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Dario Kohlbrenner,1,2 Maya Bisang,1 Sayaka S Aeschbacher,1 Emanuel Heusser,1 Silvia Ulrich,1,2 Konrad E Bloch,1,2 Michael Furian1,3 1Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland; 2Faculty of Medicine, University of Zurich, Zurich, Switzerland; 3Swiss University of Traditional Chinese Medicine, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland, Email michael.furian@usz.chStudy Objectives: To assess the diagnostic accuracy of a purpose-designed QTc-scoring algorithm versus the established hand-scoring in patients with chronic obstructive pulmonary disease (COPD) undergoing sleep studies.Methods: We collected 62 overnight electrocardiogram (ECG) recordings in 28 COPD patients. QT-intervals corrected for heart rate (QTc, Bazett) were averaged over 1-min periods and quantified, both by the algorithm and by cursor-assisted hand-scoring. Hand-scoring was done blinded to the algorithm-derived results. Bland-Altman statistics and confusion matrixes for three thresholds (460, 480, and 500ms) were calculated.Results: A total of 32944 1-min periods and corresponding mean QTc-intervals were analysed manually and by computer. Mean difference between manual and algorithm-based QTc-intervals was − 1ms, with limits of agreement of − 18 to 16ms. Overall, 2587 (8%), 357 (1%), and 0 QTc-intervals exceeding the threshold 460, 480, and 500ms, respectively, were identified by hand-scoring. Of these, 2516, 357, and 0 were consistently identified by the algorithm. This resulted in a diagnostic classification accuracy of 0.98 (95% CI 0.98/0.98), 1.00 (1.00/1.00), and 1.00 (1.00/1.00) for 460, 480, and 500ms, respectively. Sensitivity was 0.97, 1.00, and NA for 460, 480, and 500ms, respectively. Specificity was 0.98, 1.00, and 1.00 for 460, 480, and 500ms, respectively.Conclusion: Overall, 8% of nocturnal 1-min periods showed clinically relevant QTc prolongations in patients with stable COPD. The automated QTc-algorithm accurately identified clinically relevant QTc-prolongations with a very high sensitivity and specificity. Using this tool, hospital sleep laboratories may identify asymptomatic patients with QTc-prolongations at risk for malignant arrhythmia, allowing them to consult a cardiologist before an eventual cardiac event.Keywords: QTc, long-QT syndrome, COPD, algorithm, validity, ECG

Konstantinos Bitos,1 Tobias Kuehne,1 Tsogyal D Latshang,1 Sayaka S Aeschbacher,1 Fabienne Huber,1 Deborah Flueck,1 Elisabeth D Hasler,1 Philipp M Scheiwiller,1 Mona Lichtblau,1 Silvia Ulrich,1 Konrad E Bloch,1 Michael Furian1,2 1University Hospital Zurich, Department of Respiratory Medicine, Zurich, Switzerland; 2Swiss University of Traditional Chinese Medicine, Research Department, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, University Hospital Zurich, Department of Pulmonology, Raemistrasse 100, Zurich, 8092, Switzerland, Email michael.furian@usz.chBackground: Amongst the millions of travelers to high altitude worldwide are many with chronic obstructive pulmonary disease (COPD), but data regarding the effects of acute exposure to altitude on exercise performance are limited. The current study investigated how acute exposure to moderate altitude influences exercise performance in COPD patients, providing novel insights to the underlying physiological mechanisms.Methods: Twenty-nine COPD patients, GOLD grade 2– 3, median (quartile) forced expiratory volume in 1 second (FEV1) of 60% predicted (46; 69) performed cycling incremental ramp exercise test (IET) at 490 m and after acute exposure of 2– 6 hours to 2048 m or vice versa, according to a randomized cross-over design. Exercise performance and breath-by-breath analyses of the last 30 seconds of each IET were compared between locations.Results: At 2048 m compared to 490 m, the maximum power output (Wmax) was 77 watts (62;104) vs 88 watts (75;112), median reduction 5 watts (95% CI, 2 to 8, P< 0.05), corresponding