Acute Mountain Sickness Research Articles

The application of supine bicycle exercise stress echocardiograph for identification of susceptibility to acute mountain sickness

Abstract Background Exposure to high altitude is likely to lead to acute mountain sickness (AMS). At present, there are no definite parameters that can accurately predict the occurrence of AMS. Objectives The purposes of this study are (1) to assess the relationship between stress echocardiographic parameters and AMS, (2) to identify the predictors of AMS at sea level by exercise stress echocardiography. Methods A total of 36 healthy adults were enrolled and underwent resting and exercise stress echocardiography on a supine bicycle at sea level. Heart rate (HR) and blood pressure (BP) were monitored during stress echocardiography. Left ventricular (LV) ejection fraction and E/e’ were calculated at rest and peak stage. Other right ventricular systolic function parameters and pulmonary artery pressure (PAP) were calculated at the same time, which included tricuspid regurgitation velocity (TRV), tricuspid annular peak systolic excursion (TAPSE), systolic PAP (sPAP), right ventricular (RV) dimension by 2D, right ventricular area at the end of diastole (RVAD), right ventricular area at the end of systolic (RVAS),RV fraction of area change (FAC), right ventricular outflow tract velocity time integral (RVOT VTI).Pulmonary vascular resistance (PVR) was calculated. All subjects ascended to 3600m within 24 hours by bus. AMS was identified by 2018 Lake Louise Questionnaire Score. Univariable and multivariable logistic regression analysis assessed independent factors associated with AMS. Results At the altitude of 3600m, 13 of 36 subjects had AMS, which defined as AMS (+) group. And the rest was AMS (-) group. There were no significant differences in HR, BP, and LV systolic and diastolic function between the two groups (P > 0.05). TRV, sPAP, and PVR were much higher at peak stage in AMS (+) group (P < 0.05). No significant differences were found in RV systolic function at rest and peak stage between the two groups. By multivariable logistic regression model, PVR and RVAD at peak stage were significantly associated with AMS occurrence (PVR-OR =1.962,95% CI: 0.689-0.973,p =0.002; RVAD-OR =1.962,95% CI: 0.638-0.967,p =0.005;). The cutoff value to predict AMS were 1.55 for PVR (AUC: 0.831) and 11.45 cm2 for RVAD (AUC: 0.802). Conclusions Supine bicycle exercise stress echocardiography is a useful and noninvasive technique to identify subjects susceptible to AMS. Subjects with higher PVR and RVAD at peak stage were associated with susceptibility to AMS.

High altitude exercise stress echocardiograph for identification of susceptibility to acute mountain sickness

Abstract Background Acute high-altitude exposure increases the risk of acute mountain disease (AMS) and high-altitude pulmonary edema. After the initial exposure to high altitude, mountain climbers are worried about whether they will develop AMS. At high altitudes, there are no accurate indicators to predict the near future occurrence of AMS. Objectives To investigate whether treadmill exercise stress echocardiography at high altitude can predict the occurrence of AMS, and to find out some powerful factors associated with the susceptibility to AMS. Methods 36 healthy lowlanders were taken by bus from sea level to an altitude of 3600 m the next morning, during which they rested overnight at an altitude of 2150 m. Treadmill exercise stress echocardiography was performed immediately upon arrival at 2150 m, and the 2018 Lake Louise Questionnaire Score was performed the next day when arrived at the altitude of 3600 m. Heart rate (HR) and blood pressure (BP) were monitored during stress echocardiography. Left ventricular (LV) ejection fraction and E/e’ were calculated at rest and immediately after exercise. Other right ventricular systolic function parameters and pulmonary artery pressure (PAP) were calculated at the same time, which included tricuspid regurgitation velocity (TRV), tricuspid annular peak systolic excursion (TAPSE), systolic PAP (SPAP), right ventricular (RV) dimension by 2D, RV fraction of area change (FAC), right ventricular outflow tract velocity time integral (RVOT VTI). Pulmonary vascular resistance (PVR) was calculated according to the formula: TRV/RVOT VTI*10+0.16. Mean PAP (mPAP) was calculated as the formula: sPAP*0.61+2. All subjects ascended to 3600m within 24 hours by bus. AMS was identified by 2018 Lake Louise Questionnaire Score. Univariable and multivariable logistic regression analysis assessed independent factors associated with AMS. Results At the altitude of 3600m, 13 of 36 subjects had AMS, which defined as AMS (+) group. And the rest was AMS (-) group. There were no significant differences in HR, BP, SO2 and LV systolic and diastolic function between the two groups (P > 0.05). No significant differences were noted at rest except for TV s' (P < 0.05). Immediately after exercise, TRV, TAPSE, SPAP, mPAP, PVR, and RV area at the end of systole were much higher in AMS (+) group (all P < 0.05). While FAC and TVs’/SPAP were much lower in AMS (+) group (P < 0.05). By multivariable logistic regression model, mPAP immediately after exercise was significantly correlated with AMS occurrence (OR =1.332, 95% CI: 0.669-0.993, P= 003). The cutoff value of mPAP to predict AMS was 32 mmHg (AUC: 0.831, specificity: 86.7%, sensitivity: 76.9%). Conclusions The mPAP immediately after exercise upon arrival at an altitude of 2150 m is a strong predictor of near future AMS, and treadmill exercise stress echocardiography is a simple and non-invasive tool to help mountain climbers avoid more severe mountain sickness.

