Chronic Mountain Sickness Research Articles

Ethiopian Native Highlander's Adaptation to Chronic High-Altitude Hypoxia.

People living in a high-altitude environment have distinct lifelong challenges. Adaptive mechanisms have allowed high-altitude residents to survive in a low-oxygen environment for thousands of years. The purpose of this review was to provide a brief review of the Ethiopian native highlanders' adaptive mechanisms to chronic hypoxia problems at high altitude. Traditionally, an elevated hemoglobin concentration has been considered as a hallmark of lifelong adaptation to high-altitude hypoxia, though this notion has been refuted recently as a result of the establishment of the alternative adaptive responses found in Amhara highlanders living in the Simien Mountains of northern Ethiopia. These populations did not have elevated hemoglobin (no erythrocytosis) but had normal hemoglobin saturation and arterial oxygen level, which alerts researchers to explore the possibility of the presence of an alternative adaptive mechanism. Contrary to this, Oromos living in the Bale Mountains of southern Ethiopia have elevated hemoglobin. The presence of increased nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) in native Amhara highlanders suggests the possibility of adaptation via vasodilation, which would improve oxygen supply to metabolic tissues. Native Amhara highlanders showed no indications of chronic mountain sickness and had a higher pulmonary blood pressure without having a higher pulmonary vascular resistance. In addition, the cerebral circulation is sensitive to NO and carbon dioxide (CO2) but not to hypoxia, which would likely promote increased cerebral blood flow and increase oxygen delivery to the brain, making Ethiopian high-altitude natives better suited for survival at high altitudes. Further research is warranted to translate these background natural features of Ethiopian native highlanders to clinical applications.

EPR spectroscopic evidence of iron-catalysed free radical formation in chronic mountain sickness: Dietary causes and vascular consequences

Chronic mountain sickness (CMS) is a high-altitude (HA) maladaptation syndrome characterised by elevated systemic oxidative-nitrosative stress (OXNOS) due to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability. To better define underlying mechanisms and vascular consequences, this study compared healthy male lowlanders (80 m, n = 10) against age/sex-matched highlanders born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 10) and without (CMS-, n = 10) CMS. Cephalic venous blood was assayed using electron paramagnetic resonance spectroscopy and reductive ozone-based chemiluminescence. Nutritional intake was assessed via dietary recall. Systemic vascular function and structure were assessed via flow-mediated dilatation, aortic pulse wave velocity and carotid intima-media thickness using duplex ultrasound and applanation tonometry. Basal systemic OXNOS was permanently elevated in highlanders (P = <0.001 vs. lowlanders) and further exaggerated in CMS+, reflected by increased hydroxyl radical spin adduct formation (P = <0.001 vs. CMS-) subsequent to liberation of free ‘catalytic’ iron consistent with a Fenton and/or nucleophilic addition mechanism(s). This was accompanied by elevated global protein carbonylation (P = 0.046 vs. CMS-) and corresponding reduction in plasma nitrite (P = <0.001 vs. lowlanders). Dietary intake of vitamins C and E, carotene, magnesium and retinol were lower in highlanders and especially deficient in CMS + due to reduced consumption of fruit and vegetables (P = <0.001 to 0.028 vs. lowlanders/CMS-). Systemic vascular function and structure were also impaired in highlanders (P = <0.001 to 0.040 vs. lowlanders) with more marked dysfunction observed in CMS+ (P = 0.035 to 0.043 vs. CMS-) in direct proportion to systemic OXNOS (r = −0.692 to 0.595, P = <0.001 to 0.045). Collectively, these findings suggest that lifelong exposure to iron-catalysed systemic OXNOS, compounded by a dietary deficiency of antioxidant micronutrients, likely contributes to the systemic vascular complications and increased morbidity/mortality in CMS+. Trial registryClinicalTrials.gov; No: NCT01182792; URL: www.clinicaltrials.gov.

Chronic exposure to altitude. Clinical characteristics and diagnosis

ResumenLa exposición crónica a la altitud se ha asociado a hipoxia hipobárica en quienes la experimentan. Dos entidades se han asociado a la hipoxia hipobárica: la hipertensión pulmonar de la alta altitud y el mal de montaña crónico. Se describen sus características fisiológicas y de la circulación pulmonar, así como su perfil clínico y el diagnóstico.

Global Reach 2018: sympathetic neural and hemodynamic responses to submaximal exercise in Andeans with and without chronic mountain sickness.

