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Gardner, Laurel, Linda E. Keyes, Caleb Phillips, Elan Small, Tejaswi Adhikari, Nathan Barott, Ken Zafren, Rony Maharjan, and James Marvel. Women at altitude: Menstrual-cycle phase, menopause, and exogenous progesterone are not associated with acute mountain sickness. High Alt Med Biol. 00:000–000, 2024. Background: Elevated progesterone levels in women may protect against acute mountain sickness (AMS). The impact of hormonal contraception (HC) on AMS is unknown. We examined the effect of natural and exogenous progesterone on the occurrence of AMS. Methods: We conducted a prospective observational convenience study of female trekkers in Lobuche (4,940 m) and Manang (3,519 m). We collected data on last menstrual period, use of exogenous hormones, and development of AMS. Results: There were 1,161 trekkers who met inclusion criteria, of whom 307 (26%) had AMS. There was no significant difference in occurrence of AMS between women in the follicular (28%) and the luteal (25%) phases of menstruation (p = 0.48). The proportion of premenopausal (25%) versus postmenopausal women (30%) with AMS did not differ (p = 0.33). The use of HC did not influence the occurrence of AMS (HC 23% vs. no HC 26%, p = 0.47), nor did hormonal replacement therapy (HRT) (HRT 11% vs. no HRT 31%, p = 0.13). Conclusion: We found no relationship between menstrual-cycle phase, menopausal status, or use of exogenous progesterone and the occurrence of AMS in trekkers and conclude that hormonal status is not a risk factor for AMS. Furthermore, women should not be excluded from future AMS studies based on hormonal status. [ABSTRACT FROM AUTHOR]

BackgroundAltitude illness has serious effects on individuals who are not adequately acclimatized to high-altitude areas and may even lead to death. However, the individualized mechanisms of onset and preventive measures are not fully elucidated at present, especially the relationship between altitude illness and elements, which requires further in-depth research.MethodsFresh serum samples were collected from individuals who underwent health examinations at the two hospitals in Xining and Sanya between November 2021 and December 2021. The blood zinc (Zn), iron (Fe), and calcium (Ca) concentrations, as well as hypoxia-inducible factor 1-alpha (HIF-1α) concentrations, were measured. This study conducted effective sample size estimation, repeated experiments, and used GraphPad Prism 9.0 and IBM SPSS version 19.0 software for comparative analysis of differences in the expression of elements and HIF-1α among different ethnic groups, altitudes, and concentration groups. Linear regression and multiple linear regression were employed to explore the relationships among elements and their correlation with HIF-1α.ResultsThis study included a total of 400 participants. The results from the repeated measurements indicated that the consistency of the laboratory test results was satisfactory. In terms of altitude differences, except for Fe (p = 0.767), which did not show significant variance between low and high altitude regions, Zn, Ca, and HIF-1α elements all exhibited notable differences between these areas (p

Li Li, Lin Lin, Bo Wen, Peng-cheng Zhao, Da-sheng Liu, Guo-ming Pang, Zi-rong Wang, Yong Tan, and Cheng Lu. Promising natural medicines for the treatment of high-altitude illness. High Alt Med Biol. 24:175–185, 2023.—High-altitude illness (HAI) is a dangerous disease characterized by oxidative stress, inflammatory damage and hemodynamic changes in the body that can lead to severe damage to the lungs, heart, and brain. Natural medicines are widely known for their multiple active ingredients and pharmacological effects, which may be important in the treatment of HAI. In this review, we outline the specific types of HAI and the underlying pathological mechanisms and summarize the currently documented natural medicines applied in the treatment of acute mountain sickness and high-altitude cerebral edema, high-altitude pulmonary edema, chronic mountain sickness, and high-altitude pulmonary hypertension. Their sources, types, and medicinal sites are summarized, and their active ingredients, pharmacological effects, related mechanisms, and potential toxicity are discussed. In conclusion, natural medicines, as an acceptable complementary and alternative strategy with fewer side effects and more long-term application, can provide a reference for developing more natural antialtitude sickness medicines in the future and have good application prospects in HAI treatment. [ABSTRACT FROM AUTHOR]

