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c .2

PRIMARY P ULMONARY HYP ERTENSION

R eport

on a

WHO mee ling

~ 1~17 0ct0bc't 197)

SHUICHI "" TANO

. od

TOMA STIlASSER

WOR LD HEALTH ORGANIZATION Gf.NE"'''

19' 5

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\ CON TEN TS

-

Introduction . . . . 7

Classification and nomendalu,e 9

Control of Ihe pulmonarycirculation 1I

Morphology

"r

primarypulmo nary hYl"'rlen$; on 14 Eti" logy andpalho~n..i$ of primary pulmonary hYl"'rttnsion 18 Pharmaoology of the pulmonarycirculation 22 CI;nicalfeatures of primary pulmonaryhypertension 25

Epidemiology 28

Recommendations 32

Ref. ",,,ces . . JJ

Anne' I. Classification of chronic cor pulmonale according In

causativediseases 38

Anne' 2. Diagnosis of pulmonary hYJI"rte nsion by dirttl me. ,ure_

menl 40

Annex 3. List of participants . . 44

INTRO DUCTION

Pulmona ry hy~rt.nsion eau.... pulmonary h.art di..a.., a common disorder I.ading to ..v.re, oFt.n intractabl., incapacily. The first WHO m«ling "n pulmonary circulation wa, Ihat of an u~rt commiu« on chronic COr pulmonal. hdd in 1960; ilS report (I) da..ified chr"nic cor pulmonal. inlo di..a.... primarily affOCling air pa""ge. of lhe lung and Ih. alv.oli, di..a primarily aff..,ting Ih. m"".m.nt. of th. Ihoracic cage. and di..a primarily affecting the pulmnnary va..ulat ure. Mnil ca.... in lh. last-"",mi,,1led group are iOCOndary to aknown cau..; how.v.r.

in """,nt y.ars, a large number of pali. nt. wilh pulmonary hypert.nsion bUI withnutany und.r1~ingdi",...other Ihan v ul. r change, relaled10 pulmonary hypert.nsion have been observed in eral countri...

In 1967,a.udd.nincrea.. in the numberofpati.nt nWilh pulmon.ry

h~pert.nsionin "'''''' cardiology d.partments in Swit rland ga"" ri .. 10 inl.n..int.~tin this di... Asimilar inerea..wassuhsequ.ntl~ reported intheF. d.ralR. publie ofGerma ny and in Austria. Anas.wcialion belWffn pulmonary hypert.nsion and Ih. inlake "f appelit.-redn<:ing drugs was soon observc<l, and wh.n the drug, ....r. withdrawn from th. mark.t the number of new ca.... d.dined, Th. lungs of "'''''' patients who took th... drugs and died from pulmonary hypert.n,ion show.d a mor pho- logical pictur. id.ntical with that ... n in ^M primary pulmonary hy~r.

tension ~. C... with the same pulm<>nary morphnlog~ ... accumulaled ....,.ntly in India. Iran, .nd Sri Lanka (C. A. Wag. n.oarl, unpublishe<l observalions. 1974).

Primarypulmonary hy~rt.n,ion is a rare di..a..; th. total number of ca.. reportsI<> dal. isof the "rder of hundreds. Ex«pt in th. ca.... witha bistory of .dminislration of the drugs m.ntioned al>o"" . a s)'St.matie 'tudy of primary pulmonary hy~rt.n,;"n ha, been difficuh 10 perform beeau.. of th. v.ry ,mall numbers of pati.nts ...n at each centre. Fur_

thermo .. , ••rly diagn" . i. and treatm••t i, hampered becau.. symptom.

and sign. a.. sea.... unhl au irr.v.rsibl.lal••lageis reached, and becau..

lhe di.gn" sis of pulmonary hy~rtension need, 1" be confirmed by cardiac cath.terization,

In vi.w ofthe rec.ntly generated interesl in primary pulmonary hy~r.

t.nsion. lhe World H. alll! Org. nizati" n con•• 1led a m«ling to revi.w th. hitherto ..an.red ..i.ntific information and I" di..u"" the .tiology

- ,-

s

^PRIMARY PUlMON AIl,YHYPUTEl<S10S

and palh"gen~i~. pathophy>iology,morphology, clinical pallerns, dinical physiology. and ep;demiology of primary pulmonary hyperten,ion; pulmonary hyperten.ion ...,ondary to chronic pulmonary di",a", and (0 hean disca", was ou(oid. the $<XII'" of the meeting, Additional aim. of the mttling ....~ to d.fi .... problems l'C<luiring further investigation and

to consider a mulli""nt'"collaborativcstudy of the epidemiological, dini·

cal, functional, and morphological characteristics of primary pulmonary hypertension, with the purpose of a...mblingand coordinating ntherwi.., ir.olated^Of llClIltered information, testing new hypothcse!I, and eventually elucidating the cau<c, ofprimary pulmonaryhy""rten,ion.

The meeting was held in Qen""" on lS-17 Octoht:r 1973. Th. pr=nl publication contain, an account of the m«ting, ba..d on the working pape" submitted bythe panicipants' and on their discussions, The section on the control of Ihepulmonary drculation is largelyba>ed on a paper by A, p, Fi'hman, The morphologicalconcept, "'e.. d=ribcd by D. Healh andC,A.Wagenvoon . S,G. Blounl, Jr, provided Ihebackground for Ihe section on etiology and palhogenesis, while that on Ihe pharmacology of the pulmonary drculation cl"",ly fono",s the contribution ofC. N. Gillis, O.Kra upp,andJ,A.WilLThe d=ripti"n oflheclinical featore,ofprimary polmo""ry hypenensi"n is derived from contribulion, by H. P. Gunner, P, Harr is, F. Loogen, N. M, Mukharlamov, and P. Wirz, and the section on epidemiology extensivelyquotes F. H. Epstein's paper. The annexon lhe diagnosi, ofpulmonary hypertension was contribuled byH. o.:nolin.

Finally, Ihe group'sre<:<>mmendalions on ... rch to becarried oul wilh international cooperat;on are cited; some of the.. re<:<>mmendalion' arc already being implemented.

•""",,. ) conlain,a"""'P~" li"oftileporlicipon'..

C LASSIFICATION AND NOMENCLATURE

The eau," of some ca,"s of pulmonary hyperten,ion i, unknown.

Identifkation or the morphological type is difficult 'ometimes, .,..en after autol"Y. Clin;ciaos and morphologists are inclined to take different ap- proachesto thesame condition.Some morphologicaltypos may be due to different eau,",. The re,ulting terminological problems an: difficult to

.olye without both etiologkal and morpholagical classification.

t:lIoIOflkal daw lkatloo

The dinician identifies abn<>rmally high pulmanary arterial pressure by a combination of b«hide and catheterizationt<:<:hniqu". He ma~be able ta diagna," a particular eau," (pulmontlry hy~rI<!tl.lioll of kI,o..·~ ....w,).

Most conditian' kna wn ta cau", chmnic cor pulmanale (see Anne~ I) beiong ta this category. It includes chronic pulmonary thromboemboli'm or pulmonary ~no-occlu,;ye di",a", if identified, Pulmonary hypertension due ta heart di",a"" ,uch a, kFt.to- right ,hunt and mitral 'tena,i,. which are e,c1uded by definition f,om cau"" af oor pulmonale (An...., ^I), is also important in this category. In other Ca"" the Clinician will not be able to identify the etiology (pulmona,y hrp<!rtr~s;on ofWlknO"'~ cause.

traditianally known as ^M primary pulmona,y hyperten,ion "). Ca... are assigned to this cat<:gory only whcn all pos.ible known can'" have b«n e' d uded. Jn someca,"s the etiological a~nt may be: ,u,pected (pulmonary

hy(Wrlt'n,;o~ of doubtful ca"...).

