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Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500 m throughout the world. Among them, 50 000 live in the world's highest city, La Rinconada, located at 5000-5300 m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude-related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3 ± 2.4 g/dL; n = 57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1 ± 1.7 g/dL; n = 150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24 h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO 2  = 79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Since vascular responses to hypoxia in both healthy high-altitude natives and chronic mountain sickness (a maladaptive high-altitude pathology characterised by excessive erythrocytosis and the presence of symptoms-CMS) remain unclear, the role of inflammation and oxidative/nitrosative stress on the endothelium- dependent and - independent responses in both the micro- and macrocirculation, in healthy Andeans at different altitudes and in CMS patients, was examined., Methods: 94 men were included: 18 lowlanders (LL), 38 healthy highlanders permanently living at 3800 m (n = 21-HL-3800) or in La Rinconada, the highest city in the world (5100-5300 m) (n = 17-HL-5100/No CMS). Moreover, 14 participants with mild (Mild CMS) and 24 with moderate to severe CMS (Mod/Sev CMS) were recruited. All undertook two reactivity tests: i) local thermal hyperaemia (microcirculation) and ii) flow-mediated dilation (macrocirculation). Endothelium- independent function (glyceryl trinitrate) was also assessed only in La Rinconada., Findings: Conductance and skin blood flow velocity during the microcirculation test, as well as macrocirculation progressively decreased with altitude (LL > HL-3800 > HL-5100/No CMS). CMS also induced a decrease in macrocirculation (HL-5100/No CMS > Mild CMS = Mod/Sev CMS), while glyceryl trinitrate restored vascular function. Both oxidative stress and nitric oxide metabolites increased with altitude only. Principal component analysis revealed that increasing inflammation with altitude was associated with a progressive decline in both micro- and macrovascular function in healthy highlanders., Interpretation: Both micro and macrovascular function are affected by chronic exposure to hypoxia, the latter being further compounded by CMS., Funding: The "Fonds de dotation AGIR pour les maladies chroniques", the "Air Liquide Foundation", and the "French National Research Agency"., Competing Interests: None., (© 2024 The Authors.)

Objective: Obstructive Sleep Apnea (OSA) is known to impact morbidity in the perioperative period through a postoperative exacerbation of respiratory events after general anesthesia. Cardiac arrhythmias may be triggered by respiratory and/or hypoxic events, therefore we searched for a temporal link between cardiac arrhythmias and episodes of hypoxemia following surgery under general anesthesia during the nocturnal sleep phase., Methods: We included patients with a preoperative STOP-BANG questionnaire score between 3 and 8, planned for an elective surgery with general anesthesia. Patients had a preoperative sleep study (N0) and two postoperative sleep studies on the first (N1) and third (N3) night after surgery. Patients with mild-to-moderate OSA (apnea/hypopnea index (AHI) between 15 and 30) were compared to patients with an AHI <15 (nil-mild OSA group). Analysis was conducted to detect concomitant hypoxic episodes and cardiac arrhythmias as defined by auricular or ventricular premature complexes, ventricular or supraventricular arrhythmias., Main Results: 39 patients comprised the moderate-OSA group and 12 patients the nil-mild OSA group. In the whole cohort, the incidence of cardiac arrhythmias associated with hypoxic episodes was increased at N3 compared to N0 (median: 1 event per hour of recorded time [IQR: 0; 4] vs 0 [0; 2], p = 0.04). We observed this in the OSA group compared to the nil-mild OSA group (1 [0; 4] vs 1 [0; 2], respectively; p = 0.02)., Conclusion: This study indicates that more cardiac arrhythmias associated with hypoxemic episodes can be observed in the postoperative night, in patients with moderate OSA. This reinforces the importance of preoperative screening for OSA., Clinical Trial Registry: NCT02833662., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Approximately 30% of people infected with COVID-19 require hospitalization, and 20% of them are admitted to an intensive care unit (ICU). Most of these patients experience symptoms of fatigue weeks post-ICU, so understanding the factors associated with fatigue in this population is crucial., Methods: Fifty-nine patients (38-78 yr) hospitalized in ICU for COVID-19 infection for 32 (6-80) d, including 23 (3-57) d of mechanical ventilation, visited the laboratory on two separate occasions. The first visit occurred 52 ± 15 d after discharge and was dedicated to questionnaires, blood sampling, and cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function and performance fatigability were performed in the second visit 7 ± 2 d later., Results: Using the FACIT-F questionnaire, 56% of patients were classified as fatigued. Fatigued patients had worse lung function score than non-fatigued (i.e., 2.9 ± 0.8 L vs 3.6 ± 0.8 L; 2.4 ± 0.7 L vs 3.0 ± 0.7 L for forced vital capacity and forced expiratory volume in 1 s, respectively), and forced vital capacity was identified as a predictor of being fatigued. Maximal voluntary activation was lower in fatigued patients than non-fatigued patients (82% ± 14% vs 91% ± 3%) and was the only neuromuscular variable that discriminated between fatigued and non-fatigued patients. Patient-reported outcomes also showed differences between fatigued and non-fatigued patients for sleep, physical activity, depression, and quality of life ( P < 0.05)., Conclusions: COVID-19 survivors showed altered respiratory function 4 to 8 wk after discharge, which was further deteriorated in fatigued patients. Fatigue was also associated with lower voluntary activation and patient-reported impairments (i.e., sleep satisfaction, quality of life, or depressive state). The present study reinforces the importance of exercise intervention and rehabilitation to counteract cardiorespiratory and neuromuscular impairments of COVID-19 patients admitted in ICU, especially individuals experiencing fatigue., (Copyright © 2024 by the American College of Sports Medicine.)

