High-altitude pulmonary edema: the intercellular network hypothesis.

The pathophysiology of high-altitude pulmonary edema is currently attributed to exacerbated heterogeneous hypoxic pulmonary vasoconstriction. However, although other cellular mechanisms have been hypothesized, they are still poorly understood. In this review, we focused on cells of the pulmonary acinus, the distal unit for gas exchange, known to be responders to acute hypoxia, notably through many humoral or tissue factors that connect this intercellular network constituting the alveolo-capillary barrier. Hypoxia could drive alveolar edema by: 1) damaging the fluid reabsorption capacity of alveolar epithelial cells, 2) increasing the endothelial and epithelial permeability, especially by alteration of occluding junctions, 3) triggering the inflammation mainly led by alveolar macrophages, 4) increasing interstitial water accumulation by disruption of extracellular matrix architecture and tight junctions, 5) inducing pulmonary vasoconstriction through an orchestrated response of pulmonary arterial endothelial and smooth muscle cells. Hypoxia may also alter the function of fibroblasts and pericytes that contribute to the interconnection of the cells of the alveolar-capillary barrier. Due to its complex intercellular network and delicate pressure gradient equilibrium, the alveolar-capillary barrier is simultaneously affected by acute hypoxia in all its components, leading to rapid accumulation of water in the alveoli.

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. ABSTRACT: 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 V̇O2peak 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 V̇O2peak 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.

Modelling the relationships between arterial oxygen saturation, exercise intensity and the level of aerobic performance in acute hypoxia.

PURPOSE: The aim of this study was to establish a model to estimate the level of arterial oxygen saturation (SpO2) and help determine the appropriate hypoxic dose in humans exercising in acute hypoxia. METHODS: SpO2 values were collected in seven untrained (UTS) and seven endurance-trained male subjects (ETS) who performed six cycle incremental and maximal tests at sea level and at simulated altitudes of 1000, 1500, 2500, 3500 and 4500 m. Oxygen uptake was continuously measured and maximal oxygen uptake ([Formula: see text]) was determined in each subject and at each altitude. Intensity was expressed as percentage of [Formula: see text]. RESULTS: There were strong non-linear relationships between altitude and SpO2 at low, moderate and high intensity both in ETS and UTS (r = 0.97, p < 0.001). SpO2 was significantly correlated to exercise intensity at sea level and at all simulated altitudes in ETS but only from 2500 m in UTS. There were inverse correlations between SpO2 and sea-level [Formula: see text] at all altitudes, which were stronger from 2500 m and with the increase in exercise intensity. The three-variable model we established predicts (p < 0.001) the SpO2 level of individuals exercising in acute hypoxia based on their sea-level [Formula: see text], the intensity of exercise and the altitude level. CONCLUSION: The model demonstrates that the drop of SpO2 during exercise in acute hypoxia is larger with the increase in both sea-level [Formula: see text] and exercise intensity. The model also highlights that the pivotal altitude from which the fall in SpO2 is exacerbated is between 2000 and 2500 m, depending on both sea-level [Formula: see text] and exercise intensity.

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

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

Low-frequency ventilatory oscillations in hypoxia are a major contributor to the low-frequency component of heart rate variability.

PURPOSE: Heart rate variability (HRV) may be influenced by several factors, such as environment (hypoxia, hyperoxia, hypercapnia) or physiological demand (exercise). In this retrospective study, we tested the hypothesis that inter-beat (RR) intervals in healthy subjects exercising under various environmental stresses exhibit oscillations at the same frequency than ventilatory oscillations. METHODS: Spectra from RR intervals and ventilation ([Formula: see text]E) were collected from 37 healthy young male subjects who participated in 5 previous studies focused on ventilatory oscillations (or periodic breathing) during exercise in hypoxia, hyperoxia and hypercapnia. Bland and Altman test and multivariate regressions were then performed to compare respective frequencies and changes in peak powers of the two signals. RESULTS: Fast Fourier analysis of RR and [Formula: see text]E signals showed that RR was oscillating at the same frequency than periodic breathing, i.e., ~ 0.09 Hz (11 s). During exercise, in these various conditions, the difference between minimum and maximum HRV peak power was positively correlated to the same change in ventilation peak power (P < 0.05). Low-frequency (LF) peak power was correlated to tidal volume (P < 0.01) and breathing frequency (P < 0.001). CONCLUSIONS: This study suggests that low-frequency ventilatory oscillations in hypoxia are a major contributor to the LF band power of heart rate variability. CLINICAL TRIAL REG. NO.: NCT02201875.

Electrocardiographic changes during exercise in acute hypoxia and susceptibility to severe high-altitude illnesses.

