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Objectives: The aim of this study was to evaluate the feasibility and efficacy of chronic pulmonary thromboembolism assessment using photon-counting detector computed tomography (PCD-CT) iodine maps of the lung parenchyma., Materials and Methods: This institutional review board-approved retrospective study included 83 subjects (49.4% male, aged 62.4 ± 13.4 years; 50.6% female, aged 59.9 ± 17.1 years) who underwent clinically indicated PCD-CT scan to rule out chronic thromboembolic pulmonary hypertension (CTEPH). Two blinded readers used iodine maps and corresponding sharp-kernel CT reconstructions in the lung window to evaluate perfusion defects and identify patients with chronic pulmonary thromboembolism (CTEPH, CTEPH overlap with other causes of pulmonary hypertension [PH], chronic thromboembolic disease [CTED]). No other clinical or imaging information was given. Discordance was resolved in a subsequent consensus read. The clinical diagnosis was reviewed in an interdisciplinary clinical setting. The accuracy, sensitivity, and specificity of radiologic evaluation and clinical diagnosis were calculated., Results: Of the 83 subjects included, 32 were diagnosed with CTEPH, CTEPH overlap, or CTED, 35 were diagnosed with PH caused by other pathologic mechanisms, 10 had no PH, and 6 had suffered previous acute pulmonary embolism, which resolved. The interreader agreement was good (Cohen κ = 0.74). The consensus reached high accuracy (0.88), sensitivity (0.94), and specificity (0.84), as well as good agreement with interdisciplinary clinical diagnosis (Cohen κ = 0.75). No cases with confirmed CTEPH as the primary cause of PH or CTED were missed. Patients with pulmonary arterial hypertension were most frequently rated false-positive. The mean effective dose (±standard deviation) was 1.3 (±0.76) mSv., Conclusions: Accurate, sensitive, and specific diagnosis of pulmonary chronic thromboembolism at low radiation dose is possible using iodine maps reconstructed from PCD-CT scans., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Intermittent hypoxia (IH) is commonly associated with pathological conditions, particularly obstructive sleep apnoea. However, IH is also increasingly used to enhance health and performance and is emerging as a potent non-pharmacological intervention against numerous diseases. Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift long-term adaptation to maladaptation and the development of pathologies. Rather than discussing in detail the well-characterized individual responses and adaptations to IH, we here aim to summarize and integrate hypoxia-activated mechanisms into a holistic picture of the body's adaptive responses to hypoxia and specifically IH, and demonstrate how these mechanisms might be mobilized for their health benefits while minimizing the risks of hypoxia exposure., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

Care of pulmonary hypertension (PH) patients in special situations requires insightful knowledge of the pathophysiology of the cardiopulmonary system and close interaction with different specialists, depending on the situation. The role of this task force was to gather knowledge about five conditions that PH patients may be faced with. These conditions are 1) perioperative care; 2) management of pregnancy; 3) medication adherence; 4) palliative care; and 5) the influence of climate on PH. Many of these aspects have not been covered by previous World Symposia on Pulmonary Hypertension. All of the above conditions are highly affected by psychological, geographical and socioeconomic factors, and share the need for adequate healthcare provision. The task force identified significant gaps in information and research in these areas. The current recommendations are based on detailed literature search and expert opinion. The task force calls for further studies and research to better understand and address the special circumstances that PH patients may encounter., Competing Interests: Conflict of interest: I.R. Preston reports grants from Janssen, Merck, United Therapeutics and Respira, consultancy fees from Janssen, Merck, United Therapeutics, Liquidia, Gossamer and Aerovate, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen and United Therapeutics, and support for attending meetings from Janssen and United Therapeutics. L.S. Howard reports grants from MSD, consultancy fees from Ferrer, Janssen and Morphic, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen, MSD, Aerovate and Ferrer, payment for expert testimony from Janssen, support for attending meetings from Janssen and Gossamer Bio, participation on a data safety monitoring board or advisory board with MSD, Janssen, Gossamer Bio, Apollo Therapeutics and Altavant, and stock (or stock options) with Circular, ATXA Therapeutics, iOWNA, Calibre Biometrics and OneWelbeck Clinic. D. Langleben reports grants from Acceleron/Merck, Aerovate and Janssen, consultancy fees from Merck, Janssen, Actelion, Enzyvant, PhaseBio, Gossamer Bio and Bayer, payment or honoraria for lectures, presentations, manuscript writing or educational events from Merck, Janssen and Bayer, support for attending meetings from Acceleron/Merck, Janssen, Enzyvant and Gossamer Bio, and participation on a data safety monitoring board or advisory board with Phase Bio, Merck, Janssen, Actelion, Enzyvant and Gossamer Bio. M. Lichtblau reports payment or honoraria for lectures, presentations, manuscript writing or educational events from, and participation on a data safety monitoring board or advisory board with MSD, and support for attending meetings from MSD and Janssen. T. Pulido reports grants from Aerovate, Bayer, Janssen, MSD, Pfizer and United Therapeutics, consultancy fees from Bayer, MSD, Gossamer Bio, Aerovate and Ferrer, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, MSN Labs, Tuteur and Ferrer, support for attending meetings from Bayer, Janssen and Ferrer, participation on a data safety monitoring board or advisory board with Janssen, MSD, Bayer and Gossamer Bio, and is consultant and part of the advisory board for the Mexican Society of Pulmonary Arterial Hypertension. R. Souza reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer and Janssen, and participation on a data safety monitoring board or advisory board with Janssen, Bayer and MSD. K.M. Olsson reports grants from Acceleron, MSD and Janssen, consultancy fees from Acceleron, Actelion, Janssen, Ferrer, Merck, AOP Health, Gossamer and Bayer, payment or honoraria for lectures, presentations, manuscript writing or educational events from Acceleron, Actelion, AOP Health, Janssen, Bayer, MSD, Ferrer and Gossamer, and support for attending meetings from Acceleron/MSD and Janssen/Actelion., (Copyright ©The authors 2024.)

