Hypoxia andthe pulmonary circulation - BMJ

Thorax 1994;49 Supplement:S19-S24

Hypoxia and the pulmonary circulation

Inder S Anand

The first description of the effects of hypoxiaon the pulmonary circulation was made byBradford and Dean in the UK exactly 100years ago.' However, scientific interest in thisfield only began with the discovery of hypoxicpulmonary vasoconstriction in the cat by vonEuler and Liljestrand2 in 1946, and in man ayear later in Andre Coumand's laboratory.3Despite extensive research in this field fornearly half a century, we still do not fullyunderstand the mechanism of hypoxic vaso-constriction or why the response of the pul-monary vasculature to hypoxia is diametricallyopposite to that of the systemic circulation.Teleologically, hypoxic pulmonary vaso-constriction serves a useful purpose. It acts as alocal homeostatic mechanism and, by divertingblood away from the unventilated or poorlyventilated lung, helps to maintain ventilation-perfusion homogeneity and thus arterial oxy-genation. It is not surprising, therefore, to findthat a similar response exists in most animalspecies."

Mechanism of acute hypoxic pulmonaryvasoconstrictionThe mechanism by which a fall in oxygentension is sensed and translated into vaso-constriction in the pulmonary circulation isstill not fully understood. We know that pul-monary vasoconstriction is initiated within sec-onds of the onset of alveolar hypoxia,9 and thatthe pulmonary artery pressure gradually risesover the next few minutes. It is a remarkablecoincidence that the stimulus-response curveof the pulmonary vasculature to hypoxia inhumans resembles that of the carotid bodychemoreceptors to acute hypoxia and of thebone marrow to chronic hypoxia.'0'3 In eachcase the threshold of Po2 is approximately70-80 mmHg. Below this value the responsebecomes increasingly strong. The inflectionpoint of each of these curves is almost identicalto that of the haemoglobin oxygen dissociationcurve, suggesting that similar mechanisms maybe involved in the sensing of oxygen in thesediverse systems in the body.

Site of hypoxic pulmonaryvasoconstrictionThe small muscular pulmonary arteries are themajor site of hypoxic pulmonary vaso-constriction. Oxygen tension of both the al-veolar air and the pulmonary artery perfusatecan directly influence these vessels, althoughalveolar hypoxia is much more effective.'4-6Staub and colleagues used the micropuncturetechnique to show that hypoxia increased pul-monary vascular resistance predominantly in

arterial segments upstream from arterioles30-50 ,um in diameter.'7 Laser technology laterconfirmed hypoxic vasoconstriction in small(30-200 ,um diameter) arterioles.'8 How re-duced oxygen tension triggers pulmonaryvasoconstriction is still being investigated, butwe do know that a reduction in oxygen tensionin the lung depolarises resting membrane po-tential of pulmonary vascular smooth muscle,resulting in Ca2" influx through the voltagedependent Ca2" channels.'9 The mechanismby which hypoxia is sensed by the pulmonaryvascular smooth muscle remains unclear. Fora long time a vasoconstrictive mediator hasbeen thought to be involved. A number ofpotential mediators such as histamine,20 sero-tonin, noradrenaline,22 angiotensin II,23 vaso-constrictive prostaglandins,24 leukotrienes,25reduced ATP,26 and cytochrome P-45027 havebeen investigated and excluded. The en-thusiasm for a possible mediator of hypoxicpulmonary vasoconstriction has thereforewaned, and there is increasing interest in thehypothesis that oxygen tension is sensed dir-ectly by the vascular smooth muscle. The pos-sible role ofK+ channels in hypoxic pulmonaryvasoconstriction has been suggested for sometime,2829 but the most exciting development inthis field has been the finding by Weir andcolleagues that hypoxia inhibits an outward K+current in isolated pulmonary arterial smoothmuscle cells causing depolarisation of the rest-ing membrane potential.30 This could then leadto an influx of extracellular Ca2+ through thevoltage-dependent Ca2+ channels and con-sequently to vasoconstriction. It is interestingthat the type I cells in the carotid body alsosense hypoxia by a similar mechanism.3132 Fur-ther studies are needed to define these K+channels more fully, and to determine how theyare modulated by hypoxia.

