Thorax 1994;49 Supplement:S9-S13

Adaptation and acclimatisation in humans andanimals at high altitude

David Williams

Rapid ascent into high altitude or permanentresidence there leads to a wide range of dis-turbances of function or alterations in his-tological appearances in most organs of thebody. The influences which lead to thesechanges are those inherent in the environmentof high altitude, especially hypobaric hypoxiaresulting from the diminished barometric pres-sure. One of the major aspects of researchcarried out at the Department of Pathology atLiverpool over the last 25 years has been thestudy of the effects of hypobaric hypoxia onthe histological structure of the pulmonary cir-culation of lowlanders and lowland animalsexposed to high altitude, of native highlanders,and of indigenous mountain mammals.

In some mammals, including man, the hypo-baric hypoxia of high altitude induces a milddegree of pulmonary arterial hypertension withassociated alterations in the structure of theperipheral portions of the pulmonary arterialtree. In other species it does not. This papergives an account of the histological structureof the pulmonary circulation in the two groups- namely, the reactors and the non-reactors -

and seeks to establish the difference in thebiological status of the two groups. The bio-logical variety at high altitude can best be il-lustrated by taking a mental stroll around thestreets and surrounding countryside of anysmall settlement in the Andes. One such is themining town of Cerro de Pasco (4330 m) incentral Peru where much of the work atLiverpool began.Most of the people in the streets of Cerro de

Pasco are native Quechua Indians born andbred in the Andes. These people have very char-acteristic physical features and deeply poly-cythaemic and suffused conjunctivae and lips.Some will have a capacious chest which looksprominent and out of proportion to their shortstocky physique. These highlanders lead nor-mal busy lives; they shop, go to school, visit thecinema, and play football at altitudes exceedingthe summit of the Matterhorn.

Living on the pastures surrounding Cerro dePasco are examples of indigenous mountainanimals such as the llama (Lama glama), thealpaca (L pacos), the vicunia (L vicugna), andthe guanaco (L guanacoe). These species havebeen living on the Andean altiplano for manythousands of years, preceding the appearanceof the Quechuas. One cannot help but beimpressed by the vigour and activity of theanimals in an atmosphere characterised bysevere hypobaric hypoxia. Other indigenousmountain species such as the mountain vis-

h.

Figure 1 An Aymara Indian from La Paz. Most femaleAymara Indians retain a traditionalform of dress withlayers of multicoloured skirts and a brown felt hat.

cacha (Lagidium peruanum) live at even greateraltitudes exceeding 6000 m. A further bio-logical group comprises those domesticated an-imals such as cattle brought to high altitudeby man. In other parts of the world thesedomesticated species may interbreed with in-digenous relatives such as the yak (Bos grun-niens).

HumansThe human pulmonary arterial tree at lowaltitude is a thin walled, low resistance system."Muscular pulmonary arteries" less than300 gim in external diameter have a medialthickness of less than 5% of the external dia-meter of the vessel.' They give rise to pul-monary arterioles less than 70 gm in diameterwhich have a rim of circular muscle only attheir site of origin, but elsewhere have a wallconsisting of a single elastic lamina. In thehighlander the parent arteries show little orno increase in medial thickness, no fibrinoidnecrosis, and the development of primary pul-monary hypertension is unknown to the Andes.

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Department ofPathology, Universityof Liverpool, LiverpoolL69 3BX, UKD Williams

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The impact of alveolar hypoxia on the humanpulmonary arterial tree is at its most peripheralportions, composed ofthe pulmonary arteriolesand the precapillaries. These vessels showa complex remodelling with the new develop-ment of vascular smooth muscle so that thepulmonary arterioles become muscularisedwith a distinct media of circular muscle sand-wiched between inner and outer elastic lam-inae. In citizens of La Paz (3800 m) (fig 1) wehave found vessels as small as 25 IIm, hardlymore than the diameter of an alveolar macro-phage, with a distinct muscular coat lookinglike a small artery.2 This muscularisation ismore pronounced in native Aymaras than inthe mestizo or white inhabitants of the city.However, this remodelling of the terminal por-tions of the pulmonary arterial tree may becomplex. Following a report in the literaturedescribing the histopathology of the small pul-monary arterial vessels in 10 cases of hypoxiccor pulmonale3 we reviewed our material fromthe Andes. This revealed similar lesions in thenative highlanders as had been described inthe cases of chronic obstructive lung disease.Accordingly we carried out a second in-vestigation on further material from La Paz.4The additional lesions consisted of a depositionof longitudinal muscle in the intima of thepulmonary arteries and arterioles, and thedevelopment of inner muscular tubes in thelumens of these vessels (fig 2).4The smallest muscular pulmonary arteries