Champigneulle, Benoit, Ivan Hancco, Richard Renan, Stéphane Doutreleau, Emeric Stauffer, Aurélien Pichon, Julien V. Brugniaux, Hélène Péré, Pierre Bouzat, David Veyer, and Samuel Verges. High-altitude environment and COVID-19: SARS-CoV-2 seropositivity in the highest city in the world. High Alt Med Biol. 22: 000-000, 2021. Background: A reduced coronavirus disease 2019 (COVID-19) diffusion has been suggested in high-altitude areas but remained questionable. Aims of this study were to estimate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seropositivity as well as the risk factors associated in La Rinconada, the highest city in the world (5,100-5,300 m), a gold-mining town located in southeastern Peru where >50,000 dwellers live in precarious sanitary conditions. Materials and Methods: We performed a cross-sectional study during a 1-week period in October 2020, using point-of-care lateral flow serological assays allowing detection of antibodies directed against SARS-CoV-2 among voluntary dwellers in La Rinconada. Participants were also questioned about potential occupational and environmental risk factors of COVID-19 occurrence. Results: In a sample of 159 dwellers tested in La Rinconada, 48.4% [95% confidence interval, CI: 40.5-56.4] were seropositive for the SARS-CoV-2. Occurrence of at least one symptom compatible with the COVID-19 over the past 6 months remained the only significant factor associated with SARS-CoV-2 seropositivity (adjusted odds ratio: 3.27; [95% CI: 1.70-6.44]; p  < 0.001). Conclusions: The high rate of SARS-CoV-2 seropositivity observed in this small sample of highlanders does not support a protective effect of high-altitude against the COVID-19 spread and demonstrates its large dissemination in vulnerable populations. Clinical Trial Registration number: NCT04604249.

It is well established that physical activity reduces all-cause mortality and can prolong life. Ultra-endurance running (UER) is an extreme sport that is becoming increasingly popular, and comprises running races above marathon distance, exceeding 6 h, and/or running fixed distances on multiple days. Serious acute adverse events are rare, but there is mounting evidence that UER may lead to long-term health problems. The purpose of this review is to present the current state of knowledge regarding the potential long-term health problems derived from UER, specifically potential maladaptation in key organ systems, including cardiovascular, respiratory, musculoskeletal, renal, immunological, gastrointestinal, neurological, and integumentary systems. Special consideration is given to youth, masters, and female athletes, all of whom may be more susceptible to certain long-term health issues. We present directions for future research into the pathophysiological mechanisms that underpin athlete susceptibility to long-term issues. Although all body systems can be affected by UER, one of the clearest effects of endurance exercise is on the cardiovascular system, including right ventricular dysfunction and potential increased risk of arrhythmias and hypertension. There is also evidence that rare cases of acute renal injury in UER could lead to progressive renal scarring and chronic kidney disease. There are limited data specific to female athletes, who may be at greater risk of certain UER-related health issues due to interactions between energy availability and sex-hormone concentrations. Indeed, failure to consider sex differences in the design of female-specific UER training programs may have a negative impact on athlete longevity. It is hoped that this review will inform risk stratification and stimulate further research about UER and the implications for long-term health., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Antoine Charton,1 François Péronnet,2 Stephane Doutreleau,3 Evelyne Lonsdorfer,3 Alexis Klein,4 Liliana Jimenez,4 Bernard Geny,3 Pierre Diemunsch,1 Ruddy Richard5 1Department of Anesthesia and Critical Care, and EA 3072, Hôpital de Hautepierre; University of Strasbourg, Strasbourg, France; 2Department of Kinesiology, Université de Montréal, Montreal, QC, Canada; 3CHRU of Strasbourg, Physiology and Functional Explorations Department, New Civil Hospital, Strasbourg, France and University of Strasbourg, Faculty of Medicine, Physiology Department, Strasbourg, France; 4Danone Research, Palaiseau, France; 5Department of Sport Medicine and Functional Explorations, CHU Clermont-Ferrand and INRA UMR 1019, CRNH-Auvergne, Clermont-Ferrand, France Background: Oral administration of oxygenated water has been shown to improve blood oxygenation and could be an alternate way for oxygen (O2) supply. In this experiment, tissue oxygenation was compared in anesthetized pigs receiving a placebo or water enriched in O2 by injection or a new electrolytic process. Methods: Forty-two pigs randomized in three groups received either mineral water as placebo or water enriched in O2 by injection or the electrolytic process (10 mL/kg in the stomach). Hemodynamic parameters, partial pressure of oxygen in the arterial blood (PaO2), skin blood flow, and tissue oxygenation (transcutaneous oxygen pressure, or TcPO2) were monitored during 90 minutes of general anesthesia. Absorption and tissue distribution of the three waters administered were assessed using dilution of deuterium oxide. Results: Mean arterial pressure, heart rate, PaO2, arteriovenous oxygen difference, and water absorption from the gut were not significantly different among the three groups. The deuterium to protium ratio was also similar in the plasma, skin, and muscle at the end of the protocol. Skin blood flow decreased in the three groups. TcPO2 slowly decreased over the last 60 minutes of the experiment in the three groups, but when compared to the control group, the values remained significantly higher in animals that received the water enriched in O2 by electrolysis. Conclusions: In this protocol, water enriched in O2 by electrolysis lessened the decline of peripheral tissue oxygenation. This observation is compatible with the claim that the electrolytic process generates water clathrates which trap O2 and facilitate O2 diffusion along pressure gradients. Potential applications of O2-enriched water include an alternate method of oxygen supply. Keywords: transcutaneous oxygen partial pressure determination, tissue oxygenation, oxygenated water, water clathrate

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.

