\rrIG 34075PRc.2

PRIMARYPULMONARY

HYPERTENSION

Report on a WHO meeling~1~17 0ct0bc't 197)

SHUICHI " " TANO

. od

TOMA STIlASSE R

WORLD HEALTH ORGANIZATIONGf.NE"'''

19' 5

ISBN 92. 1_.

c World ","l' h Otpni",h"" I97S

Pobl"",' ioo, of ,0< World He. l,h Otpo;..';"" enjoy o:opy,.;,h, pro'«tioo in ooxord_.n« wi'h ,0< pro.i'..... of Pro'oool 2 or ,0< Uni.....1 Copyri"'1 COO..n' .... , For'i,h" of ftl'I'Od""'ion or 'ran,la,ion of WHO puhlOca''''''' in pon or In 'oIQ, . pplicahoo,hoold b< mad< '" to< Pi "",,,,, of !'ublica';.,., ..... T"",sIa'i"", World Heal' h Otpni_za'ion. 0011<'I', S"; ,,,,rlan<l. The World H.. I,h Orpni..,;.,. ...,k:ome, .U<h . w1i·ca';"""

The ....i,..' ..... omploo'«\ ond ,0< pce""'"';"'"f ,0< ma' ..iol in ,h'. Publica';""do no< im~ly ,he ..pce";"" of.~ op;o.... wha'"""", "" ,he pan or ,I>< _,.. ,of ,I>< World H..IIII Orp"jza,;on con<:emin, ,I>< I.pl ....". of ""Y «><lntl)', ' orritor)',city Of ...... Of of d • • nthoritit<, 0< conc<TIlinl tl>< d<[;mi","" of i" fron' ..... or \>nund--Tb< n..nlion of . pe<ilic <nmpanio. 0' or «'lain manor"",o..,,· prod""', do<> notimply that the)' ........orood 0< reoommen<l<d hy the Wo<ld H..I'h Otpnizaho n inpt<f<ren« '" ",1><" of .. , imila, ""'ure that _ no< m<n,ior>o:d, Em>n ...., """.......",«pled, ,I>< """". or P"'9'ie'.", product.... di..in...,isl>ed by ini,"1 capio.llet'en.

\

CON TEN TS

-Introd uction . . . . 7

Classification and nomendalu,e 9

Control of Ihe pulmonary circulation 1I

Morphology "rprimary pulmonary hYl"' rlen$; on 14

Eti" logy a nd palho~n..i$ of primary pulmonary hY l"'rttnsion 18

Pharmaoology of the pulmonary circulation 22

CI;nical features of primary pulmonary hypertension 25

Epidemiology 28

Recommendations 32

Ref. ",,,ces . . JJ

Anne' I. Classification of chronic cor pulmonale accord ing Incausa tive diseases 38

Anne' 2. Diagnosis of pulmonary hYJI"rtension by dirttl me. ,ure_menl 40

Annex 3. List of part icipants . . 44

INTRODUCTION

Pulmona ry hy~rt.nsion eau.... pulmonary h.art di..a.., a commondisorder I.ading to ..v.re, oFt.n intractabl., incapacily. The first WHOm«ling "n pulmonary circulation wa, Ihat of an u~rt commiu« onchron ic COr pulmonal. hdd in 1960; ilS report (I) da..ified chr"nic co rpulmonal. inlo di..a.... primarily affOCling air pa""ge. of lhe lung andIh. alv.oli, di..a primarily aff..,ting Ih. m"".m.nt. of th. Ihoraciccage. and di..a primarily affecting the pulmnnary va..ulat ure. Mnilca.... in lh. last-"",mi,,1led group are iOCOndary to a known cau..; how.v.r.in """,nt y.ars, a large number of pali. nt. wilh pulmonary hypert.nsionbUI withnut any u nd.r1~ing di",. .. other Ihan v ul. r change, relaled 10pulmonary hypert.nsion have been observed in eral countri...

In 1967, a .udd.n increa.. in the num ber ofpati.nt n Wilh pulmon.ryh~pert.nsion in "'''''' cardiology d.partments in Swit rland ga"" ri.. 10inl.n.. int.~t in this di...... A similar inerea.. was suhsequ.ntl~ reportedin the F. d. ral R. publie of Germa ny and in Austria. An as.wcialion belWffnpulmonary hypert.nsion and Ih. inla ke "f a ppelit.-redn<:ing dr ugs wassoon observc<l, and wh.n the drug, ....r. withdrawn from th. mar k.tthe number of new ca.... d.dined, Th. lungs of "'''''' patients who too kth... drugs and died from pulmonary hypert.n,ion show.d a morpho­logical pictur. id.ntical with that ...n in M primary pulmonary hy~r.

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

Primary pulmonary hy~rt.n,ion is a rare di..a..; th. total number ofca.. reports I<> dal. is of the "rder of hundreds. Ex«pt in th. ca.... with abistory 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 performbeeau.. 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••lage is reached, and becau..lhe di.gn"sis of pulmonary hy~rtension need, 1" be confirmed by cardiaccath.terization ,

In vi.w of the 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.wth. hitherto ..an.red ..i.ntific information and I" di..u"" the .tiology

- ,-

s PRI MARY PUlMON AIl,Y HYPUTEl<S10S

and palh"gen~i~. pathophy>iology, morphology, clinical pallerns, dinicalphysiology. and ep;demiology of primary pulmonary hyperten,ion ;pulmonary hyperten.ion ...,ondary to chronic pulmonary di",a", and (0hean disca", was ou(oid. the $<XII'" of the meeting, Additional aim. ofthe mttling .... ~ to d.fi .... problems l'C<luiring further investigation andto consider a mulli""nt'" collaborativc study of the epidemiological, dini·cal, functional, and morphological characteristics of primary pulmonaryhypertension, with the purpose of a...mbling and coordinating ntherwi..,ir.olated Of llClIltered information, testing new hypothcse!I, and eventuallyelucidating the cau<c, of primary pulmonary hy""rten,ion.

The meeting was held in Qen""" on lS-17 Octoht:r 1973. Th. pr=nlpublication contain, an account of the m«ting, ba..d on the workingpape" submitted by the panicipants ' and on their discussions, The sectionon the control of Ihe pulmonary drculation is largely ba>ed on a paper byA, p, Fi'hman, The morphological concept, "'e.. d=ribcd by D. Healhand C, A . Wagenvoon . S, G. Blounl, J r, provided Ihe background for Ihesection on etiology and palhogenesis, while that on Ihe pharmacology ofthe pulmonary d rculation cl"",ly fono",s the contribution of C. N. Gillis,O. Kra upp, and J, A. WilLThe d=ripti"n oflheclinical featore,ofprimarypolmo""ry hypenensi"n is derived from contribulion, by H. P. Gunner,P, Harr is, F. Loogen, N. M, Mukharlamov, and P. Wirz, and the sectionon epidemiology extensively quotes F. H. Epstein's paper. The annex onlhe diagnosi, of pulmonary hypertension was cont ribuled by H. o.:nolin.Finally, Ihe group's re<:<>mmendalions on ..... rch to be carried oul wilhinternational cooperat;on are cited ; some of the.. re<:<>mmendalion' arcalready being implemented.

• " "",,. ) conlain, a """'P~" li" of tile porlicipon'..

CLASSIFICATION AND NOMENCLATURE

The eau," of some ca,"s of pulmonary hyperten,ion i, unknown.Identifkation or the morphological type is difficult 'ometimes, .,..en afterautol"Y. Clin;ciaos and morphologists a re inclined to take different ap­proaches to the same condition. Some morphologicaltypos may be due todifferent eau,",. The re, ulting terminological problems an: difficult to

. olye without both etiologkal and morpholagical classification.

t:lIoIOflkal d aw lkatloo

The dinician identifies abn<>rmally high pulmanary arterial pressureby a combination of b«hide and catheterization t<:<:hniqu". He ma~ be ableta 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'mor pulmonary ~no-occlu,;ye di",a", if identified, Pulmonary hypertensiondue ta heart di",a"" ,uch a, kFt.to- right ,hunt and mitral 'tena,i,. whicha re e,c1uded by definition f,om cau"" af oor pulmonale (An...., I), isalso important in this category. In other Ca"" the Clinician will not bea ble to identify the etiology (pulmona,y hrp<!rtr~s;on of WlknO"'~ cause.traditianally known as M primary pulmona,y hyperten,ion "). Ca... areassigned to this cat<:gory only whcn all pos.ible known can'" have b«ne' d uded. Jn some ca,"s the etiological a~nt may be: ,u,pected ( pulmonaryhy(Wrlt'n,;o~ of doubtful ca"...).