BACKGROUND: The goals of this study were to compare ECG at moderate exercise in normoxia and hypoxia at the same heart rate, to provide evidence of independent predictors of hypoxia-induced ECG changes, and to evaluate ECG risk factors of severe high-altitude illness. METHODS AND RESULTS: A total of 456 subjects performed a 20-minute hypoxia exercise test with continuous recording of ECG and physiological measurements before a sojourn above 4000 m. Hypoxia did not induce any conduction disorder, arrhythmias, or change in QRS axis. The amplitude of the P wave in V1 was lower in hypoxia than in normoxia. The amplitudes of the R, S, and T waves and the Sokolow index decreased in hypoxia. Under hypoxia, the amplitude of the ST segment decreased in II and V6 and increased in V1, the ST slope rose in V5 and V6, and the J point was lower in II, V5, and V6. Multivariate regression of hypoxic/normoxic ratios of electrophysiological parameters and clinical characteristics showed a correlation between the decrease in Sokolow index and T-wave amplitude in V5 with desaturation at exercise. Trained status and low body mass index were associated with a smaller decrease in T-wave amplitude in V5 and V6. Comparison of ECG between subjects suffering or not suffering from severe high-altitude illness failed to show any difference. CONCLUSIONS: During a hypoxia exercise test, a dose-dependent hypoxia-induced decrease in the amplitude of the P/QRS/T waves was observed. No standard ECG characteristic predicted the risk of developing severe high-altitude illness. Further studies are required to clarify the cause of these electric changes and their potential predictive role in cardiac events.

Ventilatory oscillations at exercise in hypoxia: A mathematical model.

We evaluated the mechanisms responsible for the instability of ventilation control system under simultaneous metabolic (exercise) and environmental (hypoxia) stresses, promoting the genesis of periodic breathing. A model following the main concepts of ventilatory control has been tested, including cardiovascular and respiratory parameters, characteristics of peripheral and central chemoreceptors, at mild exercise in hypoxia (FIO2=0.145). Interaction between O2 and CO2 sensing was introduced following three different modalities. A sensitivity and multivariate regression analyses closely matched with physiological data for magnitude and period of oscillations. Low FIO2 and long circulatory delay from lungs to peripheral chemoreceptors (DeltaTp) lengthen the period of oscillations, while high peripheral and central chemoresponses to O2 and CO2, low FIO2 and high DeltaTp increased their magnitude. Peripheral and central O2/CO2 interactions highlight the role of CO2 on peripheral gain to O2 and the contribution of peripheral afferences on central gain to CO2. Our model supports the key role of peripheral chemoreceptors in the genesis of ventilatory oscillations. Differences in the dynamics of central and peripheral components might be determinant for the system stability.

Physiological and Clinical Implications of Adrenergic Pathways at High Altitude.

The adrenergic system is part of a full array of mechanisms allowing the human body to adapt to the hypoxic environment. Triggered by the stimulation of peripheral chemoreceptors, the adrenergic centers in the medulla are activated in acute hypoxia and augment the adrenergic drive to the organs, especially to the heart, leading to tachycardia. With prolonged exposure to altitude hypoxia, the adrenergic drive persists, as witnessed by elevated blood concentrations of catecholamines and nerve activity in adrenergic fibers. In response to this persistent stimulation, the pathways leading to the activation of adenylate cyclase are modified. A downregulation of ß-adrenergic and adenosinergic receptors is observed, while muscarinic receptors are upregulated. The expression and activity of Gi and Gs proteins are modified, leading to a decreased response of adenylate cyclase activity to adrenergic stimulation. The clinical consequences of these cellular and molecular changes are of importance, especially for exercise performance and protection of heart function. The decrease in maximal exercise heart rate in prolonged hypoxia is fully accounted for the observed changes in adrenergic and muscarinic pathways. The decreased heart rate response to isoproterenol infusion is another marker of the desensitization of adrenergic pathways. These changes can be considered as mechanisms protecting the heart from a too high oxygen consumption in conditions where the oxygen availability is severely reduced. Similarly, intermittent exposure to hypoxia has been shown to protect the heart from an ischemic insult with similar mechanisms involving G proteins and downregulation of ß receptors. Other pathways with G proteins are concerned in adaptation to hypoxia, such as lactate release by the muscles and renal handling of calcium. Altogether, the activation of the adrenergic system is useful for the acute physiological response to hypoxia. With prolonged exposure to hypoxia, the autonomous nervous system adapts to protect vital organs, especially the heart, against a too high energetic state, via a purely local autoregulation mechanism necessary for the preservation of overall homeostasis.