Altitude travelers are exposed to high-altitude pathologies, which can be potentially serious. Individual susceptibility varies widely and this makes it difficult to predict who will develop these complications. The assessment of physiological adaptations to exercise performed in hypoxia has been proposed to help predict altitude sickness. The purpose of this review is to evaluate the contribution of hypoxic exercise testing, achieved in normobaric conditions, in the prediction of severe high-altitude pathology. We performed a systematic review using the databases PubMed, Science Direct and Embase in October 2021 to collect studies reporting physiological adaptations under hypoxic exercise testing and its interest in predicting high-altitude pathology. Eight studies were eligible, concerning 3558 patients with a mean age of 46.9 years old, and a simulated mean altitude reaching of 5092 m. 597 patients presented an acute mountain sickness during their altitude travels. Three different protocols of hypoxic exercise testing were used. Acute mountain sickness was defined using Hackett's score or the Lake Louise score. Ventilatory and cardiac responses to hypoxia, desaturation in hypoxia, cerebral oxygenation, core temperature, variation in body mass index and some perceived sensations were the highlighted variables associated with acute mountain sickness. A decision algorithm based on hypoxic exercise tests was proposed by one team. Hypoxic exercise testing provides promising information to help predict altitude complications. Its interest should be confirmed by different teams. [ABSTRACT FROM AUTHOR]

Background: Altitude illness has serious effects on individuals who are not adequately acclimatized to high-altitude areas and may even lead to death. However, the individualized mechanisms of onset and preventive measures are not fully elucidated at present, especially the relationship between altitude illness and elements, which requires further in-depth research., Methods: Fresh serum samples were collected from individuals who underwent health examinations at the two hospitals in Xining and Sanya between November 2021 and December 2021. The blood zinc (Zn), iron (Fe), and calcium (Ca) concentrations, as well as hypoxia-inducible factor 1-alpha (HIF-1α) concentrations, were measured. This study conducted effective sample size estimation, repeated experiments, and used GraphPad Prism 9.0 and IBM SPSS version 19.0 software for comparative analysis of differences in the expression of elements and HIF-1α among different ethnic groups, altitudes, and concentration groups. Linear regression and multiple linear regression were employed to explore the relationships among elements and their correlation with HIF-1α., Results: This study included a total of 400 participants. The results from the repeated measurements indicated that the consistency of the laboratory test results was satisfactory. In terms of altitude differences, except for Fe ( p  = 0.767), which did not show significant variance between low and high altitude regions, Zn, Ca, and HIF-1α elements all exhibited notable differences between these areas ( p  < 0.0001, p  = 0.004, and p  < 0.0001). When grouping by the concentrations of elements and HIF-1α, the results revealed significant variations in the distribution of zinc among different levels of iron and HIF-1α ( p  < 0.05). The outcomes of the linear regression analysis demonstrated that calcium and zinc, iron and HIF-1α, calcium and HIF-1α, and zinc and HIF-1α displayed substantial overall explanatory power across different subgroups ( p  < 0.05). Finally, the results of the multiple linear regression analysis indicated that within the high-altitude population, the Li ethnic group in Sanya, and the Han ethnic group in Sanya, the multiple linear regression model with HIF-1αas the dependent variable and elements as the independent variables exhibited noteworthy overall explanatory power ( p  < 0.05)., Conclusion: The levels of typical elements and HIF-1α in the blood differ among various altitudes and ethnic groups, and these distinctions may be linked to the occurrence and progression of high-altitude illness., 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 © 2024 Guo, Lu, Zhang, Zhang, Liu, Chen and Zhang.)