Morphalol:ic. r cl."ilk.tlon

Various morphological change, are obsc..ed in the lung. dependingupon the cause (see page 14). Wbe:a the Cause is unknown. the followinghistopathological pattern. may be: identified:

(D) pulmonary yascular di",a", characterized by ooncenlric intimalfibro,i .. necrotizing ar toriti•. and pl",iform lesions;

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

(c) pulmonary thromboemboli'm ,

- ,-

ro PRI"l H V PULMONARy HVPERttMlON

While the!IC three categories ",e", accepted by all pa rticipan ts, the'"was disagretment on how to classify muscular hypertrophy of pulmonaryarteries and .n.riol.... when this is the ro le finding. Some participa nt.thought that such lesions would have developed pl.siform changes j f lbepa tient had lived longe r or if Ihe disease had betn more aggressi ye andthat these ca... ca n therdo'" bt' co n,idered a, an .arly 'lage of ca~gory (0);Olberi reIt that such an ."umpt;o" i. nol ju stified and Ihat i",late<! muscula rhypcnropby shoul d be left unclassi fIed. It wa. a lso pointed oUllha' mi..dlesions induding Iwo or threoe of Ih. aoove ",,{egonn ca" w metim... beo~rvW and that such cases cannol be classified in any of Ih. three grou ps.

Nome""blure

T he pro blem of nomenclature was di",usscd al length. Difficultiesarise !>e<;au,", Ih. term M primary pulmona ry hyper ten,ion M is u.ed inone of two quit pa rate wa~. In so me instances it is used clinically,to indicate the pr n~ of .Ievated pulmonary art.rial pressure in theabsen~ of a discernible eau.., thus co,ering the con~pt of pulmonaryhypert.nsion of unknown cause. On Ihe other hand, the term h.s .lsobeen . ..d to denote the morphalogiC<l1 pulmonary ,"scular paUem cha rae­teriO'ed by C<I~mric ;mim.1 fibro' is, necrotizing art.ritis, plexiformlesions, and ... soci.ted changes in Ihe .bsence of tung or he.rt di......PI..iform lesions may be fou nd also in e...s of pnlmonary hypertensionof known eau.., but the pathologic.1 diagnosis of M primary pulmonaryhypert.nsion M has been TCSerwd for ca ..s wh.re th. pathologi,t cannotdi"",rn the eau.. of these change,. Som. pathologists also call it M classicalp"mary pulmonary hypertension M or M va,oconmieti,e pulmonaryhypertension M (2).

Sin~ hnwrtemi"" ca nnot be m.asured po'tmortem, the partici pant,thought it d.,irable to find a n.w morphological t. rm for th. conditionwith plexiform lesions, necrotizing a rteritis, and concentric intimal fibrosiswithout a discernible cause . The term plexogmic pulm<>no'y (lI'te,iopalJryis ,uggested for this condition.

I! i' not thought practk abl. to abolish the t.rm M primary pulmonaryhypencnsion M for it has been widely u.ed a nd probably will still be u.ed .Howe...r. IhroughaU/ the pTesem Tepon (he te'm M p,ima'y pulmona'yhy~"msi"" M is usNi only la mean M pulmona,y hnunension 0/ unkno" 'ncause M. T hi' may includ. any of the morphologically disti nct condi tions.Wh........, lhe morphological . ntiti... are dealt with, the proposed mor·phological term, are u.ed .

CONTROL OF THE PULMOJ'lfA RYCIRCULATION

1.0,,-......"-"" circul.t....y . y.tem

Th. pulmonary eir<:u lalion 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.llyimpo..d ca rdior~pi r.tory . ,.nIS (3) (0« lhe accompanying figure). (4)Daring . ' .r<:i... a. blood fl ow and 'olum. ;ncrea... pulmonary arte rialp.....'ur. also incre.... (5); lhi, .lfecl i, • .agger' led al .hiIUd•. Non. th. l. ss,if the pulmonary >a"'nlar I"'" remain, an' lomically normal , bolh al ..alevel or above it. lh. " .. in pr.ssure i. g. n.rally ,m.lI a nd bursl, of in­creased blood flow induced by >igorou, phy, ical ....ei.. are to l.ra l.dwilhout di",omfort or undue slrain on 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 nor mal pulmonary cireulation in indi>iduais wilha norma l ""malocril >ala•. As Ihi. >aluc inerea.... ....i'lance 10 pulmonary

,'00

,11

'~ 1 S(1 \ n 0,\, I

e ,5 100

," •

" "00 ',-------0 0

0 0. ' 0.3 0. 'R( mm Hg/ ml/ min ) rnro ,.0,."_'=..._ ·__I· l .. I .....__ 10l· ' · .._.__......_T... '.......__ ,..

. ....' __" ..__0 · 1. _ "" ,.1

- 11 -

tz

blood flow alro inerea.... (6). The.. ;""rement> are slight and lend 10 bemost marked in the uppermost part s of the lung, where there is leastblood fl"w (1). On Ihe other hand , when non_uniform pulmonary vasculardi",.... ha. advaneW to the sta~ of pulmonary hyperkn,;on, increasedvisco, ity coupled with hypoxia may make an imponanl contribution 10Ihe pulmonary hyperten,ion ,

The bror><:hial circulation i. of liUI. haemodynamic «m.."u""", inthe normal pulmonary circulation . It may. how.""" as,ume importancewhen the pulmonary blood flow is ..,.rely curtailed , or in the pr..."""of bronchiecta'is (4).

Acti"" chang~ in pulmonary va..:ular ~i,t.an~ are known 10 "",,,ur.The change> may be chemical , nervous , or humoral

The mo't importaM agent inducing pulmonary vasoconstriction isal'«Ilar hypo..ia_ Th. low oxygen pressure of al'eolar air ap pears toaffe'" the , mooth mu,de ~II, of the mu",ula r pulmonary aneries, evenwithout a ny nervous mediation. Whether the mechanism con~rned

in,ol, es the local release of va","cti,e substances le.g., histamine frommast ",,11» is not known. Acido,i , enhanC\'<; the vasopressor eff..: t of al¥wla rhypoxia, whe,eas alkalo' is dimini'hes it,

The large pulmonary aneries a nd veins a re richly supplied with ne"es,but there a re few or 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 walls of the large pulmonary arteries ratherthan in= ase resi'tance l<] blood ftow at the level of the mu",ul ar pulmonaryarte ries; the result is a ,liSht rise in sy, tolic pressure, while dia. tolic pres' ureis not elevated in the normal lung. This eff..:t of nerve stimulation or SC<"I ionha' been demonstrated in animal' but not in man ,

The peripheral art.,-ial chemorectptors (carotid bodies) are connectedby refte' pathway. 10 the pulmonary ci«ulation. Thus, part of the pul­mona ry vasoconstriction induced by hypo.ia is mediated by the peripheralchemoreceptors in some animals. Thi, ,asop""sor etrect is, however, notlarge and ha' not been demonstrated in man. The etrecl. of a number ofnatur ally occurring va","cti"" ,ubstan~s on the pulmonary circulationh..e been ' tudied in man but no important humoral mechanism of controlha, b«n demon, trat.d. Acetylcholine acts a, a vasodilator ; S-hyd"'''y ­trypt amine increases pulmonary va",ular resistan~ in animals bul notsubsta ntially in man ; brad ykinin has a ,"riable effect; angioten, in hasno ~rt.in etrect. A number of such agents are changed or destroyed du ringtheir pa, sage through the lung (see page 24),

~ u'O"T O~ A WHO ,,"ETING

The fOfal cireulaTioo

The ab<"e consideration' apply exclu,i"ely To the beha. iour of Theadnlt pulmonary circulation. In geDeral, Ihe same ,..,gulatory mechani.m'operate in the fetu., differing primarily in the vigour of re'ponse. Fore.ample, the pulmonary circulation of the neona te ,..,spond, briskly 10vasomotor and pharmacological .tim uli; Tbe respon;eTo bypo<i. dimini'h..wiTh age (as the muscular wall, grow thin) and both local (chemical) andperipheral (nef'lous) influences a,.., ;n"ol.ed in the pressor response toacute hypo.i. (9).

Pulmonary d rcull Tioo at bigh alTitlld..