Comparative ventilatory strategies of acclimated rats and burrowing plateau pika (Ochotona curzoniae) in response to hypoxic-hypercapnia.

The objective of this study was to compare the different ventilatory strategies that help in coping with hypoxic-hypercapnia environment among two species: use acclimated rats and plateau pikas (Ochotona curzoniae) that live in Tibetan plateaus, and have been well adjusted to high altitude. Arterial blood samples taken at 4100 m of elevation in acclimatized rats and adapted pikas revealed inter-species differences with lower hemoglobin and hematocrit and higher blood pH in pikas. A linear and significant increase in minute ventilation was observed in pikas, which help them to cope with hypoxic-hypercapnia. Pikas also displayed a high inspiratory drive and an invariant respiratory timing regardless of the conditions. Biochemical analysis revealed that N-methyl-D-aspartate receptor (NMDA) receptor gene and nNOS gene are highly conserved between rats and pikas, however pikas have higher expression of NMDA receptors and nNOS compared to rats at the brainstem level. Taken together, these results suggest that pikas have developed a specific ventilatory pattern supported by a modification of the NMDA/NO ventilatory central pathways to survive in extreme conditions imposed on the Tibetan plateaus. These physiological adaptive strategies help in maintaining a better blood oxygenation despite high CO2 concentration in burrows at high altitude.

Cardiovascular physiology and pathophysiology at high altitude.

Oxygen is vital for cellular metabolism; therefore, the hypoxic conditions encountered at high altitude affect all physiological functions. Acute hypoxia activates the adrenergic system and induces tachycardia, whereas hypoxic pulmonary vasoconstriction increases pulmonary artery pressure. After a few days of exposure to low oxygen concentrations, the autonomic nervous system adapts and tachycardia decreases, thereby protecting the myocardium against high energy consumption. Permanent exposure to high altitude induces erythropoiesis, which if excessive can be deleterious and lead to chronic mountain sickness, often associated with pulmonary hypertension and heart failure. Genetic factors might account for the variable prevalence of chronic mountain sickness, depending on the population and geographical region. Cardiovascular adaptations to hypoxia provide a remarkable model of the regulation of oxygen availability at the cellular and systemic levels. Rapid exposure to high altitude can have adverse effects in patients with cardiovascular diseases. However, intermittent, moderate hypoxia might be useful in the management of some cardiovascular disorders, such as coronary heart disease and heart failure. The aim of this Review is to help physicians to understand the cardiovascular responses to hypoxia and to outline some recommendations that they can give to patients with cardiovascular disease who wish to travel to high-altitude destinations.

A Step Test to Evaluate the Susceptibility to Severe High-Altitude Illness in Field Conditions.

Hermand, Eric, Léo Lesaint, Laura Denis, Jean-Paul Richalet, and François J. Lhuissier. A step test to evaluate the susceptibility to severe high-altitude illness in field conditions. High Alt Med Biol. 25:158-163, 2024.-A laboratory-based hypoxic exercise test, performed on a cycle ergometer, can be used to predict susceptibility to severe high-altitude illness (SHAI) through the calculation of a clinicophysiological SHAI score. Our objective was to design a field-condition test and compare its derived SHAI score and various physiological parameters, such as peripheral oxygen saturation (SpO2), and cardiac and ventilatory responses to hypoxia during exercise (HCRe and HVRe, respectively), to the laboratory test. A group of 43 healthy subjects (15 females and 28 males), with no prior experience at high altitude, performed a hypoxic cycle ergometer test (simulated altitude of 4,800 m) and step tests (20 cm high step) at 3,000, 4,000, and 4,800 m simulated altitudes. According to tested altitudes, differences were observed in O2 desaturation, heart rate, and minute ventilation (p < 0.001), whereas the computed HCRe and HVRe were not different (p = 0.075 and p = 0.203, respectively). From the linear relationships between the step test and SHAI scores, we defined a risk zone, allowing us to evaluate the risk of developing SHAI and take adequate preventive measures in field conditions, from the calculated step test score for the given altitude. The predictive value of this new field test remains to be validated in real high-altitude conditions.

Denis Jourdanet (1815-1892) and the early recognition of the role of hypoxia at high altitude.

