Xtreme Everest 2: unlocking the secrets of the Sherpa phenotype?

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Abstract

Xtreme Everest 2 (XE2) was part of an ongoing programme of field, laboratory and clinical research focused on human responses to hypoxaemia that was conducted by the Caudwell Xtreme Everest Hypoxia Research Consortium. The aim of XE2 was to characterise acclimatisation to environmental hypoxia during a standardised ascent to high altitude in order to identify biomarkers of adaptation and maladaptation. Ultimately, this may lead to novel diagnostic and treatment strategies for the pathophysiological hypoxaemia and cellular hypoxia observed in critically ill patients. XE2 was unique in comparing participants drawn from two distinct populations: native ancestral high-altitude dwellers (Sherpas) and native lowlanders. Experiments to study the microcirculation, mitochondrial function and the effect that nitric oxide metabolism may exert upon them were focal to the scientific profile. In addition, the genetic and epigenetic (methylation and histone modification) basis of observed differences in phenotype was explored. The biological samples and phenotypic metadata already collected during XE2 will be analysed as an independent study. Data generated will also contribute to (and be compared with) the bioresource obtained from our previous observational high-altitude study, Caudwell Xtreme Everest (2007).

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Most cited references 20

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Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans.

W Xu, S. Ghosh, Serpil Erzurum … (2007)

The low barometric pressure at high altitude causes lower arterial oxygen content among Tibetan highlanders, who maintain normal levels of oxygen use as indicated by basal and maximal oxygen consumption levels that are consistent with sea level predictions. This study tested the hypothesis that Tibetans resident at 4,200 m offset physiological hypoxia and achieve normal oxygen delivery by means of higher blood flow enabled by higher levels of bioactive forms of NO, the main endothelial factor regulating blood flow and vascular resistance. The natural experimental study design compared Tibetans at 4,200 m and U.S. residents at 206 m. Eighty-eight Tibetan and 50 U.S. resident volunteers (18-56 years of age, healthy, nonsmoking, nonhypertensive, not pregnant, with normal pulmonary function) participated. Forearm blood flow, an indicator of systemic blood flow, was measured noninvasively by using plethysmography at rest, after breathing supplemental oxygen, and after exercise. The Tibetans had more than double the forearm blood flow of low-altitude residents, resulting in greater than sea level oxygen delivery to tissues. In comparison to sea level controls, Tibetans had >10-fold-higher circulating concentrations of bioactive NO products, including plasma and red blood cell nitrate and nitroso proteins and plasma nitrite, but lower concentrations of iron nitrosyl complexes (HbFeIINO) in red blood cells. This suggests that NO production is increased and that metabolic pathways controlling formation of NO products are regulated differently among Tibetans. These findings shift attention from the traditional focus on pulmonary and hematological systems to vascular factors contributing to adaptation to high-altitude hypoxia.

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High-altitude physiology and pathophysiology: implications and relevance for intensive care medicine

Michael Grocott, Hugh Montgomery, Andre Vercueil (2007)

Cellular hypoxia is a fundamental mechanism of injury in the critically ill. The study of human responses to hypoxia occurring as a consequence of hypobaria defines the fields of high-altitude medicine and physiology. A new paradigm suggests that the physiological and pathophysiological responses to extreme environmental challenges (for example, hypobaric hypoxia, hyper-baria, microgravity, cold, heat) may be similar to responses seen in critical illness. The present review explores the idea that human responses to the hypoxia of high altitude may be used as a means of exploring elements of the pathophysiology of critical illness.

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Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara.

Kingman Strohl, J. Ramirez Vargas, Ricardo A Alarcon … (1998)

Elevated hemoglobin concentrations have been reported for high-altitude sojourners and Andean high-altitude natives since early in the 20th century. Thus, reports that have appeared since the 1970s describing relatively low hemoglobin concentration among Tibetan high-altitude natives were unexpected. These suggested a hypothesis of population differences in hematological response to high-altitude hypoxia. A case of quantitatively different responses to one environmental stress would offer an opportunity to study the broad evolutionary question of the origin of adaptations. However, many factors may confound population comparisons. The present study was designed to test the null hypothesis of no difference in mean hemoglobin concentration of Tibetan and Aymara native residents at 3,800-4,065 meters by using healthy samples that were screened for iron deficiency, abnormal hemoglobins, and thalassemias, recruited and assessed using the same techniques. The hypothesis was rejected, because Tibetan males had a significantly lower mean hemoglobin concentration of 15.6 gm/dl compared with 19.2 gm/dl for Aymara males, and Tibetan females had a mean hemoglobin concentration of 14.2 gm/dl compared with 17.8 gm/dl for Aymara females. The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States, whereas the Aymara distribution was shifted toward 3-4 gm/dl higher values. Genetic factors accounted for a very high proportion of the phenotypic variance in hemoglobin concentration in both samples (0.86 in the Tibetan sample and 0.87 in the Aymara sample). The presence of significant genetic variance means that there is the potential for natural selection and genetic adaptation of hemoglobin concentration in Tibetan and Aymara high-altitude populations.

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Author and article information

Contributors

Daniel S Martin

Edward Gilbert-Kawai

Denny ZH Levett

Kay Mitchell

Rajendra Kumar BC

Michael G Mythen

Michael PW Grocott

Journal

Journal ID (nlm-ta): Extrem Physiol Med

Journal ID (iso-abbrev): Extrem Physiol Med

Title: Extreme Physiology & Medicine

Publisher: BioMed Central

ISSN (Electronic): 2046-7648

Publication date Collection: 2013

Publication date (Electronic): 23 October 2013

Volume: 2

Page: 30

Affiliations

[1 ]UCL Centre for Altitude, Space and Extreme Environment Medicine, Portex Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

[2 ]Division of Surgery and Interventional Science, University College London, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK

[3 ]NIHR University College London Hospitals Biomedical Research Centre Research & Development, Maple House 1st floor 149 Tottenham Court Road, London W1T 7NF, UK

[4 ]Integrative Physiology and Critical Illness Group, Clinical and Experimental Sciences, Mailpoint 810, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK

[5 ]Anaesthesia and Critical Care Research Unit, University Hospital Southampton NHS Foundation Trust, Mailpoint 27, D Level, Centre Block, Tremona Road, Southampton SO16 6YD, UK

[6 ]NIHR Southampton Respiratory Biomedical Research Unit, Southampton SO16 5ST, UK

[7 ]Nepal Health Research Council, Ramshah Path, Kathmandu 44601, Nepal

Article

Publisher ID: 2046-7648-2-30

DOI: 10.1186/2046-7648-2-30

PMC ID: 3853703

PubMed ID: 24229457

SO-VID: 7e78284e-c858-4120-9d56-c0994b388c0c

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 8 May 2013

Date accepted : 12 September 2013

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Xtreme Everest 2: unlocking the secrets of the Sherpa phenotype?

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Most cited references 20

Higher blood flow and circulating NO products offset high-altitude hypoxia among Tibetans.

High-altitude physiology and pathophysiology: implications and relevance for intensive care medicine

Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara.

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Cited by 6