Pulmonary Hypertension in High-Altitude Dwellers: Novel Mechanisms, Unsuspected Predisposing Factors

  • Urs Scherrer
  • Pierre Turini
  • Sébastien Thalmann
  • Damian Hutter
  • Carlos Salinas Salmon
  • Thomas Stuber
  • Sidney Shaw
  • Pierre -Yves Jayet
  • Céline Sartori-Cucchia
  • Mercedes Villena
  • Yves Allemann
  • Claudio Sartori
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 588)


Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.


Nitric Oxide Pulmonary Hypertension Down Syndrome Hypoxic Pulmonary Vasoconstriction Hypoxic Pulmonary Hypertension 
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  1. 1.
    Ahsan A, Charu R, Pasha MA, Norboo T, Afrin F, and Baig MA. eNOS allelic variants at the same locus associate with HAPE and adaptation. Thorax 59: 1000–1002, 2004.PubMedCrossRefGoogle Scholar
  2. 2.
    Barker DJP. Mothers, babies, and disease in later life. London: BMJ Books, 1994.Google Scholar
  3. 3.
    Beall CM. Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol 72: 201–228, 2000.PubMedGoogle Scholar
  4. 4.
    Beall CM, Decker MJ, Brittenham GM, Kushner I, Gebremedhin A, and Strohl KP. An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Natl Acad Sci US A 99: 17215–17218, 2002.CrossRefGoogle Scholar
  5. 5.
    Beall CM, Laskowski D, Strohl KP, Soria R, Villena M, Vargas E, Alarcon AM, Gonzales C, and Erzurum SC. Pulmonary nitric oxide in mountain dwellers. Nature 414: 411–412, 2001.PubMedCrossRefGoogle Scholar
  6. 6.
    Blitzer ML, Loh E, Roddy MA, Stamler JS, and Creager MA. Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans. J Am Coll Cardiol 28: 591–596, 1996.PubMedGoogle Scholar
  7. 7.
    Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, and Voelkel NE Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med 169: 764–769, 2004.PubMedCrossRefGoogle Scholar
  8. 8.
    Bras A, Monteiro C, and Rueff J. Oxidative stress in trisomy 21. A possible role in cataractogenesis. Ophthalmic Paediatr Genet 10: 271–277, 1989.PubMedGoogle Scholar
  9. 9.
    Brennan LA, Steinhorn RH, Wedgwood S, Mata-Greenwood E, Roark EA, Russell JA, and Black SM. Increased Superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase. Circ Res 92: 683–691, 2003.PubMedCrossRefGoogle Scholar
  10. 10.
    Carratelli M, Porcaro L, Ruscica M, De Simone E, Bertelli AA, and Corsi MM. Reactive oxygen metabolites and prooxidant status in children with Down’s syndrome. Int J Clin Pharmacol Res 21: 79–84, 2001.PubMedGoogle Scholar
  11. 11.
    Cook S, Vollenweider P, Menard B, Egli M, Nicod P, and Scherrer U. Increased NOS and pulmonary iNOS expression in eNOS null mice. Eur Respir J 21: 770–773, 2003.PubMedCrossRefGoogle Scholar
  12. 12.
    de Haan JB, Susil B, Pritchard M, and Kola I. An altered antioxidant balance occurs in Down syndrome fetal organs: implications for the “gene dosage effect” hypothesis. J Neural Transm Suppl: 67–83, 2003.Google Scholar
  13. 13.
    Deem S, Gladwin MT, Berg JT, Kerr ME, and Swenson ER. Effects of S-nitrosation of hemoglobin on hypoxic pulmonary vasoconstriction and nitric oxide flux. Am J Respir Crit Care Med 163: 1164–1170, 2001.PubMedGoogle Scholar
  14. 14.
    Deem S, Swenson ER, Alberts MK, Hedges RG, and Bishop MJ. Red-blood-cell augmentation of hypoxic pulmonary vasoconstriction: hematocrit dependence and the importance of nitric oxide. Am J Respir Crit Care Med 157: 1181–1186, 1998.PubMedGoogle Scholar
  15. 15.
    Droma Y, Hanaoka M, Ota M, Katsuyama Y, Koizumi T, Fujimoto K, Kobayashi T, and Kubo K. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation 106: 826–830, 2002.PubMedCrossRefGoogle Scholar
  16. 16.
    Duplain H, Sartori C, Lepori M, Egli M, Allemann Y, Nicod P, and Scherrer U. Exhaled nitric oxide in high-altitude pulmonary edema. Role In the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Respir Crit Care Med 162: 221–224, 2000.PubMedGoogle Scholar
  17. 17.