Background: Hypoxia is a trigger for sympathetic activation and autonomic cardiovascular dysfunction. Pulmonary vascular disease (PVD) is associated with hypoxaemia, which increases with altitude. The aim was to investigate how exposure of patients with PVD to hypobaric hypoxia at altitude affects autonomic cardiovascular regulation., Methods: In a randomised crossover study, patients with PVD were studied for 1 day and one night at an altitude of 2500 m (hypobaric hypoxia) and low altitude at 470 m in a random order. Outcomes were heart rate variability (HRV) in the time domain and in the frequency domain (low frequency (LF)/high frequency (HF) and LF/HF) and heart rate (HR) during day and night and baroreflex sensitivity (BRS)., Results: In 25 patients with PVD (72% pulmonary arterial hypertension and 28% distal chronic thromboembolic pulmonary hypertension; mean±sd age 60.7±13.6 years), exposure to altitude resulted in significant increases in awake HR by 9.4 bpm (95% confidence interval (CI) 6.3-12.4, p<0.001) and nocturnal HR by 9.0 bpm (95% CI 6.6-11.4, p<0.001) and significant changes in awake and particularly nocturnal HRV indicating decreasing parasympathetic and increasing sympathetic activity (change in daytime LF/HF 1.7 (95% CI 0.6-2.8), p=0.004; nocturnal LF/HF 1.9 (95% CI 0.3-3.4), p=0.022) and a significant decrease in BRS (-2.4·mmHg -1 (95% CI -4.3- -0.4, p=0.024))., Conclusion: Exposure of PVD patients to altitude resulted in a significant change in HRV indicating an increase in sympathetic activity and a decrease in BRS. The relative change in HRV at altitude was more pronounced during sleep., Competing Interests: Conflict of interest: S. Ulrich reports grants or contracts from Swiss National Science Foundation, Zurich, and Swiss Lung League; unrestricted grants from Orpha Swiss and MSD, outside the submitted work; consulting fees from Orpha Swiss, MSD SA and Janssen SA, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events for Orpha Swiss, MSD SA, Janssen SA and Novartis SA, outside the submitted work; support for attending meetings and/or travel from Orpha Swiss, MSD SA, Janssen SA and Novartis SA, outside the submitted work; participation on a data safety monitoring or advisory board for Orpha Swiss, MSD SA and Janssen SA, outside the submitted work; leadership or fiduciary roles for the Swiss Society of Pulmonology, European Respiratory Society and Swiss Society of Pulmonary Hypertension, outside the submitted work. Conflict of interest: M. Lichtblau reports receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from MSD SA, outside the submitted work; support for attending meetings and/or travel from Orpha Swiss, Janssen and MSD, outside the submitted work; and participation on a data safety monitoring or advisory board for MSD SA, outside the submitted work. Conflict of interest: E.I. Schwarz reports receiving lecture fees from ResMed outside the submitted work and is Secretary of Assembly 4 of the European Respiratory Society (unpaid) outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: Patients with pulmonary vascular disease (PVD) often suffer from nocturnal hypoxaemia, but also from sleep apnoea. Short-term use of acetazolamide increases ventilation due to metabolic acidosis and also reduces loop gain. We investigated whether prolonged use of acetazolamide improves sleep disordered breathing in PVD., Methods: In a randomised controlled crossover trial, patients with PVD were randomly assigned to acetazolamide 250 mg and placebo twice daily for 5 weeks. Patients underwent respiratory polygraphy at baseline and at the end of each intervention phase. Outcomes of interest were the effect of acetazolamide on mean nocturnal oxygen saturation ( S pO 2 ), time with oxygen saturation <90% ( t <90 ), apnoea-hypopnoea index (AHI) and sleep apnoea severity., Results: In 20 patients with PVD (55% women, nine with pulmonary arterial hypertension, 11 with distal chronic thromboembolic pulmonary hypertension; mean±sd nocturnal S pO 2 88.8±3.5%, obstructive AHI 12.6±12.3 events·h -1 ), 5 weeks of acetazolamide resulted in a significant improvement in nocturnal oxygenation compared to placebo (mean nocturnal S pO 2 +2.3% (95% CI 1.3-3.3%); p<0.001 and t <90 -18.8% (95% CI -29.6- -8.0%); p=0.001). Acetazolamide increased the proportion of patients with mean nocturnal S pO 2 ≥90% from 45% to 85%. The percentage of patients with AHI >5 events·h -1 was reduced from 75% to 60% and with AHI >15 events·h -1 from 30% to 15%. Two patients discontinued the study because of mild side-effects., Conclusions: Acetazolamide given for 5 weeks reduces nocturnal hypoxaemia in PVD to a clinically relevant level and reduces the proportion of patients with obstructive sleep apnoea., Competing Interests: Conflicts of interest: M. Lichtblau reports being early career member of European Respiratory Society (ERS) Assembly 13 (Pulmonary Vascular Disease), outside the submitted work. K.E. Bloch reports support for the present manuscript from the Swiss National Science Foundation. S. Ulrich reports support for the present manuscript from the Swiss National Science Foundation and is Chair of ERS Group 13.01 (Pulmonary Hypertension), outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Importance: Prior study in healthy subjects has shown a reduction of partial pressure of arterial oxygen (PaO 2 ) by -1.60 kPa/kilometre of altitude gain. However, the association of altitude-related change in PaO 2 and altitude-related adverse health effects (ARAHE) in patients with chronic obstructive pulmonary disease (COPD) remain unknown., Objective: To provide an effect size estimate for the decline in PaO 2 with each kilometre of altitude gain and to identify ARAHE in relation to altitude in patients with COPD. www.crd.york.ac.uk/prospero: CRD42020217938., Data Sources: A systematic search of PubMed and Embase was performed from inception to May 30, 2023., Study Selection: Peer-reviewed and prospective studies in patients with COPD staying at altitudes >1500 m providing arterial blood gases within the first 3 days at the target altitude., Data Extraction and Synthesis: Aggregate data (AD) on study characteristics were extracted, and individual patient data (IPD) were requested. Estimates were pooled using random-effects meta-analysis., Main Outcome and Measures: Relative risk estimates and 95 % confidence intervals for the association between PaO 2 and altitude in patients with COPD., Results: Thirteen studies were included in the AD analysis, of which 6 studies (222 patients, 45.2 % female) provided IPD, thus were included in the quantitative analysis. The estimated effect size of PaO 2 was -0.84 kPa [95 %CI, -0.92 to -0.76] per 1000 m of altitude gain (I 2 =65.0 %, P < 0.001). In multivariable regression analysis, COPD severity, baseline PaO 2 , age and time spent at altitude were predictors for PaO 2 at altitude. Overall, 37.8 % of COPD patients experienced an ARAHE, whereas older age, female sex, COPD severity, baseline PaO 2, and target altitude were predictors for the occurrence of ARAHE (area under ROC curve: 0.9275, P < 0.001)., Conclusions and Relevance: This meta-analysis, providing altitude-related decrease in PaO 2 and risk of ARAHE in patients with COPD ascending to altitudes >1500 m, revealed a lower altitude-related decrease in PaO 2 in COPD patients compared with healthy. However, these findings might improve patient care and facilitate decisions about initiating preventive measures against hypoxaemia and ARAHE in patients with COPD planning an altitude sojourn or intercontinental flight, i.e. supplemental oxygen or acetazolamide., Competing Interests: Conflicts of interest The authors declare no conflict of interest concerning this work., (Copyright © 2024 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Over 80 Mio people worldwide live >2500 m, including at least as many patients with pulmonary vascular disease (PVD), defined as pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH), as elsewhere (estimated 0.1‰). Whether PVD patients living at high altitude have altered disease characteristics due to hypobaric hypoxia is unknown. In a cross-sectional study conducted at the Hospital Carlos Andrade Marin in Quito, Ecuador, located at 2840 m, we included 36 outpatients with PAH or CTEPH visiting the clinic from January 2022 to July 2023. We collected data on diagnostic right heart catheterization, treatment, and risk factors, including NYHA functional class (FC), 6-min walk distance (6MWD), and NT-brain natriuretic peptide (BNP) at baseline and at last follow-up. Thirty-six PVD patients (83% women, 32 PAH, 4 CTEPH, mean ± SD age 44 ± 13 years, living altitude 2831 ± 58 m) were included and had the following baseline values: PaO 2 8.2 ± 1.6 kPa, PaCO 2 3.9 ± 0.5 kPa, SaO 2 91 ± 3%, mean pulmonary artery pressure 53 ± 16 mmHg, pulmonary vascular resistance 16 ± 4 WU, 50% FC II, 50% FC III, 6MWD 472 ± 118 m, BNP 490 ± 823 ng/L. Patients were treated for 1628 ± 1186 days with sildenafil (100%), bosentan (33%), calcium channel blockers (33%), diuretics (69%), and oxygen (nocturnal 53%, daytime 11%). Values at last visit were: FC (II 75%, III 25%), 6MWD of 496 ± 108 m, BNP of 576 ± 5774 ng/L. Compared to European PVD registries, ambulatory PVD patients living >2500 m revealed similar blood gases and relatively low and stable risk factor profiles despite severe hemodynamic compromise, suggesting that favorable outcomes are achievable for altitude residents with PVD. Future studies should focus on long-term outcomes in PVD patients dwelling >2500 m., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Pollution and climate change constitute a combined, grave and pervasive threat to humans and to the life-support systems on which they depend. Evidence shows a strong association between pollution and climate change on cardiovascular and respiratory diseases, and pulmonary vascular disease (PVD) is no exception. An increasing number of studies has documented the impact of environmental pollution and extreme temperatures on pulmonary circulation and the right heart, on the severity and outcomes of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH), on the incidence of pulmonary embolism, and the prevalence and severity of diseases associated with PH. Furthermore, the downstream consequences of climate change impair health care systems' accessibility, which could pose unique obstacles in the case of PVD patients, who require a complex and sophisticated network of health interventions. Patients, caretakers and health care professionals should thus be included in the design of policies aimed at adaptation to and mitigation of current challenges, and prevention of further climate change. The purpose of this review is to summarize the available evidence concerning the impact of environmental pollution and climate change on the pulmonary circulation, and to propose measures at the individual, healthcare and community levels directed at protecting patients with PVD., Competing Interests: L. P. reports research grants from Janssen and Ferrer; personal fees from Janssen, Ferrer, United Therapeutics, M. S. D. and Liquidia, not related to this article. M. L. reports travel grants and honoraria from M. S. D., Janssen and Orpha Swiss, not related to this article. L. M. declares no conflict of interest., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Objective: To investigate the ventilatory and circulatory differences between eccentric (ECC) and concentric (CON) cycling exercise at submaximal, low-dose intensity from onset to end-exercise in healthy middle-aged participants., Design: Randomized controlled crossover trial., Setting: The participants underwent 1 ECC and 1 CON test according to stepwise incremental exercise protocols at identical, submaximal intensities. Breath-by-breath analyses of ventilatory gas exchange and echocardiography were used to assess cardiopulmonary function during exercise., Participants: 24 healthy middle-aged, untrained participants (14 women, 10 men, 50±14 years) were included., Interventions: 1 ECC and 1 CON test at submaximal intensities., Main Outcome Measure: The main outcome was oxygen uptake (V'O 2 )., Results: The V'O 2 increase was reduced by -422 mL/min (-52%, 95% confidence interval: -513 to -292, P <.001) during ECC, as well as the ventilatory drive. Echocardiographic parameters, heart rate (-14%), cardiac output (-21%), stroke volume (-15%), and pulmonary artery pressure by tricuspid regurgitation pressure gradient (TRPG) (-26%) were also significantly reduced during ECC compared with CON at identical intensities. Participants reported significantly less dyspnea and unchanged perceived leg fatigue in ECC., Conclusion: ECC was well tolerated, and significant reductions were observed in V'O 2 , ventilation, and right ventricular load compared with CON, even at low intensity levels. This study, conducted on healthy middle-aged participants, did not raise concerns that would hinder further investigation of the effects of ECC in patients with severely limited cardiopulmonary disease, and it calls for further research on this topic., (© 2024 The Authors.)

Background: Our objective was to investigate the effect of a day-long exposure to high altitude on peak exercise capacity and safety in stable patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: In a randomised controlled crossover trial, stable patients with PAH or distal CTEPH without resting hypoxaemia at low altitude performed two incremental exercise tests to exhaustion: one after 3-5 h at high altitude (2500 m) and one at low altitude (470 m)., Results: In 27 patients with PAH/CTEPH (44% females, mean±sd age 62±14 years), maximal work rate was 110±64 W at 2500 m and 123±64 W at 470 m (-11%, 95% CI -16- -11%; p<0.001). Oxygen saturation measured by pulse oximetry and arterial oxygen tension at end-exercise were 83±6% versus 91±6% and 6.1±1.9 versus 8.6±1.9 kPa (-8% and -29%; both p<0.001) at 2500 versus 470 m, respectively. Maximal oxygen uptake was 17.8±7.5 L·min -1 ·kg -1 at high altitude versus 20±7.4 L·min -1 ·kg -1 at low altitude (-11%; p<0.001). At end-exercise, the ventilatory equivalent for carbon dioxide was 43±9 at 2500 m versus 39±9 at 470 m (9%, 95% CI 2-6%; p=0.002). No adverse events occurred during or after exercise., Conclusions: Among predominantly low-risk patients with stable PAH/CTEPH, cycling exercise during the first day at 2500 m was well tolerated, but peak exercise capacity, blood oxygenation and ventilatory efficiency were lower compared with 470 m., Competing Interests: Conflict of interest: None of the authors have any conflicts of interest in relation to this manuscript., (Copyright ©The authors 2024.)