Andeans with chronic mountain sickness (CMS) and polycythemia have similar maximal oxygen uptakes to healthy Andeans. Therefore, this study aimed to explore potential adaptations in convective oxygen transport, with a specific focus on sympathetically mediated vasoconstriction of nonactive skeletal muscle. In Andeans with (CMS+, n = 7) and without (CMS-, n = 9) CMS, we measured components of convective oxygen delivery, hemodynamic (arterial blood pressure via intra-arterial catheter), and autonomic responses [muscle sympathetic nerve activity (MSNA)] at rest and during steady-state submaximal cycling exercise [30% and 60% peak power output (PPO) for 5 min each]. Cycling caused similar increases in heart rate, cardiac output, and oxygen delivery at both workloads between both Andean groups. However, at 60% PPO, CMS+ had a blunted reduction in Δtotal peripheral resistance (CMS-, -10.7 ± 3.8 vs. CMS+, -4.9 ± 4.1 mmHg·L-1·min-1; P = 0.012; d = 1.5) that coincided with a greater Δforearm vasoconstriction (CMS-, -0.2 ± 0.6 vs. CMS+, 1.5 ± 1.3 mmHg·mL-1·min-1; P = 0.008; d = 1.7) and a rise in Δdiastolic blood pressure (CMS-, 14.2 ± 7.2 vs. CMS+, 21.6 ± 4.2 mmHg; P = 0.023; d = 1.2) compared with CMS-. Interestingly, although MSNA burst frequency did not change at 30% or 60% of PPO in either group, at 60% Δburst incidence was attenuated in CMS+ (P = 0.028; d = 1.4). These findings indicate that in Andeans with polycythemia, light intensity exercise elicited similar cardiovascular and autonomic responses compared with CMS-. Furthermore, convective oxygen delivery is maintained during moderate-intensity exercise despite higher peripheral resistance. In addition, the elevated peripheral resistance during exercise was not mediated by greater sympathetic neural outflow, thus other neural and/or nonneural factors are perhaps involved.NEW & NOTEWORTHY During submaximal exercise, convective oxygen transport is maintained in Andeans suffering from polycythemia. Light intensity exercise elicited similar cardiovascular and autonomic responses compared with healthy Andeans. However, during moderate-intensity exercise, we observed a blunted reduction in total peripheral resistance, which cannot be ascribed to an exaggerated increase in muscle sympathetic nerve activity, indicating possible contributions from other neural and/or nonneural mechanisms.

Platelets and High-Altitude Exposure: A Meta-Analysis.

Wang, Yuliang, Xuewen Huang, Weibo Yang, and Qingxian Zeng. Platelets and high-altitude exposure: a meta-analysis. High Alt Med Biol. 23:43-56, 2022. Background: How high-altitude hypoxia influences platelets is controversial. We attempted to quantify the impact of high-altitude exposure on platelets through meta-analysis. Methods: We systematically searched electronic databases (PubMed, Embase, Web of Science, VIP, Wanfang, and CNKI) and identified articles reporting an association between platelet count (PC) or platelet indices (platelet distribution width, mean platelet volume [MPV], and plateletcrit) and high-altitude exposure. The mean and standard deviation were extracted, and the standard mean difference (SMD) was estimated using random-effects models. Stata 15.3 was used to analyze statistical data. Results: Thirty-two studies were ultimately included. For acute high-altitude hypoxia (1-14 days), no significant difference was detected, even in patients with acute mountain disease. For the chronic high-altitude hypoxia (≥1 month) group, a significant decrease in PC (SMD [95% confidence interval, CI] = -0.34 [-0.63 to -0.04]) and increase in MPV (SMD [95% CI] = 1.55 [0.60 to 2.49]) were detected compared with those in the control group. Subgroup analysis showed that the tendency was more obvious in the group with longer exposure (≥1 year). Moreover, the PC of the chronic mountain sickness group was less compared with the healthy altitude control group (SMD [95% CI] = -1.82 [-2.74 to -0.91]). Conclusion: A reduced PC and an increased MPV are associated with chronic exposure to high-altitude hypoxia. Moreover, acute high-altitude exposure has no significant influence on platelets.

Implications of a patent foramen ovale for environmental physiology and pathophysiology: do we know the 'hole' story?

