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Background: Many Andean highlanders exposed to chronic hypoxemia are susceptible to excessive erythrocytosis (EE) and chronic mountain sickness (CMS). Nocturnal hypoxemia is more marked than diurnal hypoxemia and includes sustained and intermittent components. The potential for cognitive impairments related to nocturnal hypoxemia in this population has not been extensively studied, but improved understanding may provide opportunities for the prevention of long-term effects of EE and CMS. Methods: To examine this relationship, 48 participants residing permanently at 4,340 m completed an overnight sleep study and a battery of cognitive function tests that examined a broad range of cognitive domains. Results: Greater nocturnal hypoxemia was associated with longer reaction times on Balloon Analogue Risk Task (BART) ( p < 0.01) and Emotion Recognition Test (ERT) ( p < 0.01). Longer completion times of Trail Making Task were also associated with increased nocturnal hypoxemia ( p = 0.03). Increased hematocrit was similarly associated with longer reaction times on the ERT ( p = 0.01) and the BART ( p = 0.01). Conclusion: Overall, our results showed that increased nocturnal hypoxemia and higher hematocrit were associated with impairments in cognitive performance in individuals residing permanently at high altitude.

Millions of people visit high-altitude regions annually and more than 80 million live permanently above 2,500 m. Acute high-altitude exposure can trigger high-altitude illnesses (HAIs), including acute mountain sickness (AMS), high-altitude cerebral oedema (HACE) and high-altitude pulmonary oedema (HAPE). Chronic mountain sickness (CMS) can affect high-altitude resident populations worldwide. The prevalence of acute HAIs varies according to acclimatization status, rate of ascent and individual susceptibility. AMS, characterized by headache, nausea, dizziness and fatigue, is usually benign and self-limiting, and has been linked to hypoxia-induced cerebral blood volume increases, inflammation and related trigeminovascular system activation. Disruption of the blood-brain barrier leads to HACE, characterized by altered mental status and ataxia, and increased pulmonary capillary pressure, and related stress failure induces HAPE, characterized by dyspnoea, cough and exercise intolerance. Both conditions are progressive and life-threatening, requiring immediate medical intervention. Treatment includes supplemental oxygen and descent with appropriate pharmacological therapy. Preventive measures include slow ascent, pre-acclimatization and, in some instances, medications. CMS is characterized by excessive erythrocytosis and related clinical symptoms. In severe CMS, temporary or permanent relocation to low altitude is recommended. Future research should focus on more objective diagnostic tools to enable prompt treatment, improved identification of individual susceptibilities and effective acclimatization and prevention options., (© 2024. Springer Nature Limited.)

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1 , a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.

Excessive erythrocytosis (EE) is a major hallmark of patients suffering from chronic mountain sickness (CMS, also known as Monge's disease) and is responsible for major morbidity and even mortality in early adulthood. We took advantage of unique populations, one living at high altitude (Peru) showing EE, with another population, at the same altitude and region, showing no evidence of EE (non-CMS). Through RNA-Seq, we identified and validated the function of a group of long noncoding RNAs (lncRNAs) that regulate erythropoiesis in Monge's disease, but not in the non-CMS population. Among these lncRNAs is hypoxia induced kinase-mediated erythropoietic regulator (HIKER)/LINC02228, which we showed plays a critical role in erythropoiesis in CMS cells. Under hypoxia, HIKER modulated CSNK2B (the regulatory subunit of casein kinase 2). A downregulation of HIKER downregulated CSNK2B, remarkably reducing erythropoiesis; furthermore, an upregulation of CSNK2B on the background of HIKER downregulation rescued erythropoiesis defects. Pharmacologic inhibition of CSNK2B drastically reduced erythroid colonies, and knockdown of CSNK2B in zebrafish led to a defect in hemoglobinization. We conclude that HIKER regulates erythropoiesis in Monge's disease and acts through at least one specific target, CSNK2B, a casein kinase.