    Duplain H, Vollenweider L, Delabays A, Nicod P, Bärtsch P, and Scherrer U. Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high altitude pulmonary edema. Circulation 99: 1713–1718, 1999.PubMedGoogle Scholar
  18. 18.
    Durmowicz AG. Pulmonary edema in 6 children with Down syndrome during travel to moderate altitudes. Pediatrics 108: 443–447, 2001.PubMedCrossRefGoogle Scholar
  19. 19.
    Egli M, Duplain H, Lepori M, Cook S, Nicod P, Hummler E, Sartori C, and Scherrer U. Defective respiratory amiloride-sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice. J Physiol 560: 857–865, 2004.PubMedCrossRefGoogle Scholar
  20. 20.
    Hakim TS and Mortola JP. Pulmonary vascular resistance in adult rats exposed to hypoxia in the neonatal period. Can J Physiol Pharmacol 68: 419–424, 1990.PubMedGoogle Scholar
  21. 21.
    Hayman R, Brockelsby J, Kenny L, and Baker P. Preeclampsia: the endothelium, circulating factor(s) and vascular endothelial growth factor. J Soc Gynecol Investig 6: 3–10, 1999.PubMedCrossRefGoogle Scholar
  22. 22.
    Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, Noda M, Tabata T, Voelkel NF, and Fujimura S. Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol 90: 1299–1306, 2001.PubMedGoogle Scholar
  23. 23.
    Howell K, Preston RJ, and McLoughlin P. Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation. J Physiol 547: 133–145, 2003.PubMedCrossRefGoogle Scholar
  24. 24.
    Iannello RC, Crack PJ, de Haan JB, and Kola I. Oxidative stress and neural dysfunction in Down syndrome. J Neural Transm Suppl 57: 257–267, 1999.PubMedGoogle Scholar
  25. 25.
    Irodova NL, Lankin VZ, Konovalova GK, Kochetov AG, and Chazova IE. Oxidative stress in patients with primary pulmonary hypertension. Bull Exp Biol Med 133: 580–582, 2002.PubMedCrossRefGoogle Scholar
  26. 26.
    Joanny P, Steinberg J, Robach P, Richalet JP, Gortan C, Gardette B, and Jammes Y. Operation Everest III (Comex’97): the effect of simulated sever hypobaric hypoxia on lipid peroxidation and antioxidant defence systems in human blood at rest and after maximal exercise. Resuscitation 49: 307–314, 2001.PubMedCrossRefGoogle Scholar
  27. 27.
    Jovanovic SV, Clements D, and MacLeod K. Biomarkers of oxidative stress are significantly elevated in Down syndrome. Free Radic Biol Med 25: 1044–1048, 1998.PubMedCrossRefGoogle Scholar
  28. 28.
    Kourembanas S, McQuillan LP, Leung GK, and Faller DV. Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia. J Clin Invest 92: 99–104, 1993.PubMedCrossRefGoogle Scholar
  29. 29.
    Krasney JA. A neurogenic basis for acute altitude illness. Med Sci Sports Exerc 26: 195–208, 1994.PubMedCrossRefGoogle Scholar
  30. 30.
    Morin FC and Stenmark KR. Persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 151: 2010–2032, 1995.PubMedGoogle Scholar
  31. 31.
    Nagaoka T, Morio Y, Casanova N, Bauer N, Gebb S, McMurtry I, and Oka M. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 287: L665–672, 2004.PubMedCrossRefGoogle Scholar
  32. 32.
    Owlya R, Vollenweider L, Trueb L, Sartori C, Lepori M, Nicod P, and Scherrer U. Cardiovascular and sympathetic effects of nitric oxide inhibition at rest and during exercise in humans. Circulation 96: 3897–3903, 1997.PubMedGoogle Scholar
  33. 33.
    Penaloza D, Arias-Stella J, Sime F, Recavarren S, and Marticorena E. The Heart and Pulmonary Circulation in Children at High Altitudes: Physiological, Anatomical, and Clinical Observations. Pediatrics 34: 568–582, 1964.PubMedGoogle Scholar
  34. 34.
    Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, Nicod P, and Scherrer U. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 346: 1631–1636, 2002.PubMedCrossRefGoogle Scholar
  35. 35.
    Sartori C, Allemann Y, Trueb L, Delabays A, Nicod P, and Scherrer U. Augmented vasoreactivity in adult life associated with perinatal vascular insult. Lancet 353: 2205–2207, 1999.PubMedCrossRefGoogle Scholar
  36. 36.