The foramen ovale is an essential component of the fetal circulation contributing to oxygenation and carbon dioxide elimination that remains patent under certain circumstances in ∼30% of the healthy adult population, without major negative sequelae in most. Adults with a patent foramen ovale (PFO) have a greater tendency to develop symptoms of acute mountain sickness and high-altitude pulmonary oedema upon ascent to high altitude, and PFO presence is associated with worse cardiopulmonary function in chronic mountain sickness. This increase in altitude illness prevalence may be related to dysregulated cerebral blood flow associated with altered respiratory chemoreflex sensitivity; however, the mechanisms remain to be elucidated. Interestingly, men with a PFO appear to have a shift in thermoregulatory control to higher internal temperatures, both at rest and during exercise, and they have blunted thermal hyperpnoea. The teleological 'reason' for this thermoregulatory shift is unclear, but the shift of ∼0.5°C in core body temperature does not appear to be sufficient to have any significant negative consequences in terms of risk of heat illness. Further work in this area is needed, particularly in women, to evaluate mechanisms of heat storage and dissipation in these individuals compared to people without a PFO. Consequences of a PFO in SCUBA divers include a greater incidence of unprovoked decompression sickness, but whether PFO is beneficial or detrimental to breath hold diving remains unexplored. Whether PFO presence will explain interindividual variability in responses to, and consequences from, other environmental stressors such as spaceflight remain entirely unknown.

A narrative review of research advances in hypoxic pulmonary hypertension.

Background and ObjectiveHypoxic pulmonary hypertension (HPH) is a pathological syndrome characterized by pulmonary vasoconstriction and pulmonary vascular remodeling caused by hypoxia, which eventually leads to right heart failure or death. There are 2 stages of onset of HPH: hypoxic pulmonary vasoconstriction (HPV) and hypoxic pulmonary vascular remodeling (HPVR). It is an important pathophysiological link in the pathogenesis of chronic obstructive pulmonary disease (COPD) and chronic mountain sickness (CMS), and its severity is closely related to the course and prognosis of COPD and CMS. However, there is a lack of systematic review on the diagnosis, pathogenesis and treatment of HPH. The objective of this paper is to review the diagnosis, pathogenesis, treatment of HPH.MethodsIn this paper, the method of literature review is adopted to obtain the information about HPH. Based on the literature, comprehensive and systematic review is made. The diagnosis, pathogenesis, treatment of HPH are summarized.Key Content and FindingsRight heart catheterization is the gold standard for diagnosing HPH. Hypoxia-inducible factor, oxidative stress, metal metabolism, ion channel, inflammatory cytokines, cell apoptosis and vascular factors are the main pathogenesis of HPH. The treatment of HPH includes long-term oxygen therapy, statins, prostaglandins, phosphodiesterase inhibitor and ET receptor antagonists.ConclusionsAlthough great progress has been made in the pathophysiology and molecular biology of HPH, it is still unclear which factors play a leading role in the pathogenesis of HPH, and no breakthrough has been made in the treatment of HPH. It is believed that the specific mechanism will be revealed as the research continues, and earlier diagnosis and the development of more effective targeted drugs will be the focus of future research.

Oxidative Stress and Diseases Associated with High-Altitude Exposure.

Several diseases associated with high-altitude exposure affect unacclimated individuals. These diseases include acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), chronic mountain sickness (CMS), and, notably, high-altitude pulmonary hypertension (HAPH), which can eventually lead to right ventricle hypertrophy and heart failure. The development of these pathologies involves different molecules and molecular pathways that might be related to oxidative stress. Studies have shown that acute, intermittent, and chronic exposure to hypobaric hypoxia induce oxidative stress, causing alterations to molecular pathways and cellular components (lipids, proteins, and DNA). Therefore, the aim of this review is to discuss the oxidative molecules and pathways involved in the development of high-altitude diseases. In summary, all high-altitude pathologies are related to oxidative stress, as indicated by increases in the malondialdehyde (MDA) biomarker and decreases in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant activity. In addition, in CMS, the levels of 8-iso-PGF2α and H2O2 are increased, and evidence strongly indicates an increase in Nox4 activity in HAPH. Therefore, antioxidant treatments seem to be a promising approach to mitigating high-altitude pathologies.

High-Altitude Erythrocytosis: Mechanisms of Adaptive and Maladaptive Responses.

Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among in high-altitude populations. Although a modest increase in blood O2-carrying capacity may be beneficial for life in highland environments, erythrocytosis can also become excessive and lead to maladaptive syndromes such as chronic mountain sickness (CMS).