Clinically healThy ""ident . of locations aT bigh altiTudt. who ha"e, pent a lifetime under hypo.ic conditions may often ba"e longer and moremuscular resistance ....sel, in The pulmonary circulaTion than do sea-leveldwellers (10, 11). ConsequenTly, Ihe baseliDe ,..,.i"anee To blood flowTbrou gh The lung, of the altiTude dweller is highe. than that of the sea-leveldweller; during e.erci... the incremenT in pulmonary artery pres.u re isgreaTer (12). The hypert rophied muscle of the pulmonary vascular t=can ....pond more "igorously in the high_altiTude dweller Tban can thethinner pulmonary "ascular . month muscle of the sea-level dweller.

Simply by being bor n al altitude, tbe indi. idual may be started onthe road 10 pulmonary hypertension . How far down The road he willcontinue probably depend, on the interplay of intrinsic and ambienTinflDences.

II

MORPHOLOGY OF PRIMARY PULMO NARYHYPERTENSION

Multipl . patbot:......i> of pulmooory hyport....IOII

The'" a", ma oy cau,", of pulmonary arterial hyperten.ion and th...,a", u$>ocialed with diffe",nt form' of hyporten,i.. puimonary vasculardi",a",. '" that the .truetural change> in the pulmonary vascul.tu'" cannotbo predic led from. known ie..1 of pulmon.ry . nerial blood proMU'" (13).The type of hYPl'rtcnsi.. pulmonary va",ular di",a", induced depend,on the meehani.m of prod <lClion of the unde rlying pulmonary hypert en,ion.Thu. the type of h~pertcn';.. pulmonary vascul.r di",.", a"""ialed with,tate, of chronic hypoxia 'Peh ., ch ronic bronchiti••nd emphy",m.or living at high alt itude (11) i, diffe",nt from that occurring in .ssociationwith large congenital cardiac .hunu (14). Both the morphology and Ihephy. iology, e.g., the re.." ibility of both the pulmonary h~perten.ion

and the pulmonary vascular di",a",. a", diffe",nt in th..., two form. (l S-(7).Primary pulmonary hype"en.ion i. a l", 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 d i",a .. of the hean or lungsor of cirrho.i. of the liver, lh"'" di'tinct pathological ent iti.. may p....mthe dinical picture 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,topalho­logieal fe.tu .... are •• follow, :

(I ) I""rea..d medial thick"... of ~ muscula r pulmonary a"eri.. ".Such arteri .. a", botween 100 and 1000 pm in ..ternal diameter and normallyh.ve. thin media ofcireui.rly .rranged 'month muscle ,"ndwiched botween

- 14 -

UPuI<T ON" ....HO '''lYING "in~ and , ,,",,,,I dulic Iaminx. n.. medial Ihick_ ol lM normal- IIlllSCll'" pul ry a11ft)' 8 .... bttn Jioen a. l-Sy' 01 IM diamekfollM amry, "d '" ollM ad_ilia (1C)...21).

(2) n.. a ppnnace ol llnall "'........Iar vaadl lcM lhan SO .-no in dhoJnflerwilh a d;OUIlI:\ lIlf<iia 01 cimllar mllOdo bounded by in~ and.,,~

dulic ..mi.... Sudo ...-h do lIIOC nioI ia IM DOI'mal lune. ..Iwft IMpuln'OOftU)" ...mob ha'" a ..an eonoiItin, 0Aly ola lill,x daIlic: Ja"U...~ al IIwtr immtdia" onJiIl from .-mll m....:ular puln'OOftU)" anma..

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

(4) n.. dc.dop"..,,. ol k<ali.... - di lalatioa Iniono - wch .. pexiformor a llPomatoid. Iniono i" IM Iidc brandln of IIIn;l1lar pullllOlWY at'Ifrinpro~imal 10 si," 01 o,:<:lIlIioa by imimal fibro-da01oW1. Such dilatalionIfIionI comi01 ol dilalfd bnu,ch,'1 wilh lhill ...11. a>m pooed 01 a sin,1tdaolic lamina a nd lintd by • ctllul• • endolhd;.l proIifnalion 'Ihowin,a plc:~i(orm . rra n,.......nl (25).

(5) """ P""'~ in ....... iMtallCn of _ ilin, . " ... ili. i" IM .... Ihol mUlCul• • pulmon. ry . n ,,",,_This m.y M _ " j " . " acule (onn wilhlibrinoid noc.osi. ollM mtdi• •which i. inlillraltd by lIWlrophil polymorph•.I1 m.y M .eta in • •uhac ule form "'i'h , ranu!om.lou' ch.n.... in IM. rte ri. 1 ",.11• • nd « du.ion ol lM lumen by .n o. p ni"" 0. OfpnizingIhrombu•.

The hi'lopalhologica1 f, al Ur« of plexoll"nic: pulmonary arte. iopa lhyare ch. racler i. l ic: buI nol pa lhognomonic of One di",.",. ldenlical micro­>copic: ~hani<" in Ihe lungs occu., lleConda.ily. in la. ,.. pre-tricuspidconFnil.1 ~.rdiac . hun" .uch a. alria l ",pial defen. la'F posl·lnc u. pidco ngenil.1 cardiac . hunt> . uch as ~enlricula. "'plal <!efen, . nd lhe rare"lIeS 01 cirrl>os.il of IM Ii",. Ihal are co mplic.1f<l by pulmonary .rterialhypertension (26, 27).

A dia"""" of ~ primal')' ~ pl.....,.,nic a "erio.-Ihy may M co nlidcred...... 10..... or all oi l'" hislopalh<>l<>Pcal (ealu,," 1ilted under OHS).bove. n: pRIC"" i. I'" . boena 01conF nitaJ ca rdiac shun" orcitrbolis ofl... I;""'-.

l lemI m_w onio»-skin - inti mal libroelaslosis. (<4Hilala !ion 1nionl,and(S)-_izin, arteritis an: ...gest~ of I'" diaJf'O&il. 1....... (1)and. (2) are 'ti"...JIy of DO walucaIotw: lina (l) _ 11i" __ (onns and (2)in tI1f fonns 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.nleuit if; .......... 10 be aa early Ita", of~ puln'OOftU)" arteriopalhy.

For I"" """"'" _ bads of . rterial IDOIl"!><>tlkU-Y are of DO ......e ill lIw;dia........ of plc:~ puln'OOftU)" &i u ,i0p8lhy. n..~of a Ilahllicany siJllilic:am incmooe in med;.l Ihid_ merely indK:alellha' _ form of hypen""'''' 1"'11"0"'1')' ...cvIa. diwalle if; ptnftIl.

" P R' MU V PULMONARY HYPERTENSION

,.,,

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

pk.iform l..ion., and """ roti,ing art.r;li, is p~",nt. ~ Secondary · ple.a­genic pulmonary aneriopathy i' diagnosed when lesions appear in ."od_alio n wilh congenital or ••perimen'al cardiac ,hunts (28, 29) or cirrho<i.of the Jiver (26, 27)

Pulmonary wno-<>cdu';ve di.mu"

Thi, rare di...", ha' been ,e<ognittd recently. It may be easily mis­diagnosed clinically as primary pulmonary hypenension (19) but may be,ecognized from the radiological app"arances of pulmonary plethora (18, 3Ol.It o<x:un in young i ndi~iduab of both se.es : th~ a~rag~ age of 24 patientowas 19 ~a~ (C. A. Wagen~oon, unpublished obsc....ations, 1973).

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

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

fibrosis I~adi ng to widespread occlusion of th~ pulmonary ,~ins and ~nules.

In almost all case< th rombi, rettnt or in the prOttU of organization, appearto underly th~ intimal fibrosis in Ih~ pulmonary v~ins, and th~ appearan=ar~ suggest;~ of organization of thrombus ;n th~ pu lmonary v~ins. Suchthrombi may abo occur in th~ pulmonary arteries and art~rioles. Arterialah~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 oftenpr~..,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 areregular findings. Thi. morphological pielurc ,ugg~S1S that inflammationand not congestio n und~r1ies th~ fibrosis (94).