Non-communicable diseases (NCDs), including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression and cancers, are on the rise worldwide and are often associated with a lack of physical activity (PA). Globally, the levels of PA among individuals are below WHO recommendations. A lack of PA can increase morbidity and mortality, worsen the quality of life and increase the economic burden on individuals and society. In response to this trend, numerous organisations came together under one umbrella in Hamburg, Germany, in April 2021 and signed the 'Hamburg Declaration'. This represented an international commitment to take all necessary actions to increase PA and improve the health of individuals to entire communities. Individuals and organisations are working together as the 'Global Alliance for the Promotion of Physical Activity' to drive long-term individual and population-wide behaviour change by collaborating with all stakeholders in the community: active hospitals, physical activity specialists, community services and healthcare providers, all achieving sustainable health goals for their patients/clients. The 'Hamburg Declaration' calls on national and international policymakers to take concrete action to promote daily PA and exercise at a population level and in healthcare settings., Competing Interests: Competing interests: EV is Editor in Chief of BMJ Open Sports & Exercise Medicine., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Nitric oxide (NO) precursor supplementation has been shown to increase NO bioavailability and can potentially improve vascular function and exercise performance. It remains unclear whether the combination of NO precursor supplementation and exercise training has synergic effects on exercise performance. This study aims to assess the effect of chronic nitrate and citrulline intake on exercise training adaptations in healthy young individuals., Methods: In this randomized, double-bind trial, 24 healthy young (12 females) subjects performed vascular function assessment (blood pressure, pulse wave velocity, postischemia vasodilation, and cerebrovascular reactivity) and both local (submaximal isometric unilateral knee extension) and whole-body (incremental cycling) exercise tests to exhaustion before and after a 2-month exercise training program and daily intake of a placebo or a nitrate-rich salad and citrulline (N + C, 520 mg nitrate and 6 g citrulline) drink. Prefrontal cortex and quadriceps oxygenation was monitored continuously during exercise by near-infrared spectroscopy., Results: N + C supplementation had no effect on vascular function and muscle and cerebral oxygenation during both local and whole-body exercise. N + C supplementation induced a significantly larger increase in maximal knee extensor strength (+5.1 ± 3.5 vs +0.2 ± 5.5 kg, P = 0.008) as well as a trend toward a larger increase in knee extensor endurance (+35.2 ± 26.1 vs +24.0 ± 10.4 contractions, P = 0.092) than placebo, but no effect on exercise training-induced maximal aerobic performance improvement., Conclusion: These results suggest that chronic nitrate and citrulline supplementation enhances the effect of exercise training on quadriceps muscle function in healthy active young individuals, but this does not translate into improved maximal aerobic performances.

Objective: To determine whether changes in pulmonary vascular resistance (PVR) and changes in pulmonary artery compliance ( C pa ) are associated with changes in exercise capacity assessed either by changes in peak oxygen consumption ( V ' O 2 ) or by changes in 6-min walk distance (6MWD) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing balloon pulmonary angioplasty (BPA)., Methods: Invasive haemodynamic parameters, peak V ' O 2 and 6MWD were measured within 24 h, before and after BPA (interval 3.1±2.4 months) in 34 CTEPH patients without significant cardiac and/or pulmonary comorbidities, of whom 24 received at least one pulmonary hypertension-specific treatment. C pa was calculated according to the pulse pressure method: C pa =((SV/PP)/1.76+0.1), where SV is the stroke volume and PP is the pulse pressure. The resistance-compliance (RC)-time of the pulmonary circulation was calculated as the PVR and C pa product., Results: After BPA, PVR decreased (562±234 versus 290±106 dyn·s·cm -5 ; p<0.001); C pa increased (0.90±0.36 versus 1.63±0.65 mL·mmHg -1 0.321±0.083 s; p=0.75). There were improvements in peak versus 0.321±0.083 s; p=0.75). There were improvements in peak V ' O 2 (1.11±0.35 versus 1.30±0.33 L·min -1 ; p<0.001) and in 6MWD (393±119 versus 432±100 m; p<0.001). After adjustment for age, height, weight and gender, changes in exercise capacity, assessed either by peak V ' O 2 or 6MWD, were significantly associated with changes in PVR, but not with changes in C pa ., Conclusions: Contrary to what has been reported in CTEPH patients undergoing pulmonary endarterectomy, in CTEPH patients undergoing BPA, changes in exercise capacity were not associated with changes in C pa ., Competing Interests: Conflict of interest: The authors do not have any conflict of interest to declare relative to the present study. The results of the present study are presented clearly, honestly, and without fabrication, falsification or inappropriate data manipulation., (Copyright ©The authors 2023.)