Denis Jourdanet (1815-1892) was a French physician who spent many years in Mexico studying the effects of high altitude. He was a major benefactor of Paul Bert (1833-1886), who is often called the father of high-altitude physiology because his book La pression barométrique was the first clear statement that the harmful effects of high altitude are caused by the low partial pressure of oxygen. However, Bert's writings make it clear that the first recognition of the critical role of hypoxia at high altitude should be credited to Jourdanet. Jourdanet noted that some of his patients at high altitude had features that are typical of anemia at sea level, including rapid pulse, dizziness, and occasional fainting spells. These symptoms were correctly attributed to the low oxygen level in the blood and he coined the terms "anoxyhémie" and "anémie barométrique" to draw a parallel between the effects of high altitude on the one hand and anemia at sea level on the other. He also studied the relations between barometric pressure and altitude, and the characteristics of the native populations in Mexico at different altitudes. Jourdanet believed that patients with various diseases including pulmonary tuberculosis were improved if they went to altitudes above 2,000 m. This led him to recommend "aérothérapie" in which these patients were treated in low-pressure chambers. Little has been written about Jourdanet, and his work deserves to be better known.

Effect of inositol hexaphosphate-loaded red blood cells (RBCs) on the rheology of sickle RBCs.

BACKGROUND: The recent in vitro demonstration that inositol hexaphosphate-loaded red blood cells (IHP-RBCs) may reduce the risks of sickling of sickle RBCs (SS RBCs) exposed to hypoxia make these modified RBCs potentially useful in transfused sickle cell anemia (SCA) patients. STUDY DESIGN AND METHODS: Hemorheologic properties of IHP-RBCs, normal RBCs (AA RBCs), SS RBCs, SS RBCs plus AA RBCs, and SS RBCs plus IHP-RBCs were compared under normoxia and/or after hypoxic challenges. RESULTS: Although IHP-RBCs have reduced deformability compared with SS RBCs or AA RBCs, IHP-RBCs exhibited lower aggregability than AA RBCs and SS RBCs and, when mixed with SS RBCs, the aggregation level was below the one of SS RBCs alone or SS RBCs plus AA RBCs. Blood viscosity of SS RBC plus IHP-RBC suspension was lower than the viscosity of SS RBCs alone and greater than viscosity of SS RBCs plus AA RBCs. The hypoxic challenge was detrimental for deformability and viscosity of SS RBCs alone or SS plus AA RBC suspension but not for SS plus IHP-RBC suspension. CONCLUSION: Our results support the fact that IHP-RBCs could be useful in SCA by decreasing RBC aggregation and blunting the adverse effects of hypoxia on RBC deformability and blood viscosity.

Physiological risk factors for severe high-altitude illness: a prospective cohort study.

RATIONALE: An increasing number of persons, exposed to high altitude for leisure, sport, or work, may suffer from severe high-altitude illness. OBJECTIVES: To assess, in a large cohort of subjects, the association between physiological parameters and the risk of altitude illness and their discrimination ability in a risk prediction model. METHODS: A total of 1,326 persons went through a hypoxic exercise test before a sojourn above 4,000 m. They were then monitored up at high altitude and classified as suffering from severe high-altitude illness (SHAI) or not. Analysis was stratified according to acetazolamide use. MEASUREMENTS AND MAIN RESULTS: Severe acute mountain sickness occurred in 314 (23.7%), high-altitude pulmonary edema in 22 (1.7%), and high-altitude cerebral edema in 13 (0.98%) patients. Among nonacetazolamide users (n = 917), main factors independently associated with SHAI were previous history of SHAI (adjusted odds ratios [aOR], 12.82; 95% confidence interval [CI], 6.95-23.66; P < 0.001), ascent greater than 400 m/day (aOR, 5.89; 95% CI, 3.78-9.16; P < 0.001), history of migraine (aOR, 2.28; 95% CI, 1.28-4.07; P = 0.005), ventilatory response to hypoxia at exercise less than 0.78 L/minute/kg (aOR, 6.68; 95% CI, 3.83-11.63; P < 0.001), and desaturation at exercise in hypoxia equal to or greater than 22% (aOR, 2.50; 95% CI, 1.52-4.11; P < 0.001). The last two parameters improved substantially the discrimination ability of the multivariate prediction model (C-statistic rose from 0.81 to 0.88; P < 0.001). Preventive use of acetazolamide reduced the relative risk of SHAI by 44%. CONCLUSIONS: In a large population of altitude visitors, chemosensitivity parameters (high desaturation and low ventilatory response to hypoxia at exercise) were independent predictors of severe high-altitude illness. They improved the discrimination ability of a risk prediction model.

Effects of a high-carbohydrate versus high-protein meal on acute responses to hypoxia at rest and exercise.