Hypoxia reduces mouse urine output via HIF1α–mediated up–regulation of renal AQP1

Introduction: Patients with acute mountain sickness (AMS) due to hypoxia at high altitudes often exhibit abnormal water metabolism. Hypoxia-inducible factors (HIFs) are major regulators of adaptive responses to hypoxia. As transcription factors, HIFs are involved in the regulation of erythropoiesis, iron metabolism, angiogenesis, energy metabolism, and cell survival by promoting the transcriptional expression of hundreds of target genes. Roxadustat, a novel drug for the treatment of anemia associated with chronic kidney disease, acts by inhibiting the degradation of HIFs to increase their protein levels. However, the clinical use of roxadustat is frequently associated with peripheral edema, suggesting the involvement of HIFs in regulating the body's water balance possibly by modulating water reabsorption in the kidney. Methods: we first evaluated the effect of hypoxia (8% O2) on mouse urine output. We then performed in vitro experiments using hypoxia (1% O2) and roxadustat on mouse primary proximal tubular cells (mPTCs). The qPCR, western blot, and immunofluorescence were used to assess AQP1 mRNA and protein expression levels. Luciferase, CHIP, and EMSA were used to investigate the transcriptional regulation of AQP1 by HIF1α. Results: We found that mice exposed to hypoxia (8% O2) had significantly reduced urine volume compared to mice exposed to normoxia (21% O2). Hypoxia significantly elevated AQP1 expression at both mRNA and protein levels. In vitro experiments using mouse primary cultured proximal tubular cells (mPTCs) revealed that both hypoxia and roxadustat increased AQP1 expression. Mechanistically, overexpression of HIF1α, but not HIF2α, markedly increased AQP1 protein expression. Furthermore, the up-regulation of AQP1 by hypoxia and roxadustat can be blocked by the HIF1α inhibitor PX-478 in mPTCs. Finally, we found that the AQP1 gene promoter contains a putative hypoxia response element (HRE) and confirmed that AQP1 is a target gene of HIF1α using Luciferase reporter, CHIP, and EMSA assays. Conclusion: This study demonstrates that hypoxia can reduce the urine volume of mice via upregulating AQP1 expression by HIF1α in the proximal tubular epithelial cells. Our findings also suggest a potential mechanism involved in water metabolism disorders in patients with AMS and in patients with chronic kidney disease (CKD) receiving roxadustat treatment.

Exploring the Blood Biomarkers and Potential Therapeutic Agents for Human Acute Mountain Sickness Based on Transcriptomic Analysis, Inflammatory Infiltrates and Molecular Docking.

A high-altitude, low-pressure hypoxic environment has severe effects on the health and work efficiency of its residents, and inadequate preventive measures and adaptive training may lead to the occurrence of AMS. Acute exposure to hypoxia conditions can have a less-favorable physiological effect on the human immune system. However, the regulation of the immune system in high-altitude environments is extremely complex and remains elusive. This study integrated system bioinformatics methods to screen for changes in immune cell subtypes and their associated targets. It also sought potential therapeutically effective natural compound candidates. The present study observed that monocytes, M1 macrophages and NK cells play a crucial role in the inflammatory response in AMS. IL15RA, CD5, TNFSF13B, IL21R, JAK2 and CXCR3 were identified as hub genes, and JAK2 was positively correlated with monocytes; TNFSF13B was positively correlated with NK cells. The natural compound monomers of jasminoidin and isoliquiritigenin exhibited good binding affinity with JAK2, while dicumarol and artemotil exhibited good binding affinity with TNFSF13B, and all are expected to become a potential therapeutic agents.

Genetic Adaptations of the Tibetan Pig to High-Altitude Hypoxia on the Qinghai-Tibet Plateau.