    Sartori C, Allemann Y, Trueb L, Lepori M, Maggiorini M, Nicod P, and Scherrer U. Exaggerated pulmonary hypertension is not sufficient to trigger high-altitude pulmonary oedema in humans. Schweiz Med Wochenschr 130: 385–389, 2000.PubMedGoogle Scholar
  37. 37.
    Sartori C, Lepori M, Busch T, Duplain H, Hildebrandt W, Bartsch P, Nicod P, Falke KJ, and Scherrer U. Exhaled nitric oxide does not provide a marker of vascular endothelial function in healthy humans. Am J Respir Crit Care Med 160: 879–882, 1999.PubMedGoogle Scholar
  38. 38.
    Sartori C, Lepori M, and Scherrer U. Interaction between nitric oxide and the cholinergic and sympathetic system in cardiovascular control in humans. Pharmacology & Therapeutics 106: 209–220, 2005.CrossRefGoogle Scholar
  39. 39.
    Sartori C, Turini P, Allemann Y, Salinas C, Rodriguez A, Hutter D, Thalmann S, Villena M, and Scherrer U. Protective effect of female sex hormones against pulmonary hypertension in bolivian high altitude natives. High Altitude Medicine and Biology 3: A430, 2003.Google Scholar
  40. 40.
    Sartori C, Vollenweider L, Loffler BM, Delabays A, Nicod P, Bartsch P, and Scherrer U. Exaggerated endothelin release in high-altitude pulmonary edema. Circulation 99: 2665–2668, 1999.PubMedGoogle Scholar
  41. 41.
    Scherrer U, Sartori C, Lepori M, Allemann Y, Duplain H, Trueb L, and Nicod P. High-altitude pulmonary edema: from exaggerated pulmonary hypertension to a defect in transepithelial sodium transport. Adv Exp Med Biol 474: 93–107, 1999.PubMedGoogle Scholar
  42. 42.
    Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger G-R, Fikrle A, Ballmer PE, Nicod P, and Bärtsch P. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med 334: 624–629, 1996.PubMedCrossRefGoogle Scholar
  43. 43.
    Settergren G, Angdin M, Astudillo R, Gelinder S, Liska J, Lundberg JO, and Weitzberg E. Decreased pulmonary vascular resistance during nasal breathing: modulation by endogenous nitric oxide from the paranasal sinuses. Acta Physiol Scand 163: 235–239, 1998.PubMedCrossRefGoogle Scholar
  44. 44.
    Sime F, Banchero N, Penaloza D, Gamboa R, Cruz J, and Marticorena E. Pulmonary hypertension in children born and living at high altitudes. Am J Cardiol 11: 143–149, 1963.PubMedCrossRefGoogle Scholar
  45. 45.
    Smith APL, Emery CJ, and Higenbottam TW. Perinatal chronic hypoxia decreases endothelial nitric oxide synthase (NOS III) and increases preproendothelin-1 (ppET-1) mRNA levels in rat. Eur Respir J 10: 433s (Abstract), 1997.Google Scholar
  46. 46.
    Taylor RN, de Groot CJ, Cho YK, and Lim KH. Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Semin Reprod Endocrinol 16: 17–31, 1998.PubMedCrossRefGoogle Scholar
  47. 47.
    Thalmann S, Allemann Y, Jayet PY, Hutter D, Salinas C, Stuber T, Shaw S, Villena M, Sartori C, and Scherrer U. Oxidative stress mediated chronic pulmonary hypertension in re-entry pulmonary edema-prone high altitude dwellers. FASEB J 19(5): A1333, 2005.Google Scholar
  48. 48.
    Ward MP, Milledge JS, and West JB. High Altitude Medicine and Physiology. Philadelphia: University of Pennsylvania Press, 1989.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Urs Scherrer
    • 1
  • Pierre Turini
    • 1
  • Sébastien Thalmann
    • 1
  • Damian Hutter
    • 2
  • Carlos Salinas Salmon
    • 4
  • Thomas Stuber
    • 2
  • Sidney Shaw
    • 3
  • Pierre -Yves Jayet
    • 1
  • Céline Sartori-Cucchia
    • 1
  • Mercedes Villena
    • 4
  • Yves Allemann
    • 2
  • Claudio Sartori
    • 1
  1. 1.Department of Internal Medicine and the Botnar Center for Clinical ResearchCentre Hospitalier Universitaire VaudoisLausanne
  2. 2.Swiss Cardiovascular CenterUniversity HospitalBerneSwitzerland
  3. 3.Department of Clinical Research (S.S.)University HospitalBerneSwitzerland
  4. 4.Instituto Boliviano de Biologia de AlturaLa PazBolivia

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