Morphalol:ic. r cl."ilk.tlon

Various morphological change, are obsc..ed in the lung. depending upon thecause (see page 14). Wbe:a the Cause is unkno wn. the following histopathological pattern. may be: identified:

(D) pulmonary yascular di",a", characterized by ooncenlric intimal fibro,i .. necrotizing artoriti•. and pl",iform lesions;

(b) pulmonary veno-occlusiYe di",ase,in which the pathological changes OCCur mainly ;n the pulmonary vein' and 'enules; or

(c) pulmonary thromboemboli'm,

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^{PRI"l H V}PULMONARy HVPERttMlON

While the!IC three catego ries ",e", accepted by all participants, the'"

was disagretment on howto classify muscular hypertrophy of pulmonary arteries and .n.riol.... when this is the role find ing. Some participant.

though t that such lesions wo uld have developed pl.siform changes jf lbe patient had lived longer or if Ihe disease had betn more aggressiye and that these ca ... can therdo'"bt'con,idereda, an .arly 'lageofca~gory(0);

OlberireItthat suchan ."umpt;o"i. nol justifiedand Ihat i",late<! muscular hypcnropbyshould be left unclassifIed. It wa.also pointed oUllha' mi..d lesions induding Iwo or threoe of Ih. aoove ",,{egonn ca" wmetim... be

o~rvWandthat such cases cannolbe classifiedin anyof Ih. three grou ps.

Nome""blure

The problem of nomenclature was di",usscd al length. Diffic ulties arise !>e<;au,", Ih. ter m ^M primary pul mo na ry hyper ten,ion^M is u.ed in one of two quit parate wa~. In some instances it is used clinically, to indicate the pr n~ of .Ievated pulmonary art.rial pressure in the

absen~of a discernible eau.., thus co,ering the con~pt of pulmonary hypert.nsion of unknown cause. On Ihe other hand, the term h.s .lso been ...d to denote the morphalogiC<l1 pulmonary ,"scular paUemcharae- teriO'ed by C<I~mric ;mim.1 fibro'is, necrotizing art.ritis, plexiform lesions, and ... soci.ted changes in Ihe .bsence of tung or he.rt di...

PI..iform lesions maybe found also in e...s of pnlmonary hypertensio n of kno wn eau.., but the pathologic.1 diagnosis of ^M primary pulmonary hypert.nsion^M has been TCSerwd for ca ..s wh.re th. pathologi,t cannot di"",rn the eau.. of these change,. Som. pathologists also call it^M classical p"mary pulmonary hy pertension^M or ^M va,oconmieti,e pulmonary hypertension^M (2).

Sin~ hnwrtemi"" cannot be m.asured po'tmortem, the participant, thought it d.,irable to find a n.w morphological t. rm for th. condition with plexiform lesions, necrotizing arteritis, and concentric intimal fibrosis with o ut a discernible cause. The term plexogmic pulm<>no'y (lI'te,iopalJry is ,uggested for this condition.

I! i' not thought practk abl. to abolish the t.rm ^M primary pulmo nary hypencnsion^M for it has been widely u.ed and probably will still be u.ed. Ho we...r. IhroughaU/ the pTesem Tepon (he te'm ^M p,ima'y pulmona'y

hy~"msi""^M is usNionly la mean ^M pulmona,yhnunension 0/unkno"'n cause^M. Thi' may includ. any of the morphologically distinct conditions.

Wh..., lhe morphological .ntiti... are dealt wit h, the proposed mor·

phological term, are u.ed.

CONT ROL OF THE PULMOJ'lfA RY CIR CULATION

1.0,,-.... .."-""

circul.t....y .y.tem

Th. pulmonary eir<:ulalion i. a low-pre,"ur. and low-re.i.tance eir<:uil.

i.•.• it is influ.nced predominantly in a p....i"" m.nn.r by .xl.rn.lly impo..d cardior~pir.tory .,.nIS(3) (0« lhe accompanying figure).(4) Daring .'.r<:i... a. blood flow and 'olum. ;ncrea... pulmonary arterial p...'ur. also incre.... (5); lhi, .lfecl i, • .agger'ledal .hiIUd•. Non. th. l.ss, if the pulmonary >a"'nlar I"'" remain, an'lomically normal, bolh al ..a level or above it. lh. " .. in pr.ssure i.g. n.rally ,m.lIand bursl, of in- creased blood flow induced by >igorou, phy,ical ....ei.. are tol.ra l.d wilhout di",omfort or undueslrainon lhe righl h••rl (4). However, when ....i.lance and di'l.nsibilily are curtailed. lh. n.w pr.ssu~fl ow_>olum.

relalion,hips predispose to sustained pulmonary hyperl.n,ion ,

The>isco, ity of the blood is g.n.r.lly eon,id.red to be unimportant in lh. regulalion of the normal pulmona ry cireulation in indi>iduais wilh a normal""malocril >ala•. As Ihi. >aluc inerea...i'lance10pulmonary

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blood flow alro inerea.... (6). The.. ;""rement>are slight and lend 10 be most marked in the uppermost parts of the lung, where there is least blood fl"w(1). On Iheother hand,when non_uniformpulmonary vascular di",.... ha. advaneW to the sta~ of pulmonary hyperkn,;on, increased visco, ity coupled with hypoxia may make an imponanl contribution 10 Ihe pulmonary hyperten,ion,

The bror><:hial circulation i. of liUI. haemodynamic «m.."u""", in the normal pulmonary circulation . It may. how.""" as, ume importance when the pulmonary blood flowis ..,.rely curtailed, or in the pr..."""

ofbronchiecta'is (4).

Acti"" chang~ in pulmonary va..:ular ~i,t.an~ are known 10 "",,,ur. Thechange> may bechemical,nervous ,or humoral

The mo't importaM agent inducing pulmonary vasocon striction is al'«Ilar hypo..ia_Th. low oxygen pressure of al'eolar air appears to affe'" the ,mooth mu,de ~II, of the mu",ular pulmonary aneries, even without any nervous mediation. Whether the mechanism con~rned

in,ol, es the local release of va","cti,e substances le.g., histamine from mast",,11» isnotknown. Acido,i ,enhanC\'<;the vasopre ssor eff..:t ofal¥wlar hypoxia, whe, eas alkalo' is dimini'hes it,

The large pulmonary aneriesandveinsare richly supplied with ne"es, but there arefewor no ",,"e' to the ,man mu",ular pulmonary arteries.

Ne"es eud in the advenhtia and not the media. The effect of ne"ou.

stimulation (SI i' to 'tiffen the wallsof the large pulmonary arteries rather than in= ase resi'tance^l<] blood ftowat thelevelof the mu",ul ar pulmonary arteries ;the resultis a,liSht riseinsy,tolic pressure,whiledia. tolicpres' ure is not elevated in the normal lung. This eff..:tof nerve stimulation orSC<"Iion ha' been demonstrated inanimal' but not in man,

The peripheral art.,-ial chemorectptors (carotid bodies) are connected by refte' pathway. 10 the pulmonary ci«ulation. Thus, part of the pul- mona ry vasoconstriction induced byhypo.ia is mediated by the peripheral chemorecepto rs in someanimals. Thi, ,asop""sor etrect is, however, not large and ha' not been demonstrated in man.Theetrecl. of a number of naturally occurring va","cti"" ,ubstan~s on the pulmonary circulation h..ebeen'tudiedin man but no important humoral mechanism of control ha, b«n demon ,trat.d. Acetylcholine acts a, a vasodilator; S-hyd"'''y - tryptamine increases pulmonary va",ular resistan~ in animals bul not substantially in man; brad ykinin has a ,"riable effect; angioten, in has no~rt.inetrect.A numberof such agents arechanged or destroyed during their pa, sagethrough the lung(seepage 24),

~u'O"TO~ A WHO,,"ETING

The fOfal cireulaTioo

The ab<"e consideration' apply exclu,i"ely To the beha. iour of The adnlt pulmonary circulatio n. In geDeral, Ihe same ,..,gulatory mechani. m' operate in the fetu., differing primarily in the vigour of re'ponse. For e.ample, the pulmonary circulation of the neonate ,..,spond, briskly 10 vasomotorandpharmacological.timuli;Tberespon;eTo bypo<i. dimini'h..

wiTh age (as the muscular wall, growthin) and both local (chemical) and peripheral (nef'lous) influences a,.., ;n"ol.ed in the pressor response to acute hypo.i.(9).