The Tibetan Plateau's distinctive high-altitude environment, marked by extreme cold and reduced oxygen levels, presents considerable survival challenges for both humans and mammals. Natural selection has led to the accumulation of adaptive mutations in Tibetan pigs, enabling them to develop distinctive adaptive phenotypes. Here, we aim to uncover the genetic mechanisms underlying the adaptation of Tibetan pigs to high-altitude hypoxia. Therefore, we conducted a systematic analysis of 140 whole-genome sequencing (WGS) data points from different representing pig populations. Our analysis identified a total of 27,614,561 mutations, including 22,386,319 single-nucleotide variants (SNVs) and 5,228,242 insertions/deletions (INDELs, size < 50 bp). A total of 11% (2,678,569) of the SNVs were newly identified in our project, significantly expanding the dataset of genetic variants in Tibetan pigs. Compared to other pig breeds, Tibetan pigs are uniquely adapted to high-altitude environments, exhibiting the highest genetic diversity and the lowest inbreeding coefficient. Employing the composite of multiple signals (CMS) method, we scanned the genome-wide Darwinian positive selection signals and identified 32,499 Tibetan pig positively selected SNVs (TBPSSs) and 129 selected genes (TBPSGs), including 213 newly discovered genes. Notably, we identified eight genes (PHACTR1, SFI1, EPM2A, SLC30A7, NKAIN2, TNNI3K, and PLIN2) with strong nature selection signals. They are likely to improve cardiorespiratory function and fat metabolism to help Tibetan pigs become adapted to the high-altitude environment. These findings provide new insights into the genetic mechanisms of high-altitude adaptation and the adaptive phenotypes of Tibetan pigs.

Physiological and Genetic Basis of High-Altitude Indigenous Animals' Adaptation to Hypoxic Environments.

Adaptation is one of the fundamental characteristics of life activities; humans and animals inhabiting high altitudes are well adapted to hypobaric hypoxic environments, and studies on the mechanisms of this adaptation emerged a hundred years ago. Based on these studies, this paper reviews the adaptive changes in hypoxia-sensitive tissues and organs, as well as at the molecular genetic level, such as pulmonary, cardiovascular, O2-consuming tissues, and the hemoglobin and HIF pathway, that occur in animals in response to the challenge of hypobaric hypoxia. High-altitude hypoxia adaptation may be due to the coordinated action of genetic variants in multiple genes and, as a result, adaptive changes in multiple tissues and organs at the physiological and biochemical levels. Unraveling their mechanisms of action can provide a reference for the prevention and treatment of multiple diseases caused by chronic hypoxia.

Pushing Scuba to New Heights: Approach, Decompression, and Logistical Considerations for High-Altitude Diving.

There is interest among technical, expedition, commercial, and military divers in expanding diving operations to high altitude. However, altitude diving presents unique challenges including acclimatization, increased decompression sickness (DCS) risk, and logistical and equipment considerations. Divers must plan altitude acclimatization strategies conservatively to reduce risk of acute mountain sickness and dehydration before diving. Several methods of augmenting sea level diving tables to be used at altitude have been theorized and tested both in simulated dives and high-altitude expeditions. With proper acclimatization, augmentation of standard diving tables, equipment, and safety planning, diving at high altitude may be performed in many contexts safely while minimizing risk of DCS or injury.

Safety and efficacy of electro-thumbtack needle for acute mountain sickness patients: a protocol of a randomized, single-blinded, and placebo-controlled study

BackgroundAcute mountain sickness (AMS) is considered the most common altitude sickness. It can be detrimental to the health of tourists who rapidly ascend high mountains, and can also impair the performance of individuals who move to the plateau for work or education. Acupuncture has been shown to improve AMS as a simple, safe, and effective nonpharmacological method, in case electro-thumbtack needle (ETN) is a more convenient form of acupuncture for both doctor and patient. There are no studies validating the effectiveness of electro-thumbtack needle in improving symptoms in participants with AMS. In this study, we will conduct a randomized controlled trial to evaluate the clinical efficacy and safety of electro-thumbtack needle in participants with AMS. Our hypothesis is that electro-thumbtack needle is safe and effective in treating participants with AMS.MethodsThis study is a single-center, randomized, single-blinded, and placebo-controlled study involving at least 114 participants who were diagnosed with AMS. The participants randomly assigned in a 1:1 ratio to the electro-thumbtack needle group and the sham acupuncture group. The treatment protocol involved stimulation of seven predefined acupuncture points, including Zhong Wan (RN12), bilateral Nei Guan (PC6), bilateral He Gu (LI4), and bilateral Tai Yang (EX-HN5), for approximately one minute each, with continuous application over 48 h. The primary outcome was improvement in 2018 Lake Louise score (LLS) after 48 h of treatment. Secondary outcome indicators included the incidence of participants with moderate-to-severe AMS (AMS > 5)and AMS, the LLS, visual analogue scale of headache, clinical functioning scores, the Groningen Sleep Quality Survey, the Stanford Somnolence Scale, blood pressure, oxygen saturation, and heart rate, in addition to treatment-related adverse events were also captured.DiscussionThis trial aims to ascertain the therapeutic benefits of ETN in mitigating AMS symptoms, thereby contributing to the evidence base for traditional medical practices, particularly acupuncture, in high-altitude medicine.Trial registrationChinese Clinical Trials Registry: ChiCTR2300073882. Registered on 24 July 2023.