Effects of chronic hypoxiaThe clinical effects of hypoxia are most evidentin chronic hypoxic states. In addition to vaso-constriction, structural changes in the terminalportions of the pulmonary arterial tree33 andpolycythaemia34 contribute to the maintenanceof chronic hypoxic pulmonary hypertension.This occurs when the alveolar oxygen tensionremains below the threshold for pulmonaryvasoconstriction of approximately 75 mm Hg.Such a degree of chronic hypoxia is seen inconditions like chronic bronchitis and em-physema, hypoventilatory states, and in its pureform at high altitude. It is therefore interestingthat an almost identical "remodelling" of thepulmonary vasculature occurs in response toalveolar hypoxia in these diverse states. In 1968Donald Heath and his colleagues coined the

VA Medical Center,Minneapolis,Minnesota 55417, USAI S Anand

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term "hypoxic hypertensive pulmonary vas-culature disease" to describe this form of pul-monary vascular disease.35 The most strikingeffect of alveolar hypoxia is muscularisation ofpulmonary arterioles <70 ,um in diameter whichnormally contain only a single elastic laminawithout any smooth muscle. This distal ex-tension of smooth muscle causes the smallpulmonary arterioles to develop a distinctmedia with smooth muscle sandwiched be-tween an inner and an outer elastic lamina.This was first described in Quechua Indians ofCerro de Pasco (4330 m) in the Peruvian Andesby Arias-Stella and Saldafia.36 Later Heath andcoworkers37-39 made a number of studies onQuechuas, Aymaras, mestizos, and white res-idents of La Paz, Bolivia (3800 m) and, whileconfirming muscularisation of pulmonary ar-terioles, found that remodelling was much morecomplex than had originally been envisaged byArias-Stella and Saldafia.36 Moreover, con-siderable individual and ethnic variations in theresponse to high altitude hypoxia were seen.Remodelling was more common in the Aymaraand Quechua Indians than the mixed mestizosor long term white residents of La Paz. Heathet al also found longitudinal smooth muscle inthe intima of small pulmonary arteries anddevelopment of inner muscular tubes of cir-cularly orientated smooth muscle cells, internalto the fascicles oflongitudinal muscle, lining thepulmonary arteries and arterioles.3839 Similarhistological changes are seen in patients withchronic obstructive lung disease at sea level,40but the development of longitudinal muscleand inner muscular tubes in the intima is muchmore prominent and occurs more frequently.The similarity of the remodelling in cor pul-monale and in the natives of high altitudesuggests that it is caused by sustained alveolarhypoxia. It remains unclear, however, how pul-monary arterioles come to be muscularised. Itis unlikely to be the result of work hypertrophysince these vessels have no muscle in normalsubjects and hypoxic vasoconstriction occursin vessels proximal to these arterioles. It is morelikely that some smooth muscle growth factorsare involved. Once pulmonary arterioles be-come muscularised they can constrict in re-sponse to hypoxia and vasoconstriction movesto a more peripheral site in the pulmonary vas-cular tree.4'

Pulmonary artery pressure at highaltitudeThe structural changes described in the nativehighlanders are associated with chronic pul-monary hypertension. As stated above, how-ever, pulmonary hypertension does not developin high altitude residents until the alveolaroxygen tension falls below 75 mm Hg, whichoccurs at an altitude of approximately 2100 M.42Thus the pulmonary artery pressure is normal(15 (3) mmHg) in residents of Denver, Co-lorado (1600 m), borderline (19(6) mm Hg) inFlagstaff, Arizona (2100 m), and raised (24 (7)mm Hg) in Leadville, Colorado (3100 m).'0In contrast to North American high altituderesidents, the Aymaras and Quechuas of the

Andes who have lived at high altitude far longerthan their American counterparts appear todevelop a lesser degree of pulmonary hyper-tension despite being at higher altitude. Pul-monary artery pressures are normal in thesesubjects at 2240 m (15 (2) mm Hg)43 and2640 m (13 (3) mm Hg),44 mildly increased ataltitudes between 3700 and 4370 m (20 (3) to23 (4) mm Hg),45-4 and moderately increasedat an altitude of 4540 m (28 (10) mm Hg).49The curve relating pulmonary artery pressureand ambient oxygen tension is less steep in theAndean people than in their North Americancounterparts, which suggests a blunted hypoxicvasoconstrictive response. This may be amanifestation of adaptation to chronic hypoxia.