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

Tbis di..,a.., may ap pear as primary pulmonary bypemnsion, botbclinically and from th~ results of radiology, electrocardiography, a ndcardiac cath~terization, Pathologically it is a distinel condition (2) butits bistological features hue "''''''times been confused with th~ ~arly,

and rom~time, th~ terminal, 'lag~s of pl~.ogenic pulmonary arteTiopathy.As in pi~.ogenic pulmonary an~riopa\hy, th~re is medial hypertrophyof muscular pulmonary arteries and musculariza tion of pulmonary arteriol~"

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

• • I'OIlT ON ... W IIO ... FJ1NG

or lhrombMmboli Ihal a~ o l\cn fa:t'nlncally , illl.lled in the ves>el soIhal 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 ioncon';," inilially of fi brobla . lS. Dilalalion Ie<ion, do nol occur in recurTenfpulmonary Ihrom llo-<lmboliml _ uodul poinl of di<tinction in lhe dif_ferenlial di.aJl")loi1..

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

Sections of lhe pulmonary uu nk in Does of pln.otmic pu lmonaryar1eriopalhy i~ odulu show a ..11ft1I of da<tic !i..ue oonoi'\enl wilh lheO<:quiml variety of pul_ ry hypn remioro. Thi, i, not al..ays so ,nchildren. ..hett I"" pu lmonary hYJ'fflnlYoa may be: prnml from binh.

RidtI·..........) ..........,

Tlw eliuo:1la 01pulmonary- bypmnn,jon may be: diool:oYnal al ""'OV'yfrom the findi". 01.. ill<ftlWd ...... of t.bt: rilhl Ynltrick and aa inctea<edlhicb.,.. of t.bt: ptdPMlDlry artery. Mea.u_ u 01 the thil;-k_ 01 t.bt:ri"'l .-mlriaalu...n an IlDrdil bk aad bypertropby of this chamber is bnldetermillot'd by -;P;.... a flcof mr-al of lhe altadwd ral (32). Normally lhe-cipl 01ee ripr Ynl,"",1ar rift ...n don _ ncud 6S J. while !he' ratio01 the -;.hl oflhe Id'! Ymtridt: (iodudi"l the KpIum) 10 lhal oIlhe rilbl.-mlrintlar rift ...n is uoUIIIy ill lhe ....... 2.)..).). III rip l "..,.,triI;uIarbypnlrophy il -ciJlos O'er 10 • aDdill it.olaltd riP I .-mtril;ular bypmrophylhe ralio be Gmu 10eu lhan 2.0. The ratio of lbe thid".,., ,,(rbe pulmonarylnIa k 10 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 PATHOGENESIS OF PRIMA RYPULMONARY HYPERTENSION

:\Ia lliplr r liolOllY

As .talrd on page 9, pulmonary hyperten.ion of unknown origin isreferrrd 10as pr;""" J' pulmonary hypertension . The morphological . ub"'alOof primary pulmonary hyperten.ion varies as d"",ribe:d on page 14.

Any thwry of etiology bas to explain why primary pulmona ry hyper­IOnsion appears to be: congenital in some ca.., and acquirrd in others.In cbildren the inciden"" i. the samr in mal.. and females, while in youngadull. the female i. predominanl . It i. most probable that .."..eral differentba.ic proces..s are invol'fed, leading 10 pulmona ry hypertension and uhi­mately to the de\<Clopmcnt of the morphologjcal changes in the small..pulmonary arleri...

VawconSlrk tion of lhe muscular pulmonary arte ries has been con,iderrd10 be the precipitating e. ent in primary pulmonary hyperlension. Tbeocca.ion al finding of an increased muscle ma" of the media", the onlyabnormal morphological change, and the finding of a significant fall inpulmonary art ery p.... ure and ,-e,;i,tan"" afler injection into the intrapul­monary artery of v",odilating drugs such as tolalOline, aCdylcholine, andisoprenaline in men have given ri.. 10 the vasocontrict;on theory (33). Theyounger lhe pal",nt, the more frequently are non,pecific morphologicalchange, of pulmonary arte";" encountered. The occurren"" of Raynaud'sdi..a.. or Raynaud's phenomenon as a sole concomitant condilion in apalient with primary pulmonary hypertension may lend Further .upport tothis ba.ic COn<epl OS, 36). Both condilion . art of unknown etiology andmay re"eet an unusual . ta te of byperrraetivi ty involving the digilal arteri""as well as the muscular pulmonar y arterie"

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

_ 18 -

"lrodi,,",..." in t~ population. Iuo"", increaKd mu"""r.'i....t ion of the pIlI_moNI}' arterial 11ft and il ......... IU<OfUII* to ....PP<* thol this increao.edbulk 01 mlttde i. maintai""" by 11 chronic increa~ in tOM. The pulmonaryarterial prnwfe, ""-. does "'" co"""""ly reach the Ind roul>d inpolitft.. ..itb nt.bli, hcd primal}' pulmonary hy~_ PfimaJ)' pul­monary hypmenWon tw. bcm repxtod a. hi,h .lliludn. but ;\ does not

....... I ..... i l l 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 ca llSed by a n tocq>l;"""lIy pokftl -nnorWm••h.. Of• • 1, IiYdy. some r_ "d.... th.an pvno ..._ riclioniI optraunl-

V_llinion maJ _11 "" initia ted by or,," t1Ivi......mem.1 rac'lors.dru, io,ntion. 01 d id, « in othtr••,~1 UMUlpccllOd, ... ~ The....,.." C'Pd<'mic 01 pri"",ry pulm onary hyponen",," OOXIIrrin. in S..itler­brod (37). lhe Federal R"'P"bli<: of (knnany 011), a ftd Austria (J9) appcanto "'..e been auociatnl "'ith the ingestion of 1he .~lil.....kprnsinl drugamin orex rum.note (_ ""~ 29). Allk".,h 11 c. u~and.., lfKl relationshiphas not bn-n clearly n tabli shed, the ci,cu m'la ntiar .., ide,," in it, fayouris imprn. i.c. Aminofex is 11 compound rela lt<! 10 .mph~tam;M and hasboth a lpha. I nd btta.ld",norgi(, receptor .timulaling ~ffM" It ha. be<:n. hown 10 ha~ ' 0 "'" ~a'OC<InmiC1or ~ffecl in acul~ e>p<ri"",n l' on l h~

ptJhnona '}' arl~r i... of animals. as obser\'ed Wilh ot h~r . ympathomimeliccompo und. (40. 93. 97). Pa li~n l' dying wilh primary pulmona ry h)'p<rl~n•• ion in I,,,,,,ia li,, n Wilh amino"" in~l ion ha"" be<:n found 10 ha,~ lhe pul.m "",, '}' arl~r ia l dilata lion Ieoion' CharaCl~ri.tic of O\l\<,r pat ~nl!. withprimary pul"""", ry hypert~MiOft. Ho_~r. rNd in, dop and oome Oll\<,ranimal. ..ilh am;lI<II'el ha. not .....ulkd in a ny a bnonnality in IM lIIOfl'holosYof IMir pulmonary ' a"",laIU"'_ ~he\n.s, il is ntimatN lhal appro l i.malt ly o nly 2 p" I lXXl~ ta king am inottl dnotl oped tilt di~_ (41).iO il ........ likely lhal 00fI"It additional factor m.... b< prne<>t that mak...anain ,...room outeq>liblt_

Il.ndl. "" . r ''' ,j ....Ol"f ID . ...... Of..

Amon' .......... """'* lbert is a comi&rabk ....riot""" in 1Ilt .-..ospoosm(I( 11.. ..... monary ci' culalioa in rnponot to hypo,.. or OIhcT ....KIOICIi'.,.,.,.,It (33. 42) and il is po<Sillk , hal ",""" variot""" in rncti";f)' conl ribut ..10 I"" In.. i..c.du~ (I( tM diocasc in 11\<, pr ~ .."" (I( a posorhW (:II.usati""

"""1"'""" as ami ..........

I

PR IMAR Y P UL..O><.UY KY PEIlTE>;SKJN

Pulmonary hyperten$ion may be produ~ in rat. by the admini,tralionof futvine. a pyrrolizjdi~ alkaloid derived from lhe $«d, of Ihe planlCrolalaria !"ha. 11 has been 'hown that after a single do.. of ful'ine ratsmay develop marked right , entr icular hypertrophy and n« rotil ing a rterili,of the mus<u lar pulmonary arterie' and arteriole. (43). Thi' proceduremighl be u..d as an experimental model for pulmonary .rterial hypertension ,In ralS lhere were no distinct differeJlC<'s between the effect. of oral a ndintraperitoneal admini,t ration.