Incidence and risk factors of acute mountain sickness during ascent to Hoh Xil and the physiological responses before and after acclimatization

Abstract OBJECTIVES: Ascending to altitudes &gt;2500 m may lead to acute mountain sickness (AMS). METHODS: The demographics, height, weight, body mass index (BMI), smoking, and alcohol consumption of 104 healthy controls were collected in Chengdu (500 m). Heart rate (HR), saturation of pulse oxygen (SpO2), and AMS-related symptoms were collected in Hoh Xil (4200 m). A headache with Lake Louise score ≥3 was defined as AMS. RESULTS: The incidence of AMS was 60.58%. AMS group had a lower SpO2 and higher HR than non-AMS group. Alcohol consumption seemed a risk factor for AMS. There was no difference in the BMI, age, height, weight, and smoking between AMS and non-AMS groups. The most common AMS symptom was headache, followed by dyspnea, insomnia, dizziness, lassitude, and anorexia. Women were prone to suffer from dizziness. The value of SpO2 and HR was improved both in AMS and non-AMS groups after hypoxia acclimatization, and the value showed greater improvement in AMS group. Oxygen therapy decreased the AMS-induced tachycardia, which had no any effect on SpO2 and symptom alleviating time. CONCLUSION: Lower SpO2 and higher HR following exposure to high altitude were associated with AMS susceptibility. The anthropometric data changes were larger in AMS group than non-AMS group before and after hypoxia acclimatization.

Maternal AMPK pathway activation with uterine artery blood flow and fetal growth maintenance during hypoxia.

High-altitude (HA) hypoxia lowers uterine artery (UtA) blood flow during pregnancy and birth weight. Adenosine monophosphate kinase (AMPK) activation has selective, uteroplacental vasodilator effects that lessen hypoxia-associated birth weight reductions. In this study, we determined the relationship between AMPK-pathway gene expression and metabolites in the maternal circulation during HA pregnancy as well as with the maintenance of UtA blood flow and birth weight at HA. Residents at HA (2,793 m) versus low altitude (LA; 1,640 m) had smaller UtA diameters at weeks 20 and 34, lower UtA blood flow at week 20, and lower birth weight babies. At week 34, women residing at HA versus women residing at LA had decreased expression of upstream and downstream AMPK-pathway genes. Expression of the α1-AMPK catalytic subunit, PRKAA1, correlated positively with UtA diameter and blood flow at weeks 20 (HA) and 34 (LA). Downstream AMPK-pathway gene expression positively correlated with week 20 fetal biometry at both altitudes and with UtA diameter and birth weight at LA. Reduced gene expression of AMPK activators and downstream targets in women residing at HA versus women residing at LA, together with positive correlations between PRKAA1 gene expression, UtA diameter, and blood flow suggest that greater sensitivity to AMPK activation at midgestation at HA may help offset later depressant effects of hypoxia on fetal growth.NEW & NOTEWORTHY Fetal growth restriction (FGR) is increased and uterine artery (UtA) blood flow is lower at high altitudes (HA) but not all HA pregnancies have FGR. Here we show that greater UtA diameter and blood flow at week 20 are positively correlated with higher expression of the gene encoding the α1-catalytic subunit of AMP protein kinase, PRKAA1, suggesting that increased AMPK activation may help to prevent the detrimental effects of chronic hypoxia on fetal growth.

Pre-treatment with notoginsenoside R1 from Panax notoginseng protects against high-altitude-induced pulmonary edema by inhibiting pyroptosis through the NLRP3/caspase-1/GSDMD pathway

High-altitude pulmonary edema (HAPE) is a potentially fatal condition that occurs when exposed to high-altitude hypoxia environments. Currently, there is no effective treatment for HAPE, and available interventions focus on providing relief. Notoginsenoside R1 (NGR1), a major active constituent of Panax notoginseng (Burkill) F.H.Chen (sānqī), has demonstrated heart and lung-protective effects under hypobaric hypoxia. However, there is a lack of clarity regarding the precise mechanisms that underlie the protective effects of NGR1 against inflammation.In this study, a rat model of HAPE was developed to assess the effect of NGR1 on this pathology. High-altitude hypoxia corresponding to 6000m altitude was simulated with a hypobaric chamber. We found that NGR1 dose-dependently alleviated pulmonary oxidative stress damage and inflammatory response, and prevented acid-base balance disruption. In addition, NGR1 restored the expression levels of hypoxia-inducible factor-1 alpha, vascular endothelial growth factor, and aquaporin protein-5, correlated with the development of pulmonary edema induced by hypobaric hypoxia. Furthermore, NGR1 pre-treatment remarkably mitigated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-induced pyroptosis, and this effect was partially counteracted by the use of an NLRP3 agonist. Thus, NGR1 may exert a lung-protective effect against HAPE by ameliorating hypoxia-induced lung edema, oxidative damage, and inflammation through inhibition of the NLRP3/Caspase-1/ GSDMD signaling pathway.

