatment, fasting preconditioning activated AMPK, induced autophagy, decreased ROS levels, and inhibited NF-κB signaling in the cardiac tissues of rats. Our results suggested that fasting effectively improved the acute hypoxia tolerance of rats, which was gradually enhanced with prolongation of fasting. In addition, the acute hypoxia tolerance of young rats was significantly higher than that of adult rats. These experimental results lay the foundation for achieving rapid adaptation to acute hypoxia in humans.

Photoplethysmography behind the Ear Outperforms Electrocardiogram for Cardiovascular Monitoring in Dynamic Environments.

An increasing proportion of occupational mishaps in dynamic, high-risk operational environments have been attributed to human error, yet there are currently no devices to routinely provide accurate physiological data for insights into underlying contributing factors. This is most commonly due to limitations of commercial and clinical devices for collecting physiological data in environments of high motion. Herein, a novel Photoplethysmography (PPG) sensor device was tested, called SPYDR (Standalone Performance Yielding Deliberate Risk), reading from a behind-the-ear location, specifically designed for high-fidelity data collection in highly dynamic high-motion, high-pressure, low-oxygen, and high-G-force environments. For this study, SPYDR was installed as a functional ear-cup replacement in flight helmets worn by rated US Navy aircrew. Subjects were exposed to reduced atmospheric pressure using a hypobaric chamber to simulated altitudes of 25,000 feet and high G-forces in a human-rated centrifuge up to 9 G acceleration. Data were compared to control devices, finger and forehead PPG sensors, and a chest-mounted 12-lead ECG. SPYDR produced high-fidelity data compared to controls with little motion-artifact controls in the no-motion environment of the hypobaric chamber. However, in the high-motion, high-force environment of the centrifuge, SPYDR recorded consistent, accurate data, whereas PPG controls and ECG data were unusable due to a high-degree-motion artifacts. The data demonstrate that SPYDR provides an accurate and reliable system for continuous physiological monitoring in high-motion, high-risk environments, yielding a novel method for collecting low-artifact cardiovascular assessment data important for investigating currently inaccessible parameters of human physiology.

Variability in venous gas emboli following the same dive at 3,658 meters

Update: originally posted in Vol 48 #2 Exposure to a reduction in ambient pressure such as in high-altitude climbing, flying in aircrafts, and decompression from underwater diving results in circulating vascular gas bubbles (i.e., venous gas emboli [VGE]). Incidence and severity of VGE, in part, can objectively quantify decompression stress and risk of decompression sickness (DCS) which is typically mitigated by adherence to decompression schedules. However, dives conducted at altitude challenge recommendations for decompression schedules which are limited to exposures of 10,000 feet in the U.S. Navy Diving Manual (Rev. 7). Therefore, in an ancillary analysis within a larger study, we assessed the evolution of VGE for two hours post-dive using echocardiography following simulated altitude dives at 12,000 feet. Ten divers completed two dives to 66 fsw (equivalent to 110 fsw at sea level by the cross correction method) for 30 minutes in a hyperbaric chamber. All dives were completed following a 60-minute exposure at 12,000 feet. Following the dive, the chamber was decompressed back to altitude for two hours. Echocardiograph measurements were performed every 20 minutes post-dive. Bubbles were counted and graded using the Germonpré and Eftedal and Brubakk method, respectively. No diver presented with symptoms of DCS following the dive or two hours post-dive at altitude. Despite inter- and intra-diver variability of VGE grade following the dives, the majority (11/20 dives) presented a peak VGE Grade 0, three VGE Grade 1, one VGE Grade 2, four VGE Grade 3, and one VGE Grade 4. Using the cross correction method for a 66-fsw dive at 12,000 feet of altitude resulted in a relatively low decompression stress and no cases of DCS.

Pharmacokinetics of Acetaminophen and Metformin Hydrochloride in Rats After Exposure to Simulated High Altitude Hypoxia.