Pulmonary vascular diseases such as pulmonary embolism and pulmonary hypertension are important and frequently under-recognised conditions. This article provides an overview of key highlights in pulmonary vascular diseases from the European Respiratory Society International Congress 2023. This includes insights into disease modification in pulmonary arterial hypertension and novel therapies such as sotatercept and seralutinib. Exciting developments in our understanding of the mechanisms underpinning pulmonary hypertension associated with interstitial lung disease are also explored. A comprehensive overview of the complex relationship between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension (CTEPH) is provided along with our current understanding of the molecular determinants of CTEPH. The importance of multidisciplinary and holistic care cannot be understated, and this article also addresses advances beyond medication, with a special focus on exercise training and rehabilitation., Competing Interests: Conflict of interest: S. Cullivan reports travel grant from Janssen outside the submitted work. Conflict of interest: A. Boucly reports honoraria for lectures or travel support from AOP Orphan, Janssen, Ferrer and MSD outside the submitted work. Conflict of interest: M. Jevnikar reports travel grants from MSD, Janssen and AstraZeneca, and consulting fees from Janssen, outside the submitted work. Conflict of interest: B. Lechatier reports participation on advisory boards and travel grants from MSD and Janssen outside the submitted work. Conflict of interest: S. Ulrich receives grant money from the Swiss National Science Foundation and Swiss Lung League; and received grant money, travel fees, consultancy and for patient enrolment into trials from Janssen SA, MSD SA, Novartis SA and OrPha Swiss. Conflict of interest: L. Bertoletti reports personal fees and nonfinancial support from BMS/Pfizer, LEO-Pharma and Viatris; grants from Bayer; and grants, personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: O. Sitbon reports relationships with pharmaceutical companies including Merck, Janssen, Enzyvant, Gossamer Bio, Respira Therapeutics, Ferrer and AOP Orphan, outside the submitted work; relationships include grants for research and educational programmes, fees for lectures and membership of scientific advisory boards. Conflict of interest: A. Vonk-Noordegraaf reports participation on advisory boards for Ferrer, MSD and Johnson & Johnson, outside the submitted work. A. Bokan has nothing to declare. D-H. Park reports support for attending meetings and/or travel from Janssen, outside the submitted work. Conflict of interest: L. Genecand has nothing to declare. Conflict of interest: J. Guiot reports grants paid to his institution from Roche, Janssen and Merk; consulting fees from Oncoradiomics, Janssen, Boehringer Ingelheim, Pfizer and AstraZeneca; honoraria from Janssen, SMB, GSK and Chiesi; and travel support from Merck and Chiesi, all outside the submitted work. Conflict of interest: E-M. Jutant reports consulting fees from Chiesi; honoraria from Chiesi, GSK, MSD and AstraZeneca; and travel support from Janssen and MSD. Conflict of interest: L. Piccari reports grants from Janssen and Ferrer; lecture honoraria from Janssen, Ferrer, MSD and United Therapeutics; participation on advisory boards with Janssen, Ferrer and United Therapeutics; and travel support from Janssen, Ferrer and MSD, outside the submitted work. Conflict of interest: M. Lichtblau reports travel support, lecture honoraria and participation on advisory boards from Janssen, MSD and Orpha Swiss, outside the submitted work., (Copyright ©The authors 2024.)

Background: Hypoxia and old age impair postural control and may therefore enhance the risk of accidents. We investigated whether acetazolamide, the recommended drug for prevention of acute mountain sickness, may prevent altitude-induced deterioration of postural control in older persons. Methods: In this parallel-design trial, 95 healthy volunteers, 40 years of age or older, living <1,000 m, were randomized to preventive therapy with acetazolamide (375 mg/d) or placebo starting 24 h before and during a 2-day sojourn at 3,100 m. Instability of postural control was quantified by a balance platform with the center of pressure path length (COPL) as primary outcome while pulse oximetry (SpO 2 ) was monitored. Effects of altitude and treatment on COPL were evaluated by ordered logistic regression. www.ClinicalTrials.gov NCT03536429. Results: In participants taking placebo, ascent from 760 m to 3,100 m increased median COPL from 25.8 cm to 27.6 cm (odds ratio 3.80, 95%CI 2.53-5.70) and decreased SpO 2 from 96% to 91% (odds ratio 0.0003, 95%CI 0.0002-0.0007); in participants taking acetazolamide, altitude ascent increased COPL from 24.6 cm to 27.3 cm (odds ratio 2.22, 95%CI 1.57-3.13), while SpO 2 decreased from 96% to 93% (odds ratio 0.007, 95%CI 0.004-0.012). Altitude-induced increases in COPL were smaller with acetazolamide vs. placebo (odds ratio 0.58, 95%CI 0.34-0.99) while drops in SpO 2 were mitigated (odds ratio 19.2, 95%CI 9.9-37.6). Conclusion: In healthy individuals, 40 years of age or older, postural control was impaired after spending a night at 3,100 m. The altitude-induced deterioration of postural control was mitigated by acetazolamide, most likely due to the associated improvement in oxygenation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mutschler, Furian, Lichtblau, Buergin, Schneider, Appenzeller, Mayer, Muralt, Mademilov, Abdyraeva, Aidaralieva, Muratbekova, Akylbekov, Shabykeeva, Sooronbaev, Ulrich and Bloch.)

Introduction: Acetazolamide (AZA) improves nocturnal and daytime blood oxygenation in patients with pulmonary vascular disease (PVD), defined as pulmonary arterial and distal chronic thromboembolic pulmonary hypertension (CTEPH), and may improve exercise performance., Methods: We investigated the effect of 5 weeks of AZA (250 mg bid) versus placebo on maximal load during incremental cycling ramp exercise in patients with PVD studied in a randomized controlled, double-blind, crossover design, separated by &gt; 2 weeks of washout., Results: Twenty-five patients (12 pulmonary arterial hypertension, 13 CTEPH, 40% women, age 62 ± 15 years) completed the trial according to the protocol. Maximum load was similar after 5 weeks of AZA versus placebo (113 ± 9 vs. 117 ± 9 watts [W]), mean difference -4 W (95% CI: -9 to 1, p = 0.138). With AZA, maximum (max)-exercise partial pressure of O2 (PaO2) was significantly higher by 1.1 kPa (95% CI: 0.5-1.8, p = 0.003), while arterial pH and partial pressure of CO2 were significantly lower. Gas exchange threshold was reached at a higher load with AZA (108 ± 8 W vs. 97 ± 8 W) and was therefore delayed by 11 W (95% CI: 3-19, p = 0.013), while the ventilatory equivalent for O2 and CO2 were significantly higher at both the max-exercise and gas exchange threshold with AZA versus placebo., Conclusion: AZA for 5 weeks did not significantly change maximum exercise capacity in patients with PVD despite a significant increase in PaO2. The beneficial effects of increased blood oxygenation may have been diminished by increased ventilation due to AZA-induced metabolic acidosis and increased dyspnea., (© 2024 S. Karger AG, Basel.)

Ever since the second world symposium on pulmonary hypertension (PH) held in Evian, France, in 1998, PH has been classified into five major clinical groups. Group 5 PH includes a variety of distinct conditions with unclear and/or multifactorial underlying pathologies. Management of these patients is challenging as the number of patients within these groups is often small, not all individuals with certain underlying conditions are affected by PH and patients exhibit distinct symptoms due to different underlying diseases. Studies and clinical trials in these groups are largely lacking and mostly restricted to case series and registry reports. Nonetheless, the worldwide burden of group 5 PH is estimated to be significant in terms of the prevalence of some associated diseases. Group 5 PH encompasses six subgroups, including haematological disorders (inherited and acquired chronic haemolytic anaemia and chronic myeloproliferative disorders), systemic disorders (sarcoidosis, pulmonary Langerhans's cell histiocytosis and neurofibromatosis type 1), metabolic disorders (glycogen storage diseases and Gaucher disease), chronic renal failure with or without haemodialysis, pulmonary tumour thrombotic microangiopathy and fibrosing mediastinitis., Competing Interests: Conflict of interest: M. Lichtblau reports lecture honoraria and advisory board participation from MSD; and travel support from Orpha Swiss, Janssen and MSD, outside the submitted work. S. Ulrich reports grants from the Swiss National Science Foundation, Swiss Lung Foundation, MSD SA and Orpha Swiss; consulting fees, travel support and lecture honoraria from Janssen SA, Actelion SA, MSD SA and Orpha Swiss; and advisory board participation for Janssen SA, Actelion SA and MSD SA, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