Populations of the Caucasus as an object for studying the process of adaptation to conditions of high-altitude hypoxia

The work examines the main mechanisms responsible for the process of acclimatization of the population of high mountain regions to the conditions of hypobaric hypoxia. The purpose of this review is to describe the pathways of genetic, epigenetic and physiological control in the adaptation of indigenous populations of highlands to reduced barometric pressure and oxygen tension in the environment. It has been shown that populations living in different high-mountain regions demonstrate different ways of adaptation in response to a decrease in the partial pressure of oxygen in the inspired air. The changes that occur in the body in response to stressful conditions are extremely diverse. These include changes in the respiratory, cardiovascular, hematological systems and cellular adaptation. In this review, we examine genomic variations leading to evolutionary adaptation to life at high altitudes, gene expression, pathophysiological and metabolic features, and long-term adaptation in various high-altitude populations. We also consider the peoples of the Caucasus as one of the most promising populations for further study of complex adaptation mechanisms.

Exogenous ketosis attenuates acute mountain sickness and mitigates normobaric high-altitude hypoxemia.

Acute mountain sickness (AMS) represents a considerable issue for individuals sojourning to high altitudes with systemic hypoxemia known to be intimately involved in its development. Based on recent evidence that ketone ester (KE) intake attenuates hypoxemia, we investigated whether exogenous ketosis might mitigate AMS development and to identify underlying physiological mechanisms. Fourteen healthy, male participants were enrolled in two 29h protocols (simulated altitude of 4,000-4,500m) receiving either KE or a placebo (CON) at regular timepoints throughout the protocol in a randomized, crossover manner. Physiological responses were characterized after 15min and 4h in hypoxia, and the protocol was terminated prematurely upon development of severe AMS (Lake Louise Score ≥ 10). KE ingestion induced a consistent diurnal ketosis ([ßHB] of ~3 mM), whereas blood [ßHB] remained low (<0.6 mM) in CON. Each participant tolerated the protocol equally long or longer (n=6 or n=8, resp.) in KE. Protocol duration increased by 32% on average with KE, and doubled upon KE for severe AMS-developing participants (n=9). Relative to CON, KE induced a mild metabolic acidosis, hyperventilation, and relative sympathetic dominance. KE also inhibited the progressive hypoxemia that was observed between 15min and 4h in hypoxia in CON, while concomitantly increasing cerebral oxygenation and capillary pO2 within this timeframe despite a KE-induced reduction in cerebral oxygen supply. These data indicate that exogenous ketosis attenuates AMS development. The key underlying mechanisms include improved arterial and cerebral oxygenation, in combination with lowered cerebral blood flow and oxygen delivery, and increased sympathetic dominance.

Multi- and poly-pharmacology of carbonic anhydrase inhibitors.

Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described in organisms allover the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons, and are involved in pH regulation, chemosensing and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or for Alzheimer's/Parkinson's disease management. CAs from pathogenic bacteria, fungi, protozoans and nematodes started to be considered as drug targets in recent years, with notable advances registered ultimately. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future, due to the emergence of drug design approaches which afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, (iso)coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed since drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide and high-ceiling diuretics) show efective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. Significance Statement Carbonic anhydrase inhibitors have multiple pharmacologic applications as diuretics, antiglaucoma, antiepileptic, antiobesity, anti-acute mountain sickness, anti-idiopathic intracranial hypertension and as antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations started to be investigated recently. Parasite carbonic anhydrases are also drug targets for antiinfectives with novel mechanisms of action which can by pass drug resistance to commonly used such agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.

Pulse oximetry for the prediction of acute mountain sickness: A systematic review.

Acute mountain sickness (AMS) causes serious illness for many individuals ascending to high altitude (HA), although preventable with appropriate acclimatisation. AMS is a clinical diagnosis, with symptom severity evaluated using the Lake Louise Score (LLS). Reliable methods of predicting which individuals will develop AMS have not been developed. This systematic review evaluates whether a predictive relationship exists between oxygen saturation and subsequent development of AMS. PubMed, PubMed Central, MEDLINE, Semantic Scholar, Cochrane Library, University of Birmingham Library and clinicaltrials.gov databases were systematically searched from inception to 15 June 2023. Human studies involving collection of peripheral blood oxygen saturation ( ) from healthy lowlanders during ascent to HA that evaluated any relationship between and AMS severity were considered for eligibility. Risk of bias was assessed using a modified Newcastle-Ottawa Tool for cohort studies (PROPSPERO CRD42023423542). Seven of 980 total identified studies were ultimately included for data extraction. These studies evaluated and AMS (via LLS) in 1406 individuals during ascent to HA (3952-6300m). Risk of bias was 'low' for six and 'moderate' for one of the included studies. Ascent profiles and measurement methodology varied widely, as did the statistical methods for AMS prediction. Decreasing oxygen saturation measured with pulse oximetry during ascent shows a positive predictive relationship for individuals who develop AMS. Studies have high heterogeneity in ascent profile and oximetry measurement protocols. Further studies with homogeneous methodology are required to enable statistical analysis for more definitive evaluation of AMS predictability by pulse oximetry.