The pharmacokinetic characteristics of drugs were altered under high altitude hypoxia, thereby affecting the absorption, distribution, metabolism, and excretion of drug. However, there are few literatures on the pharmacokinetic changes of antipyretic and pain-relieving drugs and cardiovascular system drugs at high altitude. This study aimed to evaluate the pharmacokinetics of acetaminophen and metformin hydrochloride in rats under simulated high altitude hypoxia condition. Mechanically, the protein and mRNA expression of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) and organic cation transporter 2 (OCT2) were investigated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Compared with the normoxia group, the t1/2 and AUC of acetaminophen were significantly increased, and the CL/F was significantly decreased in rats after exposure to simulated high altitude hypoxia. The t1/2 of metformin hydrochloride was significantly increased by simulated high altitude hypoxia. No significant differences in AUC and CL/F of metformin hydrochloride were observed when comparing the hypoxia group with the normoxia group. The protein and mRNA expression of UGT1A1 and OCT2 were decreased significantly under hypoxia in rats. This study found obvious changes in the pharmacokinetics of acetaminophen and metformin hydrochloride in rats after exposure to simulated high altitude hypoxia, and they might be due to significant decreases in the expressions of UGT1A1 and OCT2. To sum up, our data suggested that the pharmacokinetics of acetaminophen and metformin hydrochloride should be reexamined, and the optimal dose should be reassessed under hypoxia exposure.

Ganoderma lucidum Induces Myogenesis Markers to Avert Damage to Skeletal Muscles in Rats Exposed to Hypobaric Hypoxia.

Jatwani, Arti, and Rajkumar Tulsawani. Ganoderma lucidum induces myogenesis markers to avert damage to skeletal muscles in rats exposed to hypobaric hypoxia. High Alt Med Biol. 24:287-295, 2023. Background: Hypobaric hypoxia (HH) has been reported to induce skeletal muscle loss and impair myogenesis. Aqueous extract of G. lucidum (AqGL) contains bioactive metabolites attributed to various pharmacological effects. In this study, protective effect of AqGL in ameliorating muscle mass loss following acute HH has been reported. Materials and Methods: Male Sprague-Dawley rats were divided into following five groups of six rats in each group: unexposed control (Group 1), 6 hours of HH exposure (Group 2), 6 hours of HH exposure+AqGL extract 50 mg/kg body weight (BW) (Group 3), 6 hours of HH exposure+AqGL extract 100 mg/kg BW (Group 4), and 6 hours of HH exposure+AqGL extract 200 mg/kg BW (Group 5). Experimental animals from all groups, except Group, 1 were exposed to HH, simulated altitude of 25,000 ft for 6 hours. After exposure period, gastrocnemius muscle was collected, weighed, and morphological, biochemical, and molecular markers were analyzed. Results: HH-exposed rat muscle showed significant (p < 0.05) increase in oxidative stress markers (reactive oxygen species & malondialdehyde), which was concomitant with decrease in its mass compared to controls. AqGL treatment significantly (p < 0.05) prevented muscle oxidative stress, restored reduced glutathione content, reduced protein carbonyl content and advanced oxidation protein product, and restored muscle mass loss at effective dose of 100 mg/kg BW. Furthermore, AqGL supplementation enhanced Myf5 (p < 0.01), MyoD (p < 0.01), MyoG (p < 0.05), and Mrf4 (nonsignificantly), brain-derived neurotrophic factor (p < 0.01), and interleukin 6 (p < 0.01) expression along with restoration of tumor necrosis factor alpha (p < 0.001) and myostatin (p < 0.05) in hypoxia-exposed muscle, evidencing induction of myogenesis markers. Moreover, histological analysis showed increased myocyte number; nuclei shifted toward the periphery in the treatment group supporting muscle regeneration. Conclusion: AqGL supplementation attenuates muscle mass loss by preventing oxidative stress and inducing modulation in myogenesis markers under HH environment.