Pulmonary drcull Tioo at bigh alTitlld..

Clinically healThy ""ident . of locations aT bigh altiTudt. who ha"e ,penta lifetimeunder hypo .icconditionsmay oftenba"elonger and more muscularresistance ....sel, in The pulmonary circulaTionthan do sea-level dwellers (10, 11). ConsequenTly, Ihe baseliDe ,..,.i"anee To blood flow Tbrou gh The lung,of thealtiTudedweller is highe. than that of thesea-level dweller; during e.erci... the incremenT in pulmonary artery pres.ure is greaTer(12). The hypert rophied muscle of the pulmonary vascular t=

can ....pond more "igorously in the high_altiTude dweller Tban can the thinner pulmonary"ascular .month muscleof thesea-level dweller.

Simply by being born al altitude, tbe indi. idual may be started on the road 10 pulmonary hypertension. How far down The road he will continue probably depend, on the interplay of intrinsic and ambienT inflDences.

I I

MORPHOLOGY OF PRIMAR Y PULMO NARY HYPERTENSION

Multipl. patbot:...i>of pulmoooryhyport....IOII

The'" a", maoy cau,", of pulmonary arterial hyperten.ion and th..., a", u$>ocialed with diffe",nt form' of hyporten,i.. puimo nary vascular di",a",.'" that the .trueturalchange> in the pulmonary vascul.tu'"cannot bo predicled from. known ie..1of pulmon.ry .nerialblood proMU'"(13).

The type of hYPl'rtc nsi.. pulmonary va",ular di",a", induced depend, onthemeehani.m ofprod <lClion of the underlyingpulmo naryhyperten,ion.

Thu. the type of _h~pertcn';.. pulmonary vascul.r di",.", a"""ialed with ,tate, of chronic hypoxia 'Peh ., chro nic bronchiti• • nd emphy",m.

or livingat high altitude(11)i, diffe",ntfrom that occurring in .ssociatio n with large congenital cardiac .hunu(14). Both the morphology and Ihe phy. iology, e.g., the re.."ibility of both the pulmonary h~perten.ion

andthe pulmonary vascular di",a",.a", diffe",ntin th...,two form.(lS-(7).

Primary pulmonary hype"en.ion i. al", a'sociated with ch...cteri.t..

hi,tolog;cal I..ion•.

Vano... typn of patholoKY io primary pulmooory hypert....irHI

In the aboen.. of primary or congenital di",a.. of the hean or lungs or of cirrho.i. of the liver, lh"'" di'tinct pathological entiti.. may p....m the dinicalpictu re of primary _pulmonar~hYPl'''en,;on(see.1", page 9):

(a) plexogenic pulmonary arteriopathy;

(b) pulmonary ..no-ocdu,i .. di",.", (lg, 19,94); or (..) recurrent p11lmonary thromboemboli.m(2).

Plu ogeni.. pulmOmiTY"".,;opa/hy .

In any description of pulmonary ,a",ular pathology ;1 i. e,..mi.1 10 define with great ca", the type or pulmonary blood , ..",I boing ""n'idered, The recommended da..ification i. th.t of Brenner (20). The hi,topalho- logieal fe.tu .... are ••follow, :

(I) I""rea..d medial thick"... of ~ muscular pulmonary a"eri.. ".

Sucharteri .. a", botween 100and 1000pm in ..ternal diameter and normally h.ve.thin mediaofcireui.rly .rranged 'month muscle ,"ndwiched botween

- 14 -

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in~ and ,,,",,,,Idulic Iaminx.

n..

^{medial Ihick_ ollM normal}

- IIlllSCll'" pul ry a11ft)'8 .... bttn Jioen a. l-Sy' 01 IM diamekf ollM amry,"d '"ollM ad_ilia(1C)...21).

(2)

n..

^appnnaceolllnall "'...IarvaadllcMlhanSO

.-no

indhoJnfler wilh a d;OUIlI:\ lIlf<iia 01cimllar mllOdo bounded by in~ and.,,~

dulic ..mi. . .. Sudo...-h do lIIOC nioI ia IM DOI'mal lune. ..Iwft IM puln'OOftU)" ...mob ha'" a ..

an

^{eonoiItin,0Aly ola lill,x}daIlic: Ja"U...

~al IIwtr immtdia" onJiIlfrom .-mll m....:ularpuln'OOftU)"

anma..

(3) """ dc.doJlllW"1 01 intimal librooil and lihroriaolOli&, atTJ.n,ed illa charaamIlic~oniooa-Ik.u.⁸ _li...tioa (2<4).

(4)

n..

dc.dop"..,,. olk<ali....-dilalatioaIniono- wch ..pexiform orallPomatoid.Inionoi"IMIidcbrandlnofIIIn;l1lar pullllOlWY at'Ifrin

pro~imal 10 si," 01 o,:<:lIlIioa by imimal fibro-da01oW1. Such dilatalion IfIionI comi01 oldilalfd bnu,ch,'1 wilh lhill ...11. a>mpooed 01 a sin,1t daolic lamina and lintd by • ctllul•• endolhd;.l proIifnalion 'Ihowin, a _plc:~i(orm .rra n,...nl (25).

(5) """ P""'~in ...iMtallCn of _ ilin, ." ...ili. i" IM ....Ih ol mUlCul•• pulmon . ry .n ,,",,_This m.y M _ " j" ." acule (onn wilh librinoidnoc.osi.ollMmtdi••which i. inlillraltdbylIWlrophilpolymorph•.

I1 m.y M .eta in • •uhacule form "'i'h ,ranu!om.lou' ch.n.... in IM .rteri. 1",.11• •nd «du.ion ol lM lumen by .n o. p ni"" 0. Ofpnizing Ihrombu•.

The hi'lopalhologica1 f, al Ur« of plexoll"nic: pulmonary arte. iopa lhy are ch.racler i.lic: buI nol palhognomonic of One di",.",. ldenlical micro-

>copic: ~hani<" in Ihe lungs occu., lleConda.ily. in la. ,.. pre-tric uspid conFnil.1~.rdiac.hun".uch a. alria l ",pial defen. la'F posl·l nc u. pid congenil.1card iac .hunt>.uch as ~enlricula. "'plal <!efen, .nd lhe rare

"lIeS

⁰¹cirrl>os.il ofIM Ii",. Ihal are complic.1f<l by pulmonary .rterial hypertension (26,27).

A dia"""" of~ primal')'~ pl...,.,nic a"erio.-Ihy may M conlidcred

...10...or alloil'"hislopal h<>l<>Pcal (ealu,," 1ilted under OHS).bove

. n:

pRIC""i. I'".boena01conF nitaJcardiacshun" orcitrbolisofl... I;""'-. llemI

m _

^wonio»-skin - intimal libroe laslosis. (<4H ilala !ion 1nionl, and(S)-_ i z i n , arteritis an: ...gest~ of I'" diaJf'O&il. 1...(1)

and.^{(2) are}'ti"...JIyofDO walucaIotw:lina(l)_ 11i"_ _(onns and(2) in tI1ffonns of h)p<neftliw 1"'1_1')' vascular d.isaw. W1lm items(I) and(2).re I'" sole lindinp. lIw; cood,tioa may M Iril. wdasaifx<i. u.nleu it if; ...10beaa early Ita",of _~puln'OOftU)" arteriopalhy.

For I"" """"'"_ badsof .rterial IDOIl"!><>tlkU-Yareof DO ...e illlIw;

dia... of plc:~ puln'OOftU)" &iu ,i0p8l hy.

n..

~

of a Ilahllicany siJllilic:am incmooe in med;.l Ihid_ merely indK:alel lha' _ form of hypen""'''' 1"'11"0"'1')' ...cvIa. diwalle if; ptnftIl.