to a median reduction of 6% (95% CI, 2 to 11, P< 0.05) compared to 490 m. The peak oxygen uptake (V’O2peak) was 70% predicted (56;86) at 2048 m vs 79% predicted (63;90) at 490 m, median reduction of 6% (95% CI, 3 to 9, P< 0.05). The oxygen saturation by pulse oximetry (SpO2) at 2048 m was reduced by 8% (95% CI, 4 to 9, P< 0.05) compared to 490 m. The minute ventilation (V’E) increased by 2.8L/min (95% CI, 0.9 to 4.2, P< 0.05) at 2048 m. The maximum heart rate and the subjective sense of dyspnea and leg fatigue did not change.Conclusion: Lowlanders with moderate-to-severe COPD acutely exposed to 2048 m reveal small but significant reduction in cycling IET along with a reduced V’O2peak. As dyspnea perception and maximal heart rate were unchanged, the lower blood oxygenation and exaggerated ventilatory response were culprit factors for the reduced performance.Keywords: COPD, exercise, high altitude, hypoxia, hypoxemia, cardiopulmonary exercise testing

Saroj K Pradhan,1– 3 Felix Angst,2 Jie Xu,1,3 Andreas R Gantenbein,4 Susanne Lehmann,2 Peter S Sandor,4 Yiming Li,1– 3 Michael Furian1 1Research Department, Swiss University of Traditional Chinese Medicine, Bad Zurzach, Switzerland; 2Research Department, Rehaklinik Bad Zurzach, Bad Zurzach, Switzerland; 3TCM Ming Dao, Bad Zurzach, Switzerland; 4Neurorehabilitation & Research Department, Rehaklinik Bad Zurzach, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, Swiss University of Traditional Chinese Medicine, Langwiesstrasse 7, Bad Zurzach, 5330, Switzerland, Tel +41 79 403 75 86, Email michael.furian@tcmuni.chIntroduction: Chronic low back pain (CLBP) cannot sufficiently be treated by pharmacological therapy and generates substantial health-care costs worldwide. Acupuncture, a cost-effective, safe and non-pharmacological therapy, has shown promising results in relieving acute low back pain; however, the optimal acupuncture therapy for CLBP remains controversial. This study will compare two acupuncture methods for pain relief in CLBP.Methods and Analysis: This randomized, controlled, single-blind, parallel trial will be conducted in patients with clinically diagnosed CLBP with a disease duration ≥ 3 months and an average pain intensity of ≥ 4 points on an 11-point Pain Intensity Numerical Rating Scale (pain-NRS) on the previous 7 days. Patients will be randomized to 9-week acupuncture therapy using Jiu Gong Points (termed Swiss low back acupuncture, SLBA) or standard acupuncture (SA) therapy (weeks 1– 6: two sessions/week, weeks 7– 9: one session/week, 15 sessions/patient in total). Measurements will be conducted before the first session (T1), at the end of the 9-week therapy (T2) and after 3- and 6-month follow-up (T3 and T4). The primary hypothesis is that 9 weeks of SLBA will be superior in reducing the pain severity assessed by the pain-NRS compared to SA therapy for CLBP. Secondary outcomes will be derived from the Short-Form 36, Oswestry Disability Index, Multidimensional Pain Inventory questionnaire, Symptom Checklist-90 – Revised questionnaire and a daily pain diary. Assuming a minimal clinically important difference in the pain-NRS of 0.39 and an effect size of ≥ 0.6 between SLBA and SA, 80% power, 0.05 alpha level and 20% dropouts, a total of 55 patients/arm will be required. The primary outcome will be analyzed in the intention-to-treat population using chained linear regression models. Patients, outcome assessors and data analysts will be blinded to the treatment arm.Trial Registration: Clinicaltrials.gov Identifier: NCT05232487.Keywords: Chinese medicine, chronic disease, pain, Pain Intensity Numerical Rating Scale, Multidimensional Pain Inventory, Oswestry Disability Index, Randomized clinical trial