Identification of VEGFA-centric temporal hypoxia-responsive dynamic cardiopulmonary network biomarkers

AimsHypoxia, a pathophysiological condition, is profound in several cardiopulmonary diseases (CPD). Every individual's lethality to a hypoxia state differs in terms of hypoxia exposure time, dosage units and dependent on the individual's genetic makeup. Most of the proposed markers for CPD were generally aim to distinguish disease samples from normal samples. Although, as per the 2018 GOLD guidelines, clinically useful biomarkers for several cardio pulmonary disease patients in stable condition have yet to be identified. We attempt to address these key issues through the identification of Dynamic Network Biomarkers (DNB) to detect hypoxia induced early warning signals of CPD before the catastrophic deterioration. Materials and methodsThe human microvascular endothelial tissues microarray datasets (GSE11341) of lung and cardiac expose to hypoxia (1% O2) for 3, 24 and 48 h were retrieved from the public repository. The time dependent differentially expressed genes were subjected to tissue specificity and promoter analysis to filtrate the noise levels in the networks and to dissect the tissue specific hypoxia induced genes. These filtered out genes were used to construct the dynamic segmentation networks. The hypoxia induced dynamic differentially expressed genes were validated in the lung and heart tissues of male rats. These rats were exposed to hypobaric hypoxia (simulated altitude of 25,000 or PO2 - 282 mm of Hg) progressively for 3, 24 and 48 h. Key findingsTo identify the temporal key genes regulated in hypoxia, we ranked the dominant genes based on their consolidated topological features from tissue specific networks, time dependent networks and dynamic networks. Overall topological ranking described VEGFA as a single node dynamic hub and strongly communicated with tissue specific genes to carry forward their tissue specific information. We named this type of VEGFAcentric dynamic networks as “V-DNBs”. As a proof of principle, our methodology helped us to identify the V-DNBs specific for lung and cardiac tissues namely V-DNBL and V-DNBC respectively. SignificanceOur experimental studies identified VEGFA, SLC2A3, ADM and ENO2 as the minimum and sufficient candidates of V-DNBL. The dynamic expression patterns could be readily exploited to capture the pre disease state of hypoxia induced pulmonary vascular remodelling. Whereas in V-DNBC the minimum and sufficient candidates are VEGFA, SCL2A3, ADM, NDRG1, ENO2 and BHLHE40. The time dependent single node expansion indicates V-DNBC could also be the pre disease state pathological hallmark for hypoxia-associated cardiovascular remodelling. The network cross-talk and expression pattern between V-DNBL and V-DNBC are completely distinct. On the other hand, the great clinical advantage of V-DNBs for pre disease predictions, a set of samples during the healthy condition should suffice. Future clinical studies might further shed light on the predictive power of V-DNBs as prognostic and diagnostic biomarkers for CPD.

Accuracy and Reliability of Pulse O2 Saturation Measured by a Wrist-worn Oximeter.

This study aims to evaluate the accuracy of the Garmin Forerunner 245 heart rate (HR) and pulse O2 saturation (SpO2) sensors compared with electrocardiogram and medical oximeter, from sea level to high altitude. Ten healthy subjects underwent five tests in normoxia and hypoxia (simulated altitudes from 3000 to 5500 m), consisting in a 5-min rest phase, followed by 5-min of mild exercise. Absolute error (±10 bpm for HR and ±3% for SpO2, around criterion) and intraclass correlations (ICC) were calculated. Error rates for HR remained under 10%, except at 3000 m, and ICCs evidenced a good reliability between Garmin and criterion. Overall SpO2 was higher than criterion (P<0.001) with a >50% error rate (>80% above 4800 m), and a poor reliability with criterion. The Garmin device displayed acceptable HR data at rest and exercise for all altitudes, but failed to provide trustworthy SpO2 values, especially at high altitude, where a pronounced arterial O2 desaturation could lead to acute mountain sickness in hypoxia-sensitive subjects, and its life-threatening complications; moreover, readings of overestimated SpO2 values might induce trekkers into further hazardous behavior by pursuing an ascent while being already at risk. Therefore, its use to assess SpO2 should be proscribed in altitude for acclimatization evaluation.