High‐altitude pulmonary hypertension (HAPH) is an altitude‐related illness associated with hypoxaemia that may promote sympathetic excitation and prolongation of the QT interval. The present case‐control study tests whether QT intervals, markers of malignant cardiac arrhythmias, are prolonged in highlanders with HAPH (HAPH+) compared to healthy highlanders (HH) and healthy lowlanders (LL). The mean pulmonary artery pressure (mPAP) was measured by echocardiography in 18 HAPH+ (mPAP, 34 mmHg) and 18 HH (mPAP, 23 mmHg) at 3,250 m, and 18 LL (mPAP, 18 mmHg) at 760 m, Kyrgyzstan (p <.05 all mPAP comparisons). Groups were matched for age, sex and body mass index. Electrocardiography and pulse oximetry were continuously recorded during nocturnal polysomnography. The heart rate‐adjusted QT interval, QTc, was averaged over consecutive 1‐min periods. Overall, a total of 26,855 averaged 1‐min beat‐by‐beat periods were semi‐automatically analysed. In HAPH+, maximum nocturnal QTc was longer during sleep (median 456 ms) than wakefulness (432 ms, p <.05) and exceeded corresponding values in HH (437 and 419 ms) and LL (430 and 406 ms), p <.05, respectively. The duration of night‐time QTc >440 ms was longer in HAPH+ (median 144 min) than HH and LL (46 and 14 min, p <.05, respectively). HAPH+ had higher night‐time heart rate (median 78 beats/min) than HH and LL (66 and 65 beats/min, p <.05, respectively), lower mean nocturnal oxygen saturation than LL (88% versus 95%, p <.05) and more cyclic oxygen desaturations (median 24/hr) than HH and LL (13 and 3/hr, p <.05, respectively). In conclusion, HAPH was associated with higher night‐time heart rate, hypoxaemia and longer QTc versus HH and LL, and may represent a substrate for increased risk of malignant cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Altitude travelers are exposed to high-altitude pathologies, which can be potentially serious. Individual susceptibility varies widely and this makes it difficult to predict who will develop these complications. The assessment of physiological adaptations to exercise performed in hypoxia has been proposed to help predict altitude sickness. The purpose of this review is to evaluate the contribution of hypoxic exercise testing, achieved in normobaric conditions, in the prediction of severe high-altitude pathology. We performed a systematic review using the databases PubMed, Science Direct and Embase in October 2021 to collect studies reporting physiological adaptations under hypoxic exercise testing and its interest in predicting high-altitude pathology. Eight studies were eligible, concerning 3558 patients with a mean age of 46.9 years old, and a simulated mean altitude reaching of 5092 m. 597 patients presented an acute mountain sickness during their altitude travels. Three different protocols of hypoxic exercise testing were used. Acute mountain sickness was defined using Hackett’s score or the Lake Louise score. Ventilatory and cardiac responses to hypoxia, desaturation in hypoxia, cerebral oxygenation, core temperature, variation in body mass index and some perceived sensations were the highlighted variables associated with acute mountain sickness. A decision algorithm based on hypoxic exercise tests was proposed by one team. Hypoxic exercise testing provides promising information to help predict altitude complications. Its interest should be confirmed by different teams.

Cognitive impairment in cases of high-altitude cerebral edema is a less researched area of neuropsychiatry. Usually, it presents with depressive symptoms and can sway the treatment on the lines of organic depressive disorder and pseudodementia. We report one such case of which presented with depressive symptoms with cognitive dysfunction. The diagnosis was later revised to organic amnesic syndrome. His cognitive deficits improved with the use of cognitive retraining, especially with the use of mobile-based applications.

Keywords: Macular edema; high-altitude illness; high-altitude retinopathy; blurring of vision; travellers EN Macular edema high-altitude illness high-altitude retinopathy blurring of vision travellers 1 2 2 06/27/23 20230501 NES 230501 A 36-year-old previously healthy Thai woman presented with a sudden onset of bilateral blurring of vision during her trekking trip to Mount Kinabalu in Malaysia. Macular edema, high-altitude retinopathy, high-altitude illness, travellers, blurring of vision. [Extracted from the article]

Aims: Changes in emotions associated with mountain treks have rarely been reported. This study examined emotional state changes in sixth-grade elementary school students before and after a 3-day high-altitude mountain trek from the trailhead (2140 m) to Xue Mountain (3886 m) in Taiwan. Methods: In June 2011, 201 students participated in the trek. The round-trip distance was 21.8 km. The age, gender, blood group, and family configuration of the participants were documented before the trek. A 36-item short-form survey instrument, including the Mood and Anxiety Symptom Questionnaire and the Positive and Negative Affect Scale for Children, was used to evaluate the participants' emotional states (happiness, anticipation, sadness, and anger). The participants answered the questionnaires 1 month before and 1 week after the trek. A Likert scale was used to evaluate individual items (range 1–4; from strongly disagree to strongly agree). We calculated scores for each index before and after the trek. The incidence and presentation of acute mountain sickness (AMS) among the participants was also studied and published previously. Results: In total, 187 (112 boys and 75 girls) participants (mean age 11.9 ± 0.4 years) completed the trek and the survey. The sadness and anger scores (negative emotions) were significantly lower after than before the trek (39.5 vs. 36.6; p < 0.01). The happiness and anticipation scores (positive emotions) before and after the trek did not differ significantly (49.9 vs. 48.9; p = 0.11). No participant used AMS prophylaxis, while 78 participants met the AMS criteria. Negative emotions decreased more in those with AMS than without AMS (−4.6 vs. −1.8; p = 0.04), and the use of medications or acetazolamide did not alter the emotions. Conclusions: A 3-day high-altitude mountain trek can reduce children's negative emotions. Negative emotions decreased more in those with AMS, whereas medications or acetazolamide did not alter their emotions. [ABSTRACT FROM AUTHOR]