UNNOTICED ETIOLOGY IN ORTHOPEDIC COMPLAINTS: CHRONIC MOUNTAIN SICKNESS

Objective: Chronic mountain sickness (CMS) is a clinical syndrome with symptoms of polycythemia that may interfere with other nonspecific diseases. The current study aimed to investigate the symptoms of patients living at high altitudes, who initially presented complaints that seemed to be common orthopedic problems, and to examine their relationship with chronic mountain sickness. Material and Methods: The prospectively collected data of 104 patients were retrospectively evaluated for serum hemoglobin (Hb) and hematocrit (Hct) levels, oxygen saturation (sO2), Qinghai CMS questionnaire score, alcohol and tobacco use, “any history of acute mountain sickness, body mass index (BMI), blood pressure, heart rate, and duration of high-altitude living. Patients grouped according to the Qinghai score as healthy, mild, moderate or severe CMS. The groups were investigated in terms of parameters and demographic characteristics. Results: Of the 104 patients, 33 (31.7%) had a mild CMS score ≥6 (28 patients, 6–10, 5 patients, 11–14 points); remaining patients had no CMS. The frequency of excessive erythrocytosis was 4.5% in men and 3.3% in women. There was a significant difference in Hb, Hct and sO2 levels between the healthy and mild CMS groups (p&lt;0.001). CMS score had a positive correlation with Hct (rho 0,381 p&lt;0.001) and negative correlation between sO2 levels (rho -0.432 p&lt;0.001). Conclusions: CMS can be observed at lower altitudes than described in literature. In individuals living in high altitudes, some of the CMS symptoms may be confused with real orthopedic symptoms and orthopedists working in these areas should increase their awareness on this issue. In order to make an appropriate approach, other symptoms related to CMS should be questioned in patients living at high altitudes.

UNNOTICED ETIOLOGY IN ORTHOPEDIC COMPLAINTS: CHRONIC MOUNTAIN SICKNESS

Objective: Chronic mountain sickness (CMS) is a clinical syndrome with symptoms of polycythemia that may interfere with other nonspecific diseases. The current study aimed to investigate the symptoms of patients living at high altitudes, who initially presented complaints that seemed to be common orthopedic problems, and to examine their relationship with chronic mountain sickness. Material and Methods: The prospectively collected data of 104 patients were retrospectively evaluated for serum hemoglobin (Hb) and hematocrit (Hct) levels, oxygen saturation (sO2), Qinghai CMS questionnaire score, alcohol and tobacco use, “any history of acute mountain sickness, body mass index (BMI), blood pressure, heart rate, and duration of high-altitude living. Patients grouped according to the Qinghai score as healthy, mild, moderate or severe CMS. The groups were investigated in terms of parameters and demographic characteristics. Results: Of the 104 patients, 33 (31.7%) had a mild CMS score ≥6 (28 patients, 6–10, 5 patients, 11–14 points); remaining patients had no CMS. The frequency of excessive erythrocytosis was 4.5% in men and 3.3% in women. There was a significant difference in Hb, Hct and sO2 levels between the healthy and mild CMS groups (p&lt;0.001). CMS score had a positive correlation with Hct (rho 0,381 p&lt;0.001) and negative correlation between sO2 levels (rho -0.432 p&lt;0.001). Conclusions: CMS can be observed at lower altitudes than described in literature. In individuals living in high altitudes, some of the CMS symptoms may be confused with real orthopedic symptoms and orthopedists working in these areas should increase their awareness on this issue. In order to make an appropriate approach, other symptoms related to CMS should be questioned in patients living at high altitudes.

Study of Brain Structure and Function in Chronic Mountain Sickness Based on fMRI.

Objective: Headache and memory impairment are the primary clinical symptoms of chronic mountain sickness (CMS). In this study, we used voxel-based morphometry (VBM) and the amplitude of the low-frequency fluctuation method (ALFF) based on blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) to identify changes in the brain structure and function caused by CMS.Materials and Methods: T1W anatomical images and a resting-state functional MRI (fMRI) of the whole brain were performed in 24 patients diagnosed with CMS and 25 normal controls matched for age, sex, years of education, and living altitude. MRI images were acquired, followed by VBM and ALFF data analyses.Results: Compared with the control group, the CMS group had increased gray matter volume in the left cerebellum crus II area, left inferior temporal gyrus, right middle temporal gyrus, right insula, right caudate nucleus, and bilateral lentiform nucleus along with decreased gray matter volume in the left middle occipital gyrus and left middle temporal gyrus. White matter was decreased in the bilateral middle temporal gyrus and increased in the right Heschl's gyrus. Resting-state fMRI in patients with CMS showed increased spontaneous brain activity in the left supramarginal gyrus, left parahippocampal gyrus, and left middle temporal gyrus along with decreased spontaneous brain activity in the right cerebellum crus I area and right supplementary motor area.Conclusion: Patients with CMS had differences in gray and white matter volume and abnormal spontaneous brain activity in multiple brain regions compared to the controls. This suggests that long-term chronic hypoxia may induce changes in brain structure and function, resulting in CMS.