Heat Added to Repeated-Sprint Training in Hypoxia Does Not Affect Cycling Performance.

This study aimed to assess the influence of graded air temperatures during repeated-sprint training in hypoxia (RSH) on performance and physiological responses. Ten well-trained athletes completed one familiarization and 4 experimental sessions at a simulated altitude of 3000m (0.144FIO2) above sea level. Air temperatures utilized across the 4 experimental sessions were 20°C, 25°C, 30°C, and 35°C (all 50% relative humidity). The participants performed 3 sets of 5 × 10 seconds "all-out" cycle sprints, with 20 seconds of active recovery between sprints and 5 minutes of active recovery between sets (recovery intensity = 120W). Core temperature, skin temperature, pulse oxygen saturation, heart rate, rating of perceived exertion, and thermal sensation were collected. There were no differences between conditions for peak power, mean power, and total work in each set (P > .05). There were no condition × time interaction effects for any variables tested. The peak core temperature was highest at 30°C (38.06°C [0.31°C]). Overall, the pulse oxygen saturation was higher at 35°C than at 20°C (P < .001; d < 0.8), 25°C (P < .001; d = 1.12 ± 0.54, large), and 30°C (P < .001; d = 0.84 ± 0.53, large). Manipulating air temperature between 20°C and 35°C had no effect on performance or core temperature during a typical RSH session. However, the pulse oxygen saturation was preserved at 35°C, which may not be a desirable outcome for RSH interventions. The application of increased levels of ambient heat may require a different approach if augmenting the RSH stimulus is the desired outcome.

Acute hypobaric hypoxia and cardiac energetic response in prepubertal rats: Role of nitric oxide.

What is the central question of this study? In adult rat hearts, exposure to hypobaric hypoxia increases tolerance to hypoxia-reoxygenation, termed endogenous cardioprotection. The mechanism involves the nitric oxide system and modulation of mitochondrial oxygen consumption. What is the cardiac energetic response in prepubertal rats exposed to hypobaric hypoxia? What is the main finding and its importance? Prepubertal rats, unlike adult rats, did not increase tolerance to hypoxia-reoxygenation in response acute exposure to hypobaric hypoxia, which impaired cardiac contractile economy. This finding could be related to a failure to increase nitric oxide synthase expression, hence modulation of mitochondrial oxygen consumption and ATP production. Studies in our laboratory showed that exposure of rats to hypobaric hypoxia (HH) increased the tolerance of the heart to hypoxia-reoxygenation (H/R), involving mitochondrial and cytosolic nitric oxide synthase (NOS) systems. The objective of the present study was to evaluate how the degree of somatic maturation could alter this healthy response. Prepubertal male rats were exposed for 48h to a simulated altitude of 4400m in a hypobaric chamber. The mechanical energetic activity in perfused hearts and the contractile functional capacity of NOS in isolated left ventricular papillary muscles were evaluated during H/R. Cytosolic nitric oxide (NO), production of nitrites/nitrates (Nx), expression of NOS isoforms, mitochondrial O2 consumption and ATP production were also evaluated. The left ventricular pressure during H/R was not improved by HH. However, the energetic activity was increased. Thus, the contractile economy (left ventricular pressure/energetic activity) decreased in HH. Nitric oxide did not modify papillary muscle contractility after H/R. Cytosolic p-eNOS-Ser1177 and inducible NOS expression were decreased by HH, but no changes were observed in NO production. Interestingly, HH increased Nx levels, but O2 consumption and ATP production in mitochondria were not affectedby HH. Prepubertal rats exposed to HH preserved cardiac contractile function, but with a high energetic cost, modifying contractile economy. Although thiscould be related to the decreased NOS expression detected, cytosolic NO production was preserved, maybe through the Nx metabolic pathway, without modification of mitochondrial ATP production and O2 consumption. In this scenario, the treatment was unable to increase tolerance to H/R as observed in adult animals.