Right ventricular hypertrophy an d medial hypenrophy of pulmon.ryarte ries becomes evident within only one week. Necrotizing arterili' of thelung is pro..nt in almost all rat, .u",i,ing Ireatmenl for 4 weeks or longer.The number of maSl cell. in Ihe lung tissue ri..s ,harply after 3-4 weehThere is some dou bt whether thi, is merely a nonspecific p~enomenon (44),but il••ignificanee is a$ yel undetermined. It ha' been demon<lrated tba tintimal thickening of .mall ' enales. and les' often of larger vein•. oftenlead ing 10 complete obmuction of the ...ascul.r lumen . i. pre..nt in almost .11ral' .u",i,iug the . dministr.tion of t~e drug for 4 weeks or more (%). Theobstruction is mually in a relati""ly short segment, Ihe other part$ of thevessel remaini ng patent. The.. changes. howeve,. differ largely from Iho..in pulmon. ry 'eno-occlu,ive di..... in man. Although the fulvine ..perimenth•• demonstr. ted the possibilily that substan.... t.ken by mouth can cau..fatal pulmona ry hype,te n, ion, it is unlik ely that fulvine itself;s a cause ofpulmonary hypertension in man. The $«ds of C'Qta!a,;a!"/VIJ .nd relatedpla nt$ 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 tbrombMmboliml

Milia ry embolization and /or thrombosis in ' i/" bas .Iso received muchauention a. a pos$ible etiologi",,1 pr"""". Altbough most pathologist.would agr.. with the view e.p......d a bove that Ihere is a clear histologicaldi" il>Ct;on belween pulmonary hyperte n, ion of em bolic origin and primarypulmonary hyperlension, opinion is not unanimous on this point (2).h perimentally, pnlmonary arlery lesion, have been prod uced by theintra""nou, injection of blood clot and other 'ubstan..... The healed le'ionsshow fibroela"ic intimal thickening and medial hypertrophy of lhe smallmuscular p"lmonary arterie. (45-47) but generally the.. are dearly di.­ting"i, hable. An association bet~D ple.ogenic pulmonary arterio path yand cirrhosis of the liver has been doo;"mented. and it has been postulatedthat miliary emboli arising in the porta l ,'enou. sy"em pas. via collater.1channel. to .y.temic vein, and thenne 10 the lungs (26. 27). The fact that

"primal)' pulmonary hypclUno.ion I ppoan 10 de>'<:lop "ot inf~...ntlyfolio"' ;" , childbin" . 1", o"lI"to the pouibilily of • throm boembolicC1iology.

AIt~maliwl~, primary ""h...,....ry hnlen~n";on could bl' the <nullof Ihrom booi< ;" .i,,, . 0 • m ull cl. h) percno, ula l* 0I.1~ KCondory 10.lterN platelet ("not...... dcf_ in fibrinolpi.. or other abnormalitiesof COiIl ulation, TM da""'F th... ca uwd 10 U", endothelium milhl .....,11in an obI ilt'rali~ procno. ROttIItly. the OttIIrn""" cl ab norm al fibrinoly>.il""" bce1I KpOrled in poticnb . ith familial pulmoR.>f)' hyptrtem.ion (48).A numho. or pa tient. ..;t ll primary put_ ry hy~tMion ol>ow ~.ryin l

....t« cl hypc""",,,,Labilily and ....... ha~ dc<:In>cd pla1C'ku ...m-Jlimes (5 . G. Blown., J,. unpubl;./wd ",*~liono, 1913).

TM~ of pri.....1)' put_ry hy~ in youo, ............"be> ha~ been ta kin, onl conlra<epCi.., pills II.u aloo bn'n "<>IN rtanllyIS. G . Blounl, unpub!iohe<! oboenatiou. 1913). Ut.... in the piU maydirect/)' . "'«1 1'" w..v:I ..aJI III ad! •• Ihromhotmbolic mechan i. ms. and ilis ""miok" d Iblllh"""booi. it~hallo«d in -'""' ... ad! U ill .ei ..... Aniftl:11!&Xd 'DCidc...,. of arrlnl infamioa rdowd 10 1"" pill Ion brnldo<"umntN, and COfOftU)' throm bosil ill )"01111' .."..,.." has ako been,c"",lCd. 11........ """"bk lha' U.rombooio~ oo:aI. in IM ......Um""",larpu1moIWY ann>.. and arterioln ~ IM ~1opiIIc"t of ptimuy pul-IfIo(JIW')' h)-pnI<ftl.ion. HOM"o'Cf of Ihno posoibilil ion is ......., lhanCOfIjeaunl al~t_

-'_ ia,... .... n_ "'••••~ _ lti......

~ dixa>es with mult iple .y.um in~'"C'fnm1, rreq..... t1y rd"nm110 "COfInecli~ ~ dilordcn. _ _ imn ao;:oompollioed by pulmonaf}'

ancriaI hypnl<1lOioa and po' '''*'i_a t dwl,.. ill IM pul monary Ilrt<'rialIy.um. laduOrd in this eolC'JOf}' _ pt'OIfCIOi~ ')"UlIIic Idm>oiI (49. SO).cli..eminated luP"" nyt.......-... ('H. loOd anhri li. ('2). polyar-teril is Dodou I' ). '41.a nd Rayaaud". di (3'• .\6).

I" lhone eondi~ a" a"lOimm". rnponoe ....y k openoUDI aad il is<:on<:ei""bW that Md! •~ ..ould i,,~.., IM pul rnoaaf}' ann>.. Of

~n a«<CI lhem pri rily. ,.". POOI~ kosioM in IM pu lrroonarya nn>.. """'Id ........ ho ~r. lo k dillill<li~_

PHARMACOLOGY OF THE PULMONARYCIRCULAn ON

Th. 'tudy of pharmacological inftuen"'" on the pulmonary circulationis importanl in two asp«t~-id.ntifying . ub'la nct's that ca.n be used 10reli."" pulmonary hyperten,ion. and screening drugs to pr.v.nl Ih. mar­keting of substan"", that may cause pulmon.ry hypert. nSlon by th.mselvesor by int.raction with other innuenct's on pulmona ry circul.tion.

Experi...... laI eolMl iti..... alMl pharmaeolox;cal df"" t. on pulmonary . irculation

Pharmacologica l inn...n"", on th. pulmonary circulation are r.l.tedto cha nges affecting pulmon.ry art.ry resi'tance and p......ure. Th. changesin the re,i 'tance of the pulmonary v....l~ aff""l the actio n of the heart .Th. opposile i, also Irue. Both compo".m, im...ct 10 d.lermin. pres,urepan.r", in th. pulmona ry .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 aparticular time (see page 11 ). Pha rmacological agenlS may act both directlyand indirectly (i.•. , through th. gen.r.1 circul.tion), h.ne< gre.t difficultyis oft.n ..peri.need in th.....Iuation of the pharm.cologic.1 eff""t onthe pulmon.ry circulalion (SS. S6)

Se""..1 factors mu" be con,id.red , Sp«i.. diff.rences may be impor­tam; for inst.nce••om. a utho," .upport th. concept of "....ou, r.gul.tionof the pulmonary circul.tion (72, 73). Thi~ m""hani~m i' unconfirmed inman and o nly circumslantially docum. mN in a f.w anima l ,p«i... Th.morphology of th. pulmon.ry vaSCIIlature diff. rs wid.ly in varioussp«i., (S7---{, I). Experiment. in intact nnimal' or in man may producediffer.nt r..ult' if an anae'thetic other than local is used. The only way10 measure Ih. pulmonary component and ..parat. it from the cardiaccomponent would be to me.,ure the change resulting from infusion dur inga single circulation through the lungs. By the time a ~teady ~tate ' ituationis achiev.d the cardiac and pulmonary compon.nt. ha"" become v. rydifficult 10 sep... t. , Inv. stigation in . i", on animals with an intact cir­culation, with .i ther open ch..t or closed che't , may gi..e a differ.nt picturefrom .,perim.nt, car ried out on isolated and o n perfused lunl\$. Uoyd 'swork has shown that th. immediate .nvironm.nt of th. v....I. may al,o

- 22-

RH'ORY ON A W HO MEETING

be important in determining their response to a pharmacologieal or humorala~nl (62), H. demonmat.d that when pulmonary vesseb are pla~ in an.nvironm.nt 'imilar to those of ,yst.mic v.""ls th.y ...spond like systemicv.""ls, and vice versa.