Martina Meszaros,1 Tsogyal D Latshang,1 Sayaka S Aeschbacher,1 Fabienne Huber,1 Deborah Flueck,1 Mona Lichtblau,1 Stefanie Ulrich,1 Elisabeth D Hasler,1 Philipp M Scheiwiller,1 Lukas Reinhard,1 Silvia Ulrich,1,2 Konrad E Bloch,1– 3 Michael Furian,1 Esther I Schwarz1,3 1Department of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, Switzerland; 2Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland; 3Centre of Competence Sleep & Health, University of Zurich, Zurich, SwitzerlandCorrespondence: Esther I SchwarzDepartment of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, Zurich, SwitzerlandTel +41 44 255 11 11Fax +41 44 255 44 51Email estherirene.schwarz@usz.chPurpose: Patients with chronic obstructive pulmonary disease (COPD) are particularly vulnerable to hypoxia-induced autonomic dysregulation. Hypoxemia is marked during sleep. In COPD, altitude exposure is associated with an increase in blood pressure (BP) and a decrease in baroreflex-sensitivity (BRS). Whether nocturnal oxygen therapy (NOT) may mitigate these cardiovascular autonomic changes in COPD at altitude is unknown.Materials and Methods: In a randomized placebo-controlled cross-over trial, 32 patients with moderate-to-severe COPD living < 800 m were subsequently allocated to NOT and placebo during acute exposure to altitude. Measurements were done at low altitude at 490 m and during two stays at 2048 m on NOT (3 L/min) and placebo (3 L/min, ambient air) via nasal cannula. Allocation and intervention sequences were randomized. Outcomes of interest were BP, BRS (from beat-to-beat BP measurement), BP variability (BPV), and heart rate.Results: About 23/32 patients finished the trial per protocol (mean (SD) age 66 (5) y, FEV1 62 (14) % predicted) and 9/32 experienced altitude-related illnesses (8 vs 1, p < 0.05 placebo vs NOT). NOT significantly mitigated the altitude-induced increase in systolic BP compared to placebo (Δ median − 5.8 [95% CI − 22.2 to − 1.4] mmHg, p = 0.05) but not diastolic BP (− 3.5 [95% CI − 12.6 to 3.0] mmHg; p = 0.21) or BPV. BRS at altitude was significantly higher in NOT than in placebo (1.7 [95% CI 0.3 to 3.4] ms/mmHg, p = 0.02).Conclusion: NOT may protect from hypoxia-induced autonomic dysregulation upon altitude exposure in COPD and thus protect from a relevant increase in BP and decrease in BRS. NOT may provide cardiovascular benefits in COPD during conditions of increased hypoxemia and may be considered in COPD travelling to altitude.Keywords: COPD, altitude, oxygen, hypoxia, blood pressure, blood pressure variability, baroreflex sensitivity

Esther I Schwarz,1 Tsogyal D Latshang,1 Michael Furian,1 Deborah Flück,1 Sebastian Segitz,1 Severine Müller-Mottet,1 Silvia Ulrich,1 Konrad E Bloch,1,2 Malcolm Kohler1,2 1Department of Pulmonology and Sleep Disorders Centre, University Hospital of Zurich, Zurich, Switzerland; 2Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland Purpose: Patients with COPD might be particularly susceptible to hypoxia-induced autonomic dysregulation. Decreased baroreflex sensitivity (BRS) and increased blood pressure (BP) variability (BPV) are markers of impaired cardiovascular autonomic regulation and there is evidence for an association between decreased BRS/increased BPV and high cardiovascular risk. The aim of this study was to evaluate the effect of short-term exposure to moderate altitude on BP and measures of cardiovascular autonomic regulation in COPD patients. Materials and methods: Continuous morning beat-to-beat BP was noninvasively measured with a Finometer® device for 10 minutes at low altitude (490 m, Zurich, Switzerland) and for 2 days at moderate altitude (2,590 m, Davos Jakobshorn, Switzerland) – the order of altitude exposure was randomized. Outcomes of interest were mean SBP and DBP, BPV expressed as the coefficient of variation (CV), and spontaneous BRS. Changes between low altitude and day 1 and day 2 at moderate altitude were assessed by ANOVA for repeated measurements with Fisher’s exact test analysis. Results: Thirty-seven patients with moderate to severe COPD (mean±SD age 64±6 years, FEV1 60%±17%) were included. Morning SBP increased by +10.8 mmHg (95% CI: 4.7–17.0, P=0.001) and morning DBP by +5.0 mmHg (95% CI: 0.8–9.3, P=0.02) in response to altitude exposure. BRS significantly decreased (P=0.03), whereas BPV significantly and progressively increased (P