Purpose: Exercise-induced laryngeal obstruction (EILO) is suspected when dyspnea associated with upper airway symptoms is triggered by exercise. This condition affects mainly adolescent athletes. Visualization of the obstruction, while the patient is experiencing the symptoms during continuous laryngoscopy during exercise (CLE-test) is the gold standard for diagnosing EILO. Our study aims to evaluate the prevalence of EILO in a population presenting exercise-induced inspiratory symptoms (EIIS) or uncontrolled asthma with exertional symptoms. The second objective was to evaluate the diagnostic strength of laryngology consultation (LC) and pulmonary function tests (PFTs)., Methods: All patients referred to our center for EIIS or uncontrolled asthma with exertional symptoms were included. EILO diagnosis was made if Maat score was > 2 for patients with CLE-test or if there were inspiratory anomalies on PFTs and LC. The sensitivity and specificity of LC and PFTs as diagnostic tools were calculated considering CLE-test as the gold standard., Results: Sixty two patients were referred to our center for EIIS or uncontrolled asthma with exertional symptoms. EILO was diagnosed in 28 patients (56%) with associated asthma in 9 patients (18%). The sensibility and specificity of LC for supraglottic anomalies were 75% and 60%, respectively. The sensibility and specificity of PFTs were 61% and 89%, respectively., Conclusions: There was a high prevalence of EILO among patients with EIIS and uncontrolled asthma. Some clinical characteristics might guide the diagnosis. Nevertheless, CLE-test remained the gold standard for EILO diagnosis and identification of the dysfunctional upper airway site to provide specific management., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background -Adults with Down's syndrome (DS) present lower physical fitness associated with heightened sedentary behaviors and motor skills impairments. Their etiologies and determinants seem to be heterogeneous. This study aims to evaluate physical fitness in adults with DS and to identify specific physical fitness profiles depending on gender and physical activity levels. Methods -Forty adults with DS (16 women, 24 men, 29.7 ± 7.5 years) performed six tests from the EUROFIT Battery and Motor Assessment Battery for Children (MAB-C). Their maximal aerobic capacity was assessed using an incremental treadmill test to assess (VO 2peak ). Ecological, physical activity, and sedentary levels were evaluated subjectively (Global Physical Activity Questionnaire) and objectively using an Actigraph GT9X ® accelerometer over a seven-day period. Results -VO 2peak and isometric strength were significantly lower for women ( p < 0.01), whereas men had significantly lower flexibility than women ( p < 0.05). Using a principal component analysis and an agglomerative hierarchical analysis, we identified three clusters. Cluster 1 (n = 14; 50% men; Body Mass index = 28.3 ± 4.3) was characterized by significantly poorer physical fitness variables (VO 2peak ( p < 0.01), strength ( p < 0.01) and balance ( p < 0.05)) compared to Clusters 2 and 3. Cluster 2 (n = 19; 58% men; Body Mass index = 22.9 ± 2.0) and Cluster 3 (n = 19; 58% men; BMI = 22.9 ± 1.9) were characterized by subjects with comparable physical fitness profiles, except for the balance capacities, which were significantly lower in Cluster 3 ( p < 0.05). Conclusions -DS subjects exhibited high heterogeneity in terms of physical fitness, PA, and sedentary levels, with a significant gender effect. The present findings are important to identify subjects at higher risk of sedentary behaviors and impaired motor capacities to develop personalized PA programs.