(less than 200 pm in diameter) commonlyshowed eccentric nodules of longitudinalmuscle in the intima which bulged into thelumen. Within these nodules the cytoplasm andnuclei of the individual muscle cells could bedistinguished. Individual myocytes were sep-arated by elastic fibrils which had formedaround them. In some pulmonary arteries col-

Figure 2 A pulmonary arteriole from an Aymara Indianshowing the original thick elastic lamina, a layer oflongitudinal muscle (1), and an inner muscular tube(arrow). Stain: elastic van Gieson, magnification x 745.

lagen had developed between the muscle cellsand in isolation these appearances could havebeen misinterpreted as severe age change in-timal fibrosis. Although the lesions in the pul-monary arteries were eccentric and nodular,the appearances were not those of organisingor organised thrombus and no "colander les-ions" of recanalisation were found. Sometimesintimal nodules of longitudinal muscle werefound in muscularised pulmonary arteriolesand in expanded precapillaries arising fromthem.The beginnings of a thin muscular coat,

composed of circularly orientated smoothmuscle, could be seen lining the nodules ofintimal longitudinal muscle in some pulmonaryarteries bounded on their inner and outer sur-faces by exceedingly thin elastic laminae (fig2). The inner muscular tubes extended throughthe pulmonary arterioles with their thickersingle elastic lamina. Internal to the lamina wasa coat of longitudinal muscle which, in turn,was lined by the inner muscular tube. In smallerpulmonary arterioles the layer of longitudinalmuscle disappeared so that the muscular tubecame to lie next to the original thicker elasticlamina of the arteriole.

It has been known for many years thatQuechua Indians living in the areas of Cerrode Pasco (4330 m) and Morococha (4540 m)in Peru have pulmonary hypertension. Thisis moderate (mean pulmonary pressure45 mm Hg) in young children5 and slight (meanpulmonary arterial pressure 28 mm Hg) inadults.6 In addition, Arias-Stella and Saldafia7showed that the underlying biological basis forthe pulmonary hypertension was the associatedmuscularisation of the terminal portions of thepulmonary arterial tree. The findings of Arias-Stella and Saldafia7 were original and of greatimportance but described only part of a morecomplex overall picture.However complex this remodelling process

may be at high altitude, it is noteworthy that itis controlled, with the vascular smooth musclecells remaining adherent to one another. Thisis in striking contrast to a second form ofremodelling of the human pulmonary cir-culation at high altitude - subacute infantilemountain sickness.8 This disease occurs in in-fants of Han origin who are taken by theirChinese parents to live at high altitude in Lhasa,Tibet and is regarded as an expression of failureto achieve initial acclimatisation to hypobarichypoxia in the very young. There is a floridmigration ofvascular smooth muscle cells fromthe media of pulmonary arterioles and veinsinto the intima and lumen.

High altitude camelidsThe most common representative of this groupof animals seen in the Andes is the llama (Lamaglama) (fig 3). This species is a representativeof the high altitude camelids which have livedfor countless millennia in the Andes. Our stud-ies were designed to determine ifthe pulmonarycirculation of indigenous mountain camelidsdiffered according to whether they lived at sealevel or high altitude. In these species the

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Adaptation and acclimatisation in humans and animals at high altitude

Mean pulmonary arterial pressure in camelids9

Situation and Species and Pulmonary arterialaltitude numbers pressure (mm Hg)

Range Mean

London (Om) Llamas (3) 3-14 10Guanacos (3)

Lay Raya (4200 m) Llamas (12) 8-18 14Alpaca (1)

Figure 3 Llama from La Raya (4200 m). Followinginsertion of the catheter for cardiac catheterisation theanimal was allowed to graze freely in the paddock.

III

Ats§

7/,

x150.