Michael Furian,1,* Deborah Flueck,1,* Tsogyal D Latshang,1 Philipp M Scheiwiller,1 Sebastian Daniel Segitz,1 Séverine Mueller-Mottet,1 Christian Murer,1 Adrian Steiner,1 Silvia Ulrich,1 Thomas Rothe,2 Malcolm Kohler,1 Konrad E Bloch1 1Department of Respiratory Medicine, University Hospital of Zurich, Zurich, Switzerland; 2Zuercher RehaZentrum Davos, Davos Clavadel, Switzerland *These authors contributed equally to this work Objective: To evaluate the effects of altitude travel on exercise performance and symptoms in lowlanders with COPD. Design: Randomized crossover trial. Setting: University Hospital Zurich (490 m), research facility in mountain villages, Davos Clavadel (1,650 m) and Davos Jakobshorn (2,590 m). Participants: Forty COPD patients, Global Initiative for Obstructive Lung Disease (GOLD) grade 2–3, living below 800 m, median (quartiles) age 67 y (60; 69), forced expiratory volume in 1 second 57% predicted (49; 70). Intervention: Two-day sojourns at 490 m, 1,650 m, and 2,590 m in randomized order. Outcome measures: Six-minute walk distance (6MWD), cardiopulmonary exercise tests, symptoms, and other health effects. Results: At 490 m, days 1 and 2, median (quartiles) 6MWD were 558 m (477; 587) and 577 m (531; 629). At 2,590 m, days 1 and 2, mean changes in 6MWD from corresponding day at 490 m were -41 m (95% CI -51 to -31) and -40 m (-53 to -27), n=40, P

Background: In patients with COPD, preventive treatment with acetazolamide reduces adverse health effects during altitude travel. We investigated whether preventive acetazolamide treatment modifies exercise performance in COPD patients going to high altitude., Methods: In this randomised, double-blind trial, lowlanders with COPD, forced expiratory volume in 1 s (FEV 1 ) 40-80% predicted, were assigned to acetazolamide (375 mg per 24 h) or placebo treatment starting 24 h before ascent and while staying at 3100 m. Patients performed progressive cycling exercise to exhaustion at 760 m, before taking the study drug, and within 4 h after arrival at 3100 m. The primary outcome was the maximal power output (W max )., Results: 103 patients (32 women), mean±sd age 57.2±8.1 years, FEV 1 66±11% predicted, were included in per-protocol analyses. In 53 patients receiving acetazolamide, W max and oxygen uptake ( V ' O 2 ) at 760 m and 3100 m were 105±27 and 91±25 W, and 18.0±4.8 and 15.5±3.7 mL·min max ) at 760 m and 3100 m were 105±27 and 91±25 W, and 18.0±4.8 and 15.5±3.7 mL·min -1 ·kg -1 (p<0.001, both changes). Corresponding W max and V ' O 2 max in 50 patients receiving placebo were 107±34 and 97±28 W, and 18.9±6.0 and 17.2±5.0 mL·min -1 ·kg -1 (p<0.001, both changes). Between-group differences (95% CI) in altitude-induced W max changes were -3.0 W (-8.7 to +2.7, p=0.305) and in V ' O 2 max by 0.7 kPa (0.1 to 1.3, p=0.016). At 3100 m, maximal work rate with respiratory exchange ratio ≤1 was greater with acetazolamide than with placebo by 10.1 W (4.0 to 16.2, p=0.022).-1 ·kg -1 (-2.1 to +0.5, p=0.213). Acetazolamide mitigated the altitude-induced reduction of P aO 2 by 0.7 kPa (0.1 to 1.3, p=0.016). At 3100 m, maximal work rate with respiratory exchange ratio ≤1 was greater with acetazolamide than with placebo by 10.1 W (4.0 to 16.2, p=0.022)., Conclusions: In lowlanders with COPD, preventive treatment with acetazolamide did not modify the altitude-induced reduction in maximal work rate. However, acetazolamide enhanced arterial oxygenation and submaximal, moderate-intensity work capacity compared with placebo., Competing Interests: Conflicts of interest: M. Lichtblau reports receiving honoraria for lectures and support for attending meetings from MSD, as well as participation in an advisory board for MSD, outside the submitted work. Conflicts of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2025.)