"

^{PR'MU VPULMONARY} HYPERTENSION

, ^. , _,

A thorough and careful ,,"""'i nation of the pulmonary v•..:ulatur. at different ,it ..i.n=>ary, but biopsy oflh. lung o!ka fail' 10 idenlify the type ofdi...,What is important in th. diagnosis is to demonstrate that th. 1>1'" of di<ease characterittd by onion-$kin inlimal fibr~la'IO$is.

pk.iform l..ion., and """roti,ingart.r;li, isp~",nt. ~Secondary· ple.a- genic pulmonary aneriopathy i' diagnosed when lesions appear in ."od_

alion wilh congenital or ••perimen'al cardiac ,hunts (28, 29) or cirrho<i.

of the Jiver (26, 27)

Pulmonarywno-<>cdu';ve di.mu"

Thi, rare di...", ha' been ,e<ognittd recently. It may be easily mis- diagnosed clinically as primary pulmonary hypenension (19) but may be ,ecognized from the radiological app"arancesof pulmonaryplethora (18, 3Ol.

It o<x:un in young indi~iduabof both se.es:th~ a~rag~age of 24patiento was 19~a~(C. A.Wagen~oon, unpublished obsc....ations, 1973).

Th~ pathological f~atures of the condition are quite distinct from those of plc.ogenic pulmonary aneriopalhy, th~ pulmonary ~ins beingaffect~d

rathe' Ihan th~ pulmonary amries; th~re is I"""", barophilic ~lIular

fibrosisI~adi ngto widespreadocclusion ofth~pulmonary,~insand ~nules.

In almost all case< thrombi,rettnt or in the prOttUoforganization, appear to underlyth~ intimal fibrosis inIh~ pulmonary v~ins, and th~ appeara n=

ar~ suggest;~of organization of thrombus ;n th~ pulmonary v~ins. Such thrombi may abo occur inth~ pulmonary arteries and art~rioles. Arterial

ah~rations are usually limited to a varying d~gree of medial hypertrophy, probably secondary to the increa..,d po:st-c.apiUary pressure.

Th~ lung ti..u~ r~v~als eon~tion, pulmonary oedema, and ha~mo­

sid~rosis. Interstitial pn~umonia and focal int~rslitial fibrosis arc often

pr~..,nt in th~ ..m~ area.. and broncbilis and broncbioliti' with increa.., of goblct cells in Ihe epithelial la~r and of broll<'hial mU<XIu, glands are regular findings. Thi. morphological pielurc ,ugg~S1S that inflammation and not congestionund~r1ies th~ fibrosis (94).

Ru nrr...' pal"""",,>, ,lrrtmlbMmboli.m

Tbis di..,a.., may appear as primary pulmonary bypemnsion, botb clinically and from th~ results of radiology, electrocardiography, and cardiac cath~terization, Pathologically it is a distinel condition (2) but its bistological features hue "''''''times been confused with th~ ~arly,

and rom~time, th~ terminal, 'lag~sofpl~.ogenic pulmona ry arteTiopathy.

As in pi~.ogenic pulmonary an~riopa\hy, th~re is medial hypertrophy of muscularpulmonary arteries and muscularizationofpulmonaryarteriol~"

HOwe>'ef, the nature of the intimal proliferation is quite different from the COncentric ^M onion-skin^W fibrocla'IOSis. as it represents organizatio n

••I'OIlTON... WIIO ... FJ1NG

or lhrombMmboli Ihal a~ ol\cn fa:t'nlncally ,illl.lled in the ves>el so Ihal lhe inlimal proliferalH:>n i, ~n a, an ecttnlnc ~ of fibroclaslos is.

E<:ttnlOc rcca....li...'u H:>n chu""l. a~ common. Tlw inlimal proliferal ion con';," iniliallyoffibrobla . lS. Dilalalion Ie<ion, do nol occur in recurTenf pulmonary Ihromllo-<lmboliml_ uodul poinl of di<tinction in lhe dif_

ferenlialdi.aJl")loi1..

1::1I_ ..tlof , . - . , .l. - l

Sections of lhe pulmonary uunk in Does of pln.otmic pulmonary ar1eriopalhy i~ odulu show a . .11ft1I of da<tic !i..ue oonoi'\enl wilhlhe O<:quiml variety of pul_ ry hypn remioro. Thi, i, not al..ays so ,n children. ..hett

I ""

^{pulmonary hYJ'fflnlYoa may be: prnml from binh.}

RidtI·...) ...,

Tlweliuo:1la01pulmonary-bypmnn,jonmaybe:diool:oYnalal""'OV'y from thefindi".01 . .ill<ftlWd ...oft.bt:rilhlYnltrickandaa inctea<ed lhicb.,.. of t.bt: ptdPMlDlry artery. Mea.u_ u 01 the thil;-k _ 01t.bt:

ri"'l .-mlriaalu...nanIlDrdil bkaad bypertropby ofthis chamberis bnl determillot'dby-;P;....aflcofmr-aloflhealtadwd ral(32). Normallylhe -cipl 01eeriprYnl,"",1arrift ...ndon _ ncud 6SJ.while!he'ratio 01the- ; .hloflheId'!Ymtridt:(iodudi"lthe KpIum)10lhal oIlherilbl .-mlrintlar rift ...n is uoUIIIy ill lhe ... 2.)..).). IIIrip l "..,.,triI;uIar bypnlrophy il-ciJlosO'er10 •aDd illit.olaltdriP I .-mtril;ular bypmrophy lhe ralio be Gmu 10eulhan2.0.The ratio oflbethid".,., ,,(rbepulmonary lnIak10 lha. of!he'aorta is

...u,

^{ill lhe ra....0.•-0.7. I" lbe} preoc:"'"

of pulmonary hypmnn,jon Ibis fipte ll'JlR*'ba

«

_y c~ UDity

""

ETIOLOGY AND PATHOG ENESIS OF PRIMA RY PULM ONARY HYPERTENSION

:\Ia lliplrrliolOllY

As .talrd on page 9, pulmonary hyperten.ion of unknown origin is referrrd 10aspr;"""J'pulmonary hypertension. The morphological.ub"'alO of primary pulmonary hyperten.ion variesas d"",ribe:d on page 14.

Any thwry of etiology bas to explain why primary pulmonary hyper- IOnsion appears to be: congenital in some ca.., and acquirrd in others.

In cbildren the inciden"" i. the samr in mal.. and females, whilein young adull. thefemale i. predominanl. It i. most probable that .."..eraldifferent ba.ic proces..s are invol'fed, leading 10 pulmonaryhypertension and uhi- mately to the de\<Clopmcnt of the morphologjcal changes in the small..

pulmonary arleri...

VawconSlrk tion of lhe muscularpulmonaryarterieshasbeen con,iderrd 10 be the precipitating e. ent in primary pulmonary hyperlension. Tbe occa.ional findingof an increased muscle ma" of the media", the only abnormal morphological change, and the finding of a significant fall in pulmonary artery p....ure and ,-e,;i,tan"" afler injection into the intrapul- monary artery of v",odilating drugs such as tolalOline,aCdylcholine, and isoprenaline in men have given ri.. 10 the vasocontrict;on theory (33). The younger lhe pal",nt, the more frequently are non,pecific morphological change, of pulmonary arte";" encountered. The occurren"" of Raynaud's di..a.. or Raynaud's phenomenon as a sole concomitant condilion in a palient with primary pulmonary hypertension maylend Further .upport to this ba.ic COn<epl OS, 36). Both condilion. art of unknown etiology and may re"eet an unusual .ta te of byperrraetivityinvolvingthe digilalarteri""

as well as the muscular pulmonaryarterie"

Acule hypoxia cau.., pulmonary hypertension dur to pulmouary arterial vasoconstriction . A ""rtain degree of elevation of the pulmonary blood p,-e,;,ure is normally found in population. living al high altitude"

_ 18 -

"

lrodi,,",..." in t~ population.Iuo"", increaKd mu"""r.'i....tion of the pIlI_

moNI}' arterial11ftand il ...IU<OfUII*to ....PP<* thol thisincreao.ed bulk 01mlttdei.maintai""" by11 chronicincrea~in tOM.The pulmonary arterial prnwfe, " " -. does "'" co"""""ly reach the Ind roul>d in politft.. ..itb nt.bli,hcd primal}' pulmonary hy~_ PfimaJ)' pul- monary hypmenWon tw. bcm repxtod a. hi,h .lliludn. but ;\ does not

...I ...ill incid<na: it.i~III

hi'"

