Hypoxic ventilatory response

Hypoxic ventilatory response (HVR) is the increase in ventilation induced by hypoxia that allows the body to take in and transport lower concentrations of oxygen at higher rates. It is initially elevated in lowlanders who travel to high altitude, but reduces significantly over time as people acclimatize.^[1][2] In biological anthropology, HVR also refers to human adaptation to environmental stresses resulting from high altitude.^[3]

In mammals, HVR invokes several physiological mechanisms. It is a direct result of the decrease in partial pressure of oxygen in arterial blood, and leads to increased ventilation. The body has different ways of coping with acute hypoxia. Mammals that rely on pulmonary ventilation will increase their ventilation to account for the lack of oxygen reaching the tissues.^[2] Mammals will also experience decreases in aerobic metabolism and oxygen demand, along with increases in ATP production.

The physiological mechanisms differ in effect and in course of time. HVR is time dependent and can be divided into two phases: the first (0–5 minutes) of ventilation increase, and the second (5–20 minutes) of slow decline.^[4]

The initial increase in ventilation from HVR is initiated by the carotid bodies, which are bilaterally located at the port of brain circulation.^[2] Carotid bodies contain oxygen-sensitive cells that become more active in response to hypoxia. They send input to the brainstem which is then processed by respiratory centers. Other mechanisms include hypoxia-inducible factors, particularly HIF1.^[2] Hormonal changes have also been associated with HVR, particularly those that affect the functioning of the carotid bodies.^[5]

As HVR is a response to decreased oxygen availability,^[1] it shares the same environmental triggers as hypoxia. Such precursors include travelling to high altitude locations^[6] and living in an environment with high levels of carbon monoxide.^[7] Combined with climate, HVR can affect fitness and hydration.^[2] Especially for lowlanders who traverse past 6000 meters in altitude, the limit of prolonged human exposure to hypoxia, HVR may result in hyperventilation and ultimately the deterioration of the body. Oxygen consumption is reduced to a maximum of 1 liter per minute.^[8]

Travelers acclimatized to high altitudes exhibit high levels of HVR, as it provides advantages such as increased oxygen intake, enhanced physical and mental performance, and lower susceptibility to illnesses associated with high altitude.^[1] Adaptations in populations living at high altitudes range from cultural to genetic, and vary among populations. For example, Tibetans living at high altitudes have a more sensitive hypoxic ventilatory response than do Andean peoples living at similar altitudes,^[5][9] even though both populations exhibit greater aerobic capacity compared to lowlanders.^[10] The cause of this difference is most likely genetic, although developmental factors may also contribute.^[10]

Physiology

Acute hypoxic ventilatory response

Acute response (AR)

The first stage of the hypoxic ventilatory response consists of the initial reaction to a hypoxic environment leading up to the peak known as short-term potentiation (STP).^[11] The process is induced by a decrease in oxygen partial pressure in blood. Type I glomus cells of carotid bodies detect the change in oxygen levels and release neurotransmitters towards the carotid sinus nerve, which in turn stimulates the brain, ultimately resulting in increased ventilation.^[2] The period of increased ventilation varies among different individuals but typically lasts under ten minutes.^[12]

Short-term potentiation (STP)

STP is the increase in ventilation after the acute hypoxic response and the eventual return of ventilation to its equilibrium after carotid sinus nerve stimulation, which causes a slowing in heart rate. This mechanism usually lasts between one and two minutes.^[13] STP is most apparent in tidal volume or the amplitude of phrenic neural output.

Short-term depression (STD)

STD is a temporary jump in respiratory frequency at the beginning of carotid chemo afferent stimulation or a temporary drop in respiratory frequency at the end of chemo afferent stimulation. This mechanism lasts from a span of several seconds to a few minutes.^[14] STP has only been found in the respiratory frequency of phrenic nerve stimulation, which produces contraction of the diaphragm.