Unfortunately few data are available fromthe Himalayas where large populations also liveat high altitude. Roy catheterised seven men atLeh, Ladakh (3600 m) who were presumablyofLadakhi origin. 50 The pulmonary artery pres-sure at rest was 20 (4 5) mm Hg and rose to26 (5) mm Hg with modest exercise. The rest-ing pressures are, therefore, almost identical tothose quoted for the Andean people at similaraltitude. The Andean highlanders, however,showed a greater increase in pulmonary arterypressure with similar exercise (32 (8) mm Hg).Does this mean that the Himalayan people areless reactive to hypobaric hypoxia than theAndean highlanders? Groves and coworkershave recently reported the pulmonary arterypressures in the native Tibetan highlanders ofLhasa, Tibet (3600 M).5' They found normalpressures at rest (15 (1) mg, PIo2 = 97 mm Hg)which did not increase significantly with furtherhypoxia (19 (3) mm Hg, PIo2 = 62 mm Hg).Higher pulmonary artery pressures have beenreported in two Chinese studies from Quinghaiprovince in Tibet (3950 m) but it is un-clear whether they studied Tibetan or Hansubjects.5253We have examined the lungs of seven La-

dakhi highlanders who had never been to lowaltitude and who suffered accidental deaths.Their small pulmonary arteries were thin walledwith no medial hypertrophy of the muscularpulmonary arteries, muscularisation of the ar-terioles, or any of the other changes describedin the pulmonary vasculature of the Andeanhighlander.54 Similar thin walled pulmonaryarteries with normal pulmonary artery pres-sures are seen in a number of mammals in-digenous to high altitude - for example, thellama,5556 mountain viscacha,57 yak, 5859 andsnow pig.60 Heath and Harris have suggestedthat this lack of pulmonary vascular re-modelling and absence of pulmonary hyper-tension in these animals is an expression ofgenetic adaptation to hypobaric hypoxia.57By losing the property of pulmonary vaso-constriction the species finds it advantageousto avoid the harmful effects of pulmonaryhypertension at high altitude at the expense ofthe benefits of ventilation-perfusion homo-geneity. Indeed, the hypoxic pulmonary vaso-constrictive response appears to be geneticallydetermined,6' and the loss or blunting of thisresponse in certain species indigenous to highaltitude may be explained in simple Mendelian

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terms.62 The absence of muscularisation of pul-monary arterioles and the lack of pulmonaryhypertension in the Ladakhi and Tibetanpeople, who come from the same ethnic stockand have lived in the Himalayas longer thentheir Andean counterparts,63 therefore suggeststhat the pulmonary circulation of the nativeHimalayan people is remarkably well adaptedto hypobaric hypoxia and perhaps better ad-apted than that of the Andean people.Does this difference in the degree of ad-

aptation of the Andean and Himalayan peoplereally matter? Several differences in the re-sponse of these populations to alveolar hypoxiahave been reported. Tibetan residents have ahigher alveolar ventilation and increased vent-ilatory sensitivity to hypoxia than the nativeAndean highlanders.64 The haemoglobin re-sponse is lower in the Himalayan than theAndean highlander.65 These factors may ex-plain why chronic mountain sickness is com-mon in the Andean people but is seldom seenin the native Himalayan population, althoughit is frequently found amongst the Han Chineseresidents of Tibet.66

Subacute mountain sicknessThe benefits of adaptation to alveolar hypoxiain the Tibetan people are best seen when theyare compared with lowlanders who migrate tolive permanently at high altitude. One suchlarge experiment occurred with the Chineseoccupation of Tibet in 1952 when large num-bers of Chinese people of Han origin movedfrom mainland China to live permanently inTibet at altitudes of3000-4000 m. This enorm-ous demographic change offered a unique op-portunity for scientists to study the differencesin the long term effects of alveolar hypoxia onpeople of different ethnic backgrounds.

SUBACUTE INFANTILE MOUNTAIN SICKNESSIn 1987 we went to Tibet to study the Hima-layan variety of chronic mountain sickness.66During these studies we came across a newdisease which was termed "subacute infantilemountain sickness",6768 and were able to ex-amine the records of 15 patients who had diedof this syndrome. The condition was found ininfants and children of both sexes aged 3-16(mean 9) months. Of the 15 patients 14 wereof Han origin and one was Tibetan. All exceptthe Tibetan infant and a Han girl of 14 monthswere born at low altitude and later taken tolive in Lhasa (3700 m). The average durationof their stay at high altitude was only 2- 1months. The infants presented with features ofcongestive heart failure including dyspnoea,cough, irritability, sleeplessness, cyanosis,puffiness of the face, and oliguria. Clinicalexamination revealed tachycardia, tachypnoea,cardiomegaly, heptomegaly, and rales in thechest. Chest radiography confirmed the pres-ence of cardiac enlargement. Haemoglobinlevels were not increased.The most striking feature at postmortem