Aims: A unique Andean population lives in the highest city of the world (La Rinconada, 5100 m, Peru) and frequently develops a maladaptive syndrome, termed chronic mountain sickness (CMS). Both extreme altitude and CMS are a challenge for the cardiovascular system. This study aims to evaluate cardiac remodelling and pulmonary circulation at rest and during exercise in healthy and CMS highlanders., Methods and Results: Highlanders living permanently at 3800 m (n = 23) and 5100 m (n = 55) with (n = 38) or without CMS (n = 17) were compared with 18 healthy lowlanders. Rest and exercise echocardiography were performed to describe cardiac remodelling, pulmonary artery pressure (PAP), and pulmonary vascular resistance (PVR). Total blood volume (BV) and haemoglobin mass were determined in all people. With the increase in the altitude of residency, the right heart dilated with an impairment in right ventricle systolic function, while the left heart exhibited a progressive concentric remodelling with Grade I diastolic dysfunction but without systolic dysfunction. Those modifications were greater in moderate-severe CMS patients. The mean PAP was higher both at rest and during exercise in healthy highlanders at 5100 m. The moderate-severe CMS subjects had a higher PVR at rest and a larger increase in PAP during exercise. The right heart remodelling was correlated with PAP, total BV, and SpO2., Conclusion: Healthy dwellers at 5100 m exhibit both right heart dilatation and left ventricle concentric remodelling with diastolic dysfunction. Those modifications are even more pronounced in moderate-severe CMS subjects and could represent the limit of the heart's adaptability before progression to heart failure., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Chronic mountain sickness (CMS) is a condition characterized by excessive erythrocytosis in response to chronic hypobaric hypoxia. CMS frequently triggers cardiorespiratory diseases such as pulmonary hypertension and right or left heart failure. Ambient hypoxia might be further amplified night-time by intermittent hypoxia related to sleep-disordered breathing (SDB) so that sleep disturbance may be an important feature of CMS. Our aim was to characterize in a cross-sectional study nocturnal hypoxaemia, SDB, blood pressure (BP), arterial stiffness and carotid intima-media thickness (CIMT) in highlanders living at extreme altitude., Methods: Men aged 18 to 55 years were prospectively recruited. Home sleep apnoea test, questionnaires (short-form health survey; Montreal cognitive assessment; Pittsburgh Sleep Questionnaire Index and the Insomnia severity index), 24-h ambulatory BP monitoring, CIMT and arterial stiffness were evaluated in 3 groups: i) Andean lowlanders (sea-level); ii) highlanders living at 3,800 m and iii) highlanders living at 5,100 m. Analyses were conducted in sub-groups according to 1) CMS severity 2) healthy subjects living at the three different altitude., Results: Ninety-two males were evaluated at their living altitudes. Among the 54 highlanders living at 5,100 m, subjects with CMS showed lower mean nocturnal oxygen saturation (SpO 2 ), SpO 2 nadir, lower pulse wave velocity and higher nocturnal BP variability than those with no-CMS. Lower nocturnal SpO 2 nadir was associated with higher CMS severity (ß= -0.14, p =.009). Among the 55 healthy subjects, healthy highlanders at 5,100 m were characterized by lower scores on quality of life and sleep quality scales and lower mean SpO 2 compared to lowlanders., Conclusions: Lower nocturnal SpO 2 and higher nocturnal BP variability are associated with CMS severity in individuals living permanently at high altitude. The role of lower SpO 2 and higher nocturnal BP variability in the cardiovascular progression of CMS and in the overall prognosis of the disease need to be evaluated in further studies.

Objectives: The aim of the current study was to investigate the level of cardiorespiratory fitness and neuromuscular function of ICU survivors after COVID-19 and to examine whether these outcomes are related to ICU stay/mechanical ventilation duration., Design: Prospective nonrandomized study., Setting: Patients hospitalized in ICU for COVID-19 infection., Patients: Sixty patients hospitalized in ICU (mean duration: 31.9 ± 18.2 d) were recruited 4-8 weeks post discharge from ICU., Interventions: None., Measurements and Main Results: Patients visited the laboratory on two separate occasions. The first visit was dedicated to quality of life questionnaire, cardiopulmonary exercise testing, whereas measurements of the knee extensors neuromuscular function were performed in the second visit. Maximal oxygen uptake (V o2 max) was 18.3 ± 4.5 mL·min -1 ·kg -1 , representing 49% ± 12% of predicted value, and was significantly correlated with ICU stay/mechanical ventilation (MV) duration ( R = -0.337 to -0.446; p < 0.01 to 0.001), as were maximal voluntary contraction and electrically evoked peak twitch. V o2 max (either predicted or in mL· min -1 ·kg -1 ) was also significantly correlated with key indices of pulmonary function such as predicted forced vital capacity or predicted forced expiratory volume in 1 second ( R = 0.430-0.465; p ≤ 0.001) and neuromuscular function. Both cardiorespiratory fitness and neuromuscular function were correlated with self-reported physical functioning and general health status., Conclusions: V o2 max was on average only slightly above the 18 mL·min -1 ·kg -1 , that is, the cut-off value known to induce difficulty in performing daily tasks. Overall, although low physical capacities at admission in ICU COVID-19 patients cannot be ruled out to explain the association between V o2 max or neuromuscular function and ICU stay/MV duration, altered cardiorespiratory fitness and neuromuscular function observed in the present study may not be specific to COVID-19 disease but seem applicable to all ICU/MV patients of similar duration., Competing Interests: Dr. Millet’s institution received funding from Idex Lyon Fellowship and Idex Lyon COVID. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Combining moderate-intensity exercise training with hypoxic exposure may induce larger improvement in cardiometabolic risk factors and health status compared with normoxic exercise training in obesity. Considering the greater cardiometabolic effects of high-intensity intermittent training (HIIT), we hypothesized that hypoxic high-volume HIIT (H-HIIT) would induce greater improvement in cardiorespiratory fitness and health status despite a lower absolute training workload than normoxic HIIT (N-HIIT) in overweight/obesity. Thirty-one subjects were randomized to an 8-week H-HIIT [10 male and 6 female; age: 51.0 ± 8.3 years; body mass index (BMI): 31.5 ± 4 kg·m -2 ] or N-HIIT (13 male and 2 female; age: 52.0 ± 7.5 years; BMI: 32.4 ± 4.8 kg·m -2 ) program (3 sessions/week; cycling at 80% or 100% of maximal workload for H-HIIT and N-HIIT, respectively; target arterial oxygen saturation for H-HIIT 80%, [Formula: see text] ∼0.12, i.e., ∼4,200 meters above sea level). Before and after training, the following evaluations were performed: incremental maximal and submaximal cycling tests, pulse-wave velocity, endothelial function, fasting glucose, insulin, lipid profile, and body composition. Maximal exercise (V̇o 2peak : H-HIIT +14.2% ± 8.3% vs. N-HIIT +12.1 ± 8.8%) and submaximal (ventilatory thresholds) capacity and exercise metabolic responses (power output at the crossover point and at maximal fat oxidation rate) increased significantly in both groups, with no significant difference between groups and without other cardiometabolic changes. H-HIIT induced a greater peak ventilatory response (ANOVA group × time interaction F = 7.4, P = 0.016) compared with N-HIIT. In overweight/obesity, the combination of normobaric hypoxia and HIIT was not superior for improving cardiorespiratory fitness improvement compared with HIIT in normoxia, although HIIT in hypoxia was performed at a lower absolute training workload.