With an estimated prevalence of around 1%, pulmonary hypertension (PH) presents a relevant burden worldwide. In this review, we aim to give an overview of the novelties from the revised European Society of Cardiology (ESC) /European Respiratory Society (ERS) guidelines for the diagnosis and treatment of PH and their implication for the everyday clinical practice., Competing Interests: Declaration of Competing Interest None of the authors report any conflict of interest in relation to this manuscript. Dr. med. M. Lichtblau reports travel grants and lecture/consultation fees from Johnson and Johnson, Switzerland, MSD and Orpha Swiss outside of the submitted work. Prof. Dr. med. S. Ulrich reports grants from the Swiss National Science Foundation, Zurich Lung, Swiss Lung, Johnson and Johnson, MSD and Orpha Swiss unrelated to the present work. SU received personal fees and travel support from Actelion, MSD, Janssen, Novartis and Orpha Swiss, outside the submitted work., (Copyright © 2023. Published by Elsevier B.V.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Within the last decade, the age at diagnosis of patients with pulmonary arterial hypertension has increased, which led to a change of the clinical phenoype being associated with more comorbidities. Cluster analyses of registry data have identified cardiac, cardio-pulmonary and classical phenotypes of pulmonary arterial hypertension.Subgroup analyses of randomised controlled trials and registry data indicate, that in patients with pulmonary arterial hypertension and cardiac comorbidities, especially the left-heart phenotype, a closely supervised combination treatment may be considered. The 4-strata model may be used for monitoring and risk stratification in these patients. Individual treatment decisions should be made in the pulmonary hypertension centre. Factors such as hemodynamics, age, phenotype, number and severity of comorbidities, therapy response, adverse reactions and the wish of the patient should be considered.Prospective, randomized studies to assess the efficacy and safety profile of pulmonary arterial hypertension treatments are desirable. Patients with a mainly pulmonary phenotype (smoking, diffusion capacity of the lung < 45 % and/or lung parenchymal changes) may have less benefit of oral medication., Competing Interests: E.G. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GEBRO, GSK, Janssen und OMT erhalten. Forschungsförderung für klinische Studien wurde von Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, Janssen, Novartis, OMT, Pfizer, REATE und United Therapeutics erhalten.M.H. hat Honorare für Vorträge/Konsultationen von AstraZeneca, Janssen und MSD erhalten.C.N. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GSK, Janssen und OMT erhalten.J.B. erhielt Honorare für Vorträge und Beratertätigkeit von Astra-Zeneca, Biogen, Boehringer-Ingelheim, BMS, Ferrer, Novartis, Roche und Sanofi-Genzyme. Für Tätigkeiten im Rahmen von Data Monitoring and Safety Boards erhielt er Honorare von Actelion und Galapagos. Es besteht kein Zusammenhang mit der vorliegenden Publikation.K.M.K. hat Vortrags- und/oder Beratungshonorare erhalten von AOP, AstraZeneca, Chiesi, GSK, Janssen, MSD, Novartis, Sanofi.J.R. hat keinen Interessenkonflikt.M.L.: Unterstützung zur Teilnahme an medizinischen Kongressen/Fort- und Weiterbildungen von MSD, Orpha Swiss, Janssen. Advisory-Board-Tätigkeiten für MSD (bezahlt) und Orpha Swiss (unbezahlt).N.B. erhielt Vortragshonorare des Universitätsspitals Zürich für Vortragstätigkeiten.T.J.L. hat Honorare für Vorträge und/oder Beratungstätigkeit und/oder Unterstützung für die Teilnahme an Fortbildungen erhalten von Acceleron Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Ferrer, Gossamer Bio, Janssen Cilag, MSD, Orphacare und Pfizer.S.U. hat Forschungsgelder des Schweizerischen Nationalfond, der Zürcher und Schweizer Lungenliga, der EMDO-Foundation, zudem Forschungsgelder und Unterstützung für Vorträge, Reisen und Beratungshonorare von Janssen SA, Orpha Swiss, MSD und Novartis erhalten, alle nicht im Zusammenhang mit dieser Arbeit.H.W.: Referenten- und/oder Beratertätigkeit für Bayer AG, Biotest, Boehringer Ingelheim, Daiichi Sanchyo, Ferrer, GSK, Janssen, MSD und Roche.C.G.: Advisory Board Treffen: Pfizer, Janssen, Bayer.D.S.: Vortrags- und Beratungshonorare und/oder Forschungsunterstützung von AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD, Sanofi, DFG, BMBF., (Thieme. All rights reserved.)

Care of patients with pulmonary arterial hypertension (PAH) needs a multi-facetet concept and measures, including management of adverse reactions, right heart insufficiency as well as information on pregnancy, travels by air, psychosocial support, physical exercise training and prophylaxis by vaccination.Positive study results led to an higher recommendation of specialized exercise training in pulmonary hypertension. Also, the recommendation on iron substitution was amended according to the current evidence.In the current guidelines, special focus was given to the elaboration of recommendations regarding pregnancy, including patient information, contraception and patient management in case of pregnancy.This article aims to provide an overview on the recommendations of general measuremes, special circumstances and patient management according to the ESC/ERS guidelines. Amendments to the guideline recommendations are given as comments from the authors of this article., Competing Interests: M.L.: Unterstützung zur Teilnahme an medizinischen Kongressen/Fort- und Weiterbildungen: MSD, Orpha Swiss, Janssen. Advisory Boards: MSD (bezahlt), Orpha Swiss (unbezahlt).S.H., R.N., F.M.W., S.U., A.F.: kein Interessenkonflikt.E.G. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GEBRO, GSK, Janssen und OMT erhalten. Forschungsförderung für klinische Studien wurde von Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, Janssen, Novartis, OMT, Pfizer, REATE und United Therapeutics erhalten.H.J.K.: Reise-/Übernachtungskosten, Honorare, Forschungsunterstützung von folgenden Firmen: Anamed; AstraZeneca; Bayer; Berlin Chemie/Menarini; Bezirksärztekammer Südbaden, Boehringer Ingelheim; Chiesi; Daiichi-Sankyo; Deutsche Forschungsgemeinschaft; Dräger; Fisher & Paykel Healthcare; Grifols; GSK; Heinen & Löwenstein; Janssen Johnson & Johnson; Lilly; MSD; Mundipharma; Novartis; Pfizer; Portola; Philips Healthcare; Pulmonx; ResMed; Roche; Sanofi Genzyme; Sapio Life; Weinmann.D.R. erhielt Honorare für Vortragstätigkeiten von Janssen und MSD.N.B. erhielt Honorare für Vortragstätigkeit durch das Universitätsspital Zürich., (Thieme. All rights reserved.)

The 2022 guidelines on pulmonary hypertension from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) provide therapeutic strategies that account for the variability in the clinical presentation of newly diagnosed patients. We summarize treatment recommendations for pulmonary arterial hypertension (PAH) in patients without significant comorbidities, particularly for idiopathic, hereditary, drug/toxin-induced, or connective tissue disease-associated PAH. In this group of patients, multidimensional assessments for short-term mortality risk guide initial treatment decisions and treatment decisions during follow-up. Upfront dual combination therapy (phosphodiesterase type-5 inhibitor and endothelin receptor antagonist) is recommended for low- and intermediate-risk patients, and triple therapy including a parenteral prostacyclin should be considered in high- or intermediate-high-risk patients. If a low or intermediate-low-risk profile cannot be achieved during therapy, sequential add-on therapy escalation with parenteral prostacyclin or a prostacyclin receptor agonist should be considered, and switching from a phosphodiesterase type-5 inhibitor to a guanylate cyclase stimulator may also be considered., Competing Interests: H.K.: Honorare für Vorträge und/oder Beratungstätigkeit und/oder Unterstützung für die Teilnahme an Fortbildungen von Bayer, Gossamer Bio, Janssen Cilag, MSD, Orphacare und Pfizer, OMT, UT.L.H.: Vortragshonorare von Janssen-Cilag und AOP Health sowie Forschungsmittel von MSD.M.J.R.: Vortrags- und/oder Beratungshonorare von Bayer vital, Janssen, MSD.M.L.: Unterstützung zur Teilnahme an medizinischen Kongressen/Fort- und Weiterbildungen von MSD, Orpha Swiss und Janssen. Advisory Board-Tätigkeiten für MSD (bezahlt) und Orpha Swiss (unbezahlt).S.H.: Vortrags- und/oder Beratungshonorare von OMT, Janssen, MSD.K.M.K.: Vortrags- und/oder Beratungshonorare von AOP-Pharma, Ferrer, Janssen, MSD.T.J.L.: Honorare für Vorträge und/oder Beratungstätigkeit und/oder Unterstützung für die Teilnahme an Fortbildungen von Acceleron Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Ferrer, Gossamer Bio, Janssen Cilag, MSD, Orphacare und Pfizer., (Thieme. All rights reserved.)

Background: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (CTEPH) with accessible lesions. Breathing pure oxygen (hyperoxia) during right heart catheterization (RHC) allows for the calculation of the right-to-left shunt fraction (Qs/Qt). In the absence of intracardiac shunt, Qs/Qt can be used as a marker of ventilation-perfusion mismatch in patients with CTEPH. This study involved investigating Qs/Qt after PEA and its relation to other disease-specific outcomes., Study Design and Methods: This study is a retrospective study that focuses on patients with operable CTEPH who had Qs/Qt assessment during RHC before and 1 year after PEA. Additionally, 6 min walking distance (6MWD), WHO functional class (WHO-FC), and NT-proBNP were assessed to calculate a four-strata risk score., Results: Overall, 16 patients (6 females) with a median age of 66 years (quartiles 55; 74) were included. After PEA, an improvement in mean pulmonary artery pressure (38 [32; 41] to 24 [18; 28] mmHg), pulmonary vascular resistance (5.7 [4.0; 6.8] to 2.5 [1.4; 3.8] WU), oxygen saturation (92 [88; 93]% to 94 [93; 95]%), WHO-FC, and risk score was observed (all p < 0.05). No improvement in median Qs/Qt could be detected (13.7 [10.0; 17.5]% to 13.0 [11.2; 15.6]%, p = 0.679). A total of 7 patients with improved Qs/Qt had a significant reduction in risk score compared to those without improved Qs/Qt., Conclusion: PEA did not alter Qs/Qt assessed after 1 year in operable CTEPH despite an improvement in hemodynamics and risk score, potentially indicating a persistent microvasculopathy. In patients whose shunt fraction improved with PEA, the reduced shunt was associated with an improvement in risk score.

Introduction: This prospective cohort study assessed the effects of chronic hypoxaemia due to high-altitude residency on the cerebral tissue oxygenation (CTO) and cerebrovascular reactivity. Methods: Highlanders, born, raised, and currently living above 2,500 m, without cardiopulmonary disease, participated in a prospective cohort study from 2012 until 2017. The measurements were performed at 3,250 m. After 20 min of rest in supine position while breathing ambient air (FiO 2 0.21) or oxygen (FiO 2 1.0) in random order, guided hyperventilation followed under the corresponding gas mixture. Finger pulse oximetry (SpO 2 ) and cerebral near-infrared spectroscopy assessing CTO and change in cerebral haemoglobin concentration (cHb), a surrogate of cerebral blood volume changes and cerebrovascular reactivity, were applied. Arterial blood gases were obtained during ambient air breathing. Results: Fifty three highlanders, aged 50 ± 2 years, participated in 2017 and 2012. While breathing air in 2017 vs. 2012, P aO 2 was reduced, mean ± SE, 7.40 ± 0.13 vs. 7.84 ± 0.13 kPa; heart rate was increased 77 ± 1 vs. 70 ± 1 bpm ( p < 0.05) but CTO remained unchanged, 67.2% ± 0.7% vs. 67.4% ± 0.7%. With oxygen, SpO 2 and CTO increased similarly in 2017 and 2012, by a mean (95% CI) of 8.3% (7.5-9.1) vs. 8.5% (7.7-9.3) in SpO 2 , and 5.5% (4.1-7.0) vs. 4.5% (3.0-6.0) in CTO, respectively. Hyperventilation resulted in less reduction of cHb in 2017 vs. 2012, mean difference (95% CI) in change with air 2.0 U/L (0.3-3.6); with oxygen, 2.1 U/L (0.5-3.7). Conclusion: Within 5 years, CTO in highlanders was preserved despite a decreased P aO 2 . As this was associated with a reduced response of cerebral blood volume to hypocapnia, adaptation of cerebrovascular reactivity might have occurred., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Luyken, Appenzeller, Scheiwiller, Lichtblau, Mademilov, Muratbekova, Sheraliev, Abdraeva, Marazhapov, Sooronbaev, Ulrich, Bloch and Furian.)