^{.hi ll.dn. Si...~hypo ....}

iI the a-.l ~ul ~ h_n. pri....'Y puJ...,.hypn-_

tllft&ioa, is pm.u bly callSedby an tocq>l;"""lIy pokftl

- n n o r

Wm••h..^{Of• •}1, IiYdy. some r _ "d.... th.an pvno ..._ riclion iIoptraunl-

V_ l linion maJ _11 "" initia ted by or,," t1Ivi...mem.1 rac'lors.

dru, io,ntion. 01 did, « in othtr••, ~1 UMUlpccllOd, ..._~ The

....,.." C'Pd<'mic 01pri"",ry pulmonary hyponen",," OOXIIrrin. in S..itler- brod(37). lhe Federal R"'P"bli<:of(knnany 011),aftdAustria(J9)appcan to "'..e been auociatnl "'ith the ingestion of1he .~lil...kprnsinl drug aminorex rum.note(_ ""~ 29). Allk".,h 11 c.u~and.., lfKl relati on ship has not bn-n clearlyn tablished, the ci,cum'la ntiar ..,ide,," in it, fayour is imprn.i.c. Am inofex is 11 compound relalt<!10 _.mph~tam;M and has both alpha. Ind btta.ld",norgi(, receptor .timulaling ~ffM" It ha. be<:n .ho wn 10 ha~ '0 "'" ~a'OC<InmiC1or ~ffecl in acul~ e>p<ri"",nl' on lh~

ptJhno na '}' arl~ri... of animals. as obser\'ed Wilh ot h~r .ympatho mimelic compo und. (40. 93. 97). Pa li~n l' dying wilh primary pulmona ry h)'p<rl~n•

• ion inI,,,,,,iali,,nWilhamino"" in~lionha""be<:nfound10 _ha,~lhepul.

m"",, '}' _arl~rial dilatalion Ieoion' CharaCl~ri.tic of O\l\<,r pat~nl!. with primary pul"""", ry hypert~MiOft. Ho_~r. rNdin, dop and oome Oll\<,r animal...ilham;lI<II'el ha.not ...ulkd inanyabnonnalityinIM

lIIOfl'holosY

ofIMir pulmon ary 'a"",laI U"'_~he\n.s, il isntimatN lhal appro li.

malt lyonly2p " IlXXl_~ taking aminottl dnotloped tilt _{di~_}(41).

iO il ... likely lhal 00fI"Itadditional factor m.... b<prne<>t that mak...

anain

,...room

outeq>liblt_

Il.ndl. ""

. r '''

^,j ....Ol"fID....Of. .

Amon' ...

"""'*

^lbertisa comi&rabk ....riot"""in1Ilt .-..ospoosm (I(11.. ...monary ci' culalioa in rnponot to hypo,.. or OIhcT ....KIOICIi'.,

.,.,.,It

^{(33.42) and ilis}po<Sillk,hal ",""" variot"""inrncti";f)' conlribut..

10 I"" In.. i..c.du~ (I(tM diocasc in 11\<,pr~.."" (I(a posorhW (:II.usati""

"""1 "'"""

^asami ...

I

PRIMAR YPUL..O><.UY KYPEIlTE>;SKJN

Pulmonary hyperten$ion may beprodu~ in rat. by theadmini,tralion of futvine. a pyrrolizjdi~ alkaloid derived from lhe $«d, of Ihe planl Crolalaria !"ha. 11 has been 'hown that after a single do .. of ful'ine rats may develop marked right,entr icular hypertrophy and n« rotil ing arterili, of the mus<u lar pulmonary arterie' and arteriole. (43). Thi' procedure mighl be u..d as an experimentalmodel forpulmonary .rterial hypertension, In ralS lhere were no distinct differeJlC<'s between the effect. of oral and intraperitoneal admini,tration.

Right ventricular hypertrophy and medial hypenrophy of pulmon.ry arteriesbecomes evident within only one week.Necrotizing arterili' ofthe lung is pro..nt inalmost allrat, .u",i,ingIreatmenlfor 4 weeks or longer.

The numberof maSl cell. in Ihe lung tissue ri..s ,harply after 3-4 weeh Thereis somedoubt whether thi, ismerely a nonspecificp~enomenon(44), but il••ignificanee is a$yel undetermined. It ha' been demon<lrated tbat intimal thickening of .mall 'enales. and les' often of larger vein•. often lead ing10complete obmuction ofthe ...ascul.r lumen.i. pre..nt in almost .11 ral' .u",i,iug the .dministr.tion oft~edrugfor4weeks or more^(%). The obstruction is mually ina relati""ly short segment, Ihe other part$ of the vessel remainingpatent.The.. changes.howeve,. differ largelyfrom Iho..

inpulmon. ry 'eno-occlu,ive di... in man. Although the fulvine..periment h••demonstr. ted the possibilily that substan.... t.ken by mouth can cau..

fatal pulmona ry hype,te n, ion, it isunlikely that fulvineitself;sa cause of pulmonary hypertension in man. The $«ds ofC'Qta!a,;a!"/VIJ.nd related pla nt$ have been ingested by individual•. especi.lly in the We. t rndies.

but no case of pulmon.ry hypertension has ever been reported lhere.

R~rl'fllt tbro mbMmboliml

Milia ry embolization and/or thrombosisin 'i/ " bas .Iso received much auention a. a pos$ible etiologi",,1 pr"""". Altbough most pathologist.

wouldagr.. with theviewe.p...d above that Ihere is a clear histological di" il>Ct;on belween pulmonary hyperten, ionof embolicorigin and primary pulmonary hyperlension, opinion is not unanimous on this point(2).

h perimentally, pnlmonary arlery lesion, have been prod uced by the intra""nou,injection of blood clot and other 'ubstan...The healedle'ions show fibroela"ic intimal thickening and medial hypertrophy oflhe small muscular p"lmonary art erie. (45-47) but generally the.. are dearly di.- ting"i, hable. An association bet~D ple.ogenic pulmonary arteriopath y and cirrhosis ofthe liver has been doo;"mented. and it has been postulated that miliary emboli arising in the porta l ,'enou. sy"em pas. via collater.1 channel. to .y.temic vein, and thenne 10 the lungs (26. 27).The fact that

"

primal)' pulmonary hypclUno.ion Ippoan 10 de>'<:lop "ot inf~...ntly folio"' ;", childbin" .1", o"lI"to the pouibilily of • throm boem bo lic C1iology.

AIt~maliwl~, primary ""h...,....ry hnlen~n";on could bl' the <null ofIhrom booi< ;"

.i,,,

^{.0• m ull cl. h)}percno, ula l* 0I.1~KCondory10 .lterN platelet ("not... dcf_ in fibrinolpi.. or other abnormalities ofCOiIl ulation, TM da""'F th... cauwd 10 U", endothelium milhl ...,11 in an _obIilt'rali~procno. ROttIItly.the OttIIrn"""clab norm al fibrinoly>.il

""" bce1I KpOrled in poticnb . ith familial pulmoR.>f)' hyptrtem.ion (48).

A numho. or patient. ..;tll primary put_ ry hy~tMion ol>ow ~.ryin l ....t« cl hypc""",,,,Labilily and ... ha~ dc<:In>cd pla1C'ku ...m-J limes (5.G. Blown.,

J , .

unpubl;./wd",*~liono,1913).

TM_~ ofpri...1)' put _ry hy~ in youo, ...