High altitude exposes humans to hypobaric hypoxia, which induces various physiological and molecular changes. Recent studies point toward interaction between circadian rhythms and the hypoxic response, yet their human relevance is lacking. Here, we examine the effect of different high altitudes in conjunction with time of day on human whole-blood transcriptome upon an expedition to the highest city in the world, La Rinconada, Peru, which is 5,100 m above sea level. We find that high altitude vastly affects the blood transcriptome and, unexpectedly, does not necessarily follow a monotonic response to altitude elevation. Importantly, we observe daily variance in gene expression, especially immune-related genes, which is largely altitude dependent. Moreover, using a digital cytometry approach, we estimate relative changes in abundance of different cell types and find that the response of several immune cell types is time- and altitude dependent. Taken together, our data provide evidence for interaction between the transcriptional response to hypoxia and the time of day in humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Left/right prefrontal cortex (PFC) activation is linked to positive/negative affects, respectively. Besides, larger left PFC oxygenation during exercise relates to higher cardiorespiratory fitness (CRF). High-intensity interval training (HIIT) is superior to moderate-intensity continuous training (MICT) in improving CRF. The influence of training on PFC oxygenation and affects during exercise in individuals with obesity is, however, currently unknown. Twenty participants with obesity (14 males, 48 ± 8 years, body-mass index = 35 ± 6 kg·m -2 ) were randomised to MICT [50% peak work rate (WR peak )] or HIIT (1-min bouts 100% WR peak ; 3 sessions/week, 8 weeks). Before/after training, participants completed an incremental ergocycle test. Near-infrared spectroscopy and the Feeling Scale assessed PFC oxygenation and affects during exercise, respectively. Improvements in CRF (e.g., WR peak : 32 ± 14 vs 20 ± 13 W) were greater after HIIT vs MICT ( p < 0.05). Only HIIT induced larger left PFC oxygenation (haemoglobin difference from 7 ± 6 to 10 ± 7 μmol) and enhanced affective valence (from 0.7 ± 2.9 to 2.2 ± 2.0; p < 0.05) at intensities ≥ second ventilatory threshold. Exercise-training induced changes in left PFC oxygenation correlated with changes in CRF [e.g., WR peak (% predicted), r = 0.46] and post-training affective valence (r = 0.45; p < 0.05). HIIT specifically improved left PFC oxygenation and affects during exercise in individuals with obesity. Implementing HIIT in exercise programmes may therefore have relevant implications for the management of obesity, since greater affective response to exercise is thought to be associated with future commitment to physical activity.

Background: There is a paucity of data on cardiovascular sequelae of asymptomatic/mildly symptomatic SARS-Cov-2 infections (COVID)., Objectives: The aim of this prospective study was to characterize the cardiovascular sequelae of asymptomatic/mildly symptomatic COVID-19 among high/elite-level athletes., Methods: 950 athletes (779 professional French National Rugby League (F-NRL) players; 171 student athletes) were included. SARS-Cov-2 testing was performed at inclusion, and F-NRL athletes were intensely followed-up for incident COVID-19. Athletes underwent ECG and biomarker profiling (D-Dimer, troponin, C-reactive protein). COVID(+) athletes underwent additional exercise testing, echocardiography and cardiac magnetic resonance imaging (CMR)., Results: 285/950 athletes (30.0%) had mild/asymptomatic COVID-19 [79 (8.3%) at inclusion (COVID(+) prevalent ); 206 (28.3%) during follow-up (COVID(+) incident )]. 2.6% COVID(+) athletes had abnormal ECGs, while 0.4% had an abnormal echocardiogram. During stress testing (following 7-day rest), COVID(+) athletes had a functional capacity of 12.8 ± 2.7 METS with only stress-induced premature ventricular ectopy in 10 (4.3%). Prevalence of CMR scar was comparable between COVID(+) athletes and controls [COVID(+) vs. COVID(-); 1/102 (1.0%) vs 1/28 (3.6%)]. During 289 ± 56 days follow-up, one athlete had ventricular tachycardia, with no obvious link with a SARS-CoV-2 infection. The proportion with troponin I and CRP values above the upper-limit threshold was comparable between pre- and post-infection (5.9% vs 5.9%, and 5.6% vs 8.7%, respectively). The proportion with D-Dimer values above the upper-limit threshold increased when comparing pre- and post-infection (7.9% vs 17.3%, P = 0.01)., Conclusion: The absence of cardiac sequelae in pauci/asymptomatic COVID(+) athletes is reassuring and argues against the need for systematic cardiac assessment prior to resumption of training (clinicaltrials.gov; NCT04936503)., (© 2022. The Author(s).)