Background: The course of pulmonary arterial wedge pressure (PAWP) during exercise in patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH), further abbreviated as pulmonary vascular disease (PVD), is still unknown. The aim of the study was to describe PAWP during exercise in patients with PVD., Methods: In this cross-sectional study, right heart catheter (RHC) data including PAWP, recorded during semi-supine, stepwise cycle exercise in patients with PVD, were analysed retrospectively. We investigated PAWP changes during exercise until end-exercise., Results: In 121 patients (59 female, 66 CTEPH, 55 PAH, 62±17 years) resting PAWP was 10.2±4.1 mmHg. Corresponding peak changes in PAWP during exercise were +2.9 mmHg (95% CI 2.1-3.7 mmHg, p<0.001). Patients ≥50 years had a significantly higher increase in PAWP during exercise compared with those <50 years (p<0.001). The PAWP/cardiac output (CO) slopes were 3.9 WU for all patients, and 1.6 WU for patients <50 years and 4.5 WU for those ≥50 years., Conclusion: In patients with PVD, PAWP increased slightly but significantly with the onset of exercise compared to resting values. The increase in PAWP during exercise was age-dependent, with patients ≥50 years showing a rapid PAWP increase even with minimal exercise. PAWP/CO slopes >2 WU are common in patients with PVD aged ≥50 years without exceeding the PAWP of 25 mmHg during exercise., Competing Interests: Conflict of interest: E. Grünig has received fees for lectures and/or consultations from Actelion, Bayer/MSD, Ferrer, GEBRO, GSK, Janssen and OMT. Research grants to his institution have been received from Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, GSK, Janssen, Novartis, OMT, Pfizer, REATE and United Therapeutics. Conflict of interest: None of the other authors have any conflicts of interest in the context of this manuscript., (Copyright ©The authors 2023.)

Bloch, Konrad E., Talant M. Sooronbaev, Silvia Ulrich, Mona Lichtblau, and Michael Furian. Clinician's corner: counseling patients with chronic obstructive pulmonary disease traveling to high altitude. High Alt Med Biol . 24:158-166, 2023.-Mountain travel is increasingly popular also among patients with chronic obstructive pulmonary disease (COPD), a highly prevalent condition often associated with cardiovascular and systemic manifestations. Recent studies have shown that nonhypercapnic and only mildly hypoxemic lowlanders with moderate to severe airflow obstruction owing to COPD experience dyspnea, exercise limitation, and sleep disturbances when traveling up to 3,100 m. Altitude-related adverse health effects (ARAHE) in patients with COPD include severe hypoxemia, which may be asymptomatic but expose patients to the risk of excessive systemic and pulmonary hypertension, cardiac arrhythmia, and even myocardial or cerebral ischemia. In addition, hypobaric hypoxia may impair postural control, psycho-motor, and cognitive performance in patients with COPD during altitude sojourns. Randomized, placebo-controlled trials have shown that preventive treatment with oxygen at night or with acetazolamide reduces the risk of ARAHE in patients with COPD while preventive dexamethasone treatment improves oxygenation and altitude-induced excessive sleep apnea, and lowers systemic and pulmonary artery pressure. This clinical review provides suggestions for pretravel assessment and preparations and measures during travel that may reduce the risk of ARAHE and contribute to pleasant mountain journeys of patients with COPD.

Aims: Pulmonary hypertension (PH) is a complex clinical condition, and left heart disease is the leading cause. Little is known about the epidemiology and prognosis of combined post- and pre-capillary PH (CpcPH)., Methods and Results: This retrospective analysis of the Swiss PH Registry included incident patients with CpcPH registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient baseline characteristics [age, sex, mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP), pulmonary vascular resistance (PVR), and risk factors, including World Health Organization (WHO)-functional class (FC), 6 min walk distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-proBNP), treatment, days of follow-up, and events (death or loss to follow-up) at last visit] were analysed by Kaplan-Meier and Cox regression analyses. Two hundred and thirty-one patients (59.3% women, age 65 ± 12 years, mPAP 48 ± 11 mmHg, PAWP 21 ± 5 mmHg, PVR 7.2 ± 4.8 WU) were included. Survival analyses showed a significantly longer survival for women [hazard ratio (HR) 0.58 (0.38-0.89); P = 0.01] and a higher mortality risk for mPAP > 46 mmHg [HR 1.58 (1.03-2.43); P = 0.04] but no association with age or PVR. Patients stratified to high risk according to four-strata risk assessment had an increased mortality risk compared with patients stratified to low-intermediate risk [HR 2.44 (1.23-4.84); P = 0.01]. A total of 46.8% of CpcPH patients received PH-targeted pharmacotherapy; however, PH-targeted medication was not associated with longer survival., Conclusion: Among patients with CpcPH, women and patients with an mPAP ≤46 mmHg survived longer. Furthermore, risk stratification by using non-invasively assessed risk factors, such as WHO-FC, 6MWD, and NT-proBNP, as proposed for pulmonary arterial hypertension, stratified survival in CpcPH, and might be helpful in the management of these patients., Competing Interests: Conflict of interest: A.M.D. reports personal fees from Astra Zeneca, Gebro Pharma, GSK, and MSD and financial support to attend scientific meetings from Janssen and OrPha Swiss outside the submitted work. S.A.G. reports grants and personal fees from MSD, Gebro, and Orpha outside the submitted work. M.L. reports personal fees from Janssen, personal fees from MSD, and personal fees from OrphaSwiss outside the submitted work. S.U. receives research grants from the Swiss National Science Foundation, Zurich, and Swiss Lung League and EMDO foundation and grants, travel support and consultancy fees from Orpha Swiss, Janssen SA, MSD SA, and Novartis, all unrelated to the present work. All other authors report no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Importance: With increasing altitude, the partial pressure of inspired oxygen decreases and, consequently, the Pao2 decreases. Even though this phenomenon is well known, the extent of the reduction as a function of altitude remains unknown., Objective: To calculate an effect size estimate for the decrease in Pao2 with each kilometer of vertical gain among healthy unacclimatized adults and to identify factors associated with Pao2 at high altitude (HA)., Data Sources: A systematic search of PubMed and Embase was performed from database inception to April 11, 2023. Search terms included arterial blood gases and altitude., Study Selection: A total of 53 peer-reviewed prospective studies in healthy adults providing results of arterial blood gas analysis at low altitude (<1500 m) and within the first 3 days at the target altitude (≥1500 m) were analyzed., Data Extraction and Synthesis: Primary and secondary outcomes as well as study characteristics were extracted from the included studies, and individual participant data (IPD) were requested. Estimates were pooled using a random-effects DerSimonian-Laird model for the meta-analysis., Main Outcomes and Measures: Mean effect size estimates and 95% CIs for reduction in Pao2 at HA and factors associated with Pao2 at HA in healthy adults., Results: All of the 53 studies involving 777 adults (mean [SD] age, 36.2 [10.5] years; 510 men [65.6%]) reporting 115 group ascents to altitudes between 1524 m and 8730 m were included in the aggregated data analysis; 13 of those studies involving 305 individuals (mean [SD] age, 39.8 [13.6] years; 185 men [60.7%]) reporting 29 ascents were included in the IPD analysis. The estimated effect size of Pao2 was -1.60 kPa (95% CI, -1.73 to -1.47 kPa) for each 1000 m of altitude gain (τ2 = 0.14; I2 = 86%). The Pao2 estimation model based on IPD data revealed that target altitude (-1.53 kPa per 1000 m; 95% CI, -1.63 to -1.42 kPa per 1000 m), age (-0.01 kPa per year; 95% CI, -0.02 to -0.003 kPa per year), and time spent at an altitude of 1500 m or higher (0.16 kPa per day; 95% CI, 0.11-0.21 kPa per day) were significantly associated with Pao2., Conclusions and Relevance: In this systematic review and meta-analysis, the mean decrease in Pao2 was 1.60 kPa per 1000 m of vertical ascent. This effect size estimate may improve the understanding of physiological mechanisms, assist in the clinical interpretation of acute altitude illness in healthy individuals, and serve as a reference for physicians counseling patients with cardiorespiratory disease who are traveling to HA regions.