Athnwle"muscularpulmonaryarteispo dtob very"

sethionedledadhpulmonaryarterioles(rrw)deoiaod

a wall which consisted of a single elastic lamina

(fig 4)*9It is not surprising that a pulmonary arterial

tree with such a histological structure exhibits

only a meagre response to environmental hyp-oxia. Direct measurement ofpulmonary arterial

pressure by cardiac catheterisation undertaken

by Professor Peter Harris of the University of

London showed that such animals manifest

only a very slight rise in pulmonary arterial

pressure above that shown by members of the

same species living at sea level (table) .9Although it was argued that these ob-

servations support the concept of evolutionaryforces at work to diminish the magnitude of

the hypoxic pulmonary constrictor reflex, ithas to be conceded that the camel family ischaracterised by a thin walled pulmonary vas-culature. The suggestion that the preservationof a thin walled pulmonary vasculature can bea feature of residence at high altitude and maybe regarded as evidence ofgenetic adaptation tohypobaric hypoxia rather than acclimatisationrequires further examination. It may be thatthe lack of muscularisation of the pulmonaryarterial tree of the llama at high altitude is areflection of the zoological affiliations of thespecies, rather than providing convincing evid-ence of genetic adaptation.

High altitude rodentsMost rodents, such as the mouse and the rat,respond to environmental hypoxia by mus-cularisation of the peripheral portion of thepulmonary arterial tree, which often leads tofatal congestive cardiac failure. However, cer-tain rodents live exposed to natural high al-titude for their entire lives. One such speciesliving in the Andes is the mountain viscacha(Lagidium peruanum). It lives in the southernpart of the Andes at altitudes up to 6500 mwhere it is exposed to a significant degree ofenvironmental hypoxia. Like the llama, themountain viscacha maintains an exceedinglythin walled pulmonary arterial tree and haspulmonary arterioles devoid of a muscularmedia.'0 This is in contrast to the effect thatalveolar hypoxia has upon the pulmonary ar-terial tree of lowland rodents, and supports theconcept that genetic adaptation to high altitudemay be expressed in the pulmonary circulationas a loss or gross weakening of the hypoxicpulmonary vasoconstrictor response.

Support has also come from studies of thepulmonary circulation of an indigenous moun-tain rodent living at high altitude in a part ofthe world remote from the Andes. The animalconcerned comes from Tibet where it is knownas the Tibetan snow pig, despite being a varietyof marmot (Marmota himalayana). Haemo-dynamic measurements revealed a low pul-monary arterial mean pressure and pulmonaryarterial resistance," associated with a thinwalled pulmonary arterial tree. The pulmonaryarterioles were devoid of a muscular coat."These findings lend further weight to the con-cept that indigenous mountain species may begenetically adapted to high altitude and expressthis through a great weakening of the hypoxicpulmonary vasoconstrictor response.

CattleThe hypothesis that a thin walled pulmonaryvasculature may be a feature of genetic adapt-

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Figure 5 "Muscular pulmonary artery" from a cow at sea level showing a thick walledvessel with a medial thickness of 16%. Stain: elastic van Gieson, magnification x 375.

ation may be further tested if it could be shownthat a representative from a family with a nat-urally muscular pulmonary arterial tree, livingat high altitude, had thin walled vessels incontrast to its sea level zoological relatives.Such an animal is the yak (Bos grunniens).Domesticated cattle (Bos taurus) have a verymuscular pulmonary arterial tree'2 (fig 5) and,when taken to high altitude, they develop mod-erate pulmonary hypertension. The naturallymuscular pulmonary arteries of cattle seem

particularly susceptible to constriction in re-sponse to the alveolar hypoxia.

Furthermore, there is evidence of variationin the susceptibility of different strains of cattleto hypobaric hypoxia.'3 From one herd livingat an altitude of3000 m in Colorado two groupsof cattle were selected. Fifteen animals withthe lowest pulmonary arterial pressures were

designated "resistant" to the development ofhypoxic pulmonary hypertension, and a further10 animals with the highest pressures were

considered to be "susceptible".'3 Both groupswere allowed to descend to an altitude of1500m. They were kept separate from one

another and their offspring were again studiedat low and high altitudes. It was found that,on exposure to hypobaric hypoxia at 3000 m,there was a much more pronounced rise inpulmonary arterial pressure in animals in thesusceptible group than in those in the resistantgroup. A second generation of the two originalgroups was bred and the same striking differ-ences emerged. These observations gave furthersupport to the hypothesis that a genetic factormay be of importance in determining the re-

activity of the pulmonary vasculature to thehypoxia of high altitude.

