title: Changes in acute pulmonary vascular responsiveness to hypoxia during a progressive ascent to high altitude (5300 m).
abstract: What is the central question of this study? Do the pulmonary vascular responses to hypoxia change during progressive exposure to high altitude and can alterations in these responses be related to changes in concentrations of circulating biomarkers that affect the pulmonary circulation? What is the main finding and its importance? In our field study with healthy volunteers, we demonstrate changes in pulmonary artery pressure suggestive of remodelling in the pulmonary circulation, but find no changes in the acute responsiveness of the pulmonary circulation to changes in oxygenation during 2 weeks of exposure to progressive hypoxia. Pulmonary artery pressure changes were associated with changes in erythropoietin, 8-isoprostane, nitrite and guanosine 3',5'-cyclic monophosphate. We sought to determine whether changes in pulmonary artery pressure responses to hypoxia suggestive of vascular remodelling occur during progressive exposure to high altitude and whether such alterations are related to changes in concentrations of circulating biomarkers with known or suspected actions on the pulmonary vasculature during ascent. We measured tricuspid valve transvalvular pressure gradients (TVPG) in healthy volunteers breathing air at sea level (London, UK) and in hypoxic conditions simulating the inspired O2partial pressures at two locations in Nepal, Namche Bazaar (NB, elevation 3500 m) and Everest Base Camp (EBC, elevation 5300 m). During a subsequent 13 day trek, TVPG was measured at NB and EBC while volunteers breathed air and hyperoxic or hypoxic mixtures simulating the inspired O2partial pressures at the other locations. For each location, we determined the slope of the relationship between TVPG and arterial oxygen saturation (SaO2) to estimate the pulmonary vascular response to hypoxia. Mean TVPG breathing air was higher at any SaO2 at EBC than at sea level or NB, but there was no change in the slope of the relationship between SaO2 and TVPG between locations. Nitric oxide availability remained unchanged despite increases in oxidative stress (elevated 8-isoprostane). Erythropoietin, pro-atrial natriuretic peptide and interleukin-18 levels progressively increased on ascent. Associations with TVPG were observed only with erythropoietin, 8-isoprostane, nitrite and guanosine 3',5'-cyclic monophosphate. Although the increased TVPG for any given SaO2 at EBC suggests that pulmonary vascular remodelling might occur during 2 weeks of progressive hypoxia, the lack of change in the slope of the relationship between TVPG and SaO2 indicates that the acute pulmonary vascular responsiveness to changes in oxygenation does not vary within this time frame.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Andrew M
authors.identifier: 0000-0003-1438-7464
authors.initials: AM
authors.lastname: Luks
authors.affiliation: University College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals National Institute for Health Research (UCLH NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, London, UK.|Anaesthesia and Critical Care Research Unit, University Hospital Southampton National Health Service Foundation Trust, Southampton, UK.|Integrative Physiology and Critical Illness Group, Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Southampton National Institutes for Health Research (NIHR) Respiratory Biomedical Research Unit, Southampton, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Denny
authors.initials: D
authors.lastname: Levett
authors.affiliation: University College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals National Institute for Health Research (UCLH NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, London, UK.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Martin
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Goss
authors.affiliation: University College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals National Institute for Health Research (UCLH NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, London, UK.|Anaesthesia and Critical Care Research Unit, University Hospital Southampton National Health Service Foundation Trust, Southampton, UK.|Integrative Physiology and Critical Illness Group, Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Southampton National Institutes for Health Research (NIHR) Respiratory Biomedical Research Unit, Southampton, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Kay
authors.initials: K
authors.lastname: Mitchell
authors.affiliation: Integrative Physiology and Critical Illness Group, Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.|Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: Integrative Physiology and Critical Illness Group, Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Southampton National Institutes for Health Research (NIHR) Respiratory Biomedical Research Unit, Southampton, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.|Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: University College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals National Institute for Health Research (UCLH NIHR) Biomedical Research Centre, Institute of Sport and Exercise Health, London, UK.|Anaesthesia and Critical Care Research Unit, University Hospital Southampton National Health Service Foundation Trust, Southampton, UK.|Integrative Physiology and Critical Illness Group, Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.|Southampton National Institutes for Health Research (NIHR) Respiratory Biomedical Research Unit, Southampton, UK.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Grocott
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.|Medical Service, Veterans Affairs (VA) Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Swenson
mesh_terms: D000531:Altitude; D000532:Altitude Sickness / Q000378:metabolism / Q000503:physiopathology; D001784:Blood Gas Analysis / Q000379:methods; D001794:Blood Pressure / Q000502:physiology; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D020382:Interleukin-18 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000502:physiology*; D011652:Pulmonary Circulation / Q000502:physiology*; D011659:Pulmonary Gas Exchange / Q000502:physiology
chemical_list: D020382:Interleukin-18; D004921:Erythropoietin; D009569:Nitric Oxide; D010100:Oxygen
keywords: high altitude; hypoxia; hypoxic pulmonary vasoconstriction