"be>ha~ been takin, onl conlra<epCi.., pillsII.ualoobn'n "<>IN rtanlly IS. G. Blou nl, unpub!iohe<! oboenatiou. 1913). Ut. . . . in the piUmay direct/)'."'«1 1'"w..v:I ..aJIIIIad! ••Ihromhotmbolic mechani.ms.and il is""miok" d Iblllh"""booi.it~hallo«din - ' " " '...ad! U ill.ei ...An iftl:11!&Xd 'DCidc...,. of arrlnl infamioa rdowd 10 1"" pill Ion brnl do<"umntN, and COfOftU)' throm bosil ill )"01111' .."..,.." has ako been ,c"",lCd.11 ... """"bk lha'U.rombooio~oo:aI.inIM ...Um""",lar pu1moIWY ann>.. and arterioln ~ IM ~1opiIIc"tof ptimuy pul-

IfIo(JIW')' h)-pnI<ftl.ion. HOM"o'Cf of Ihno posoibilil ionis ..., lhan COfIjeaunlal ~t_

-'_ ia,... .... n _ "'••••

~

_

^{lti ...}

~dixa>es with multiple. y.um_in~'"C'fnm1,rreq...t1yrd"nm110 "

COfInecli~ ~ dilordcn. _ _ imn ao;:oompollioed by pulmonaf}' ancriaI hypnl<1lOioa and po' '''*'i_a tdwl,.. ill IM pulmonary Ilrt<'rial Iy.um.laduOrdin this eolC'JOf}'_ pt'OIfCIOi~')"UlIIicIdm>oiI(49. SO).

cli..eminated luP"" nyt...- . . . ('H. loOd anhrili. ('2). polyar- terilisDodouI' ). '41.and Rayaaud". di (3'•.\6).

I" lhoneeondi~a"a"lOimm". rnponoe....yk openoUDIaad il is

<:on<:ei""bW that Md! • ~ ..ould _i,,~..,IM pulrnoaaf}' ann>..^Of

~n a« <CI lhem pri rily. ,.". POOI~ kosioM in IM pulrroonary ann>.."""'Id ... ho ~r. lok dillill<li~_

P HA RMAC OLOGY OF THE P ULMONARY CIRCULAn ON

Th. 'tudy of pharmacological inftuen"'" on the pulmonary circulation is importanl in two asp«t~-id.ntifying .ub'la nct's that ca.n be used 10 reli."" pulmonary hyperten,i on. andscreening drugs to pr.v.nl Ih. mar- keting of substan"",that maycause pulmon.ryhypert. nSlon by th.mselves or by int.ractionwithotherinnuenct'son pulmonarycircul.tion.

Experi...laIeolMl iti...alMl pharmaeolox;caldf"" t. onpulmonary .irculation

Pharmacologica l inn...n"", on th. pulmonary circulation are r.l.ted tochangesaffecting pulmon.ry art.ry resi'tance and p...ure. Th. changes in the re,i'tance of the pulmonary v....l~ aff""l the action of the heart. Th. opposile i, also Irue. Both compo".m, im...ct 10 d.lermin. pres,ure pan.r", in th. pulmonary .rt.ry. 11 is import.nl to know wh.th.r pul.

mO"ary blood now or r..i'tane< i~ exerting Ihe dominant inft uenee at a particular time(seepage 11). Pharmacological agenlS mayactboth directly and indirectly (i.•. ,through th. gen.r.1 circul.tion),h.ne< gre.t difficulty is oft.n ..peri.need in th. ....Iuation of the pharm.cologic.1 eff""t on the pulmon.rycirculalion(SS.S6)

Se""..1 factors mu" be con,id.red, Sp«i.. diff.rences may be impor- tam; for inst.nce••om.autho," .upportth. concept of "....ou, r.gul.tion of the pulmonary circul.tion (72, 73). Thi~ m""hani~m i' unconfirmed in man and onlycircumslantially docum.mN in a f.wanimal ,p«i... Th.

morphology of th. pulmon.ry vaSCIIlature diff. rs wid.ly in various sp«i.,(S7---{, I). Experiment. in intact nnimal' or in man may produce differ.nt r..ult' if an anae'thetic other than local is used. The only wa y 10 measure Ih. pulmonary component and ..parat. it from the cardiac component would be to me.,ure the change resultingfrom infusion during a single circulation through the lungs. By the time a ~teady~tate 'ituation is achiev.d the cardiac and pulmonary compon.nt. ha"" become v. ry difficult 10 sep... t., Inv. stigation in .i", on animals with an intact cir- culation,with.itheropen ch..t orclosed che't,may gi..eadiffer.nt picture from .,perim.nt, carried out on isolated andon perfused lunl\$. Uoyd's work has shown that th. immediate .nvironm.nt of th. v....I. may al,o

- 22-

RH'ORY ON A WHO MEETING

beimportant in determining their response toapharmacologiealorhumoral

a~nl(62), H.demonmat.d that when pulmonary vesseb are pla~ in an .nvironm.nt 'imilarto those of ,yst.mic v.""ls th.y ...spond like systemic v.""ls, and vice versa.

Th. findingofpulmonary hypertension in many patients in Switzerland, Ihe Federal Republic ofG. rmany. and Austria laking Ih. drugam i nore~

stimulated further int. rest in th. action of drugs on the circulation of the lung.

Kraupp andhi, co-worken (40, 92,9),97)have studiedthe effectsof Iwo

alpha·.~m l"'thom i mnic ,ubsta""". (norepi...phrin. and m.tho.. mine) and a beta-,ympathomim.tic drug (i,oprenaline) as typical of each category.

Owing to a different temporal courseIhe effect ofalpha..~mpathomimetic

,uMtaJl<:e1; wa, not Ihesame and this findingwas interpreted as being due 10abeta's~ml"'thomimeticcomponent of no... pin.phri .... It wa, concluded that the alpha·51imulating activities of these drug, do not lead to any substantial change in pulmonarypressureand ""i"ance,in ,pite of marked va"'onstriction in Ih. periph.ral circulation. On th. oth. r hand. th. beta- slimulating drug isoprenaline induced a highly significant increase in pulmonary pm..re, pressure gradient, and pulmonary flow, with a con- comitant decrease in l.ft atrial J>l'CS'u~h. opposite of m.tho.. mine.

Pulmonary va",ular resi"ance decr.ased only slightly, whe..a. peripheral ..,istance decrea",d mar1edly. The elTecl' w... dose·d.p"nd.nt. In all ca... an appreciabl. ine..ase in right ventricular work was found. This .ffectma~ be important in th. . .ported cardiac faHure and right v.ntricular dilatation in ca... of i,oprenaline a.rosol overdose(6),64).Other "",r1.ri, however, have demon.lrated opposite effect. of beta·.ympathomimetic agents.The diff.r.n.... in findings may ..fleet diff.rences in animal mod.1 pr.p....ion and anaesth ••ia. Th. longer the alkyl residue of 'imilar

,,,b-

stan""", the mo.. the alpha."imulaling activity dccrea"'d and Ihe beta- .ympothomim. lic compon.nte' predominared (98). Amino..~ ,how, borh alpha and beta activity. which may account for the increase inpulmonary va",ular ..,i"a""" d.monmatodin acute .,perim.nts,similar to those with N-ethylamphetamine.

It ha. been ,uggest.d Ihat the.~mpathomimetic prop"rt~ of amino.., contributed to the dev.lopm.nt of pulmonary hypert.n,ion observed in ,ome patients receiving the drug. but animal upenm.nts have so far fa iled to support Ihis Iheory. Amph.tami.... ar. wid.l ~ used in lhe USA bul no inc..ase in tbe fr.qu.nc~ of ~primary ^W pulmonary hypert.n,ion ha< been r.port.d in that countr~.

.'

11><10"11. . ...'.bolitoq:an

Many ,ubstanc.. arc affected by p...ge through Ih. lung circulation (6S,66). So"", compound. are jn.eti~.te<,l, othe ... art aCli~aled or syn·

thtsiud, while still othe" arc unaltered. The .pecificity of the lung activity i,.hown by Ih. following <.ampl." prosta glandin. E,and E, are completely inaClivated during a single passage through lung; pro.taglandin. A, and A. are unaffected; n<lrepintphri"" is extracted; epinephrine is unchanged.