Ventilatory response to sustained hypoxia

A continued presence in a hypoxic environment of more than 24 hours leads to a steady flow of ventilation.^[11] This contingency in the environment causes hypocapnia which decreases ventilation.^[15]

Chronic hypoxic ventilatory response

Chronic hypoxia results in further physiological changes due to the transcription factor hypoxia-inducible factor (HIF). HIF is a dimer composed of the HIF-1α and HIF-1β subunit. HIF-1α is normally unable to bind with HIF-1β. However, lower oxygen partial pressure induces post-transcriptional modification of HIF-1α, allowing HIF-1α to dimerize with HIF-1β to form HIF-1. HIF-1 induces many physiological changes that help the body adapt to the lower availability of oxygen including angiogenesis, increased erythropoietin production, and promoting anaerobic metabolism.^[2]

Neurology

The nervous system plays a key role in the hypoxic ventilatory response. The process is triggered by the peripheral nervous system's detection of a low blood oxygen level. In particular, the neurotransmitter glutamate has been shown to have a direct correlation to a rise in ventilation. A study conducted in dogs investigated how their cardiovascular systems respond to various levels of oxygen before and after being given MK-801, which is a glutamate antagonist. With the MK-801, there was a noticeable decrease in both heart rate and breaths per minute under hypoxia. According to the study, the fact that the HVR was lessened when glutamate was inhibited demonstrates that glutamate is essential to the response.^[16]

High altitude adaptation

Main article: High-altitude adaptation in humans

 

This image depicts the three high altitude areas where studied populations have adapted to their environment: (From left to right) Andean Altiplano, Simian Plateau, and Tibetan Plateau.^[17]

Populations residing in altitudes above 2,500 meters have adapted to their hypoxic environments.^[18] Chronic HVR is set of adaptations found among most human populations historically native to high-altitude regions, including the Tibetan Plateau, the Andean Altiplano, and the Simian Plateau.^[17] Up to 140 million people in total reside in such areas, although not all possess these adaptations.^[19] Populations that have permanently settled in high altitude locations show virtually no reaction to acute hypoxia. Natives of the Andes and the Himalayas have been shown to develop adaptation to hypoxia from birth to neonatal years in the form of larger lungs and greater gas exchange surface area.^[20] This response can be attributed to genetic factors, but the development of the resistance to acute hypoxia is highly affected by when the individual is exposed to high altitude;^[20] while genetic factors play an indefinite role in a person's HVR, because long term migrants do not show reduction in their reactions of high altitude even after living in high altitudes in long term, the discrepancy suggests that reaction to HVR is the combination of environmental exposure and genetic factors.^[18]

Anthropology

Populations

Andeans

 

Cusco, Peru, which has an altitude of 11,000 ft

The Andean peoples are one of three central populations of study that have a decreased HVR. These populations notably inhabit areas in and around the Andes mountain range, which has an average altitude of 13,000 feet (4,000 m).^[21] HVR has been studied in inhabitants of Cusco, Peru, which lies at 11,000 feet (3,400 m).^[21] Living in such high altitudes has led to cultural adaptations, including the consumption of coca tea. Coca tea is an extract made by boiling the leaves of the coca plant in water and contains the stimulant Cocaine. For millennia, Andeans have used coca tea as a treatment for acute altitude sickness,^[22] and to this day it is still given to those travelling to the high altitude regions of Peru, though, its effectiveness has been disputed.^[23] In a 2010 study published in the Journal of Travel Medicine, the consumption of coca tea was actually associated with an increase in the incidence of altitude sickness experienced by travelers visiting the city of Cusco, Peru.^[23]

It has been found that the ventilatory response is substantially less pronounced in the Andean populations than in the Tibetans, with the HVR response of Tibetans roughly double that of Andeans at an altitude of around 4,000 metres (13,000 ft).^[24] The altitude adaptations also appear to be less permanent than those seen in the Tibetan populations, as the Andeans have a much higher prevalence of Chronic Mountain Sickness (CMS), where the body develops a harmful reaction to low oxygen levels over many years.^[25]

Tibetans

 

Mount Everest, the highest peak of the Himalayas.