A carbohydrate (CHO) solution consumed before exposure to hypoxia has been reported to reduce arterial oxygen desaturation at rest. The purpose of this study was to determine whether this effect occurred during exercise and when the CHO load is part of a meal. Eleven male subjects (mean age 20.1 ± 1.8 years, BMI 24.3 ± 2.4 kg m(2)) consumed either a high-CHO (2,340 kJ, 70 % CHO, 12 % protein) or an isoenergetic high-protein (35 % CHO, 48 % protein) breakfast meal 60 min before being exposed to 15 min of hypoxia (F(I)O(2) = 13.5 %) followed by 30 min of exercise in hypoxia (60 % of VO2max). Saturation of oxygen via a pulse oxymeter (SpO(2)), ventilatory parameters, substrate oxidation, interstitial glucose concentrations, and heart rate variability (HRV) were monitored continuously during the whole session. Results showed no effect from the type of meal on SpO(2) at rest but a 3.1 ± 0.4 % reduction of desaturation during exercise (P < 0.005) compared to the high-protein version. This was associated with higher levels of ventilation (P < 0.05) and CO(2) production (P < 0.01). Glucose oxidation was higher after the high-CHO than the high-protein breakfast over the whole session (+19.4 + 4.0 %, P < 0.0001), whereas the interstitial glucose levels were increased only at rest (P < 0.001). HRV indices were not different between conditions. In conclusion, a high-CHO meal consumed prior to moderate exercise in hypoxia condition reduced oxygen desaturation compared to a high-protein meal.

The Impact of COVID-19 on the Response to Hypoxia.

Louis, Alexandre, Charlotte Pröpper, Yann Savina, Corentin Tanne, Guy Duperrex, Paul Robach, Pascal Zellner, Stéphane Doutreleau, Jean-Michel Boulet, Alain Frey, Fabien Pillard, Cristina Pistea, Mathias Poussel, Thomas Thuet, Jean-Paul Richalet, and François Lecoq-Jammes. The impact of COVID-19 on the response to hypoxia. High Alt Med Biol. 24:321-328, 2023. Background: Severe high-altitude illness (SHAI) and coronavirus disease 2019 (COVID-19), while differing in most aspects of pathophysiology, both involve respiratory capacity. We examined the long-term impact of COVID-19 on response to hypoxia in individuals free of symptoms but having tested positive during the pandemic. The need for recommendations for such individuals planning a stay at high altitude are discussed. Methods: This multicenter study recruited participants from the multiSHAI cohort, all of whom had previously undergone a hypoxic exercise test. These participants were classified into two groups depending on whether they had since suffered mild-to-moderate COVID-19 (COVID+) or not (Control) and then asked to retake the test. Primary outcomes were: desaturation induced by hypoxia at exercise (ΔSpE), hypoxic cardiac response at exercise, hypoxic ventilatory response at exercise, and SHAI risk score. Results: A total of 68 participants retook the test, 36 classified in the COVID+ group. Analyses of primary outcomes showed no significant differences between groups. However, the COVID+ group showed significantly increased ventilation (VE) parameters during both hypoxic (p = 0.003) and normoxic exercise (p = 0.007). However, only the VE/oxygen consumption relationship during hypoxic exercise was significantly different. Conclusion: This study demonstrates no negative impact of COVID-19 on response to hypoxia as evaluated by the Richalet test. Clinical Trial Registration: NTC number: NCT05167357.

Ageing and cardiorespiratory response to hypoxia.

The risk of severe altitude-induced diseases is related to ventilatory and cardiac responses to hypoxia and is dependent on sex, age and exercise training status. However, it remains unclear how ageing modifies these physiological adaptations to hypoxia. We assessed the physiological responses to hypoxia with ageing through a cross-sectional 20 year study including 4675 subjects (2789 men, 1886 women; 14-85 years old) and a longitudinal study including 30 subjects explored at a mean 10.4 year interval. The influence of sex, training status and menopause was evaluated. The hypoxia-induced desaturation and the ventilatory and cardiac responses to hypoxia at rest and exercise were measured. In men, ventilatory response to hypoxia increased (P < 0.002), while desaturation was less pronounced (P < 0.001) with ageing. Cardiac response to hypoxia was blunted with ageing in both sexes (P < 0.001). Similar results were found in the longitudinal study, with a decrease in cardiac and an increase in ventilatory response to hypoxia with ageing. These adaptive responses were less pronounced or absent in post-menopausal women (P < 0.01). At exercise, desaturation was greater in trained subjects but cardiac and ventilatory responses to hypoxia were preserved by training, especially in elderly people. In conclusion, respiratory response to hypoxia and blood oxygenation improve with ageing in men while cardiac response is blunted with ageing in both sexes. Training aggravates desaturation at exercise in hypoxia, improves the ventilatory response and limits the ageing-induced blunting of cardiac response to hypoxia. Training limits the negative effects of menopause in cardiorespiratory adaptations to hypoxia.