It therefore seemed of great biological in-terest to study the pulmonary circulation of theyak. Despite being a member of the cattlefamily which is characterised by a thick walled,muscular pulmonary vasculature (fig 5) res-

Figure 6 "Muscular pulmonary artery" from a yak fromSakti (4500 m) in the Himalayas showing a very thinmedia with a medial thickness ofjust over 3%. Stain:elastic van Gieson, magnification x 375.

ponding to hypoxia by constriction, the yak isindigenous to altitudes exceeding 4000 m inthe Himalayas. In spite of this its muscularpulmonary arteries are exceedingly thin (fig 6)with a mean medial thickness of only 4-5% ofthe external diameter of the vessel.'415 Therewas no muscularisation of the pulmonaryarterioles.Anand and colleagues'6 had previously in-

vestigated the pulmonary haemodynamics ofsix yaks at sea level and five at high altitude.They found that in the yaks at sea levelthe pulmonary arterial mean pressure was19 mm Hg with a wedge pressure of 1 1 mm Hg,a cardiac output of25 4 1/min, and a pulmonaryarterial resistance of 0 34 mm Hg/l/min. In theyaks from the Ladakh Himalayas the pul-monary arterial mean pressure was 20 mm Hgwith a wedge pressure of 7 mm Hg, a cardiacoutput of 22-9 1/min, and a pulmonary arterialresistance of 0 58 mm Hg/l/min. It was con-cluded that the pulmonary arterial pressure ofLadakhi yaks, at an altitude of about 4500 m,was not significantly different from that foundin the yaks bred at low altitude. Anand and hiscolleagues therefore concluded that the yak hasadapted genetically to high altitude by largelyeliminating the hypoxic pulmonary vaso-constrictor response. 16An intriguing aspect of such adaptation to

high altitude by the yak is that it will readilycrossbreed with cattle. It is therefore possibleto observe the results of mating a member ofthe cattle family adapted to high altitude (yak)with one that is acclimatised and not verysatisfactorily at that (cattle at high altitude).The commonest crossbreed arises from themating of a cow with a male yak and is calleda dzo. The female dzo is commonly mated withbulls to produce a further crossbreed called thestol. Anand et al'6 found that the dzo had

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Adaptation and acclimatisation in humans and animals at high altitude

pulmonary haemodynamics similar to thosefound in the yak. On the other hand, halfof the stols had pulmonary haemodynamicssimilar to those of the yak, while in the otherhalf the findings resembled those in the cow.These results suggested to Anand and his col-leagues that the genetic attenuation of thehypoxic vasoconstrictor response is transmittedas a simple Mendelian autosomal dominanttrait. 16 The argument outlined with respectto the diminished pulmonary vasoconstrictorresponse of the high altitude camelids androdents may also therefore be applied to theyak. It would appear that the yak has a greatlydiminished pressor response to hypobaric hyp-oxia, which has probably been lost throughcountless millennia of genetic adaptation to themountain environment. Presumably natural se-lection has caused these animals to lose thethick walled, highly reactive pulmonary arteriescharacteristic of the genus in favour of thosewhich are thin walled and relatively unreactive.This is powerful evidence in support of theconcept that animals indigenous to high al-titudes become genetically adapted to theirhypoxic environment. This has enabled themto survive at high altitudes, in contrast to theirzoological relatives (domestic cattle) whichfare badly in mountains owing to the vaso-constrictive effects of hypoxia acting on theirthick walled pulmonary arteries.

ConclusionsThis programme of research has shown thatthe pulmonary arterial tree is frequently mod-ified in humans and mammals living at highaltitude, the nature of the modification de-pending on the biological status of the group ofhumans or animals being considered. Naturalacclimatisation in humans is exemplified by thenative Aymara or Quechua Indians ofthe Andeswho have not lost their hypoxic pulmonarypressor response to alveolar hypoxia5 6 and showabnormal muscularisation of the pulmonaryarterioles.24 These vessels maintain an in-creased pulmonary vascular resistance and leadto slight pulmonary arterial hypertension. In aminority of native highlanders there is a morecomplex remodelling of the pulmonary arterialtree which is benign.4 It is hardly more than amarker of chronic alveolar hypoxia and haslittle or no effect on the wellbeing of the nativehighlander who carries out an active life ofsustained manual work.An alternative route to successful survival