examination was an enlarged heart, right vent-ricular hypertrophy and dilatation, and a

dilated pulmonary trunk. Histological ex-amination of the lung was carried out by Don-ald Heath in Liverpool and showed changes inthe pulmonary arteries, arterioles, and venules.The pulmonary arteries showed severe medialhypertrophy with crenation of the elastic lam-inae, suggesting vasoconstriction. There wasmuscularisation of the pulmonary arterioles. Incontrast, the Tibetan age matched controls hadthin walled pulmonary arteries and a singleelastic lamina in the pulmonary arterioles.Clearly, alveolar hypoxia was responsible forthe pulmonary vascular disease in these patientscausing pulmonary hypertension, right vent-ricular hypertrophy and dilatation, and con-gestive heart failure. Lack of intimalproliferation, plexiform lesions, fibrinoid nec-rosis, or necrotising arteritis distinguished thiscondition from cases of primary pulmonaryhypertension described in infants and childrenliving at high altitude in Colorado.69 In onecase of subacute infantile mountain sickness,however, there was migration of myocytes fromthe media of small pulmonary arteries into theintima.68 Heath has shown that such featuresare characteristic ofearly plexogenic pulmonaryarteriopathy, forming the pathological basis ofprimary pulmonary hypertension.70 Could thismean that the disease described in infants andchildren in Colorado was a late manifestationof infantile subacute mountain sickness?The possibility of further investigating this

infantile syndrome is now unlikely because,since its recognition, Han infants born at lowlevel are no longer taken to high altitude. Theincidence ofthe disease has therefore decreasedconsiderably. Recent data show, however, thatthe arterial oxygen saturation is higher inTibetan than Han newborn infants at Lhasa,7'suggesting that alveolar hypoventilation in theHan infants may have contributed to the pul-monary hypertension in subacute infantilemountain sickness. The rarity with whichTibetan infants develop this syndrome is anotherindication that the Tibetan people are adaptedto alveolar hypoxia. Subacute infantile moun-tain sickness has not been seen in other highaltitude areas. This is probably because such alarge movement of lowlanders to high altitudehas not occurred anywhere else. There is, how-ever, some historical evidence that a similarcondition might have affected infants born toSpanish immigrants to the Andean miningtown of Potosi (4070 m) during the 16th cen-tury. The Spanish soon learned not to taketheir infants to Potosi until they were over theage of one year.72

ADULT SUBACUTE MOUNTAIN SICKNESSThe sudden movement of large numbers ofIndian troops to high altitude in the Himalayasduring the 1962 India-China war was re-sponsible for our increasing awareness ofmountain-related illnesses and, in particular,of acute mountain sickness.73 This experienceencouraged formulation of rational ac-climatisation protocols that allowed men to bedeployed at much higher altitudes. The recentexperience of military activity at extreme al-

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titudes (>6000 m) in the Himalayas has madeus aware of another syndrome called "adultsubacute mountain sickness".74

In 1988 40 healthy soldiers (average age22 years) stationed at extreme altitude(5800-6700 m) for an average of 18 weeksexhibited this syndrome. All were Garhwalisfrom the same ethnic background and wereborn and had spent most of their lives at analtitude of about 2000 m. They were movedto high altitude after a proper acclimatisationprocedure spread over five weeks. None ofthem had developed acute mountain sickness.The posts they manned were snowbound withno local inhabitants or permanent settlementsin the vicinity. Access to most of these areaswas only possible by helicopter. The averagenight temperature at their posts varied from-200C to -400C. Their daily routine con-sisted of patrolling several kilometres of theslopes and other combat activities.The illness started after the soldiers had spent