Th. finding of pulmonary hypertension in many patients in Switzerland,Ihe Federal Republic of G. rmany. and Austria la king Ih. dru g am i nore~

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

Kraupp and hi, co-worken (40, 92, 9) , 97) have studied the effectsof Iwoalpha·.~m l"'thom imnic ,ubsta""". (norepi...phrin. and m.tho..mine)and a beta-,ympathomim.tic drug (i,oprenaline) as typical ofeach category.Owing to a different temporal course Ihe effect of alpha..~mpathomimetic,uMtaJl<:e1; wa, not Ihe same and this finding was interpreted as being due10 a beta's~ml"'thomimetic component of no... pin.phri .... It wa, concludedthat the alpha·51imulating activities of these drug, do not lead to anysubstantial change in pulmonary pressure a nd ""i"ance, in ,pite of mar kedva"'onstriction in Ih. periph.ral circulation. On th. oth. r hand . th. beta­slimulating drug isoprenaline induced a highly significant increase inpulmonary pm..re, pressure gradient , and pulmonary flow, with a con­comitant decrease in l.ft atr ial 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 allca... an appreciabl. ine..ase in right ventricular work was found. This. ffect ma~ be important in th...ported cardiac faHureand right v.ntriculardilatation in ca... of i,oprenaline a.rosol overdose (6) , 64). Other "",r1.ri,however, have demon.lrated opposite effect. of beta· .ympathomimeticagents. The diff.r.n.... in findings may ..fleet diff.rences in animal mod.1pr.p....ion and anaesth••ia. Th. longer the alkyl residue of 'imilar ,,,b­stan""" , the mo.. the alpha."imulaling activity dccrea"'d and Ihe beta­. ympothomim. lic compon.nte' predominared (98). Amino..~ ,how, borhalpha and beta activity. which may account for the increase in pulmonaryva",ular ..,i"a""" d.monmatod in acute .,perim.nts, similar to those withN-ethylamphetamine.

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

. '

11>< 10"11 ... ....' .bolit oq: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 activityi, .hown by Ih. following <.ampl." prosta glandin. E, and E, are completelyinaClivated 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 i ncrca~ capacity of the lung 10remove 5-hydroxytryptam;ne and norepinephrine following cardiopul.monary bypass operation, in patients with normal pulmonary arterialprn'ures(66-68); Ih~ wilh pulmonary hypertension had a decrea>O<l,,"-pac;ty for biogenic amine removal afie, , he bypass operation ,The presenceof norepinephrine and 5.hydroxytryptamine could be demon'trated intile capillary end6lnelium and {)f S-hydrO:>lytrypl!lmint in Il>e alveolarepitnelium of rahbit. on perfu,ion al 3S0 C but not at 6· C. Acetylcnolinemay be demoyed in tile plasma, and otner substance. such a. S_hydroxy.tryptamine may be abso rbed b~ platelu•. Transit time through the lungin relati"n t" upta ke mu,t be <XImidered . The role "f vawactive hormonemetab<>1i'm by the lung in primary pulmonary h~pcnension merits study ;changed pallerns of pulmonary circulation may be a..""iated with dif_ferences in the upta ke of normally eirculaling , a""active h"rm"...,_

CLIN ICAL FEATURES OF PRIMARYPULMO NARY HYPERTENSION

Early su g.

Th. recognilion of Ih. earl~ <lage' of Ihe disease i' a difficult diagno'ticproblem, Patient• • re almo'l neVeT setn by lhe physici.n bt:fore Ih. onselof symplOms. No physical. radiographic. or .lectrocardiographic , igns of.arly slages of primary pulmonary h~pertension a re l nown. Direcl m.a,ure­m.nt of pulmon.ry artery p....u.. by calhet.rilalion is al p.....nllh. only..Iiabl. diagnoslic procedure , In Ih. inilial slagn of pulmonary hypert.nsionhigh blood pressure may apl"'ar only on elfort , Non·invasive techniques areal presenl not adequat.ly d....lop«! for use in del<lmining pulmonaryhypertension ,

[ stabli>bod stage

Th. mosl prominent s~mplom of establish.d se"re pulmonary hyper­tension is lach~pnoea , oft.n associal.d wilh a sen", of brealhl...n...and occurring particularly on ..erei"" R_ nl obsc..ations on lhe juxta­capillary rec.plors (J-receplors) of Ih. lung, (69) and on lhe .ffects of vagalblock on Ihe tachypnoea of pulmonary vascular obstruction (70) suggestIhat reA.x ,timuli may be invoh'ed in Ih. pathog.....,is of lhe respiralOrystimulation. Somelim.s there i' relro'terna l pain On exerci.. . Occasionallyanacls 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'ualRighl ventricular hYl"'rtrophy m.y eau... sy>tolic pulsation 10 lhe left ofthe ,t<lnum. The pulmonary compon.nt of th. second sound i' incr....d.nd lhere m.y be an . udible fourth sound, An imm.diate di.Slolie murmurof pulmonary incompel.oce sometime' occurs. The physical sign, specific10 primary cardiac or respir'lory causes of pulmonary hyperten,ion .r•• bsent.

The impainnent of the con tractility of the right ventricle in Chroniccor pulmonale and in parlicular in primary pulmonary hypert.n,ion basbeen d.monslrated. bal il is sliII 10 be determined how e.rly or how lalelhese ebangn may apl"'ar .nd what their diagnoslic importaT>C(: is.

_ 25_

PRIMARY PULMONARY IlYPERTESSJON

The chesl radiograph may be normal. In the eslabli.hed case it often.hows enlargement of Ihe pulmonary lrun k, while lhe small peripheralbranches appear normal or even reduced in ,ize. In the l'ler ,tages th.cardiac shadow becomes enlarged. Pulmonary veno-Qcdu,i.edisease may bedistingui,hed by Ih. p.....nce of e.idence of a raised pulmonary v.nouspm,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 venlricularhypertrophy in excess of left, wilh low spedfidty. Some changes in IheIracing may be allri t>Uled 10 the change in the po<ilion of lhe heart in IheIhorax or 10 Ih. ah.ratiQn of lhe lran,mi..ion media. Many .tudies haveanalysed Ihe relalionships between Ihe right pulmQnary andlor ,'entricularpressom and Ihe panern oflhe ECG, in order 10 identify the mO$l,pecific<ign, of right venlricular hypertrophy. and conlra,ling r••oll. have beenohtained. The relaliQ n belween the .Ieclrocardiographic appearance andIhe level of Ihe pulmonary artery p"",ure i. nol dose, the rapidity of Ibe. 1e. aliQn Qf lhe pulmon.ry ""'ular mi.tance and lhe .Iale of the my<>­car<!ium being mitigating faCIQrs.

Lung ",anning and pulmonary arteriQgraphy ,hould ,how no .vid.nce of.bUI cannot completdy e""lude, embolization. Re,piralory function lemwill .how whelh.. Qr nol there i, a mpiratQry eau.. for lhe pulmonaryhypertension .

While lh... dinical features and in,.sligation, may ,uggtSl lh. presenceof primary pulmonary hyperten<ion. Ihe d.finiti"e diago",i. mU on theresolls of cardiac calh.terization (Annex 2), Thi. pr<>cedore reveal, asob'tantial increase in Ihe polmonary art.rial pr.ssure. which may bee.ac.rbated doring exercise. Tbe polmonary "edge pr.ssure is normal inIhe primary arterial form. In pulmonary . en<>-ocdo,ive disease the wedgepres.ure may be incr.ased. bUllhis is nor always Ihe case. Righl venlricolarend.dia'tolic pres,ure may be increased a nd the right atrial " a MW".abnormally large. The cardiac OUlpnt i, lower than normal and does norr.spond normally 10 ..ereise. There may be wm. decrease in the ,ysI.micart.rial oxygen lension and oxyg.n saturation. Ihe arterial carbon dioxideten,ion heing normal or low. Cardiac catheteri..lion and angiographymay help to exdude Ih. p.....nce Qf congenilal malformation I.adi ng 10pulmonary hypertension. Pulmonary art.riography may help ro excll.depulmonary 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, .od 1_ 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 MEETING

pro~ the exccption to this rule and. when the initial pulmonary hyper.ten,ion ha. been moderale, a stable stale of pulmonary hypertension ore,en regression has been observed. 1I seem, possible that thi' unusualcourse or e""nlS may be d ue to the withdrawal of lhe stimulating factor.