Background: COPD may predispose to symptomatic pulmonary hypertension at high altitude. We investigated haemodynamic changes in lowlanders with COPD ascending to 3100 m and evaluated whether preventive acetazolamide treatment would attenuate the altitude-induced increase in pulmonary artery pressure (PAP)., Methods: In this randomised, placebo-controlled, double-blind, parallel-group trial, patients with COPD Global Initiative for Chronic Obstructive Lung Disease grades 2-3 who were living <800 m and had peripheral oxygen saturation ( S pO 2 ) or placebo capsules, starting 24 h before ascent from 760 m and during a 2-day stay at 3100 m. Echocardiography, pulse oximetry and clinical assessments were performed at 760 m and after the first night at 3100 m. Primary outcome was PAP assessed by tricuspid regurgitation pressure gradient (TRPG).-1 ) or placebo capsules, starting 24 h before ascent from 760 m and during a 2-day stay at 3100 m. Echocardiography, pulse oximetry and clinical assessments were performed at 760 m and after the first night at 3100 m. Primary outcome was PAP assessed by tricuspid regurgitation pressure gradient (TRPG)., Results: 112 patients (68% men, mean±sd age 59±8 years, forced expiratory volume in 1 s (FEV 1 ) 61±12% pred, S 95±2%) were included. Mean±sd TRPG increased from 22±7 to 30±10 mmHg in 54 patients allocated to placebo and from 20±5 to 24±7 mmHg in 58 patients allocated to acetazolamide (both p<0.05) resulting in a mean (95% CI) treatment effect of -5 (-9 to -1) mmHg (p=0.015). In patients assigned to placebo at 760/3100 m, mean±sd pO 2 95±2%) were included. Mean±sd TRPG increased from 22±7 to 30±10 mmHg in 54 patients allocated to placebo and from 20±5 to 24±7 mmHg in 58 patients allocated to acetazolamide (both p<0.05) resulting in a mean (95% CI) treatment effect of -5 (-9 to -1) mmHg (p=0.015). In patients assigned to placebo at 760/3100 m, mean±sd S pO 2 was 95±2%/88±3%; in the acetazolamide group, the respective values were 94±2%/90±3% (both p<0.05), resulting in a treatment effect of +2 (1 to 3)% (p=0.001)., Conclusions: In lowlanders with COPD travelling to 3100 m, preventive acetazolamide treatment attenuated the altitude-induced rise in PAP and improved oxygenation., Competing Interests: Conflict of interest: M. Lichtblau received funding from the Swiss Lung League for this study. S. Ulrich reports grants from the Swiss National Science Foundation and Lung Zuerich. K.E. Bloch was supported by Swiss National Science Foundation (grant ID: 172980). S. Saxer, L. Mayer, U. Sheraliev, M. Mademilov, M. Furian, A. Buergin, P.M. Schweiwiller, S.R. Schneider, F.C. Tanner and T. Sooronbaev have nothing to declare., (Copyright ©The authors 2023.)

Background: The aim of this study was to investigate the overall and differential effect of breathing hyperoxia (inspiratory oxygen fraction ( F IO 2 ) 0.5) versus placebo (ambient air, F IO 2 0.21) to enhance exercise performance in healthy people, patients with pulmonary vascular disease (PVD) with precapillary pulmonary hypertension (PH), COPD, PH due to heart failure with preserved ejection fraction (HFpEF) and cyanotic congenital heart disease (CHD) using data from five randomised controlled trials performed with identical protocols., Methods: 91 subjects (32 healthy, 22 with PVD with pulmonary arterial or distal chronic thromboembolic PH, 20 with COPD, 10 with PH in HFpEF and seven with CHD) performed two cycle incremental (IET) and two constant work-rate exercise tests (CWRET) at 75% of maximal load (W max ), each with ambient air and hyperoxia in single-blinded, randomised, controlled, crossover trials. The main outcomes were differences in W max (IET) and cycling time (CWRET) with hyperoxia versus ambient air., Results: Overall, hyperoxia increased W max by +12 W (95% CI: 9-16, p<0.001) and cycling time by +6:13 min (4:50-7:35, p<0.001), with improvements being highest in patients with PVD (W max /min: +18%/+118% versus COPD: +8%/+60%, healthy: +5%/+44%, HFpEF: +6%/+28%, CHD: +9%/+14%)., Conclusion: This large sample of healthy subjects and patients with various cardiopulmonary diseases confirms that hyperoxia significantly prolongs cycling exercise with improvements being highest in endurance CWRET and patients with PVD. These results call for studies investigating optimal oxygen levels to prolong exercise time and effects on training., Competing Interests: Conflict of interest: None of the authors has any financial or nonfinancial disclosures in context to this manuscript., (Copyright ©The authors 2023.)

Background/aims: Amongst numerous travellers to high altitude (HA) are many with the highly prevalent COPD, who are at particular risk for altitude-related adverse health effects (ARAHE). We then investigated the hypoxia-altitude simulation test (HAST) to predict ARAHE in COPD patients travelling to altitude., Methods: This prospective diagnostic accuracy study included 75 COPD patients: 40 women, age 58±9 years, forced expiratory volume in 1 s (FEV 1 ) 40-80% pred, oxygen saturation measured by pulse oximetry ( S pO 2 ) ≥92% and arterial carbon dioxide tension ( P ) of 15%) for 15 min, at low altitude (760 m). Cut-off values for a positive HAST were set according to British Thoracic Society (BTS) guidelines (arterial oxygen tension ( aCO 2 ) <6 kPa. Patients underwent baseline evaluation and HAST, breathing normobaric hypoxic air (inspiratory oxygen fraction ( F <85%). The following day, patients travelled to HA (3100 m) for two overnight stays where ARAHE development including acute mountain sickness (AMS), Lake Louise Score ≥4 and/or AMS score ≥0.7, severe hypoxaemia ( IO 2 ) of 15%) for 15 min, at low altitude (760 m). Cut-off values for a positive HAST were set according to British Thoracic Society (BTS) guidelines (arterial oxygen tension ( P aO 2 ) <6.6 kPa and/or S pO 2 <85%). The following day, patients travelled to HA (3100 m) for two overnight stays where ARAHE development including acute mountain sickness (AMS), Lake Louise Score ≥4 and/or AMS score ≥0.7, severe hypoxaemia ( S pO 2 <80% for >30 min or 75% for >15 min) or intercurrent illness was observed., Results: ARAHE occurred in 50 (66%) patients and 23 out of 75 (31%) were positive on HAST according to S pO 2 , and 11 out of 64 (17%) according to P aO 2 . For S pO 2 / P aO 2 we report a sensitivity of 46/25%, specificity of 84/95%, positive predictive value of 85/92% and negative predictive value of 44/37%., Conclusion: In COPD patients ascending to HA, ARAHE are common. Despite an acceptable positive predictive value of the HAST to predict ARAHE, its clinical use is limited by its insufficient sensitivity and overall accuracy. Counselling COPD patients before altitude travel remains challenging and best focuses on early recognition and treatment of ARAHE with oxygen and descent., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2023.)

Competing Interests: Competing interests: PX has received personal fees from MSD and OMT. AM has received personal fees from Bayer, outside the submitted work. NB has received consulting fees, speaker fees and/or honoraria from MSD, GSK, Actelion and Bayer Vital. BE received travel fees, consulting fees, speaking fees and/or honoraria from Actelion, MSD, Bayer and OMT (less than US$10 000 each). MG serves on an advisory Board for Bayer AG and receives lecture fees from Pfizer, MSD and Actelion Pharmaceuticals. SH has received personal fees from Bayer, MSD, Actelion and GSK, outside the submitted work. H-ML has received consulting fees, speaking fees and/or honoraria from AbbVie, BMS, Pfizer, Cellgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, AstraZeneca and Lilly (less than US$10 000 each) and research support from AbbVie, MSD, BMS, Cellgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, AstraZeneca, Lilly, Baxter, SOBI, Biogen, Actelion, Bayer Vital, Shire, Octapharm, Sanofi, Hexal, Mundipharm and Thermo Fisher. CN has received consulting fees, speaking fees and/or honoraria from Actelion, MSD, Boehringer, Novartis, Bayer and AstraZeneca (less than US$10 000 each). CB received travel support from Actelion SA and Orpha Swiss and speakers’ fee from MSD. SU received grants from the Swiss National Science foundation and the Zurich Lung League, travel support and speakers’ fees from Actelion SA, Switzerland, Bayer SA, Germany, MSD, Switzerland and Orpha Swiss. EG has received grants and personal fees from Actelion, Bayer AG and MSD; grants from GSK, Novartis and United Therapeutics; and personal fees from SCOPE, OrPha Swiss GmbH and Zurich Heart House (less than US$10 000 each). NB received speaker fees from Actelion pharmaceuticals, Bayer HealthCare and MSD. OD has received grants and personal fees from research consultancies from AM, Acceleron Pharma, Amgen, AnaMar, Bayer, Beacon Discovery, Boehringer Ingelheim, Catenion, CSL Behring, ChemomAb, Ergonex, GSK, Inventiva, Italfarmaco, iQone, iQvia, Lilly, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Blade Therapeutics, Glenmark Pharmaceuticals, Target Bio Science and UCB, outside the submitted work, to investigate potential treatments of scleroderma and its complications. In addition, OD has a patent mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143).

Pulmonary vascular diseases (PVDs), defined as arterial or chronic thromboembolic pulmonary hypertension, are associated with autonomic cardiovascular dysregulation. Resting heart rate variability (HRV) is commonly used to assess autonomic function. Hypoxia is associated with sympathetic overactivation and patients with PVD might be particularly vulnerable to hypoxia-induced autonomic dysregulation. In a randomised crossover trial, 17 stable patients with PVD (resting PaO 2 ≥ 7.3 kPa) were exposed to ambient air (FiO 2 = 21%) and normobaric hypoxia (FiO 2 = 15%) in random order. Indices of resting HRV were derived from two nonoverlapping 5-10-min three-lead electrocardiography segments. We found a significant increase in all time- and frequency-domain HRV measures in response to normobaric hypoxia. There was a significant increase in root mean squared sum difference of RR intervals (RMSSD; 33.49 (27.14) vs. 20.76 (25.19) ms; p < 0.01) and RR50 count divided by the total number of all RR intervals (pRR50; 2.75 (7.81) vs. 2.24 (3.39) ms; p = 0.03) values in normobaric hypoxia compared to ambient air. Both high-frequency (HF; 431.40 (661.56) vs. 183.70 (251.25) ms 2 ; p < 0.01) and low-frequency (LF; 558.60 (746.10) vs. 203.90 (425.63) ms 2 ; p = 0.02) values were significantly higher in normobaric hypoxia compared to normoxia. These results suggest a parasympathetic dominance during acute exposure to normobaric hypoxia in PVD.