an average of 11 weeks at that altitude. Theydeveloped increasing shortness of breath andoedema and later gross anasarca. Most ofthemresponded to intermittent doses of diuretics.After an average stay of 18 weeks at extremealtitude they were finally airlifted to sea leveland were investigated within three days. Mostofthem started spontaneous diuresis on leavingextreme altitude. Apart from features of severecongestive heart failure with oedema and as-cites, they had polycythaemia (mean haem-atocrit 61%) and 18 had papilloedema. Chestradiography, ECG and echocardiography con-firmed cardiomegaly, right ventricular hyper-trophy, and dilatation, but no left ventricularenlargement or pulmonary venous congestion.Haemodynamic measurements showed mildpulmonary hypertension (mean 26 (5) mm Hg)at rest, not responsive to oxygen, which roseto an average of 40 mm Hg with mild exercise.The pulmonary wedge pressures and cardiacoutput were normal. All the abnormalities re-verted to normal 12-16 weeks later.The pathogenesis of this condition is not

clear but a number of factors might have con-tributed to congestive heart failure - namely,hypoxic pulmonary vasoconstriction, structuralremodelling of the pulmonary vasculature, andpolycythaemia. Since none of the patients diedand no histological examination of the lungswas carried out, the structural changes in theselungs are not known. Experimental data suggestthat histological changes due to hypobaric hyp-oxia are reversible over a period of a fewmonths.3375 Similar data on humans do notexist. Other factors that might have contributedto pulmonary hypertension include the pul-monary vasoconstrictive effects of cold76 andof exercise at extreme altitude."

Since the most striking finding in the adultsyndrome was massive fluid retention, we de-cided to examine the response ofthe kidney andthe neuroendocrine system to extreme altitude.Body fluid compartments, renal blood flow,and several plasma hormones were measuredin a group of normal asymptomatic soldiersstationed at extreme altitude (>6000 m) forapproximately 10 weeks.78 The results showed

a significant increase in total body water,plasma and blood volume, and total body ex-changeable sodium. Renal blood flow fell.Plasma levels of noradrenaline, aldosterone,and erythropoietin increased but the atrialnatriuretic peptide and renin activity did notchange. These findings suggest that salt andwater accumulation seen in these normalasymptomatic subjects at extreme altitudecould have resulted from mechanisms actingto reduce the renal blood flow, independent ofchanges in haemodynamics. Similar mech-anisms could also have contributed to thepathogenesis of adult subacute mountain sick-ness.Only 10-20% of subjects stationed at ex-

treme altitude were affected by this syndrome.The factors responsible for this observation arenot yet known. The cohort stationed at extremealtitude was homogenous in terms of race, age,build, and level of exertion. The incidence ofthe syndrome increased with altitude and withthe duration of stay at extreme altitude. In-terestingly, the occurrence of the disease hasdecreased dramatically since the adoption ofmeasures to reduce the period ofstay at extremealtitude. One factor that may be importantneeds to be considered. The syndrome of adultsubacute mountain sickness was seen in itsmost florid form in only two ethnic groups: theGarhwalis74 - as described in detail here - andsix months earlier in the Gurkhas79 on whomdetailed studies could not be done. Both thesepopulations come from submountainous areasof 2000-3000 m. It is possible that the soldierswho developed this syndrome were exposed tosome degree of perinatal hypoxia. Heath hasshown in experimental animals that variableexposure to perinatal hypoxia exaggerates theeffects of agents inducing vasoconstrictive pul-monary hypertension in later life.80 Whethera similar phenomenon contributed to thepathogenesis of this syndrome remains to bedetermined.Both the human syndromes described here

have a number of similarities with brisket dis-ease in cattle. The length of exposure to hypo-baric hypoxia required for the development ofclinical features is almost identical. Hypoxicpulmonary hypertension seems to play an im-portant part in all three conditions. The com-mon clinical finding is one of severe congestiveheart failure. The morphological changes inthe lungs in brisket disease8" and in subacuteinfantile syndrome67 are entirely muscular innature. Although histological data are not avail-able for the adult syndrome, it is likely thatsimilar changes might be seen in this conditionas well. Removal from high altitude results incomplete resolution of brisket disease82 andadult subacute mountain sickness.74 There isanecdotal evidence that this also occurs in theinfantile syndrome. It would therefore appearthat both the infantile and adult forms of thesubacute syndrome are the human counterpartof brisket disease in cattle.

Even a superficial reading of this chapter willmake obvious the enormous contributions thatDonald Heath made to the subject of hypoxia

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and the pulmonary circulation. For me it hasbeen a great privilege to have been associatedwith some of his work. Over the years I havecome to know Donald well. His enquiringmind, equable humour, resilient character, andtransparent straightforwardness have alwaysshown through even during the stresses of ourscientific expeditions at high altitude.

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Hypoxia andthe pulmonary circulation - BMJ