While a number of vasoacti"" drug. have be<:n round to lower the pul.monary anerial pressure in acute stud;'.. prolonged therapy ha> beenfound qui te ineffeeti 'e. Treatment with cor ticooteroid. and anticoa gulanlsh.. ~l"" pm wrl vnl ,,~"'« nnrl a n ~ff"",i"" ' h" npy i< knnwn

EPIDEMIOLOGY

The ••lur~ or lb~ probl. m of primary pulmonary by!"'rl....,;oD

Epidemiological knowledge of primar y pulmonary hypenemion "limiled (sot pa~ 9). Although th~ publi,hed data on the frequency ofthe condilion are based on the proportion of ca... among palient , wilhcardiopulmonary disease ralher lhan o n the total population. there i,no do ubt that lbi' i, a rar. di..a... II Ifad' 10 cor pulmonal., which i,common . allhough there are al$O no reliabl• •>li m.te, of lhe frequ.ncyof the lall.r cond ition in the populalion ; primary pulmonary hyportensioncan accounl f<Jr no mme lhan a ' mall proportion of cor pulmonale pali.nl' .[n term, of it, fr«iuenC}', therefor" primary pulm<Jnary hyperten, ion canhardly be thought to p....nl a public heallh problem. Nev.rthel.... thedisease .....ntly assumed importance on accounl ofa ,udden 'mall . pidemic(sot pp. 7 and 30). Similar eveul, may oc<:ur again or might, in faet, a lreadybe taking place in epidemic O T endemic form in $Ome pan, of the w<Jrld .Be, ide" an undeManding of lhe nalure of primary pulmonary hyporten,ioncould pro ,ide n.w in,ight. inl<J Ihe eliolog)' <Jf olher. commoner va..ulardi",rdeT$.

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

llirloch<' a od col...a..-. ..... [OIl'ca.... in 0 _ ie<of '56 (lOO ~'itn" 00C1l .. a meda lclinic in S """ land ; Pa ul Wood ",pnrte<\ a freQuency nf 17 omonl " 10 (lOO con""'uhve"'''ien'' i,n caTdiova",ul.. di><a"" 1(12)], 14 of 6000 ,,"'ien.. <......ne<\ fl,)t ca",,,,,ev,I"""",, hod th< condition, accon:Iina to Nit l><n and Fobriciu, primary plJ lmonaryan"';al h~pen<o,ion ",'a, found in 0.2~1 p< ' ""nt of ' iahl ....n cath<'",i>ation.. in'M - ) .,., ""nt of au'.,.." <.0><. of cor ""1""",,,1< and in 0,08--0,2 "" IIXlO of un><ledrdan,0I" Ymaterial,

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

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

More informal ion on 'he u, ual range, of pulmonary arlery pre..ureby age and se, in normal person' i' n«<led, It i' not known what proportion<Jf penon. wilhin ' ariou' upper pro,,",. ranges p....nl dinkal or palho­logical evidence of hypen en,i'e pulmonary v.scular di...... The usuallyaccepled uppor limits of normal mean pulmonary artery pre..ure of

- 28 -

RlPORT O!< ~ WHO "ffTl~() "2S mm Hg al r..,;l . wilh a borderline range of IS-2S mm Hg, are empiricallyand arbilrarily defined. The qneslion a ri.e' whelher person' prone 10

de~lop primary pulmonary h~perteMjon aTe meTeI~ Iho.. who aTe a lTead~

al an early age in Ihe high upper TOnge of the fTequency diSlribulion Orwhelher lhe di..a.. is a distincl .nlily r..,;uhing from eliological facIo",lhal are unrelaled 10 lhe muhiple delerminants of pulmonary blood pr..,;,ur• .There is an ob.ious paraliel wilh syslemic blood pre..ure distribulion andc..cntial hype..cn.ion. It i, tr"" 'hut pat;"n.. with primary pulmonaryhyperlen,ion ha.. pre..ures lhal are relali.ely much fur lher r.mo>ed fromlhe upper limil' of K normal ~ than is lhe ca" wilh ....nlial h~ perten.i ....However, lhe pulmonary arlery pr...ure of such palienl. may have beena gTeald.al closer 10 Ihe normal range during lh. early stages of Ihe di.ea.e.Ixfore advanced obliterali~ change. in lhe .maUer pulmonary ar leri..caused addilional increa... in vascular r..,;istancc. This maller is not likelyw Ix r.sol.ed until there are non-inva,i.e melhods for ..rial pulmonaryblood pr..' ure mea. uremenl s 10 delecl and ob:ser.. lhe e.olulion of .arlyeleva,ion,.

Th . ...... to do"elop IIOII-io.... i•• diag..... lic t«hniqu..

There i, a need for non·in va,ive lechniq ..... beeau," persons suSpecledof having .arly pulmonary h~perfension must Ix sc....n.d. where indicated .for more delailed .ludi... Borderline palienls musl be monilor.d andfollowed. Relali. .. may require examinalion. in view of 'he familial agogregations thal ha.. been reported . No n.invasi.. techniqu.. would alsopermit more compreh ensive ......arch into the phY'iologi<a1 and palhologi<alranges and delerminants of pulmonary blood pressur•• 'incc elhical consider­alion. often preclude haemodynamic sludi.. requiring calheterization.Certainly. ,uch a technique W<luld be required for large·scale epidemiological"udi...

A comhination of relali..ly simple indi<alo'" of incr.a",d pulmonaryarte ry p.....ure mighl be u..ful. such as lhe QRS "is, Ihe ralio of lhesecond aortic 10 the second pulmonary sound. and some simple pulmonaryfunclion test.> 10 exclude ....pirawry di",a", . Olher po,si bilili.. are : a lowarterial oxygen len,ion or low diffusing <apacily of lhe lung in the ab.enccof bronchopulmonary di",a.. or arteriovenou, shunt, and mea.uring pul.monary capillary 1101'1 by using nilrous oxide and body plelhY'mogra ph~.

Echocardiography is not considered u.efu!. Howe..r. no current non·inva,;.. melhod is valid for the purJlO'C' oUllined abov• .

Epid<-mio1oltial dara 00 primary pulmo...l')" hyp.,,'....i""

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

Pll'MARY PU LMONA RY HY .....TESSJON

on magnitude p",sented on page 28 have limited epidemiological , ignifi­cance because they provide no etiological clues. There appear 10 be no dataon geogTa phical di'tribution e.cept for the as'ociation betw<:cn pulmonaryartery pressu", and altilude. A predominance of women i, found in mOl;tseries. especially al younger ages (73); Goodwin and hi. colleague. describea lhromboembolic form affecting largcr v....I•• presenting in middle age,with an equal se' Talio (74). In the patholo gical .tudy of Wagcnvoor t &Wagenvoo rt. bolh thromboembolic and ~ primary" groups .ho"",d femalep",ponderance (2).

Familial clustering has been descrit><d . especially al younger ages.T",I](71) .ummarile. the dota from 5 publication. reponing 47 casesin 18 families; 12 of lhe case. we", below Ihe age of 16. The only malepatienl among the 5 cases described by Krl henbiihl et al. (75) was aged 59and gave a family hi.tory of pulmonary thTomboembolism in ""-,,albrother>.

Primary pulmona ry hypertension i. nol a newly recognized disease,T"'1l (71) traces the first likely case back to 1837(Helie), According toBlount (73). the paper b~ Romberg in 1891 conta ined the fi"t documentedoc<:ur",nce of Ihe condition , Yii (76) ",yie~ Ihe literalu", up to 19SOand indicated that SO cases we'" reporled between 19SO and the lime ofhis own .tudy, which added a further 6 pat ients.

The appetite-reduci ng drug aminore. wa. imroduced in Switzerland in1965 and successively in the Federal Republic of Germany and Austriain 1966. The first repon on an e. ...sive incidence of primary pulmonaryh~perlension following the ingcotion of aminore. waSpresented b~ Gu n nerin 1968 (37, 77). Wirz &< Arbenl (78) revie~ lhe experience in Switl er­land, including the cent..s in Berne (37), Ba,le (79), Zurich (78. 80),lausanne (81. 82). and Geneva (1S). Similar Observations on aminore.w'e.. reported in Ihe Federal Republic of Germany (83) from " annover (38).Essen (84. 85), Hamburg (86). and F.. iburg (87). The'" ""'''' similar "'porlSfrom Au. tria (39, 88. g9), but in Prague. where the d rug 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 rolein Ihe opidemic. Rivier (81) ,u"e~od all cases of primary pulmonaryhypertension in the 6.. Swiss university medical centre< between 1958and 1965, and belween 1966and 1969; there was an increase from 15 casesin the first period 10 148 ca... in Ihe =ond. According 10 Rivier, not allof this increase could be ascribed to the drug . Blankarl (90) domonmateda correlalion belw<:cn lhe lime whon lhe drug appeared on the markelin the thrtt countries and Ihe rise in incidence; ho,,~ver, the incidence beganto faU while drug sal.. still contin ued to risr, which argu.. againsl a simplecause-and~ffect ",Ialion.hip.