Introduction: AR36 is a pharmaceutical-grade plant extract used to support cardiovascular health in traditional Chinese medicine. Studies suggest that AR36 may prevent acute mountain sickness (AMS) during gradual ascent to high altitude. This randomized, placebo-controlled Phase 2 trial aimed to evaluate dosing regimens and assess efficacy and safety of AR36 for AMS prevention during rapid ascent., Methods: Participants received placebo, low-dose AR36 (225 mg twice daily for 14 d prior and 5 d at altitude), or high-dose AR36 (12 d placebo, 300 mg twice daily for 2 d prior and 5 d at altitude). The primary efficacy outcome was 1993 Lake Louise Scoring System (LLSS) score on the morning after ascent. Safety was assessed through the proportion of treatment-emergent adverse events (TEAEs)., Results: One hundred thirty-two participants were randomized. Mean±SD age was 31.4±8.6 (range, 19-54) y. Baseline characteristics did not differ across groups. Lake Louise Scoring System scores on Day 16 in the placebo, low-dose, and high-dose groups were 4.03 (2.88), 4.42 (3.17), and 3.5 (2.31), respectively (placebo versus low-dose, P=0.462; placebo versus high-dose, P=0.574; n=110). The incidence of AMS on Day 16 was 66.7% in the placebo, 61.1% in the low-dose, and 55.3% in the high-dose group (P=0.66). The proportion of TEAEs in the placebo, low-dose, and high-dose groups was 38.4% (81), 28.4% (60), and 33.2% (70), respectively (P=0.205; n=127). There was no statistical difference between groups in LLSS, incidence of AMS, or TEAEs., Conclusions: AR36 did not improve LLSS or AMS incidence using the current regimens. AR36 was well tolerated., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

High-altitude pulmonary edema (HAPE) is a potentially fatal condition affecting high-altitude sojourners. The biggest predictor of HAPE development is a history of prior HAPE. Magnetic resonance imaging (MRI) shows that HAPE-susceptible (with a history of HAPE), but not HAPE-resistant (with a history of repeated ascents without illness) individuals develop greater heterogeneity of regional pulmonary perfusion breathing hypoxic gas (O2 = 12.5%), consistent with uneven hypoxic pulmonary vasoconstriction (HPV). Why HPV is uneven in HAPE-susceptible individuals is unknown but may arise from regionally heterogeneous ventilation resulting in an uneven stimulus to HPV. We tested the hypothesis that ventilation is more heterogeneous in HAPE-susceptible subjects (n = 6) compared with HAPE-resistant controls (n = 7). MRI specific ventilation imaging (SVI) was used to measure regional specific ventilation and the relative dispersion (SD/mean) of SVI used to quantify baseline heterogeneity. Ventilation heterogeneity from conductive and respiratory airways was measured in normoxia and hypoxia (O2 = 12.5%) using multiple-breath washout and heterogeneity quantified from the indexes Scond and Sacin, respectively. Contrary to our hypothesis, HAPE-susceptible subjects had significantly lower relative dispersion of specific ventilation than the HAPEresistant controls [susceptible = 1.33 ± 0.67 (SD), resistant = 2.36 ± 0.98, P = 0.05], and Sacin tended to be more uniform (susceptible = 0.085 ± 0.009, resistant = 0.113 ± 0.030, P = 0.07). Scond was not significantly different between groups (susceptible = 0.019 ± 0.007, resistant = 0.020 ± 0.004, P = 0.67). Sacin and Scond did not change significantly in hypoxia (P = 0.56 and 0.19, respectively). In conclusion, ventilation heterogeneity does not change with short-term hypoxia irrespective of HAPE susceptibility, and lesser rather than greater ventilation heterogeneity is observed in HAPE-susceptible subjects. This suggests that the basis for uneven HPV in HAPE involves vascular phenomena. [ABSTRACT FROM AUTHOR]