Background: Considering the potential greater cardiocirculatory effects of high intensity interval training (HIIT), we hypothesized that a 2-month supervised high volume short interval HIIT would induce greater improvements in CRF and cardiometabolic risk and increase long-term maintenance to physical activity compared to isocaloric moderate intensity continuous training (MICT) in overweight/obesity., Methods: Sixty (19 females) subjects with overweight/obesity were randomized to three training programs (3 times/week for 2 months): MICT (45 min, 50% peak power output-PPO), HIIT (22 × 1-min cycling at 100% PPO/1-min passive recovery) and HIIT-RM (RM: recovery modulation, i.e. subjects adjusted passive recovery duration between 30s and 2 min). After the intervention, participants no longer benefited from supervised physical activity and were instructed to maintain the same exercise modalities on their own. We assessed anthropometrics, body composition, CRF, fat oxidation, lipid profile, glycemic balance, low-grade inflammation, vascular function, spontaneous physical activity and motivation for eating at three time points: baseline (T0), 4 days after the end of the 2-month supervised training program (T2) and 4 months after the end of the training program (T6)., Results: HIIT/HIIT-RM induced greater improvement in VO 2peak (between +14% and +17%), power output at ventilatory thresholds and at maximal fat oxidation rate (+25%) and waist circumference (-1.53 cm) compared to MICT and tended to decrease insulin resistance. During the four-month follow-up period during which exercise in autonomy was prescribed, HIIT induced a greater preservation of CRF, decreases in total and abdominal fat masses and total cholesterol/HDL., Conclusion: We have shown greater short-term benefits induced by a high volume short interval (1 min) HIIT on cardiorespiratory fitness and cardiometabolic risk over an isocaloric moderate intensity continuous exercise in persons with overweight/obesity. We also showed greater long-term effects (i.e. after 4 months) of this exercise modality on the maintenance of CRF, decreases in total and abdominal fat masses and total cholesterol/HDL., Competing Interests: The authors report no competing financial interest., (© 2022 The Society of Chinese Scholars on Exercise Physiology and Fitness. Published by Elsevier (Singapore) Pte Ltd.)

Purpose: Both prolonged exercise and acute high-altitude exposure are known to induce cardiac changes. We sought to describe the cardiac responses to speed climbing at high-altitude, including left ventricular (LV) performance assessment using the myocardial work index (MWI), a new index derived from 2D speckle tracking echocardiography (STE)., Methods: Eleven elite alpinists (9 males, age: 26 ± 4 years) were evaluated before and immediately after a speed ascent of the Mont-Blanc (4808 m) by echocardiography using conventional measurements as well as STE and MWI computation with derivate parameters as global work efficiency (GWE) or global wasted work (GWW)., Results: Athletes performed a long-duration (8 h 58 min ± 60 min) and intense (78 ± 4% of maximal heart rate) ascent under gradual hypoxic conditions (minimal SpO 2 at 4808 m: 71 ± 4%). Hypoxic exercise-induced cardiac fatigue was observed post-ascent with a change in right ventricular (RV) and LV systolic function (RV fractional area change: - 20 ± 23%, p = 0.01; LV global longitudinal strain change: - 8 ± 9%, p = 0.02), as well as LV geometry and RV-LV interaction alterations with emergence of a D-shape septum in 5/11 (46%) participants associated with RV pressure overload (mean pulmonary arterial pressure change: + 55 ± 20%, p < 0.001). Both MWI and GWE were reduced post-ascent (- 21 ± 16%, p = 0.004 and - 4 ± 4%, p = 0.007, respectively). Relative decrease in MWI and GWE were inversely correlated with increase in GWW (r = - 0.86, p = 0.003 and r = -0.97, p < 0.001, respectively)., Conclusions: Prolonged high-altitude speed climbing in elite climbers is associated with RV and LV function changes with a major interaction alteration. MWI, assessing the myocardial performance, could be a new tool for evaluating LV exercise-induced cardiac fatigue., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The combined effects of acute hypoxia and exercise on cognition remain to be clarified. We investigated the effect of speed climbing to high altitude on reactivity and inhibitory control in elite climbers., Methods: Eleven elite climbers performed a speed ascent of the Mont-Blanc (4810 m) and were evaluated pre- (at 1000 m) and immediately post-ascent (at 3835 m). In both conditions, a Simon task was done at rest (single-task session, ST) and during a low-intensity exercise (dual-task session, DT). Prefrontal cortex (PFC) oxygenation and middle cerebral artery velocity (MCAv) were monitored using near-infrared spectroscopy and transcranial Doppler, respectively, during the cognitive task. Self-perceived mental fatigue and difficulty to perform the cognitive tests were estimated using a visual analog scale. Heart rate and pulse oxygenation (SpO 2 ) were monitored during the speed ascent., Results: Elite climbers performed an intense (~ 50% of the time ≥ 80% of maximal heart rate) and prolonged (8h58 ± 6 min) exercise in hypoxia (minimal SpO 2 at 4810 m: 78 ± 4%). Reaction time and accuracy during the Simon task were similar pre- and post-ascent (374 ± 28 ms vs. 385 ± 39 ms and 6 ± 4% vs. 5 ± 4%, respectively; p > 0.05), despite a reported higher mental fatigue and difficulty to perform the Simon task post-ascent (all p < 0.05). The magnitude of the Simon effect was unaltered (p > 0.05), suggesting a preserved cognitive control post-ascent. Pattern of PFC oxygenation and MCAv differed between pre- and post-ascent as well as between ST and DT conditions., Conclusions: Cognitive control is not altered in elite climbers after a speed ascent to high-altitude despite substantial cerebral deoxygenation and fatigue perception., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (∼3,800, ∼4,300, and ∼5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1 ) at 3,800 m, Andeans ( n = 7) had elevated pHa compared with Sherpas ( n = 12; P < 0.01), but not to lowlanders ( n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders ( n = 16; 21 days acclimatized) had elevated pHa compared with Andeans ( n = 32) and Sherpas ( n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas ( P = 0.01); and 3 ) at 5,000 m, lowlanders ( n = 16; 14 days acclimatized) had higher pHa compared with both Andeans ( n = 66) and Sherpas ( n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa ( P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders. NEW & NOTEWORTHY Lowlander, Andean, and Sherpa arterial blood data were combined across five independent high-altitude expeditions in the United States, Nepal, and Peru to assess acid-base status at ∼3,800, ∼4,300, and ∼5,000 m. The main finding was that Andean and Sherpa highlander populations have more acidic arterial blood, due to elevated arterial carbon dioxide and similar arterial bicarbonate compared with acclimatizing lowlanders at altitudes ≥4,300 m.

Background: Excessive ventilation (V̇E) and abnormal gas exchange during exercise are features of chronic thromboembolic pulmonary hypertension (CTEPH). In selected CTEPH patients, balloon pulmonary angioplasty (BPA) improves symptoms and exercise capacity. How BPA affects exercise hyperventilation and gas exchange is poorly understood., Methods: In this longitudinal observational study, symptom-limited cardiopulmonary exercise tests and carbon monoxide lung diffusion (DLCO) were performed before and after BPA (interval, mean (SD): 3.1 (2.4) months) in 36 CTEPH patients without significant cardiac and/or pulmonary comorbidities., Results: Peak work rate improved by 20% after BPA whilst V̇E at peak did not change despite improved ventilatory efficiency (lower V̇E with respect to CO 2 output [V̇CO 2 ]). At the highest identical work rate pre- and post-BPA (75 (30) watts), V̇E and alveolar-arterial oxygen gradient (P(Ai-a)O 2 ) decreased by 17% and 19% after BPA, respectively. The physiological dead space fraction of tidal volume (VD/VT), calculated from measurements of arterial and mixed expired CO 2 , decreased by 20%. In the meantime, DLCO did not change. The best correlates of P(Ai-a)O 2 measured at peak exercise were physiological VD/VT before BPA and DLCO after BPA., Conclusions: Ventilatory efficiency, physiological VD/VT, and pulmonary gas exchange improved after BPA. The fact that DLCO did not change suggests that the pulmonary capillary blood volume and probably the true alveolar dead space were unaffected by BPA. The correlation between DLCO measured before BPA and P(Ai-a)O 2 measured after BPA suggests that DLCO may provide an easily accessible marker to predict the response to BPA in terms of pulmonary gas exchange., Competing Interests: Disclosure statement MBN, NP, AG, SD, MS, FT, CA, HB report no disclosures. CP reports personal fees from Boehringer Ingelheim, Glaxo Smith Kline, Astra Zeneca and Sanofi outside submitted work. BA reports honoraria and consulting fees grant funding from Boehringer Ingelheim, Glaxo Smith Kline, Menarini, Chiesi, Astra Zeneca and Sanofi unrelated to the submitted work. BD reports grant funding from Novartis and honoraria and consulting fees from Boehringer Ingelheim, Nuvaira, Menarini, Chiesi, Glaxo Smith Kline, Astra Zeneca and Sanofi unrelated to the submitted work., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)