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      The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives

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          Abstract

          In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

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          Measuring high-altitude adaptation.

          High altitudes (>8,000 ft or 2,500 m) provide an experiment of nature for measuring adaptation and the physiological processes involved. Studies conducted over the past ~25 years in Andeans, Tibetans, and, less often, Ethiopians show varied but distinct O2 transport traits from those of acclimatized newcomers, providing indirect evidence for genetic adaptation to high altitude. Short-term (acclimatization, developmental) and long-term (genetic) responses to high altitude exhibit a temporal gradient such that, although all influence O2 content, the latter also improve O2 delivery and metabolism. Much has been learned concerning the underlying physiological processes, but additional studies are needed on the regulation of blood flow and O2 utilization. Direct evidence of genetic adaptation comes from single-nucleotide polymorphism (SNP)-based genome scans and whole genome sequencing studies that have identified gene regions acted upon by natural selection. Efforts have begun to understand the connections between the two with Andean studies on the genetic factors raising uterine blood flow, fetal growth, and susceptibility to Chronic Mountain Sickness and Tibetan studies on genes serving to lower hemoglobin and pulmonary arterial pressure. Critical for future studies will be the selection of phenotypes with demonstrable effects on reproductive success, the calculation of actual fitness costs, and greater inclusion of women among the subjects being studied. The well-characterized nature of the O2 transport system, the presence of multiple long-resident populations, and relevance for understanding hypoxic disorders in all persons underscore the importance of understanding how evolutionary adaptation to high altitude has occurred.NEW & NOTEWORTHY Variation in O2 transport characteristics among Andean, Tibetan, and, when available, Ethiopian high-altitude residents supports the existence of genetic adaptations that improve the distribution of blood flow to vital organs and the efficiency of O2 utilization. Genome scans and whole genome sequencing studies implicate a broad range of gene regions. Future studies are needed using phenotypes of clear relevance for reproductive success for determining the mechanisms by which naturally selected genes are acting.
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            A theoretical analysis of factors determining VO2 MAX at sea level and altitude.

            When maximal VO2 (VO2 MAX) is limited by O2 supply, it is generally thought that cardiac output (QT) is mostly responsible, but other O2 transport conductances [ventilation (VA); [Hb]; pulmonary (DLO2) and muscle (DMO2) diffusion capacities] may also influence VO2 MAX. A numerical analysis interactively linking the lungs, circulation and muscles was designed to compare the influences of each conductance component on VO2 MAX at three altitudes: PB = 760, 464 and 253 Torr. For any given set of conductances the analysis simultaneously solved six equations for alveolar, arterial, and venous PO2 and PcO2. The equations represent pulmonary mass balance, pulmonary diffusion, and muscle diffusion for both gases. At PB = 760, [Hb], DLO2 and DMO2 were as influential as QT in limiting VO2 MAX. With increasing altitude, the influence of QT and [Hb] fell while that of VA, DLO2 and DMO2 progressively increased until at PB = 253, VO2 MAX was independent of QT and [Hb]. Neither the fall in maximal QT nor rise in [Hb] with chronic hypoxia therefore appear to affect VO2 MAX. However, high values of ventilation, DLO2 and DMO2 appear to be advantageous for exercise at altitude.
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              Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m.

              Elevated pulmonary arterial pressure in high-altitude residents may be a maladaptive response to chronic hypoxia. If so, well-adapted populations would be expected to have pulmonary arterial pressures that are similar to sea-level values. Five normal male 22-yr-old lifelong residents of > or = 3,600 m who were of Tibetan descent were studied in Lhasa (3,658 m) at rest and during near-maximal upright ergometer exercise. We found that resting mean pulmonary arterial pressure [15 +/- 1 (SE) mmHg] and pulmonary vascular resistance (1.8 +/- 0.2 Wood units) were within sea-level norms and were little changed while subjects breathed a hypoxic gas mixture [arterial O2 pressure (PaO2) = 36 +/- 2 Torr]. Near-maximal exercise [87 +/- 13% maximal O2 uptake (VO2max)] increased cardiac output more than threefold to values of 18.3 +/- 1.2 l/min but did not elevate pulmonary vascular resistance. Breathing 100% O2 during near-maximal exercise did not reduce pulmonary arterial pressure or vascular resistance. We concluded that this small sample of healthy Tibetans with lifelong residence > or = 3,658 m had resting pulmonary arterial pressures that were normal by sea-level standards and exhibited minimal hypoxic pulmonary vasoconstriction, both at rest and during exercise. These findings are consistent with remarkable cardiac performance and high-altitude adaptation.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                13 August 2019
                29 July 2019
                29 July 2019
                : 116
                : 33
                : 16177-16179
                Affiliations
                [1] aCardiff School of Sport and Health Sciences, Cardiff Metropolitan University , Cardiff CF236XD, United Kingdom;
                [2] bCentre for Heart, Lung and Vascular Health, University of British Columbia Okanagan , Kelowna, BC V1V 1V7, Canada;
                [3] cDivision of Pulmonary and Critical Care, Loma Linda University School of Medicine , Loma Linda, CA 92350;
                [4] dDepartamento de Ciencias Biológicas y Fisiológicas, Universidad Peruana Cayetano Heredia , Lima 31, Perú;
                [5] eInstitute for Exercise and Environmental Medicine, The University of Texas Southwestern Medical Center , Dallas, TX 75231
                Author notes
                1To whom correspondence may be addressed. Email: mstembridge@ 123456cardiffmet.ac.uk .

                Edited by Hopi E. Hoekstra, HHMI and Harvard University, Cambridge, MA, and approved July 10, 2019 (received for review May 31, 2019)

                Author contributions: M.S., A.M.W., F.C.V., B.D.L., R.S., and P.N.A. designed research; M.S., A.M.W., C.G., T.G.D., A.D., F.C.V., and P.N.A. performed research; M.S., A.M.W., C.G., T.G.D., A.D., and P.N.A. analyzed data; and M.S., R.S., and P.N.A. wrote the paper.

                Author information
                http://orcid.org/0000-0003-0818-6420
                Article
                201909002
                10.1073/pnas.1909002116
                6697886
                31358634
                26cf03e8-da64-4d83-8e57-c8a6d61248b2
                Copyright © 2019 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 3
                Funding
                Funded by: Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC) 501100000038
                Award ID: n/a
                Award Recipient : Philip Ainslie
                Funded by: Canada Research Chairs (Chaires de recherche du Canada) 501100001804
                Award ID: n/a
                Award Recipient : Philip Ainslie
                Categories
                524
                Biological Sciences
                Physiology
                Brief Report

                hypoxia,altitude,hemoglobin,tibetans,andeans
                hypoxia, altitude, hemoglobin, tibetans, andeans

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