Cognitive impairment in cases of high-altitude cerebral edema is a less researched area of neuropsychiatry. Usually, it presents with depressive symptoms and can sway the treatment on the lines of organic depressive disorder and pseudodementia. We report one such case of which presented with depressive symptoms with cognitive dysfunction. The diagnosis was later revised to organic amnesic syndrome. His cognitive deficits improved with the use of cognitive retraining, especially with the use of mobile-based applications. [ABSTRACT FROM AUTHOR]

Background: Field studies have reported conflicting results regarding changes in biomarkers at high altitude. This study measured temporal changes in biomarkers and compared the differences between individuals with and without acute mountain sickness (AMS)., Materials and Methods: This study included 34 nonacclimatized healthy participants. Ten-milliliters of blood were collected at four time points: 3 days before ascent (T0), on two successive nights at 3150 m (T1 and T2), and 2 days after descent (T3). Participants were transported by bus from 555 m to 3150 m within 3 hours. AMS was diagnosed using the self-reported Lake Louise Scoring (LLS) questionnaire., Results: Compared with T0, significant increases in E-selectin and decreases in vascular endothelial growth factor (VEGF) levels were observed at high altitude. Significantly increased C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and S100 calcium-binding protein B (S100B) levels were observed at T2, and significantly decreased vascular cell adhesion molecule-1 (VCAM-1) levels were observed at T3. Eighteen (53%) participants developed AMS. Changes in E-selectin, CRP, MCP-1, and S100B levels were independent of AMS. Relative to individuals without AMS, those with AMS had significantly higher atrial natriuretic peptide (ANP) and VCAM-1 levels and lower plasminogen activator inhibitor-1 (PAI-1) levels at T1 and higher brain natriuretic peptide and lower VEGF and PAI-1 levels at T3. LLSs were positively correlated with ANP and VCAM-1 levels and negatively correlated with PAI-1 levels measured at T1., Conclusions: After acute ascent, individuals with and without AMS exhibited different trends in biomarkers associated with endothelial cell activation and natriuretic peptides., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Purpose: The present study evaluated the effects of a preacclimatization program comprising seven passive 1-h exposures to 4500-m normobaric hypoxia on the prevalence and severity of acute mountain sickness (AMS) during a subsequent exposure to real high altitude in persons susceptible to AMS. Methods: The project was designed as a randomized controlled trial including 32 healthy female and male participants with known susceptibility to AMS symptoms. After baseline measurements, participants were randomly assigned to the hypoxia or the control group to receive the preacclimatization program (seven passive 1-h exposures within 7 d to normobaric hypoxia or sham hypoxia). After completing preacclimatization, participants were transported (bus, cog railway) to real high altitude (3650 m, Monchsjoch Hut, Switzerland) and stayed there for 45 h (two nights). Symptoms of AMS and physiological responses were determined repeatedly. Results: AMS incidence and severity did not significantly differ between groups during the high-altitude exposure. In total, 59% of the hypoxia and 67% of the control group suffered from AMS at one or more time points during the high-altitude exposure. Hypoxic and hypercapnic ventilatory responses were not affected by the preacclimatization program. Resting ventilation at high altitude tended to be higher (P = 0.06) in the hypoxia group compared with the control group. No significant between-group differences were detected for heart rate variability, arterial oxygen saturation, and hematological and ventilatory parameters during the high-altitude exposure. Conclusion: Preacclimatization using seven passive 1-h exposures to normobaric hypoxia corresponding to 4500 m did not prevent AMS development during a subsequent highaltitude exposure in AMS-susceptible persons. [ABSTRACT FROM AUTHOR]

Human body is evolutionarily adapted to life in a fairly narrow range of physicochemical parameters of the environment. Any substantial change in ambient pressure, as well as partial pressure of air components has an impact on of physiological or pathophysiological processes. The aim of the article is to present selected health-threatening and life-threatening conditions related to high altitude exposure. [ABSTRACT FROM AUTHOR]