The Tibetan people are an ethnic group native to Tibet that live throughout the Tibetan Plateau. They live at altitudes up to 15,000 feet (4,600 m),^[26] and are thus of extreme interest to researchers investigating HVR in high altitude populations. One of these populations are the Sherpa people, a group of Tibetans who are sought after for their knowledge of and skill with navigating through the Himalayas. Historically, Sherpas have been contracted to guide expeditions up Mount Everest, but the practice has since declined in light of exploitation of the Sherpa guides. The energy and ease at which the Sherpa ascend and descend mountains is due to their ability to use oxygen more efficiently.^[27] This ability to excel at mountaineering has shifted their culture around it. Tourism has become a driving force for the financial income of the Sherpa people. The Sherpa are able to make much more money^[28] acting as travel guides due to their local knowledge, and climbing ability.

Genetic evidence suggests that the Tibetan peoples diverged from the larger Han Chinese population any time around 1,000 B.C.E.^[29][30][31] to 7,000 B.C.E.^[32][33] Given the significant mutations to the EPAS1 gene that contribute to the Tibetan resistance to altitude sickness, this suggests that the extreme evolutionary pressure on the Tibetan peoples has produced one of the fastest natural selection effects seen in a human population.^[34] The adaptations of Tibetans to their hypoxic ventilatory response interact with other adaptations to promote successful reproduction. For example, Tibetans have evolved a greater oxygen saturation during infancy, leading to a lower rate of child mortality than experienced by non-adapted populations at altitude.^[35]

Amhara

 

Simien Mountains 14,900 ft

The Amhara people are the occupants of the central and northern Highlands of Ethiopia in the Amhara Region, where the elevation ranges consistently between 1500 m (4,921 ft) to 4550 m (14,928 ft). For over 5,000 years humans have been living near the Simien Mountains at altitudes above 3,000m and over that time they genetically adapted to the hypoxic conditions of high altitude.^[36][37]

