The study of high altitude pulmonary hypertension at the Chilean Andean Altiplano

PVRI Member Authors: Emilio Herrera, German Ebensperger

Non-communicable diseases (NCD) account for more than 65% of worldwide deaths, and are determined by a mix of environmental, genetic and epigenetic factors. (1). One important NCD is pulmonary hypertension that may be triggered by environmental hypoxia. An increased risk of developing cardiovascular and pulmonary diseases has been linked with in utero adverse conditions such as chronic hypoxia (2-5). Furthermore, hypoxia in postnatal life determines cardiovascular and pulmonary responses that may turn mal-adaptive and induce chronic disease (6-8). All of the above are particularly relevant in human populations exposed to high altitude, either in chronic continuous (permanent inhabitants) or intermittent fashion (high altitude workers, mountaineers and tourists). Worldwide, it is estimated that over 140 million people live in altitudes above 2,500 m. (9). The densest populations above 3,000 m. are in the South American Andean Mountains (9). In Central and South America alone, it is estimated that more than 35,000,000 people live at high-lands (10) and in Chile more than 30,000 work in high-altitude shifts (11).

The Andean Altiplano, or Alto Andino, is a ~4,000 m. high plateau located in the Central Andean Range. It has two types of human population: a permanent one consisting mainly of quechua and aymara groups (pure and caucasic-mixed), and an intermittent one composed of mining workers and staff, tourists, mountaineers, military soldiers and customs workers . The area is rich in endemic and introduced animals permanently living under hypobaric hypoxia. All of these characteristics offer an exceptional opportunity for the study of humans and animals exposed to chronic or intermittent hypobaric hypoxia. Therefore, the Altiplano becomes a fundamental natural laboratory, where unique scientific data can be obtained from species adapted or mal-adapted to chronic hypoxia.

Currently, the Andean plateau enjoys good ground and air travelling accesibility. Given this, University of Chile created the International Center for Andean Studies (INCAS) in the early 2000s in Putre (at 3,600 m), a town located in the very north of Chile and adjacent to Peruvian and Bolivian borders. Since then, several researchers have been working on animal and human cardiovascular and pulmonary adaptations to high altitude in this Center. Dr. Anibal J. Llanos, as one of the founders of this Center, developed a pulmonary hypertensive lamb model (Ovis aries) (12-16). He and his group have extensively characterized this non-adapted neonatal model, and compared the pulmonary physiology with the llama (Lama glama), a high-altitude adapted mammal gestated, born and raised above 4,000 m. with no pulmonary hypertension, offering exclusive evolutionary selections to cope with high-altitude (14,17-23).

The Putre Research Station-INCAS is open all year long to be used by Chilean and foreign researchers interested in any scientific discipline related to high altitude environments. The Center has housed research projects in diverse areas such as physiological and molecular adaptations of the pulmonary circulation to hypoxia in fetus, newborns and adults in animals raised at high altitude. 

Capture3.JPG

Figure 1 Facilities of the International Center for Andean Studies (INCAS). The picture show an expedition by the authors of this manuscript. At the back is the housing area that can easily accommodate 4-6 persons. Further there are several hotels and hostels in town.

The Station has separated house and laboratory facilities, which can lodge comfortably 4 to 6.

 It is located in Putre, the capital of the Chilean Andean region of Arica and Parinacota, 140 km from Arica at sea level connected by a paved road. This same road can take you in only 5 h to the capital of Bolivia, La Paz, at 3,600 m (Figure 2).

Capture4.JPG

Figure 2. Location of the International Center for Andean Studies (INCAS). The research station is located in Putre, at 3,600 m. in the north of Chile with expeditious accesses.

Putre has access to basic services such as surgery-house, school, restaurants, hotels and several shops. Several studies have shown that hypoxia at high altitude should be considered a health risk during development and adulthood (24-25) and it should be taken as a public health issue. Hence, establishing the impact of oxygen restriction throughout the lifespan represent a substantial advantage in understanding the role of hypoxia in determining cardiopulmonary diseases in the highlands. Scientists must access high-altitude areas to be able to understand the physiology and pathophysiology under chronic hypoxia. The INCAS research station is available to serve this need as a unique natural Laboratory of hypobaric hypoxia.