High-altitude (HA) hypoxia may alter the structural-functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex-, age- and body mass index-matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVR CO2 ) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVR CO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light-chain (NF-L) and T-tau were consistently lower and cognition comparable to lowlanders following chronic-HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. KEY POINTS: High-altitude (HA) hypoxia has the potential to alter the structural-functional integrity of the neurovascular unit (NVU) in humans. For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders. Despite lowlanders presenting with a reduction in systemic oxidative-nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment. Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau. These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

In chronic mountain sickness (CMS), increased blood oxygen (O 2 )-carrying capacity due to excessive erythrocytosis (EE, [Hb] ≥ 21 g/dL) could be offset, especially during exercise by both impaired cardiac output (Q̇t) and O 2 diffusion limitation in lungs and muscle. We hypothesized that EE results in reduced peak V̇o 2 despite increased blood O 2 -carrying capacity, and that isovolumic hemodilution (IVHD) improves exercise capacity. In 14 male residents of Cerro de Pasco, Peru (4,340 m), six with and eight without EE, we measured peak cycle-exercise capacity, V̇o 2 , Q̇t, arterial blood gas parameters, and (resting) blood volume. This was repeated for participants with EE after IVHD, reducing hematocrit by 20% (from 67% to 53%). From these data, we quantified the major O 2 transport pathway components (ventilation, pulmonary alveolar-capillary diffusion, Q̇t, and blood-muscle mitochondria diffusion). Participants with EE had similar peak V̇o 2 , systemic O 2 delivery, and O 2 extraction as non-EE controls, however, with lower Q̇t and higher arterial [O 2 ]. After IVHD, peak V̇o 2 was preserved (but not enhanced), with lower O 2 delivery (despite higher Q̇t) balanced by greater O 2 extraction. The considerable variance in exercise capacity across the 14 individuals was explained essentially completely by differences in both pulmonary and muscle O 2 diffusional conductances and not by any differences in ventilation, [Hb], nor Q̇t. In conclusion, EE does not result in lower peak V̇o 2 in Andean males, and IVHD maintains, but does not enhance, exercise capacity. NEW & NOTEWORTHY Male Andean highlanders with and without excessive erythrocytosis (EE) have similar peak V̇o 2 at 4,340 m, with higher arterial [O 2 ] in EE and lower cardiac output (Q̇t), thus maintaining similar O 2 delivery. Peak V̇o 2 in participants with EE was unaffected by isovolumic hemodilution (hematocrit reduced from 67% to 53%), with lower O 2 delivery balanced by slightly increased Q̇t and greater O 2 extraction. Differences in lung and muscle diffusing capacity, and not hematocrit variation, accounted for essentially all interindividual variance in peak V̇o 2 .

Study Objectives: Chronic mountain sickness (CMS) is commonly observed among Andean and other highland populations. Sleep-disordered breathing (SDB) is highly prevalent at high altitude, and SDB and nocturnal hypoxemia have been observed in CMS. Phlebotomy is commonly performed to treat CMS, but it is unknown whether reducing hematocrit improves SDB. We hypothesized that isovolemic hemodilution (IVHD) in CMS would reduce SBD severity and improve sleep efficiency., Methods: Six participants with CMS and 8 without CMS, all residents of Cerro de Pasco, Peru (altitude 4340 m), completed baseline nocturnal sleep studies. CMS participants then underwent IVHD, and nocturnal sleep studies were repeated 24-48 hours after IVHD. We analyzed sleep apnea severity, nocturnal oxygenation, and sleep quality in those with CMS relative to those without CMS, and the effects of IVHD in CMS participants., Results: Participants with CMS did not have altered sleep architecture, sleep apnea severity, or nocturnal oxygenation relative to non-CMS participants. However, IVHD in CMS increased apnea-hypopnea index (40.9 ± 6.9 events/h to 61.5 ± 7.7 events/h, P  = .009). IVHD increased oxyhemoglobin desaturation index ( P  = .008) and the percentage of sleep time spent with oxyhemoglobin saturation at or below 80% ( P  = .012). There was no effect of IVHD on sleep efficiency, arousal index, or sleep staging., Conclusions: In this cohort, CMS was not associated with worsened SDB or changes in sleep architecture. IVHD, a putative therapeutic option for participants with CMS, appears to worsen nocturnal oxygenation and SDB within 48 hours post-IVHD., Citation: Sanchez-Azofra A, Villafuerte FC, DeYoung PN, et al. Isovolemic hemodilution in chronic mountain sickness acutely worsens nocturnal oxygenation and sleep apnea severity. J Clin Sleep Med . 2022;18(10):2423-2432., (© 2022 American Academy of Sleep Medicine.)