Patients with chronic obstructive pulmonary disease (COPD) may be susceptible to impairments in postural control (PC) when exposed to hypoxia at high altitude. This randomized, placebo-controlled, double-blind, parallel-design trial evaluated the effect of preventive acetazolamide treatment on PC in lowlanders with COPD traveling to 3100 m. 127 lowlanders (85 men, 42 women) with moderate to severe COPD, aged 57 ± 8 y, living below 800 m, were randomized to treatment with acetazolamide 375 mg/d starting 24 h before ascent from 760 m to 3100 m and during a 2-day sojourn in a clinic at 3100 m. PC was evaluated at both altitudes with a balance platform on which patients were standing during five tests of 30 s each. The primary outcome was the center of pressure path length (COPL). In the placebo group, COPL significantly increased from (mean ± SD) 28.8 ± 9.7 cm at 760 m to 30.0 ± 10.0 cm at 3100 m ( p = 0.002). In the acetazolamide group, COPL at 760 m and 3100 m were similar with 27.6 ± 9.6 cm and 28.4 ± 9.7 cm ( p = 0.069). The mean between-groups difference (acetazolamide-placebo) in altitude-induced change of COPL was -0.54 cm (95%CI -1.66 to 0.58, p = 0.289). Multivariable regression analysis confirmed an increase in COPL of 0.98 cm (0.39 to 1.58, p = 0.001) with ascent from 760 to 3100 m, but no significant effect of acetazolamide (0.66 cm, 95%CI -0.25 to 1.57, p = 0.156) when adjusting for several confounders. In lowlanders with moderate to severe COPD, an ascent to high altitude was associated with impaired postural control and this was not prevented by acetazolamide.

Objective: Altitude travel is increasingly popular also for middle-aged and older tourists and professionals. Due to the sensitivity of the central nervous system to hypoxia, altitude exposure may impair visuomotor performance although this has not been extensively studied. Therefore, we investigated whether a sojourn at moderately high altitude is associated with visuomotor performance impairments in healthy adults, 40y of age or older, and whether this adverse altitude-effect can be prevented by acetazolamide, a drug used to prevent acute mountain sickness., Methods: In this randomized placebo-controlled parallel-design trial, 59 healthy lowlanders, aged 40-75y, were assigned to acetazolamide (375 mg/day, n = 34) or placebo (n = 25), administered one day before ascent and while staying at high altitude (3100m). Visuomotor performance was assessed at 760m and 3100m after arrival and in the next morning (post-sleep) by a computer-assisted test (Motor-Task-Manager). It quantified deviation of a participant-controlled cursor affected by rotation during target tracking. Primary outcome was the directional error during post-sleep recall of adaptation to rotation estimated by multilevel linear regression modeling. Additionally, adaptation, immediate recall, and correct test execution were evaluated., Results: Compared to 760m, assessments at 3100m with placebo revealed a mean (95%CI) increase in directional error during adaptation and immediate recall by 1.9° (0.2 to 3.5, p = 0.024) and 1.1° (0.4 to 1.8, p = 0.002), respectively. Post-sleep recall remained unchanged (p = NS), however post-sleep correct test execution was 14% less likely (9 to 19, p<0.001). Acetazolamide improved directional error during post-sleep recall by 5.6° (2.6 to 8.6, p<0.001) and post-sleep probability of correct test execution by 36% (30 to 42, p<0.001) compared to placebo., Conclusion: In healthy individuals, 40y of age or older, altitude exposure impaired adaptation to and immediate recall and correct execution of a visuomotor task. Preventive acetazolamide treatment improved visuomotor performance after one night at altitude and increased the probability of correct test execution compared to placebo., Clinicaltrials.gov Identifier: ClinicalTrials.gov NCT03536520., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Reiser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pulmonary Endarterectomy and Treatment for Chronic Thromboembolic Pulmonary Hypertension Abstract. Chronic thromboembolic pulmonary hypertension is a relatively rare disease which mostly evolves as a complication of acute pulmonary embolism resulting from the fibrotic organization of residual thrombotic material despite adequate anticoagulation leading to precapillary pulmonary hypertension and persistence of its symptoms. The elevated pulmonary vascular resistance leads to right ventricular heart failure, its symptoms and reduced prognosis. The therapy of choice is the pulmonary endarterectomy, which leads to a reduction of symptoms, optimization of the hemodynamics and improved prognosis. Misdiagnosis and delayed referral often lead to disease progression along with poor surgical outcome. In case of more distal, surgically non-accessible disease, treatment consists of balloon pulmonary angioplasty and pulmonary vasodilator drugs.

Main pulmonary vascular diseases (PVD) with precapillary pulmonary hypertension (PH) are pulmonary arterial and chronic thromboembolic PH. Guidelines recommend supplemental oxygen therapy (SOT) for severely hypoxemic patients with PH, but evidence is scarce. The authors performed a systematic review and where possible meta-analyses on the effects of SOT on hemodynamics and exercise performance in patients with PVD. In PVD, short-term SOT significantly improved mean pulmonary artery pressure and exercise performance. There is growing evidence on the benefit of long-term SOT for selected patients with PVD regarding exercise capacity and maybe even survival., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Evidence supporting the use of balloon pulmonary angioplasty #BPA, which has drastically changed management of non-operable chronic thromboembolic pulmonary hypertension #CTEPH, and rationale for a future multimodal approach with combined medical therapy https://bit.ly/3F7ccKD., Competing Interests: Conflict of interest: T. Gille reports personal fees from Roche S.A.S., other fees from Oxyvie (oxygen provider), other fees from Vivisol France (oxygen provider), other fees from Menarini France, outside the submitted work. L. Bertoletti reports grants or contracts from MSD and Janssen, outside the submitted work; support for attending meetings and/or travel from Janssen. The remaining authors have nothing to disclose., (Copyright ©ERS 2023.)

High-altitude (HA) exposure may stimulate significant physiological and molecular changes, resulting in HA-related illnesses. HA may impact oxidative stress, antioxidant capacity, and iron homeostasis, yet it is unclear how both repeated exposure and HA acclimatization may modulate such effects. Therefore, we assessed the effects of weeklong repeated daily HA exposure (2,900-5,050 m) in altitude-naïve individuals ( n = 21 individuals, 13 females, mean ± SD, 25.3 ± 3.7 yr) to mirror the working schedule of HA workers ( n = 19 individuals, all males, 41.1 ± 9.4 yr) at the Atacama Large Millimeter Array (ALMA) Observatory (San Pedro de Atacama, Chile). Markers of oxidative stress, antioxidant capacity, and iron homeostasis were measured in blood plasma. Levels of protein oxidation ( P < 0.001) and catalase activity ( P = 0.023) increased and serum iron ( P < 0.001), serum ferritin ( P < 0.001), and transferrin saturation ( P < 0.001) levels decreased with HA exposure in both groups. HA workers had lower levels of oxidative stress, and higher levels of antioxidant capacity, iron supply, and hemoglobin concentration as compared with altitude-naïve individuals. On a second week of daily HA exposure, changes in levels of protein oxidation, glutathione peroxidase, and nitric oxide metabolites were lower as compared with the first week in altitude-naïve individuals. These results indicate that repeated exposure to HA may significantly alter oxidative stress and iron homeostasis, and the degree of such changes may be dependent on if HA is visited naïvely or routinely. Further studies are required to fully elucidate differences in HA-induced changes in oxidative stress and iron homeostasis profiles among visitors of HA.

Background: Effects of prolonged and repeated high-altitude exposure on oxygenation and control of breathing remain uncertain. We hypothesized that prolonged and repeated high-altitude exposure will improve altitude-induced deoxygenation and breathing instability. Methods: 21 healthy lowlanders, aged 18-30y, underwent two 7-day sojourns at a high-altitude station in Chile (4-8 hrs/day at 5,050 m, nights at 2,900 m), separated by a 1-week recovery period at 520 m. Respiratory sleep studies recording mean nocturnal pulse oximetry (SpO 2 ), oxygen desaturation index (ODI, >3% dips in SpO 2 ), breathing patterns and subjective sleep quality by visual analog scale (SQ-VAS, 0-100% with increasing quality), were evaluated at 520 m and during nights 1 and 6 at 2,900 m in the 1st and 2nd altitude sojourn. Results: At 520 m, mean ± SD nocturnal SpO 2 was 94 ± 1%, ODI 2.2 ± 1.2/h, SQ-VAS 59 ± 20%. Corresponding values at 2,900 m, 1st sojourn, night 1 were: SpO 2 86 ± 2%, ODI 23.4 ± 22.8/h, SQ-VAS 39 ± 23%; 1st sojourn, night 6: SpO 2 90 ± 1%, ODI 7.3 ± 4.4/h, SQ-VAS 55 ± 20% ( p < 0.05, all differences within corresponding variables). Mean differences (Δ, 95%CI) in acute effects (2,900 m, night 1, vs 520 m) between 2nd vs 1st altitude sojourn were: ΔSpO 2 0% (-1 to 1), ΔODI -9.2/h (-18.0 to -0.5), ΔSQ-VAS 10% (-6 to 27); differences in acclimatization (changes night 6 vs 1), between 2nd vs 1st sojourn at 2,900 m were: ΔSpO 2 -1% (-2 to 0), ΔODI 11.1/h (2.5 to 19.7), ΔSQ-VAS -15% (-31 to 1). Conclusion: Acute high-altitude exposure induced nocturnal hypoxemia, cyclic deoxygenations and impaired sleep quality. Acclimatization mitigated these effects. After recovery at 520 m, repeated exposure diminished high-altitude-induced deoxygenation and breathing instability, suggesting some retention of adaptation induced by the first altitude sojourn while subjective sleep quality remained similarly impaired., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Furian, Bitos, Hartmann, Muralt, Lichtblau, Bader, Rawling, Ulrich, Poulin and Bloch.)