Funding

Authors are funded by the National Fund for Scientific and Technological Development (FONDECYT-Chile) grants nº 1110595, 1120605, 1130424, 1140647 and 1151119.

 

References

1. World Health organization website (visited on March 3rd, 2015). http://www.who.int/gho/ncd/ mortality_morbidity/en/

2. Rexhaj E, Bloch J, Jayet PY, Rimoldi SF, Dessen P, Mathieu C, Tolsa JF, Nicod P, Scherrer U, Sartori C. Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms. Am J Physiol Heart Circ Physiol. 301(1):H247-52, 2011. doi: 10.1152/ ajpheart.01309.2010.

3. Schwab M, Allemann Y, Rexhaj E, Rimoldi SF, Sartori C, Scherrer U. [Pulmonary hypertension and lung edema at high altitude. Role of endothelial dysfunction and fetal programming]. Medicina (B Aires). 72(2):150-7, 2012.

4. Giussani DA, Davidge ST. Developmental programming of cardiovascular disease by prenatal hypoxia. J Dev Orig Health Dis. 4(5):328- 37, 2013. doi: 10.1017/S204017441300010X.

5. Giussani DA, Camm EJ, Niu Y, Richter HG, Blanco CE, Gottschalk R, Blake EZ, Horder KA, Thakor AS, Hansell JA, Kane AD, Wooding FB, Cross CM, Herrera EA. Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress. PLoS One. 7(2):e31017, 2012. doi: 10.1371/journal. pone.0031017.

6. Vaillancourt M, Ruffenach G, Meloche J, Bonnet S. Adaptation and Remodelling of the Pulmonary Circulation in Pulmonary Hypertension. Can J Cardiol. S0828-282X(14)01493-7, 2014. doi: 10.1016/j.cjca.2014.10.023. [Epub ahead of print]

7. Loscalzo J, Handy DE. Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series). Pulm Circ. 4(2):169-74, 2014. doi: 10.1086/675979.

8. Saco TV, Parthasarathy PT, Cho Y, Lockey RF, Kolliputi N. Role of epigenetics in pulmonary hypertension. Am J Physiol Cell Physiol. 306(12):C1101-5, 2014. doi: 10.1152/ ajpcell.00314.2013.

9. Niermeyer S, Zamudio S, Moore LG. The people. In: Hornbein T, Schoene RB editors. Adaptations to hypoxia. New York (NY): Marcel Dekker and Co; 2001, p. 43–100.

10. Moore LG, Niermeyer S, Zamudio S. Human adaptation to high altitude: regional and life-cycle perspectives. Yrbk Phys Anthropol. 41:25–64, 1998.

11. Universidad de Chile, Facultad de Medicina, Escuela de Salud Pública, División de Promoción. Elaboración de un estudio sobre la población trabajadora de faenas mineras en altura geográfica y análisis de riesgos laborales asociados a altitud. 2013, p.89

 12. Herrera EA, Pulgar VM, Riquelme RA, Sanhueza EM, Reyes RV, Ebensperger G, Parer JT, Valdéz EA, Giussani DA, Blanco CE, Hanson MA, Llanos AJ. High-altitude chronic hypoxia during gestation and after birth modifies cardiovascular responses in newborn sheep. Am J Physiol Regul Integr Comp Physiol. 292(6):R2234-40, 2007.

 13. Herrera EA, Ebensperger G, Krause BJ, Riquelme RA, Reyes RV, Capetillo M, González S, Parer JT, Llanos AJ. Sildenafil reverses hypoxic pulmonary hypertension in highland and lowland newborn sheep. Pediatr Res. 63(2):169-75, 2008.

14. Llanos AJ, Ebensperger G, Herrera EA, Reyes RV, Pulgar VM, Serón-Ferré M, Díaz M, Parer JT, Giussani DA, Moraga FA, Riquelme RA. Fetal and postnatal pulmonary circulation in the Alto Andino. Placenta. 32 Suppl 2:S100-3, 2011. doi: 10.1016/j.placenta.2011.01.001.