Altitude illness is a spectrum of conditions that affect the majority of travelers to high elevations (>8200 ft [2500 m]). The rapid decrease in arterial oxygen saturation with increasing altitude is the physiologic basis for this group of disorders. Many travelers to high altitudes will experience symptoms of acute mountain sickness including headache, fatigue, dyspnea, and dizziness. Prolonged exposure can result in more serious pulmonary, central nervous system, and circulatory disorders. Core treatments for most altitude-related illnesses include descent, rest, medications, and supportive care. Children and travelers with chronic diseases are more susceptible to altitude illness compared with the general population. Pregnant women residing at high altitudes are at increased risk for pregnancy-induced hypertension, preeclampsia, and low-birth-weight infants. Early recognition and treatment of altitude illness can prevent life-threatening situations. Primary care physicians should counsel patients traveling to high altitudes about altitude illness and discuss medications available for mountain sickness prophylaxis. [ABSTRACT FROM AUTHOR]

Acute mountain sickness is common among not acclimatized persons ascending to high altitude; the underlying mechanism is unknown, but may be related to cerebral edema. Nine healthy male students were studied before and after 6-h exposure to isobaric hypoxia. Subjects inhaled room air enriched with N2 to obtain arterial O2 saturation values of 75 to 80%. Acute mountain sickness was assessed with the environmental symptom questionnaire, and cerebral edema with 3 T magnetic resonance imaging in 18 regions of interest in the cerebral white matter. The main outcome measures were development of intra- and extracellular cerebral white matter edema assessed by visual inspection and quantitative analysis of apparent diffusion coefficients derived from diffusion-weighted imaging, and B0 signal intensities derived from T2-weighted imaging. Seven of nine subjects developed acute mountain sickness. Mean apparent diffusion coefficient increased 2.12% (baseline, 0.80±0.09; 6 h hypoxia, 0.81±0.09; P=0.034), and mean B0 signal intensity increased 4.56% (baseline, 432.1±98.2; 6 h hypoxia, 450.7±102.5; P<0.001). Visual inspection of magnetic resonance images failed to reveal cerebral edema. Cerebral acute mountain sickness scores showed a negative correlation with relative changes of apparent diffusion coefficients (r=−0.83, P=0.006); there was no correlation with relative changes of B0 signal intensities. In conclusion, isobaric hypoxia is associated with mild extracellular (vasogenic) cerebral edema irrespective of the presence of acute mountain sickness in most subjects, and severe acute mountain sickness with additional mild intracellular (cytotoxic) cerebral edema.Journal of Cerebral Blood Flow & Metabolism (2008) 28, 198–206; doi:10.1038/sj.jcbfm.9600513; published online 23 May 2007 [ABSTRACT FROM AUTHOR]

Background: Modern travel means that many travellers can arrive abruptly to high-altitude destinations without doing any trekking or climbing. Airports in high-altitude cities mean that travellers can go from sea level to over 3350-3960 m (11 000-13 000 feet) in a matter of hours, putting themselves at risk for high-altitude illness (HAI)., Methods: Acetazolamide has been shown to be an effective way to help prevent HAI on such itineraries. The risk of HAI on rapid arrival to altitudes over 3350 m (11 000 feet) has been shown to range from 35% to nearly 50%. The risk can be higher for high-altitude trekking. This risk is far higher than most travel medicine risks and is on a par with the risk of travellers' diarrhea in high risk destinations., Result: The use of prophylactic acetazolamide in a dosage of 125 mg every 12 h is highly effective at diminishing the risk of HAI., Conclusion: Travel medicine practitioners should become comfortable with assessing the risk of HAI and determining when it is appropriate to offer acetazolamide prophylaxis to prevent HAI., (© International Society of Travel Medicine 2020. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The human pulmonary vasculature vasoconstricts in response to a reduction in alveolar oxygen tension, a phenomenon termed hypoxic pulmonary vasoconstriction (HPV). This review describes the time course of this behavior, which occurs in distinct phases, and then explores the importance for HPV of the hypoxia-inducible factor (HIF) pathway. Next, the HIF-hydroxylase enzymes that act as molecular oxygen sensors within the HIF pathway are discussed. These enzymes are particularly sensitive to intracellular iron availability, which confers iron-sensing properties on the HIF pathway. Human studies of iron chelation and supplementation are then reviewed. These demonstrate that the iron sensitivity of the HIF pathway evident from in vitro experiments is relevant to human pulmonary vascular physiology. Next, the importance of iron status in high-altitude illness and chronic cardiopulmonary disease is explored, and the therapeutic potential of intravenous iron discussed. The review concludes by highlighting some further complexities that arise from interactions between the HIF pathway and other intracellular iron-sensing mechanisms., (Copyright © 2015 the American Physiological Society.)