Excessive Erythrocytosis and Chronic Mountain Sickness in the Highest City in the World: A Longitudinal Study

Excessive Erythrocytosis and Chronic Mountain Sickness in the Highest City in the World: A Longitudinal Study

Exercise is medicine for chronic mountain sickness.

Exercise is medicine for chronic mountain sickness.

Sub-maximal aerobic exercise training reduces haematocrit and ameliorates symptoms in Andean highlanders with chronic mountain sickness.

New Findings What is the central question of this study? What is the effect of sub‐maximal aerobic exercise training on signs and symptoms of chronic mountain sickness (CMS) in Andean highlanders? What is the main finding and its importance? Aerobic exercise training (ET) effectively reduces haematocrit, ameliorates symptoms and improves aerobic capacity in CMS patients, suggesting that a regular aerobic ET programme might be used as a low‐cost non‐invasive/non‐pharmacological management strategy of this syndrome. Excessive erythrocytosis is the hallmark sign of chronic mountain sickness (CMS), a debilitating syndrome associated with neurological symptoms and increased cardiovascular risk. We have shown that unlike sedentary residents at the same altitude, trained individuals maintain haematocrit within sea‐level range, and thus we hypothesise that aerobic exercise training (ET) might reduce excessive haematocrit and ameliorate CMS signs and symptoms. Eight highlander men (38 ± 12 years) with CMS (haematocrit: 70.6 ± 1.9%, CMS score: 8.8 ± 1.4) from Cerro de Pasco, Peru (4340 m) participated in the study. Baseline assessment included haematocrit, CMS score, pulse oximetry, maximal cardiopulmonary exercise testing and in‐office plus 24 h ambulatory blood pressure (BP) monitoring. Blood samples were collected to assess cardiometabolic, erythropoietic, and haemolysis markers. ET consisted of pedalling exercise in a cycloergometer at 60% of V˙O2peak for 1 h/day, 4 days/week for 8 weeks, and participants were assessed at weeks 4 and 8. Haematocrit and CMS score decreased significantly by week 8 (to 65.6 ± 6.6%, and 3.5 ± 0.8, respectively, P < 0.05), while V˙O2peak and maximum workload increased with ET (33.8 ± 2.4 vs. 37.2 ± 2.0 ml/min/kg, P < 0.05; and 172.5 ± 9.4 vs. 210.0 ± 27.8 W, P < 0.01; respectively). Except for an increase in high‐density lipoprotein cholesterol, other blood markers and BP showed no differences. Our results suggest that reduction of haematocrit and CMS symptoms results mainly from haemodilution due to plasma volume expansion rather than to haemolysis. In conclusion, we show that ET can effectively reduce haematocrit, ameliorate symptoms and improve aerobic capacity in CMS patients, suggesting that regular aerobic exercise might be used as a low‐cost non‐invasive and non‐pharmacological management strategy.

Global Research Expedition on Altitude-related Chronic Health 2018 Iron Infusion at High Altitude Reduces Hypoxic Pulmonary Vasoconstriction Equally in Both Lowlanders and Healthy Andean Highlanders