Ulrich, Silvia, Mona Lichtblau, Simon R. Schneider, Stéphanie Saxer, and Konrad E. Bloch, Clinician's corner: counseling patients with pulmonary vascular disease traveling to high altitude. High Alt Med Biol . 23:201-208, 2022.-Pulmonary vascular diseases (PVDs) with precapillary pulmonary hypertension (PH), such as pulmonary arterial or chronic thromboembolic PH, impair exercise performance and survival in patients. Vasodilators and other treatments improve quality of life and prognosis to an extent in patients who have PVDs as chronic disorders. Obviously, patients with PVD wish to participate in usual daily activities, including travel to popular settlements and mountainous regions located at high altitude. However, the pulmonary hemodynamic impairment due to PVD leads to blood and tissue hypoxia, particularly during exercise and sleep. It is thus of concern that alveolar hypoxia at higher altitude may exacerbate patients' symptoms and lead to decompensation. Current PH guidelines discourage high-altitude exposure for fear of altitude-related adverse health effects. However, several recent well-designed prospective and randomized trials show that despite altitude-induced hypoxemia, pulmonary hemodynamic changes and impairment of exercise performance in patients with PVD are similar to the responses in healthy people or in patients with mild chronic obstructive pulmonary disease. The vast majority of patients with PVD can tolerate short-term exposure to moderate altitudes up to 2,500 m. For the roughly 10% of patients with stable disease who develop severe hypoxemia when ascending to 2,500 m, they respond well to low-level supplemental oxygen support. The best low-altitude predictors for adverse health effects at high altitude are the known clinical risk factors for PVD such as symptoms, functional class, exercise capacity, and exertional oxygen desaturation, whereas hypoxia altitude simulation testing is of little additive value. In any case, patients should be instructed that altitude-related adverse health effects may be difficult to predict and that in case of worsening symptoms, immediate accompanied descent to lower altitude and oxygen therapy are required. Patients with severe hypoxemia near sea level may safely visit high-altitude regions up to 1,500-2,000 m while continuing oxygen therapy and avoiding strenuous exercise. All PH patients should be counseled before any high-altitude sojourn by doctors with experience in PVD and high-altitude medicine and have an action plan for the occurrence of severe hypoxemia and other altitude-related conditions such as acute mountain sickness.

Maximal oxygen uptake ( V ' O 2 max ), assessed by cardiopulmonary exercise testing (CPET), is an important parameter for risk assessment in patients with pulmonary hypertension (PH). However, CPET may not be available for all PH patients. Thus, we aimed to test previously published predictive models of V ' O 2 max from the 6-min walk distance (6MWD) for their accuracy and to create a new model. We tested four models (two by Ross et al . (2010), one by Miyamoto et al . (2000) and one by Zapico et al . (2019)). To derive a new model, data were split into a training and testing dataset (70:30) and step-wise linear regression was performed. To compare the different models, the standard error of the estimate (SEE) was calculated and the models graphically compared by Bland-Altman plots. Sensitivity and specificity for correct prediction into low-risk classification ( V ' O 2 max >15 mL/min/kg) was calculated for all models. A total of 276 observations were included in the analysis (194/82 training/testing dataset); 6MWD and V ' O 2 max = 1.83 + 0.031 × 6MWD (m) - 0.023 × weight (kg) - 0.015 × HRR (bpm). SEEs for the different models were 3.03, 3.22, 4.36 and 3.08 mL/min/kg for the Ross V ' O 2 max and the best fitting prediction equation was: V ' O 2 max = 1.83 + 0.031 × 6MWD (m) - 0.023 × weight (kg) - 0.015 × HRR (bpm). SEEs for the different models were 3.03, 3.22, 4.36 and 3.08 mL/min/kg for the Ross et al ., Miyamoto et al ., Zapico et al . models and the new model, respectively. Predicted mean V ' O 2 max was 16.5 mL/min/kg ( versus observed 16.1 mL/min/kg). 6MWD and V ' O 2 max reveal good correlation in all models. However, the accuracy of all models is inadequate for clinical use. Thus, CPET and 6MWD both remain valuable risk assessment tools in the management of PH., Competing Interests: Conflict of interest: The authors have no conflicts of interest in relation to the present work. S. Ulrich has received research grants outside this work from the Swiss National Science Foundation, Swiss and Zurich Lung Leagues, and Orpha Swiss; and honoraria for lectures and support for attending meetings from Actelion/Janssen SA, MSD SA and Orpha Swiss., (Copyright ©The authors 2022.)

This article presents the views of the past and current Presidents of the ERS regarding their role, perspectives on career development and vision for the Society, along with important messages to inspire ECMs to build their own successful career. https://bit.ly/3kAvxIM., Competing Interests: Conflict of interest: M. Siciliano has nothing to disclose. Conflict of interest: E. Schiavi has nothing to disclose. Conflict of interest: S. Cullivan is the Janssen Pharmaceuticals Newman Fellow in Pulmonary Hypertension and Translational Medicine; this is unrelated to the submitted work. Conflict of interest: M. Bradicich has nothing to disclose. Conflict of interest: M. Lichtblau has nothing to disclose. Conflict of interest: J. Cruz has nothing to disclose., (Copyright ©ERS 2022.)

This article aims to summarise the latest research presented at the virtual 2021 European Respiratory Society (ERS) International Congress in the field of pulmonary vascular disease. In light of the current guidelines and proceedings, knowledge gaps are addressed and the newest findings of the various forms of pulmonary hypertension as well as key points on pulmonary embolism are discussed. Despite the comprehensive coverage of the guidelines for pulmonary embolism at previous conferences, discussions about controversies in the diagnosis and treatment of this condition in specific cases were debated and are addressed in the first section of this article. We then report on an interesting pro-con debate about the current classification of pulmonary hypertension. We further report on presentations on Group 3 pulmonary hypertension, with research exploring pathogenesis, phenotyping, diagnosis and treatment; important contributions on the diagnosis of post-capillary pulmonary hypertension are also included. Finally, we summarise the latest evidence presented on pulmonary vascular disease and COVID-19 and a statement on the new imaging guidelines for pulmonary vascular disease from the Fleischner Society., Competing Interests: Conflict of interest: M. Lichtblau has nothing to disclose. Conflict of interest: L. Piccari reports grants, personal fees and nonfinancial support from Janssen, and nonfinancial support from Menarini, outside the submitted work. Conflict of interest: S. Ramjug has nothing to disclose. Conflict of interest: A. Bokan has nothing to disclose. Conflict of interest: B. Lechartier has nothing to disclose. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: M. Barata has nothing to disclose. Conflict of interest: A.R. Garcia has nothing to disclose. Conflict of interest: L.S. Howard reports grants and personal fees from Janssen, personal fees from MSD, GSK, Bayer, Third Pole, Gossamer Bio, Endotronix and United Therapeutics, outside the submitted work. Conflict of interest: Y. Adir reports personal fees from Teva, grants and personal fees from GSK and AstraZeneca, personal fees from Sanofi, grants and personal fees from Yansen, and personal fees from BI and Acceleron, outside the submitted work. Conflict of interest: M. Delcroix has nothing to disclose. Conflict of interest: L. Jara-Palomares has nothing to disclose. Conflict of interest: L. Bertoletti reports personal fees from Sanofi, personal fees and nonfinancial support from Leo-Pharma and Aspen, personal fees from Bayer, personal fees and nonfinancial support from BMS/Pfizer, and grants, personal fees and nonfinancial support from MSD, during the conduct of the study. Conflict of interest: O. Sitbon reports grants and personal fees from Acceleron Pharmaceuticals, personal fees from AOP Orphan, grants, personal fees and nonfinancial support from Bayer, personal fees from Ferrer and Gossamer Bio, grants from GlaxoSmithKline, and grants, personal fees and nonfinancial support from Janssen and MSD, outside the submitted work. Conflict of interest: S. Ulrich reports grants from Johnson and Johnson SA, the Swiss National Science Foundation, Zurich Lung and Orpha Swiss, and personal fees from MSD Switzerland and SA, outside the submitted work. Conflict of interest: A. Vonk Noordegraaf is supported by the Netherlands CardioVascular Research Initiative (CVON-2012-08 PHAEDRA and CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610). In addition, his institute has received speaker's money from Johnson & Johnson, MSD, Actelion, Bayer and Ferrer in the past 3 years. Finally, he served as a member of the scientific advisory boards of Morphogen-X, Ferrer and Johnson & Johnson., (Copyright ©The authors 2022.)

Prediction of adverse health effects at altitude or during air travel is relevant, particularly in pre-existing cardiopulmonary disease such as pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH, PH). A total of 21 stable PH-patients (64 ± 15 y, 10 female, 12/9 PAH/CTEPH) were examined by pulse oximetry, arterial blood gas analysis and echocardiography during exposure to normobaric hypoxia (NH) (FiO2 15% ≈ 2500 m simulated altitude, data partly published) at low altitude and, on a separate day, at hypobaric hypoxia (HH, 2500 m) within 20−30 min after arrival. We compared changes in blood oxygenation and estimated pulmonary artery pressure in lowlanders with PH during high altitude simulation testing (HAST, NH) with changes in response to HH. During NH, 4/21 desaturated to SpO2 < 85% corresponding to a positive HAST according to BTS-recommendations and 12 qualified for oxygen at altitude according to low SpO2 < 92% at baseline. At HH, 3/21 received oxygen due to safety criteria (SpO2 < 80% for >30 min), of which two were HAST-negative. During HH vs. NH, patients had a (mean ± SE) significantly lower PaCO2 4.4 ± 0.1 vs. 4.9 ± 0.1 kPa, mean difference (95% CI) −0.5 kPa (−0.7 to −0.3), PaO2 6.7 ± 0.2 vs. 8.1 ± 0.2 kPa, −1.3 kPa (−1.9 to −0.8) and higher tricuspid regurgitation pressure gradient 55 ± 4 vs. 45 ± 4 mmHg, 10 mmHg (3 to 17), all p < 0.05. No serious adverse events occurred. In patients with PH, short-term exposure to altitude of 2500 m induced more pronounced hypoxemia, hypocapnia and pulmonary hemodynamic changes compared to NH during HAST despite similar exposure times and PiO2. Therefore, the use of HAST to predict physiological changes at altitude remains questionable. (ClinicalTrials.gov: NCT03592927 and NCT03637153).