Sludi.. in man have demonstrated an incrca~ capacity of the lung 10 remove 5-hydroxytryptam;ne and norepinephrine following cardiopul.

monary bypass operation, in patients with nor mal pulmonary arterial prn'ures(66-68); Ih~ wilh pulmonary hypertension had a decrea>O<l ,,"-pac;tyfo r biogenic amine removal afie,,hebypassoperation,The presence of norepinephrine and 5.hydroxytryptamine could be demon'trated in tile capillary end6lnelium and {)f S-hydrO:>lytrypl!lmint in Il>e alveolar epitnelium of rahbit. on perfu,ion al 3S0C but not at 6· C. Acetylcnoline may be demoyed in tile plasma, and otnersubstance. such a. S_hydroxy.

tryptamine may ^beabsorbed b~ platelu•. Transit time through the lung in relati"n t" uptakemu,t be<XImidered.The role "f vawactive hormone metab<>1i'm by the lung in primary pulmonary h~pcnensionmerits study; changed pallerns of pulmonary circulation may bea..""iated with dif_

ferences in the uptakeof normally eirculaling ,a""active h"rm"...,_

CLIN ICAL FEATU RES OF PRIMA RY P ULMO NARY HY PERT ENSION

Earlysug.

Th. recognilion of Ih.earl~<lage' of Ihe disease i'adifficult diagno'tic problem, Patient• • re almo'l neVeT setn by lhe physici.n bt:fore Ih. onsel of symplOms. No physical. radiographic. or .lectrocardiographic ,igns of .arly slages of primary pulmonaryh~pertensionarelnown. Direcl m.a,ure- m.nt of pulmon.ry artery p....u..bycalhet.rilalion is al p...nllh. only ..Iiabl. diagnoslic procedure, In Ih. inilial slagn of pulmonary hypert.nsion high blood pressure may apl"'ar only on elfort, Non· invasive techniquesare al presenl not adequat.ly d....lop«! for use in del<lmining pulmonary hypertension ,

[stabli>bodstage

Th. mosl prominent s~mplomof establish.d se"re pulmonary hyper- tension is lach~pnoea, oft.n associal.d wilh a sen", of brealhl...n...

and occurring particularly on ..erei"" R_ nl obsc..ations on lhe juxta- capillary rec.plors(J-receplors) of Ih.lung, (69)and on lhe .ffects of vagal block on Ihe tachypnoea of pulmonary vascular obstruction(70) suggest Ihat reA.x ,timuli may be invoh'ed in Ih. pathog...,is of lhe respiralOry stimulation. Somelim.s there i' relro'terna l pain On exerci...Occasionally anacls of unconsciousn ... may occur on e..rci... Lassilud. is a common ,ymplom,

In Ih••stabli,hed .... an increased jugular v.nou,^M a~ wave i, n'ual Righl ventricular hYl"'rtrophy m.y eau. . . sy>tolic pulsation 10 lhe left of the ,t<lnum. The pulmonary compon.nt of th. second sound i' incr....d .nd lherem.y bean .udiblefourth sound, An imm.diate di.Sloliemurmur of pulmonary incompel.oce sometime' occurs.The physical sign, specific 10 primary cardiac or respir'lory causes of pulmonary hyperten,ion .r•

• bsent.

The impainnent of the contractility of the right ventricle in Chronic cor pulmonale and in parlicular in primary pulmonary hypert.n,ion bas been d.monslrated. bal il is sliII 10be determined how e.rly or how lale lhese ebangn may apl"'ar .nd what their diagnoslic importaT>C(: is.

_ 25_

PRIMARYPULMONARY IlYPERTESSJON

The chesl radiograph may be normal. In the eslabli.hed case it often .hows enlargement of Ihe pulmonary lrunk, while lhe small peripheral branc hes appear normal or even reduced in ,ize. In the l'ler ,tages th.

cardiac shadow becomes enlarged. Pulmonary veno-Qcdu,i.ediseasemay be distingui,hed by Ih. p...nce of e.idence of a raised pulmonary v.nous

pm,ure~nlarged upper lobe 'es",h, interstilia l or al"eolar oedema.

and basal horiwnlal linos.Th....ign••r. nol always p...nl. hoWC".r.

Tbe eleclrocar<!iogram .hoW< e.iden", of righl alrial and venlricular hypertrophy in excess of left, wilh low spedfidty. Some changes in Ihe Iracing may be allrit>Uled 10 thechangein the po<ilion of lhe heart in Ihe Ihorax or 10 Ih. ah.ratiQn of lhe lran,mi..ion media. Many .tudies have analysed Ihe relalionships between Ihe right pulmQnary andlor ,'entricular pressom andIhe panern oflhe ECG,in order 10 identify the mO$l,pecific

<ign,of right venlricular hypertrophy. and conlra,ling r••oll. have been ohtained. The relaliQn belween the .Ieclrocardiographic appearance and Ihe level of Ihe pulmonary artery p"",ure i. nol dose, the rapidity ofIbe .1e. aliQn Qf lhe pulmon.ry ""'ular mi.tance and lhe .Iale of the my<>- car<!iumbeing mitigating faCIQrs.

Lung ",anning and pulmonary arteriQgraphy ,hould ,howno .vid.nce of.

bUI cannot completdy e""lude, embolization. Re,piralory function lem will .how whelh.. Qr nol there i, a mpiratQryeau.. for lhe pulmonary hypertension.

While lh... dinical featuresand in,.sligation, may ,uggtSllh.presence of primary pulmonary hyperten<ion. Ihe d.finiti"e diago",i. mU on the resolls of cardiac calh.terization (Annex 2), Thi. pr<>cedore reveal, a sob'tantial increase in Ihe polmonary art.rial pr.ssure. which may be e.ac.rbated doring exercise.Tbe polmonary "edge pr.ssure is normal in Ihe primary arterial form. In pulmonary .en<>-ocdo,ive disease the wedge pres.ure may be incr.ased. bUllhis is nor always Ihe case. Righl venlricolar end.dia'tolic pres,ure may be increased and the right atrial "a

MW".

abnormally large. The cardiac OUlpnt i, lower than normal and does nor r.spond normally 10 ..ereise. There may bewm. decreasein the,ysI.mic art.rial oxygen lension and oxyg.n saturation.Ihe arterial carbon dioxide ten,ion heing normal or low. Cardiac catheteri..lion and angiography may help to exdude Ih. p...nce Qf congenilal malformation I.ading 10 pulmonary hypertension. Pulmonary art.riography may help ro excll.de pulmonary embolization but may he normal in Ibe presence of micr<>- embolizalion; il. ri,k in patienl. wilh primary pulmonary bypertension ,hould be laken inlo acroun!.

Prog.-i, .od1_ lment

Once e'tablished, primary pulmonary hypert.n,ion i. alm",1 alway, falal. Some cases found in associalion with aminorex b.... hOWC"eT.

REI'OIl.T ON " WHO MEETIN G

pro~ the exccption to this rule and. when the initial pulmonary hyper.

ten,ion ha. been moderale, a stable stale of pulmonary hypertension or e,en regression has been observed. 1I seem, possible that thi' unusual course or e""nlS may be due to the withdrawal of lhe stimulating factor.

Whileanumberofvasoacti"" drug. have be<:n roundto lower the pul.

monary anerial pressure in acute stud;'.. prolonged therapy ha> been found quite ineffeeti'e. Treatment with corticooteroid. and anticoagulanls h..~l""pm wrl vnl,,~"'«nnrl an~ff"",i""'h" npyi<knnwn

EPIDEMIOLOGY

The ••lur~orlb~probl.mof primarypulmonaryby!"'rl....,;oD

Epidemiological knowledge of primary pulmonary hypenemion "

limiled (sot _pa~ 9). Although th~ publi,hed data on the frequency of the condilion are based on the proportion ofca... among palient, wilh cardiopulmonary disease ralher lhan on the total population. there i, no doubt that lbi' i, a rar. di..a... II Ifad' 10 cor pulmonal., which i, common. allhough there are al$O no reliabl• •>lim.te, of lhe frequ.ncy of the lall.r condition in the populalion;primarypulmonaryhyportension can accounlf<Jr nomme lhan a 'mall proportionof corpulmonale pali.nl' . [n term, of it, fr«iuenC}', therefor" primary pulm<Jnary hyperten, ion can hardly be thought to p....nl a public heallh problem. Nev.rthel.... the disease ...ntlyassumed importanceonaccounlofa,udden 'mall.pidemic (sotpp. 7and30).Similar eveul, may oc<:uragain or might,infaet,already be taking place in epidemic OT endemic form in$Ome pan, of the w<Jrld. Be, ide" an undeMandingof lhe nalureofprimary pulmonary hyporten,ion could pro,ide n.win,ight. inl<J Ihe eliolog)'<Jf olher.commoner va..ular di",rdeT$.