References

1. Cymerman, A; Rock, PB. ^[usurped]. USARIEM-TN94-2. US Army Research Inst. of Environmental Medicine Thermal and Mountain Medicine Division Technical Report. Retrieved 2009-03-05.
2. Teppema, Luc J., and Albert Dahan. "The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis." Physiological Reviews 90.2 (2010): 675-754.
3. Stanford, Craig, John S. Allen, and Susan C. Anton. Biological Anthropology : The Natural History of Humankind. 2nd ed. Upper Saddle River: Prentice Hall Higher Education, 2008. 151-52.
4. Duffin, James (1 October 2007). "Measuring the ventilatory response to hypoxia". The Journal of Physiology. 584 (Pt 1): 285–293. doi:10.1113/jphysiol.2007.138883. ISSN 0022-3751. PMC 2277066. PMID 17717019.
5. Hornbein, Thomas F., and Robert B. Schoene. High Altitude: An Exploration Of Human Adaptation. n.p., New York: Marcel Dekker, c2001., 2001. OskiCat. Web. 8 Nov. 2016.
6. "Altitude Hypoxia Explained." 10 November 2016 at the Wayback Machine Altitude Research Center. Altitude Research Center, n.d. Web. 08 Nov. 2016.
7. Karius, Diane R. "Respiratory Adaptations in Health and Disease: Forms of Hypoxia." Forms of Hypoxia. Kansas City University, n.d. Web. 08 Nov. 2016.
8. West John B (2006). "Human responses to extreme altitudes". Integrative and Comparative Biology. 46 (1): 25–34. doi:10.1093/icb/icj005. PMID 21672720.
9. Beall Cynthia M. "Tibetan and Andean patterns of adaptation to high-altitude hypoxia". Human Biology. 2000: 201–228.
10. Hochachka Peter W.; Christian Gunga Hanns; Kirsch Karl (1998). "Our ancestral physiological phenotype: An adaptation for hypoxia tolerance and for endurance performance?". Proceedings of the National Academy of Sciences. 95 (4): 1915–1920. Bibcode:1998PNAS...95.1915H. doi:10.1073/pnas.95.4.1915. PMC 19213. PMID 9465117.
11. Easton, P. A.; Slykerman, L. J.; Anthonisen, N. R. (1 September 1986). "Ventilatory response to sustained hypoxia in normal adults". Journal of Applied Physiology. 61 (3): 906–911. doi:10.1152/jappl.1986.61.3.906. ISSN 8750-7587. PMID 3759775.
12. Lipton, Andrew J.; Johnson, Michael A.; Macdonald, Timothy; Lieberman, Michael W.; Gozal, David; Gaston, Benjamin (2001). "S-Nitrosothiols signal the ventilatory response to hypoxia". Nature. 413 (6852): 171–174. Bibcode:2001Natur.413..171L. doi:10.1038/35093117. PMID 11557982. S2CID 9305953.
13. Eldridge, Frederic L.; Millhorn, David E. (1 January 2011). Comprehensive Physiology. John Wiley & Sons, Inc. doi:10.1002/cphy.cp030203. ISBN 9780470650714.
14. Hayashi, F.; Coles, S. K.; Bach, K. B.; Mitchell, G. S.; McCrimmon, D. R. (1 October 1993). "Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 265 (4): R811–R819. doi:10.1152/ajpregu.1993.265.4.R811. ISSN 0363-6119. PMID 8238451.
15. Severinghaus, J. W.; Bainton, C. R.; Carcelen, A. (1 January 1966). "Respiratory insensitivity to hypoxia in chronically hypoxic man". Respiration Physiology. 1 (3): 308–334. doi:10.1016/0034-5687(66)90049-1. PMID 5968347.
16. Ang, R. C.; Hoop, B.; Kazemi, H. (1 April 1992). "Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response". Journal of Applied Physiology. 72 (4): 1480–1487. doi:10.1152/jappl.1992.72.4.1480. ISSN 8750-7587. PMID 1350580.
17. Bigham, Abigail; Bauchet, Marc; Pinto, Dalila; Mao, Xianyun; Akey, Joshua M.; Mei, Rui; Scherer, Stephen W.; Julian, Colleen G.; Wilson, Megan J. (9 September 2010). "Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data". PLOS Genet. 6 (9): e1001116. doi:10.1371/journal.pgen.1001116. ISSN 1553-7404. PMC 2936536. PMID 20838600.
18. Beall, Cynthia M. (1 January 2002). "Tibetan and Andean Contrasts in Adaptation to High-Altitude Hypoxia". In Lahiri, Sukhamay; Prabhakar, Naduri R.; II, Robert E. Forster (eds.). Oxygen Sensing. Advances in Experimental Medicine and Biology. Vol. 475. Springer US. pp. 63–74. doi:10.1007/0-306-46825-5_7. ISBN 9780306463679. PMID 10849649.
19. Moore, L G; Regensteiner, J G (28 November 2003). "Adaptation to High Altitude". Annual Review of Anthropology. 12 (1): 285–304. doi:10.1146/annurev.an.12.100183.001441.
20. Lahiri, S.; Delaney, R. G.; Brody, J. S.; Simpser, M.; Velasquez, T.; Motoyama, E. K.; Polgar, C. (13 May 1976). "Relative role of environmental and genetic factors in respiratory adaptation to high altitude". Nature. 261 (5556): 133–135. Bibcode:1976Natur.261..133L. doi:10.1038/261133a0. PMID 1272381. S2CID 4297547.