Mountain sickness in altitude inhabitants of Latin America: A systematic review and meta-analysis.

Chronic and acute mountain sickness is known worldwide, but most of the available information comes from the eastern continent (Himalayas) without taking into account the west which has the most recent group located at altitude, the Andes. The aim of this study was to synthesize the evidence on the prevalence of acute and chronic mountain sickness in Latin American countries (LATAM). A systematic search of the variables of interest was performed until July 8, 2023 in the Web of Science, Scopus, PubMed and Embase databases. We included studies that assessed the prevalence of mountain sickness in high-altitude inhabitants (>1500 m.a.s.l) who lived in a place more than 12 months. These were analyzed by means of a meta-analysis of proportions. To assess sources of heterogeneity, subgroup analyses and sensitivity analyses were performed by including only studies with low risk of bias and excluding extreme values (0 or 10,000 ratio). PROSPERO (CRD42021286504). Thirty-nine cross-sectional studies (10,549 participants) met the inclusion criteria. We identified 5 334 and 2 945 events out of 10,000 with acute and chronic mountain sickness in LATAM countries. The most common physiological alteration was polycythemia (2,558 events), while cerebral edema was the less common (46 events). Clinical conditions were more prevalent at high altitudes for both types of MS. Acute mountain sickness (AMS) occurs approximately in 5 out of 10 people at high altitude, while chronic mountain sickness (CMS) occurs in 3 out of 10. The most frequent physiological alteration was polycythemia and the least frequent was cerebral edema.

Impact of Acute Short-term Hypobaric Hypoxia on Anterior Chamber Geometry

Précis: Hypobaric hypoxia, the major environmental factor at high altitudes, has been observed to induce pupil miosis and widening of the anterior chamber angle. This environment may be safe for individuals with narrow angle and deserves further study. Purpose: This study aimed to quantify anterior chamber biometric parameters before and after acute short-term, effortless exposure to hypobaric hypoxia (HH) in healthy lowlanders using swept-source anterior segment optical coherence tomography (SS AS-OCT). Methods: This prospective study included 25 healthy young lowlanders (50 eyes) who underwent SS AS-OCT measurements and intraocular pressure (IOP) assessments under baseline sea-level conditions (T1).They were then passively exposed to simulated 4000 m above sea level for 3 hours and underwent Acute mountain sickness (AMS) symptoms evaluation and IOP measurement after 2-hours exposure to HH (T2).Repeat SS AS-OCT measurements and IOP assessments were taken within 15 minutes after leaving the hypobaric chamber (T3). Anterior segment parameters including anterior chamber depth (ACD),lens vault (LV),angle opening distance (AOD500), trabecular-iris space area (TISA500), angle recess area (ARA500) at 500 μm from the scleral spur, iris curvature (IC), iris volume (IV), pupil diameter (PD), and central corneal thickness (CCT) were obtained through SS AS-OCT. These repeated measurements were compared using linear mixed model analysis. Results: In comparison to sea level, both IOP (16.4±3.4 vs. 14.9±2.4 mm Hg, P=0.029) and PD (5.36±0.77 vs. 4.78±0.89 mm, P=0.001) significantly decreased after exposure to HH. Significant post-HH changes (Mean difference (95% CI)) were observed in AOD500 (0.129 (0.006, 0.252), P=0.04), TISA500 (0.059 (0.008, 0.11), P=0.025), ARA500 (0.074 (0.008, 0.141), P=0.029), IV (1.623 (0.092, 3.154), P=0.038), and IC (−0.073 (−0.146, 0.001), P=0.047), while CCT, ACD, and LV remained stable. After adjusting for age, post-HH variations in AOD500 (Beta=0.553, 95% CI: 0.001, 1.105, P=0.048) and TISA500 (Beta=0.256, 95% CI: 0.02, 0.492, P=0.034) were associated with decreased IC but were not related to lowered arterial oxygen pressure or IV increase per millimeter of pupil miosis (IV/PD). These differences in anterior segment parameters were neither correlated with differences in IOP nor AMS. Conclusion: After short-term, effortless exposure to hypobaric hypoxia, pupil miosis occurred with widening of the anterior chamber angle and decreased IC. These changes in anterior chamber angle parameters were associated with decreased IC but did not correlate with the post-hypobaric variations in IV/PD, IOP, or AMS.