In hi, exten,;ve review, Trell (71),ummarizes the d.la .vail.ble from clinical serie' a, folio.... '

llirloch<' aodcol...a..-....[OIl'ca.... in0_ ie<of'56(lOO~'itn"00C1l ..ameda l clinic inS """land;Pa ul Wood",pnrte<\a freQuencynf17omonl" 10(lOOcon""'uhve

"'''ien'' i, n caTdiova",ul.. di><a"" 1(12)], 14 of6000,,"'ien..<...ne<\ fl,)tca",,,,, ev,I"""",, hod th<condition, accon:Iina to Nitl><n and Fobriciu, primary plJlmonary an"';al h~pen<o,ion ",'a, found in0.2~1 p<' ""nt of 'iahl ....n cath<'",i>ation.. in 'M- ).,., ""ntofau'.,.." <.0><. of cor ""1""",,,1<and in0,08--0,2 "" IIXlOof un><ledrd an,0I" Ymaterial,

Ho....ver, lhese figure, may includesome case, of thrombo-embolic Orlg,n.

N.t",.l hi.t....y

More informalion on 'he u,ual range, of pulmonary arlery pre..ure by age andse, in normal person' i' n«<led,Iti'not known what proportion

<Jf penon. wilhin 'ariou' upper pro,,",. ranges p....nl dinkal or palho- logical evidence of hypenen,i'e pulmonary v.scular di... The usually accepled uppor limits of normal mean pulmonary artery pre..ure of

- 28-

RlPORT^O!<~ WHO"ffTl~()

"

2Smm Hg al r..,;l.wilh a borderline range of IS-2Smm Hg, are empirically and arbilrarily defined. The qneslion ari.e' whelher person' prone 10 de~lopprimary pulmonary h~perteMjon aTemeTeI~ Iho.. who aTealTead~

al an early age in Ihe high upper TOnge of the fTequency diSlribulion Or whelher lhe di..a.. is a distincl .nlily r..,;uhing from eliological facIo", lhal are unrelaled 10lhe muhipledelerminants of pulmonary blood pr..,;,ur•. There is an ob.ious paraliel wilh syslemicblood pre..ure distribulion and c..cntial hype..cn.ion. It i, tr"" 'hut pat;"n.. with primary pulmonary hyperlen,ion ha.. pre..ures lhal are relali.elymuch furlher r.mo>ed from lhe upper limil' of^K norm al~ than is lhe ca"wilh ....nlialh~perten.i....

However, lhe pulmonary arlery pr...ure of such palienl. may have been a gTeald.al closer10Ihe normalrange during lh. early stages of Ihe di.ea.e.

Ixfore advanced obliterali~ change. in lhe .maUer pulmonary arleri..

caused addilional increa... in vascular r..,;istancc. This maller is not likely w Ix r.sol.ed until there are non-inva,i.e melhods for ..rial pulmonary blood pr..'ure mea.uremenls 10 delecl and ob:ser.. lhe e.olulion of .arly eleva,ion,.

Th. ...to do"elopIIOII-io....i•• diag... lict«hniqu..

There i, a need for non·inva,ive lechniq... beeau," persons suSpecled of having .arlypulmonaryh~perfensionmust Ix sc....n.d. where indicated. for more delailed .ludi... Borderline palienls musl be monilor.d and followed. Relali... may require examinalion. in view of 'he familial ago gregations thal ha.. been reported. Non.invasi.. techniqu.. would also permit more comprehensive...arch intothe phY'iologi<a1 and palhologi<al ranges and delerminants of pulmonary bloodpressur••'incc elhicalconsider- alion. often preclude haemodynamic sludi.. requiring calheterization.

Certainly.,uchatechniqueW<luldberequiredforlarge·scaleepidemiological

"udi...

A comhination of relali..ly simple indi<alo'" of incr.a",d pulmonary artery p...ure mighl be u..ful. such as lhe QRS "is, Ihe ralio of lhe secondaortic10the second pulmonarysound.and somesimple pulmonary funclion test.>10exclude ....pirawry di",a",.Olher po,sibilili.. are:a low arterial oxygen len,ion or low diffusing <apacily of lhe lung in the ab.encc of bronchopulmonary di",a.. or arteriovenou, shunt, and mea.uring pul.

monary capillary 1101'1by using nilrous oxide and body plelhY'mograph~.

Echocardiography is not considered u.efu!. Howe..r. no current non·

inva,;.. melhod is valid for the pur JlO'C' oUllined abov •.

Epid<-mio1oltial dara00 primarypulmo...^l')" hyp.,,'....i""

De.pil' melhodological ShOrlCOmings. a certain amount of dinical- epidemiological infonoalion has been coUected. The overall "alem.nls

Pll'MAR Y PULMON A RY HY...TESSJON

on magnitude p",sented on page 28 have limited epidemiological ,ignifi- cance becausethey provide no etiologicalclues.There appear 10 be no data on geogTa phicaldi'tribution e.cept forthe as'ociation betw<:cn pulmonary artery pressu", and altilude. A predominance ofwomen i, found in mOl;t series. especiallyal younger ages (73);Good win andhi. colleague. describe a lhromboembolic form affecting largcr v....I•• presenting in middle age, with an equal se' Talio (74). In the pathological .tudy of Wagcnvoor t &

Wagenvoo rt. bolh thromboembolic and ~primary" groups .ho"",d female p",ponderance(2).

Familial clustering has been descrit><d. especially al younger ages.

T",I](71).ummarile. the dota from 5 publication. reponing 47 cases in 18 families; 12 of lhe case. we", below Ihe age of 16. The only male patienl among the 5 cases described by Krl henbiihl et al. (75) was aged 59 and gave a family hi.tory of pulmonary thTomboembolism in ""-,,al brother>.

Primary pulmona ry hypertension i. nol a newly recognized disease, T"'1l (71) traces the first likely case back to 1837 (Helie), According to Blount(73). the paperb~ Romberg in 1891 containedthe fi"t documented oc<:ur",nce of Ihe condition, Yii (76) ",yie~ Ihe literalu", up to 19SO and indicated that SO cases we'" reporled between 19SO and the lime of his own .tudy,whichadded a further 6 patients.

The appetite-reducingdrug aminore. wa. imroduced in Switzerland in 1965 and successively in the Federal Republic of Germany and Austria in 1966. The first repon on ane....sive incidence of primary pulmonary

h~perlensionfollowingtheingcotion of aminore. waS presentedb~Gun ner in 1968 (37, 77). Wirz&< Arbenl (78) revie~ lhe experience in Switl er- land, including the cent..s in Berne(37), Ba,le (79), Zurich (78. 80), lausanne (8 1.82). and Geneva(1S). Similar Observations on aminore.

w'e.. reported in Ihe FederalRepublic ofGermany (83) from"a nnover (38).

Essen (84. 85),Hamburg (86).and F.. iburg(87). The'" ""'''' similar"'porlS from Au. tria (39,88. g9),butin Prague.where the drug was not markeled, the frequency of primary pulmonary hypertension did not increase (88).

The evidence is compelling that Ihe dru8 did, in all likelihood, pla~a role in Ihe opidemic. Rivier (81) ,u"e~od all cases of primary pulmonary hypertension in the 6.. Swiss university medical centre< between 1958 and 1965,and belween 1966 and 1969; there was an increase from 15 cases in the firstperiod 10148 ca... in Ihe =ond. According10Rivier, not all of this increase could be ascribed to the drug. Blankarl (90) domonmated a correlalion belw<:cn lhe lime whon lhe drug appeared on the markel in the thrtt countries and Ihe rise in incidence;ho,,~ver,the incidencebegan to faU whiledrug sal.. still continuedto risr, which argu.. againsl a simple

cause-and~ffect ",Ialion.hip.

Individual su=ptibiHty to aminore. cenainly ...,m. to play a role in pathogenesis. Gahlhis and co-workers (38) also calculaled, from their