21. "Andes Mountains | mountain system, South America". Encyclopædia Britannica. Retrieved 10 November 2016.
22. Rottman, April (9 December 1997). "Erythroxylum: The Coca Plant". Retrieved 11 November 2016.
23. Salazar, Hugo; Swanson, Jessica; Mozo, Karen; Clinton White, A.; Cabada, Miguel M. (1 July 2012). "Acute Mountain Sickness Impact Among Travelers to Cusco, Peru". Journal of Travel Medicine. 19 (4): 220–225. doi:10.1111/j.1708-8305.2012.00606.x. ISSN 1708-8305. PMID 22776382.
24. Beall, Cynthia M. (15 May 2007). "Two routes to functional adaptation: Tibetan and Andean high-altitude natives". Proceedings of the National Academy of Sciences of the United States of America. 104 (Suppl 1): 8655–8660. doi:10.1073/pnas.0701985104. ISSN 0027-8424. PMC 1876443. PMID 17494744.
25. Xing, Guoqiang; Qualls, Clifford; Huicho, Luis; River-Ch, Maria; Stobdan, Tsering; Slessarev, Marat; Prisman, Eitan; Ito, Soji; Wu, Hong (4 June 2008). "Adaptation and Mal-Adaptation to Ambient Hypoxia; Andean, Ethiopian and Himalayan Patterns". PLOS ONE. 3 (6): e2342. Bibcode:2008PLoSO...3.2342X. doi:10.1371/journal.pone.0002342. ISSN 1932-6203. PMC 2396283. PMID 18523639.
26. "Plateau of Tibet | plateau, China". Encyclopædia Britannica. Retrieved 10 November 2016.
27. Meera Senthilingam, for (11 November 2015). "Scientists discover why Sherpas are superhuman climbers - CNN.com". CNN. Retrieved 11 November 2016.
28. "Guide: What does a Sherpa at Mount Everest do? - CBBC Newsround". 23 April 2014. Retrieved 11 November 2016.
29. Sanders R (1 July 2010). "Tibetans adapted to high altitude in less than 3,000 years". News Centre, UC Berkeley. UC Regents. Retrieved 8 July 2013.
30. Hsu J (1 July 2010). "Tibetans Underwent Fastest Evolution Seen in Humans". Live Science. TechMediaNetwork.com. Retrieved 8 July 2013.
31. Yi, X.; Liang, Y.; Huerta-Sanchez, E.; Jin, X.; Cuo, Z. X. P.; Pool, J. E.; Xu, X.; Jiang, H.; et al. (2010). "Sequencing of 50 human exomes reveals adaptation to high altitude". Science. 329 (5987): 75–78. Bibcode:2010Sci...329...75Y. doi:10.1126/science.1190371. PMC 3711608. PMID 20595611.
32. Hu, Hao; Petousi, Nayia; Glusman, Gustavo; Yu, Yao; Bohlender, Ryan; Tashi, Tsewang; Downie, Jonathan M.; Roach, Jared C.; Cole, Amy M.; Lorenzo, Felipe R.; Rogers, Alan R. (2017). Tishkoff, Sarah A. (ed.). "Evolutionary history of Tibetans inferred from whole-genome sequencing". PLOS Genetics. 13 (4): e1006675. doi:10.1371/journal.pgen.1006675. PMC 5407610. PMID 28448578.
33. Yang, Jian; Jin, Zi-Bing; Chen, Jie; Huang, Xiu-Feng; Li, Xiao-Man; Liang, Yuan-Bo; Mao, Jian-Yang; Chen, Xin; Zheng, Zhili; Bakshi, Andrew; Zheng, Dong-Dong (2017). "Genetic signatures of high-altitude adaptation in Tibetans". Proceedings of the National Academy of Sciences. 114 (16): 4189–4194. Bibcode:2017PNAS..114.4189Y. doi:10.1073/pnas.1617042114. PMC 5402460. PMID 28373541.
34. Yi, Xin; Liang, Yu; Huerta-Sanchez, Emilia; Jin, Xin; Cuo, Zha Xi Ping; Pool, John E.; Xu, Xun; Jiang, Hui; Vinckenbosch, Nicolas (2 July 2010). "Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude". Science. 329 (5987): 75–78. Bibcode:2010Sci...329...75Y. doi:10.1126/science.1190371. ISSN 0036-8075. PMC 3711608. PMID 20595611.
35. Beall, Cynthia M.; Song, Kijoung; Elston, Robert C.; Goldstein, Melvyn C. (28 September 2004). "Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m". Proceedings of the National Academy of Sciences of the United States of America. 101 (39): 14300–14304. doi:10.1073/pnas.0405949101. ISSN 0027-8424. PMC 521103. PMID 15353580.
36. Pleurdeau, David (14 June 2006). "Human Technical Behavior in the African Middle Stone Age: The Lithic Assemblage of Porc-Epic Cave (Dire Dawa, Ethiopia)". African Archaeological Review. 22 (4): 177–197. doi:10.1007/s10437-006-9000-7. ISSN 0263-0338. S2CID 162259548.
37. Alkorta-Aranburu, Gorka; Beall, Cynthia M.; Witonsky, David B.; Gebremedhin, Amha; Pritchard, Jonathan K.; Rienzo, Anna Di (6 December 2012). "The Genetic Architecture of Adaptations to High Altitude in Ethiopia". PLOS Genet. 8 (12): e1003110. arXiv:1211.3053. doi:10.1371/journal.pgen.1003110. ISSN 1553-7404. PMC 3516565. PMID 23236293.