Preconditioning with Ginsenoside Rg3 mitigates cardiac injury induced by high-altitude hypobaric hypoxia exposure in mice by suppressing ferroptosis through inhibition of the RhoA/ROCK signaling pathway

Ethnopharmacological relevanceGinseng has historically been utilized as a conventional herbal remedy and dietary supplement to enhance physical stamina and alleviate fatigue. The primary active component of Ginseng, Ginsenoside Rg3 (GS-Rg3), possesses diverse pharmacological properties including immune modulation and anti-inflammatory effects. Furthermore, GS-Rg3 has demonstrated efficacy in mitigating tissue and organ damage associated with metabolic disorders such as hypertension, hyperglycemia, and hyperlipidemia. Nevertheless, its potential impact on high-altitude cardiac injury (HACI) remains insufficiently explored. Aim of the studyThe aim of this study was to examine the potential cardioprotective effects of Ginsenoside Rg3, and to investigate how Ginsenoside Rg3 preconditioning can enhance high-altitude cardiac injury by inhibiting the RhoA/ROCK pathway and ferroptosis in cardiac tissue. The findings of this study may contribute to the development of novel therapeutic strategies using traditional Chinese medicine for high-altitude cardiac injury, based on experimental evidence. Materials and methodsA hypobaric hypoxia chamber was employed to simulate hypobaric hypoxia conditions equivalent to an altitude of 6000 m. Through a randomization process, groups of six male mice were assigned to receive either saline, Ginsenoside Rg3 at doses of 15 mg/kg or 30 mg/kg, or lysophosphatidic acid (LPA) at 1 mg/kg. The impact of Ginsenoside Rg3 on high altitude-induced arrhythmias was evaluated using electrocardiography. Cardiac pathology sections stained with hematoxylin and eosin were evaluated for damage, with the extent of cardiomyocyte damage observed via transmission electron microscopy. The impact of Ginsenoside Rg3 on high-altitude cardiac injury was investigated through analysis of serum biomarkers for cardiac injury (CK-MB, BNP), inflammatory cytokines (TNF, IL-6, IL-1β), reactive oxygen species (ROS) and glutathione (GSH). The expression levels of hypoxia and hypoxia-related proteins in myocardial tissues from each experimental group were assessed using Western blot analysis. Following a review of the existing literature, the traditional regulatory mechanisms of ferroptosis were examined. Immunofluorescence staining of cardiac tissues and Western blotting techniques were utilized to investigate the impact of Ginsenoside Rg3 on cardiomyocyte ferroptosis through the RhoA/ROCK signaling pathway under conditions of hypobaric hypoxia exposure. ResultsPre-treatment with Ginsenoside Rg3 improved high altitude-induced arrhythmias, reduced cardiomyocyte damage, decreased cardiac injury biomarkers and inflammatory cytokines, and lowered the expression of hypoxia-related proteins in myocardial tissues. Both Western blotting and immunofluorescence staining of cardiac tissues demonstrated that exposure to high-altitude hypobaric hypoxia results in elevated expression of ferroptosis and proteins related to the RhoA/ROCK pathway. Experimental validation corroborated that the role of the RhoA/ROCK signaling pathway in mediating ferroptosis. ConclusionsThe findings of our study suggest that preconditioning with Ginsenoside Rg3 may attenuate cardiac injury caused by high-altitude hypobaric hypoxia exposure in mice by inhibiting ferroptosis through the suppression of the RhoA/ROCK signaling pathway. These findings contribute to the current knowledge of Ginsenoside Rg3 and high-altitude cardiac injury, suggesting that Ginsenoside Rg3 shows potential as a therapeutic agent for high-altitude cardiac injury.

Do acute mountain sickness and psychiatric disorders show overlapping symptoms?