at high altitude may be achieved by geneticadaptation rather than natural acclimatisation.This is manifested by indigenous mountain

mammals who appear to have lost their hypoxicpulmonary vasoconstrictor response totally orin large part.9-" As a result their pulmonaryarteries are thin walled and do not generatean increased pulmonary vascular resistance,so they do not show any noticeable rise inpulmonary arterial pressure. Such mani-festations of genetic adaptation to hypobarichypoxia are to be found in species native tothe Andes, such as the llama, alpaca,9 andmountain viscacha,'0 and to the Himalayas,such as the yak'4 and the Tibetan snow pig."This long term programme of research first

started at the Department of Pathology at theUniversity of Birmingham and for the last 25years has continued at Liverpool. During thattime there have been several research ex-peditions to two of the great mountain rangesof the world, the Andes and the Himalayas. Itis hoped that the studies of the pulmonaryvasculature in humans and animals ascendingto, or native to, these areas have shed some lighton the response of the pulmonary circulation tohigh altitudes.

1 Heath D, Best PV. The tunica media of the arteries of thelung in pulmonary hypertension. J Pathol Bacteriol 1958;76:165-74.

2 Heath D, Smith P, Rios-Dalenz J, Williams D, Harris P.Small pulmonary arteries in some natives of La Paz,Bolivia. Thorax 1981;36:599-604.

3 Wilkinson M, Langhorne CA, Heath D, Barer GR, HowardP. A pathophysiological study of 10 cases of hypoxic corpulmonale. QJIMed 1988;66:65-85.

4 Heath D, Williams D, Rios-Dalenz J, Calderon M, GosneyJ. Small pulmonary arterial vessels ofAymara Indians fromthe Bolivian Andes. Histopathology 1990;16:565-71.

5 Sime F, Banchero N, Pefialoza D, Gamboa R, Cruz J,Maricorena E. Pulmonary hypertension in children bornand living at high altitudes. Am J Cardiol 1963;11:143-9.

6 Penialoza D, Sime F, Banchero N, Gamboa R, Cruz J,Marticorena E. Pulmonary hypertension in healthy menborn and living at high altitudes. Am J Cardiol 1963;11:150-7.

7 Arias-Stella J, Saldafna M. The terminal portion of thepulmonary arterial tree in people native to high altitude.Circulation 1963;28:915-25.

8 Heath D, Harris P, Sui GJ, Liu YH, Gosney J, Harris E, et al.Pulmonary blood vessels and endocrine cells in subacuteinfantile mountain sickness. Respir Med 1989;83:77-81.

9 Harris P, Heath D, Smith P, Williams DR, Ramirez A,Kruger K, et al. Pulmonary circulation of the llama athigh and low altitudes. Thorax 1982;37:38-45.

10 Heath D, Williams D, Harris P, Smith P, Kruger K, RamirezA. The pulmonary vasculature of the mountain viscacha(Lagidiumi peruanuni). The concept of adapted and ac-climatized vascular smooth muscle. J Comp Pathol 198 1;91:293-301.

11 Sun SF, Sui GJ, Liu YH, Cheng XS, Anand I, Harris P, etal. The pulmonary circulation of the Tibetan snow pig(Marmota himalayana). J Zool 1989;217:85-91.

12 Wagenvoort CA, Wagenvoort N. The pulmonary vasculaturein normal cattle at sea level at different ages. Pathol Eur1969;4:265-73.

13 Weir EK, Tucker A, Reeves JT, Will DH, Grover RF. Thegenetic factor influencing pulmonary hypertension in cattleat high altitude. Cardiovasc Res 1974;8:745-9.

14 Heath D, Williams D, Dickinson J. The pulmonary arteriesof the yak. Cardiovasc Res 1984;18:133-9.

15 Anand I, Heath D, Williams D, Deen M, Ferrari R, BergelD, et al. The pulmonary circulation of some domesticanimals at high altitude. Int J Biometerol 1988;32:56-64.

16 Anand I, Harris E, Ferrari R, Pearce P, Harris P. Pulmonaryhaemodynamics of the yak, cattle and crossbreeds at highaltitude. Thorax 1986;41:696-700.

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