Increasing iron bioavailability attenuates hypoxic pulmonary vasoconstriction in both lowlanders and Sherpas at high altitude. In contrast, the pulmonary vasculature of Andean individuals with chronic mountain sickness (CMS) is resistant to iron administration. Although pulmonary vascular remodeling and hypertension are characteristic features of CMS, the effect of iron administration in healthy Andean individuals, to our knowledge, has not been investigated. If theinterplay between iron status and pulmonary vascular tone in healthy Andean individuals remains intact, this could provide valuable clinical insight into the role of iron regulation at high altitude. Is the pulmonary vasculature in healthy Andean individuals responsive to iron infusion? In a double-blinded, block-randomized design, 24 healthy high-altitude Andean individuals and 22 partially acclimatized lowlanders at 4,300m (Cerro de Pasco, Peru) received an IV infusion of either 200mg of iron (III)-hydroxide sucrose or saline. Markers of iron status were collected at baseline and 4h after infusion. Echocardiography was performed in participants during room air breathing (partial pressure of inspired oxygen [Pio2] of approximately 96mmHg) and during exaggerated hypoxia (Pio2 of approximately 73mmHg) at baseline and at 2 and 4h after the infusion. Iron infusion reduced pulmonary artery systolic pressure (PASP) by approximately 2.5mmHg in room air (main effect, P< .001) and by approximately 7mmHg during exaggerated hypoxia (main effect, P< .001) in both lowlanders and healthy Andean highlanders. There was no change in PASP after the infusion of saline. Iron metrics were comparable between groups, except for serum ferritin, which was 1.8-fold higher at baseline in the Andean individuals than in the lowlanders (95%CI, 74-121ng/mL vs37-70ng/mL, respectively; P= .003). The pulmonary vasculature of healthy Andean individuals and lowlanders remains sensitive to iron infusion, and this response seems to differ from the pathologic characteristics of CMS.

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.

Serum Inflammatory Factor Profiles in the Pathogenesis of High-Altitude Polycythemia and Mechanisms of Acclimation to High Altitudes.

High-altitude polycythemia (HAPC) is a common aspect of chronic mountain sickness (CMS) caused by hypoxia and is the main cause of other symptoms associated with CMS. However, its pathogenesis and the mechanisms of high-altitude acclimation have not been fully elucidated. Exposure to high altitude is associated with elevated inflammatory mediators. In this study, the subjects were recruited and placed into a plain control (PC) group, plateau control (PUC) group, early HAPC (eHAPC) group, or a confirmed HAPC (cHAPC) group. Serum samples were collected, and inflammatory factors were measured by a novel antibody array methodology. The serum levels of interleukin-2 (IL-2), interleukin-3 (IL-3), and macrophage chemoattractant protein-1 (MCP-1) in the eHAPC group and the levels of interleukin-1 beta (IL-1 beta), IL-2, IL-3, tumor necrosis factor-alpha (TNF-alpha), MCP-1, and interleukin-16 (IL-16) in the cHAPC group were higher than those in the PUC group. More interestingly, the expression of IL-1 beta, IL-2, IL-3, TNF-alpha, MCP-1, and IL-16 in the PUC group showed a remarkable lower value than that in the PC group. These results suggest that these six factors might be involved in the pathogenesis of HAPC as well as acclimation to high altitudes. Altered inflammatory factors might be new biomarkers for HAPC and for high-altitude acclimation.

Global REACH 2018: the adaptive phenotype to life with chronic mountain sickness and polycythaemia.

Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity. Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea-level inhabitants residing at high altitude. By studying this unique population, which has adapted through natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity and characterizing the transport of oxygen through blood rheology, including haemoglobin mass, blood and plasma volume and blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances through pharmacological dissection of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity.

A 1H NMR spectroscopic metabolomic study of the protective effects of irbesartan in a rat model of chronic mountain sickness

Chronic mountain sickness (CMS) is a significant pathology in most high-altitude regions globally, affecting the cardiopulmonary system and its mechanism is largely unknown. A metabonomic approach using 1H nuclear magnetic resonance spectroscopy allows for detecting differential metabolites, which provides a global view and mechanisms during CMS development. In this study, we simulated a high-altitude environment to establish a rat model of CMS. Irbesartan was administered to CMS rats at three doses (6.75, 13.5, and 27 mg/kg) once a day for 15 days. HE staining and transmission electron microscopy were used to evaluate the effect of changes on the lung. Based on 1H NMR spectra obtained from serum samples, partial least squares-discriminant analysis (PLS-DA) and its variant orthogonal PLS-DA (OPLS-DA) models were applied to distinguish the different groups. Histopathological sections showed that the alveolar structure was abnormal, inflammatory infiltration occurred in CMS rats, and CMS induced notable metabolic disorder according to the 1H NMR result. However, irbesartan reversed the imbalanced metabolites via energy metabolism, amino acid metabolism, and taurine metabolism pathways, and its effect was also confirmed by the general signs and morphology of the lung. The results revealed that irbesartan as an effective therapeutic agent to improve CMS is warranted.