15. Parrau D, Ebensperger G, Herrera EA, Moraga F, Riquelme RA, Ulloa CE, Rojas RT, Silva P, Hernandez I, Ferrada J, Diaz M, Parer JT, Cabello G, Llanos AJ, Reyes RV. Store-operated channels in the pulmonary circulation of high- and lowaltitude neonatal lambs. Am J Physiol Lung Cell Mol Physiol. 304(8):L540-8, 2013. doi: 10.1152/ ajplung.00024.2012.

 16. Torres F, Gonzalez-Candia A, Montt C, Ebensperger G, Chubretovic M, Serón-Ferré M, Reyes RV, Llanos AJ, Herrera EA. Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep. J Pineal Res., 2015. [accepted]

17. Llanos AJ, Riquelme RA, Sanhueza EM, Hanson MA, Blanco CE, Parer JT, Herrera EA, Pulgar VM, Reyes RV, Cabello G, Giussani DA. The fetal llama versus the fetal sheep: different strategies to withstand hypoxia. High Alt Med Biol. 4(2):193-202, 2003.

18. Ebensperger G, Ebensperger R, Herrera EA, Riquelme RA, Sanhueza EM, Lesage F, Marengo JJ, Tejo RI, Llanos AJ, Reyes RV. Fetal brain hypometabolism during prolonged hypoxaemia in the llama. J Physiol. 567(Pt 3):963-75, 2005.

 19. Llanos AJ, Riquelme RA, Herrera EA, Ebensperger G, Krause B, Reyes RV, Sanhueza EM, Pulgar VM, Behn C, Cabello G, Parer JT, Giussani DA, Blanco CE, Hanson MA. Evolving in thin air-lessons from the llama fetus in the altiplano. Respir Physiol Neurobiol. 158(2-3):298- 306, 2007.

20. Herrera EA, Reyes RV, Giussani DA, Riquelme RA, Sanhueza EM, Ebensperger G, Casanello P, Méndez N, Ebensperger R, Sepúlveda-Kattan E, Pulgar VM, Cabello G, Blanco CE, Hanson MA, Parer JT, Llanos AJ. Carbon monoxide: a novel pulmonary artery vasodilator in neonatal llamas of the Andean altiplano. Cardiovasc Res. 77(1):197-201, 2008.

 21. Llanos AJ, Ebensperger G, Herrera EA, Reyes RV, Moraga FA, Parer JT, Giussani DA. Counterpoint: high altitude is not for the birds! J Appl Physiol (1985). 111(5):1515-8, 2011. doi: 10.1152/japplphysiol.00821.2011a.

22. Llanos AJ, Ebensperger G, Herrera EA, Reyes RV, Moraga FA, Parer JT, Giussani DA. Last word on point:counterpoint: high altitude is/is not for the birds! J Appl Physiol (1985). 111(5):1526, 2011. doi: 10.1152/japplphysiol.01121.2011.

23. Llanos AJ, Ebensperger G, Herrera EA, Reyes RV, Cabello G, Díaz M, Giussani DA, Parer JT. The heme oxygenase-carbon monoxide system in the regulation of cardiorespiratory function at high altitude. Respir Physiol Neurobiol. 184(2):186-91, 2012. doi: 10.1016/j.resp.2012.05.003.

24. Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitudes: Healthy highlanders and chronic mountain sickness. Circulation. 115:1132-1146, 2007.

 25. Keyes LE, Armaza JF, Niermeyer S, Vargas E, Young DA, Moore LG. Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia. Pediatr Res. 54:20-25, 2003.

 

Topics

High Altitude and Hypoxia
Pulmonary Hypertension

Published in:

PVRI Chronicle Vol 2: Issue 2 cover image

July 2015

PVRI Chronicle Vol 2: Issue 2

More from this Journal

Explore the PC Journal

Pulmonary Circulation allows diverse knowledge of research, techniques, and case studies to reach a wide readership of specialists in order to improve patient care and treatment outcomes.

shutterstock_136564397.jpg