The Lake Louise Score (LLS) is a common tool for diagnosing acute mountain sickness (AMS) after a recent gain in altitude. Required symptoms (headache, dizziness, fatigue or gastrointestinal symptoms) are unspecific, subjective and not detectable by physiological parameters. (Talks et al., 2022; Boos et al., 2018) This study aimed to enhance present knowledge concerning the impact of mental health on LLS. In a cross-sectional questionnaire study, we assessed 3 groups: 100 inpatients (Ward for psychosomatic medicine – Innsbruck, PSY), 73 mentally healthy individuals (Innsbruck, Austria at an altitude of 570 m, CO) and 223 mountaineers in Nepal (Pheriche 4,371 m and Dingboche 4,410 m, NEPAL). Beside social demographics and LLS 2018 (cutoff for LLS-positivity: LLS ≥ 3 including at least 1 point for headache), we examined symptoms of anxiety (Zung Self-Rating Anxiety Scale [SAS], General Anxiety Disorder Questionnaire 7 [GAD-7]), affective states (International Positive and Negative Affect Schedule Short form [I-PANAS-SF]) and sleep (Insomnia Severity Index [ISI]). In this preliminary analysis, the average age was 39 ± 16 years in PSY, 34 ± 16 years in CO and 40 ± 14 years in NEPAL. Gender distribution showed greater portion of women in PSY and CO (PSY: 72% female 24% male 3% non-binary, CO: 64% female 36% male) contrary to NEPAL (36% female 64% male). At sea level, 67% scored LLS-positive in PSY and 12% in CO (Fishers exact test, p &lt; 0.001). In NEPAL 25% met AMS-criteria by LLS. CO and NEPAL score significantly lower in LLS than PSY (ANOVA: diff = -3.70, p &lt; 0.0001; diff = -3.68, p &lt; 0.0001, respectively). PSY and CO showed significant weak to moderate correlations (Spearman-Rho, p &lt; 0.001) of anxiety (SAS, GAD), affective states (I-PANAS-SF) and sleep impairment (ISI) with LLS-sum. NEPAL showed significant very-weak to weak correlations of insomnia, anxiety and negative affect with LLS-sum. Using logistic regression analysis (Figure 1), higher odds of LLS-positivity are significantly associated with insomnia and anxiety (ISI, SAS) in PSY, with anxiety in CO (SAS) and insomnia and negative affect in NEPAL. While of course a recent gain in altitude is a prerequisite for the diagnosis of AMS this study shows that patients with pre-existing mental illness at low altitude score more frequently false-positive on the LLS than a mentally healthy cohort. Symptoms of anxiety, negative affect and sleep disturbance can affect the AMS-defining questionnaire of LLS both at sea level and at high altitude. There is still uncertainty on a possible common pathophysiological pathway of psychiatric diseases and AMS since there is no Gold Standard in diagnosing AMS. Concerning (well-)established risk-factors for AMS like speed of ascent (Berger et al., 2023) and female sex (Hou et al., 2019), we see no evident data. The data presented here suggest that strength of expression of negative affect can cause positive LLS scoring. Acute mountain sickness and psychiatric disorders show overlapping symptoms at sea level. At high altitudes, negative affect seems to be a possible cause for the development of AMS. Further research focus should be placed on mountaineers in high altitude with psychiatric disorders and their mental state.

Novel mechanisms of intestinal flora regulation in high-altitude hypoxia

BackgroundThis study investigates the molecular mechanisms behind firmicutes-mediated macrophage (Mψ) polarization and glycolytic metabolic reprogramming through HIF-1α in response to intrinsic mucosal barrier injury induced by high-altitude hypoxia. MethodsEstablishing a hypoxia mouse model of high altitude, we utilized single-cell transcriptome sequencing to identify key cell types involved in regulating intestinal mucosal barrier damage caused by high-altitude hypoxia. Through proteomic analysis of colonic tissue Mψ and metabolomic analysis of Mψ metabolites, we determined crucial proteins and metabolic pathways influencing intestinal mucosal barrier damage induced by high-altitude hypoxia. Mechanistic validation was conducted using RAW264.7 Mψ in vitro by assessing cell viability with CCK-8 assay following treatment with different metabolites. The hypoxia mouse model was further validated in vivo by transplanting gut microbiota of Firmicutes. Histological examinations through H&E staining assessed colonic cell morphology and structure, while the FITC-dextran assay evaluated intestinal tissue permeability. Hypoxia probe signal intensity in mouse colonic tissue was assessed via metronidazole staining. Various experimental techniques, including flow cytometry, immunofluorescence, ELISA, Western blot, and RT-qPCR, were employed to study the impact of HIF-1α/glycolysis pathway and different gut microbiota metabolites on Mψ polarization. ResultsBioinformatics analysis revealed that single-cell transcriptomics identified Mψ as a key cell type, with their polarization pattern playing a crucial role in the intestinal mucosal barrier damage induced by high-altitude hypoxia. Proteomics combined with metabolomics analysis indicated that HIF-1α and the glycolytic pathway are pivotal proteins and signaling pathways in the intestinal mucosal barrier damage caused by high-altitude hypoxia. In vitro cell experiments demonstrated that activation of the glycolytic pathway by HIF-1α led to a significant upregulation of mRNA levels of IL-1β, IL-6, and TNFα while downregulating mRNA levels of IL-10 and TGFβ, thereby promoting M1 Mψ activation and inhibiting M2 Mψ polarization. Further mechanistic validation experiments revealed that the metabolite butyric acid from Firmicutes bacteria significantly downregulated the protein expression of HIF-1α, GCK, PFK, PKM, and LDH, thus inhibiting the HIF-1α/glycolytic pathway that suppresses M1 Mψ and activates M2 Mψ, consequently alleviating the hypoxic symptoms in RAW264.7 cells. Subsequent animal experiments confirmed that Firmicutes bacteria inhibited the HIF-1α/glycolytic pathway to modulate Mψ polarization, thereby mitigating intestinal mucosal barrier damage in high-altitude hypoxic mice. ConclusionThe study reveals that firmicutes, through the inhibition of the HIF-1α/glycolysis pathway, mitigate Mψ polarization, thereby alleviating intrinsic mucosal barrier injury in high-altitude hypoxia.