Häfliger, Alina, Aline Buergin, Laura C. Mayer, Maamed Mademilov, Mona Lichtblau, Talantbek Sooronbaev, Silvia Ulrich, Konrad E. Bloch, and Michael Furian. Sex-specific difference in health-related altitude-effects and their prevention by acetazolamide. Data from a randomized controlled trial. High Alt Med Biol. 00:00-00, 2024. Background: Women are underrepresented in studies on acute mountain sickness (AMS), altitude-induced sleep-disordered breathing and preventive acetazolamide use. Methods: We analyzed sex-specific altitude-effects in participants of a randomized, placebo-controlled, double-blind trial in healthy lowlanders >40 years. Participants took 375 mg/day acetazolamide or placebo starting 24 hours before ascent to and while staying 2 days at 3,100 m. Main outcomes of this analysis were sex-specific incidence of AMS (Lake Louise score ≥3), nocturnal pulse oximetry (SpO 2 ) and apnea-hypopnea index (AHI) at 3,100 m. Results: With placebo, 30 of 119 (25%) women and 4 of 51 (8%) men developed AMS ( p = 0.009 between sexes) at 3,100 m. Among women assigned to placebo, SpO 2 (mean ± SE 84 ± 0%) and AHI (16.9 ± 1.3/h) in night 1 at 3,100 m were lower compared to men (SpO 2 86 ± 0%; AHI 28.3 ± 1.9/h), despite similar baseline values at 760 m. Mean between-sex difference in altitude-effects (women-men) in SpO 2 was -1.4% (95% CI, -2.4 to -0.3%); AHI -10.7/h (95% CI, -15.7 to -5.7/h). The impact of acetazolamide on AMS was not significant for either sex but acetazolamide improved AHI in men (difference men-women, -9.8/h [95% CI, -16.8 to -2.7/h]). Conclusion: This study suggests sex-specific differences in altitude-induced hypoxemia, periodic breathing, AMS incidence, and in the response to preventive acetazolamide treatment.

Background: Hypoxic pulmonary vasoconstriction leads to an increase in pulmonary artery pressure (PAP) and potentially right heart failure in healthy individuals and patients with respiratory diseases. Previous studies in patients with chronic obstructive pulmonary disease (COPD) exposed to hypobaric hypoxia have shown an increase in PAP, while traditional echocardiographic parameters revealed only minimal changes at high altitude. Speckle-tracking-derived analysis is potentially more sensitive to assess right ventricular (RV) function and we used this method to investigate the impact on RV function of patients with COPD ascending to high altitude and compared the results with the traditional echocardiographic parameters., Methods: This post hoc analysis evaluates echocardiographic RV free wall strain (RVFWS) in patients with COPD GOLD grade 1-3 travelling from 760 m to 3100 m for a 2-day stay. An RVFWS over -20% was considered as an indicator of RV dysfunction., Results: A total of 54 patients (57% men, mean±SD age 58±9 years, forced expiratory volume in 1 s (FEV 1 % predicted 77.3±22.5)) with echocardiographs of sufficient quality were included. The mean RVFWS worsened significantly from -26.0±4.9% at 760 m to -23.9±5.4% at 3100 m (p=0.02). The number of patients with relevant RV dysfunction based on RVFWS increased from 7.4% at 760 m to 25.9% at 3100 m (p=0.02), whereas the prevalence of RV dysfunction assessed by traditional indices remained unchanged., Conclusion: Exposure to hypoxia led to RVFWS impairment in more than one quarter of patients with COPD. Strain analysis is a promising, non-invasive method for evaluating RV dysfunction, even in subclinical cases and might be prognostically relevant in patients with lung diseases., Trial Registration Numbers: NCT02450968 and NCT03173508., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Stauffer, Emeric, François Caton, Raphael Marlu, Aurélien Pichon, Landry Seyve, Michael Furian, Aymeric Paillisser, Florence Berquet, Jeremy De Abreu, Blandine Deschamps, Benoit Polack, Philippe Connes, Paul Robach, Stéphane Doutreleau, Julien V Brugniaux, Samuel Verges, and Benoit Champigneulle.Acclimatized lowlanders exhibit a hypocoagulable profile after a passive ascent at high altitude. High Alt Med