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Non, Heinrich, Gu, Alcock, Moya, Lawrence, Tift, O'Brien, Storz, Signore, Khudyakov, Milsom, Wilson, Beall, Villafuerte, Stobdan, Julian, Moore, Fuster, Stokes, Milner, West, Zhang, Shyy, Childebayeva, Vázquez-Medina, Pham, Mesarwi, Hall, Cheviron, Sieker, Blood, Yuan, Scott, Rana, Ponganis, Malhotra, Powell and Simonson.)

Despite aerobic activity requiring up to tenfold increases in air intake, human populations in high-altitude hypoxic environments can sustain high levels of endurance physical activity. While these populations generally have relatively larger chest and lung volumes, how thoracic motions actively increase ventilation is unknown. Here we show that rib movements, in conjunction with chest shape, contribute to ventilation by assessing how adulthood acclimatization, developmental adaptation, and population-level adaptation to high-altitude affect sustained aerobic activity. We measured tidal volume, heart rate, and rib-motion during walking and running in lowland individuals from Boston (~ 35 m) and in Quechua populations born and living at sea-level (~ 150 m) and at high altitude (> 4000 m) in Peru. We found that Quechua participants, regardless of birth or testing altitudes, increase thoracic volume 2.0-2.2 times more than lowland participants (p < 0.05). Further, Quechua individuals from hypoxic environments have deeper chests resulting in 1.3 times greater increases in thoracic ventilation compared to age-matched, sea-level Quechua (p < 0.05). Thus, increased thoracic ventilation derives from a combination of acclimatization, developmental adaptation, and population-level adaptation to aerobic demand in different oxygen environments, demonstrating that ventilatory demand due to environment and activity has helped shape the form and function of the human thorax., (© 2022. The Author(s).)

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 O 2 -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).

At high altitude Andean region, hypoxia-induced excessive erythrocytosis (EE) is the defining feature of Monge's disease or chronic mountain sickness (CMS). At the same altitude, resides a population that has developed adaptive mechanism(s) to constrain this hypoxic response (non-CMS). In this study, we utilized an in vitro induced pluripotent stem cell model system to study both populations using genomic and molecular approaches. Our whole genome analysis of the two groups identified differential SNPs between the CMS and non-CMS subjects in the ARID1B region. Under hypoxia, the expression levels of ARID1B significantly increased in the non-CMS cells but decreased in the CMS cells. At the molecular level, ARID1B knockdown (KD) in non-CMS cells increased the levels of the transcriptional regulator GATA1 by 3-fold and RBC levels by 100-fold under hypoxia. ARID1B KD in non-CMS cells led to increased proliferation and EPO sensitivity by lowering p53 levels and decreasing apoptosis through GATA1 mediation. Interestingly, under hypoxia ARID1B showed an epigenetic role, altering the chromatin states of erythroid genes. Indeed, combined Real-time PCR and ATAC-Seq results showed that ARID1B modulates the expression of GATA1 and p53 and chromatin accessibility at GATA1/p53 target genes. We conclude that ARID1B is a novel erythroid regulator under hypoxia that controls various aspects of erythropoiesis in high-altitude dwellers., (© 2022. The Author(s).)

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.

Background: 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 the interplay 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., Research Question: Is the pulmonary vasculature in healthy Andean individuals responsive to iron infusion?, Study Design and Methods: In a double-blinded, block-randomized design, 24 healthy high-altitude Andean individuals and 22 partially acclimatized lowlanders at 4,300 m (Cerro de Pasco, Peru) received an IV infusion of either 200 mg of iron (III)-hydroxide sucrose or saline. Markers of iron status were collected at baseline and 4 h after infusion. Echocardiography was performed in participants during room air breathing (partial pressure of inspired oxygen [Pio 2 ] of approximately 96 mm Hg) and during exaggerated hypoxia (Pio 2 of approximately 73 mm Hg) at baseline and at 2 and 4 h after the infusion., Results: Iron infusion reduced pulmonary artery systolic pressure (PASP) by approximately 2.5 mm Hg in room air (main effect, P < .001) and by approximately 7 mm Hg 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, 74-121 ng/mL vs 37-70 ng/mL, respectively; P = .003)., Interpretation: 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., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)