Biol. 00:00-00, 2024. Background: Discordant results have been previously reported regarding the impact of high-altitude (HA) exposure on coagulation. We aimed to investigate changes in coagulation parameters in lowlanders exposed to HA for 14 days using a combination of dynamic coagulation assays and conventional in vitro tests. Material and Methods: We assessed coagulation in 10 lowlanders using whole-blood rotational thromboelastometry (ROTEM), thrombin generation assay (TGA) on poor-platelet plasma, and conventional coagulation tests. Tests were performed at low altitude (LA, 210 m) and at the end of a 14-day sojourn at HA, including passive ascents to 3,800 m for 6 days and then to 5,100 m for 8 days. Results: Conventional tests revealed significant changes in coagulation factors and inhibitors after HA exposure, although these changes remained within normal ranges. ROTEM assays demonstrated a delayed clot initiation in EXTEM/FIBTEM, without any alteration in clot firmness, in HA versus LA ( p < 0.01). TGA changes showed an increase in time to peak ( p < 0.01), a decrease in endogenous thrombin potential ( p < 0.05), and a decrease in thrombin peak ( p < 0.001). Conclusions: We found no evidence of hypercoagulability in lowlanders after a 14-day sojourn at HA. In contrast, dynamic coagulation assays (ROTEM and TGA) revealed a hypocoagulable pattern.

Aims: More than 220 Mio people live at altitudes above 2000 m, many of whom have pre-existing chronic diseases, including pulmonary vascular diseases (PVDs) such as pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH). We investigated the acute effects of high-dose supplemental oxygen on pulmonary haemodynamics assessed by echocardiography in patients with PVD permanently living at 2850 m., Methods and Results: In a randomized, single-blind, placebo-controlled crossover trial, patients with PVD diagnosed with PAH or CTEPH were allocated to receive 10 L/min supplemental oxygen (FiO 2 ≈ 95%) and placebo air administered via a facial mask with reservoir near their living altitude in Quito at 2850 m (FiO 2 0.21, PiO 2 ≈ 60% of sea level) in random order with a washout period of >2 h. After >15 min of breathing the respective FiO 2 , systolic pulmonary artery pressure (sPAP), cardiac output (CO), and other parameters were assessed by echocardiography. Furthermore, radial arterial blood gases were analysed. Twenty-eight patients with PVD (24 females, 26 PAH, age 45 ± 12 years) treated with phosphodiesterase-5 inhibitors ( n = 28) and endothelin receptor antagonists ( n = 9) were included. With oxygen vs. placebo air, sPAP was 57 ± 23 vs. 68 ± 24 mmHg, mean difference -11 mmHg (-15 to -6 mmHg, P < 0.001), CO was 3.2 ± 0.9 vs. 3.9 ± 1.1 L/min; -0.7 L/min (-0.9 to -0.4 L/min, P < 0.001), while sPAP/CO was unchanged, and the right ventriculo-arterial coupling was increased. PaO 2 was 22.5 ± 9.7 vs. 7.6 ± 1.5 kPa; 14.9 kPa (11.4-18.4 kPa, P < 0.001)., Conclusion: High-dose oxygen therapy in prevalent patients with PVD living near 2850 m significantly lowered sPAP but also CO by a reduced heart rate, resulting in an unchanged pulmonary resistance. Whether longer-term oxygen therapy would improve pulmonary vascular resistance requires further investigation., Registration: NCT06084559 URL: https://clinicaltrials.gov/study/NCT06084559., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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.)

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO 2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO 2 , and CO 2 concentration in the canopy (i.e. inspiratory CO 2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO 2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO 2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P = 0.035). Increased inspiratory CO 2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO 2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO 2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO 2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)