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

M. PORT ON A WItO M. fl ING n

dat a based on a .u rvey of a random population sample In Hannover, thatonly about two pe~ns per 1000 taking the drug devdop pulmonary h~per_

tension. The drug wa, withdr awn in thelaUer pan of 1%8. The number ofpa tient. developing pulmonary hypcnension dccrea"'d afterward'. Thegroup in Hannover found a relation between the do'" of aminore. and therisk a nd ",verit~ of pulmonary h~pcrten.ion, but others did not.

The aminorex episode dre w aUention to other agents that act On thepulmonary vasculature (91). The alkaloid monocrotaline is active in ratsand closely related 10 fulvine, which causes veno-oc<:l usive liver di"'a'"( .cc page. Ig a nd 22). Prepara tio n, of ragwort. which eauses pulmonaryvascular d'",a", in rals (43) bul not in man a re freely availahle in ~ healthstores M .

An overall asses.me nt of pre..ntly available information indicatesthat primary pulmonary hypertension and its precursor .tage, probab lyhave no single eau",. As in the ea.. of systemic blood pressure or athero­sclerosis, a num ber of noxious stimuli scem to be ab le to aClivate a ~ finalcommon path ~, cau,i ng pulmonary narrowing thro ugh va....pasm. micro­emboli, or a combination of mechanism•. A number of possibililie. forfurthe r research derivcd from these considerations arc incorporated intothe re<:ommenda tions from the meeling.

RECOMMENDAn ONS

1. There is a need to collale .uch inform.tion ., i' ...il.ble. privately.nd in publi'htd malerial . concerning the pressure in the norm.1 pulmonarycirculalion and its relation to se~. age. and e~e~se,

2. Before any new ,ympathomimetic or anorectic drug i. introdllC<'<l forclinical use. careful studies should be made of it, eff.,.;t o n the pulmonaryclr<ulation of animal'. In any subsequent pilot study in man it will alsobe =r.sary to examine most c.refull ~ the possible eff.,.;ts on the pulmonarycirculation .

3. The establishment of a contral regi'ter of p.tients with prim.r~

pulmonary hyperten,;on $t<:n in cent"" throughout the world would behelpful For ' hi' purpose a protocol shoold be establishtd includ ing dataon the ingestion of drug,. the en'ironment. a nd p.tholog",.1 detail,.among other factol'$. Linkage with e~i'ting national registries of ad•.....,reactions to drugs and the international drug monitorin g ,y,tem of WHOcould provide information on addition.1 t:.... of pulmonary hyperten,ionreported in conoe.ion with drug u...

4. The large number of patient, ,till available with this di..ase followingthe ~nl epidemic in Europe should be urgently examintd u,i ng les'con.entional techn iques lh. n are u,ually applied to thi' situation. Con·ditions predisposing them to pulmonary hypertension need to be identiried.Collaborative work in this dirmion involving new methodology such"' endocrinological and immunological method' not generally a ppliedin haemodyn.mic laboralori.. should be encour.ged. There is a particularneed to study the natural history of these patients . nd to carry oul family,ludi... Pathological 'tudies of m.teri.1 av.il.ble from thi, group ofpatients hould be ellCOur.ged.

~. There is a gre.t need for ,imple or non-inv",i~ sc=ning tech­niques 10 identify indi.idu.I, who have .n e.rl~ st. ge of pulmon.ryh~pe""nsion or who are likely to dew:lop pulmonary hyperlension ,Specifically. there i, a need for a non-in..sive t.,.;hnique that would indicateele..ted pulmon. ry .rtery p""sure.

6. A da..ification i' recommended. t.king inlo actount both clinical(eliologic.1) consider.tions .nd morphological ch.raeteri'tics. A "p.ralecllnic.1 and morphological nomendature is snggested.

_ 32_

REFERENCES

l. WHO T«hnical R.port Se, ie•• No, 21). 1961 (ReporI of ,he WHO E,pen Commi"ooon Cbron" Co< Puhn ona lel

2. W""' ''''''''''T. C. A. & W""""VOOIlT. N. Pri""'", pul"."....". h,pe"<"' ''''' ' ap"'holo;i< "udy of'he 'on, ......1. in lS6 <lino.:.llydial'K"Cd ...... Cl"""",;.... 42;116)· 1J84 (1970)

3. 1.-". G . D£ S. Re, ob ' ''''' or 'he po,oh'nonary<''''''bhon. &-I,W. H~" S""'ntd. 33(sowl.): 11-26 097])

• . FII""AN, A. 1'. D, nami<:s of ,he polmona", <i"",b"on, I": H. mil'on. W. F. 4 Dow.P.•<d. Hand_ of ph,,""-._,"'" 2: cireul.."",. Wa"'inaton. D. C . Amera nPhyoiolot:ical Soc ielj'. 196). vol , 2. pp. 166J·1743

~. 8'.' 0<;'"0. S. .-rAL. Tb<.lfe<:! of bo<J, po.i"on on ,he cl"ub'ion ., r,,,' .nd dwi".:."""i... with .pecialref.re-no:< on ,be inn...""" on "'O~. ",Iume. A" " phr.lokgl<aS""NimoWca. 49: 279-2'JR (1960)

6. PA.... '.•• W. H. 4 A,,,a""AL. S. B. Tb< <If<a. of red UII """"'"or"""'"" pul""""",blood flow, Ptopm I" R" p/fa,a'Y Rr"",,~, S: 8-1·92 (1910)

7. Wtsr. S. B. Re" "",,1dilfere""". in hlood flow and .,.n, 'b ,"'" in ,"" Jon., I", Caro.C. G.. <d. Ad....""" lu "on'" ph,....,..,.". & I,i_ . Williamo & Willin•• 1966

8. Sz''''''', S, P, & Fill ,. . A. P. Ao'onorni< <OII'rol of ,he 1'01""""", cl"","';on.I": Fioluna". A. P. &. 11"""' , H . H.• <d. Tb< pulmo..", '""",b ' ;on ..d in'.....;' ..1.(10.«.Chica,.,. Uui~,y of Chi<a,o Pr<... 1969. pp . 239-268

9. C.." , ...",. A , 0 , M , tT 'L. /'u t"."....". ..""""",.11"=';"0 in . whY''' dun.. OI<>M.<i"ob""" be' ,...n 'win f"" ..llamM. J"",,,,,I./ I'hp lokg, . 192 : 111·12 1 (1967)

10. N.. , ,,,. R. L. &. BK'U""AN. 11. A. Tb< .If<<l. of h)'po""m" on ,"" polmona",. rteriol bed in ~o"",,,, a nd "'l> , ' '''-'a';''' !'n>«<din." . 18 49J (19.19)

11. H""-LTON. P. H AL Hype" . n. i"" puhno..", , ....... b.r di..... ;n " a", of<hron"hypo. ... )"",,,,,1 . / Pn'~Y """ 1Ja<I..~y.M: 431-440 (19681

12, PE~"-""". D. H " L Pulmon.", h,per1<n.i"" in heallh)' men bom at>d !i'in. a' hi'". I,i,"""" M<dk ma ,!>q,,,,,,,lu. I' , 449--«(1 ( 1'lli2)

IJ , H... ,.. 1'. '" !J<ATH , D. Tb< human p0,0lmo..", <i"ol"ion. Edinbo,jh. Ll,;nl·,,_ , 1962

14. H, ..TH. D. & EDW... "'. J. E. Tb< ""boIoo> or hyP<J'<""""~ ....ulo'di..... : a de><rip'"", of .i , arad<' of "'"<"0"" <han... ;n ,"" pulmona", a""ri<.", ;oh , ,,,,,,"1 ref..."", '0 oonaeni'al a<db.< «plOl del..,. Ci.-,MIa'Ioft . 18: ~J3-$047

(I9}8)

11, HU TH . D. ... " L, Graded pu1mooluy ...."'ob, <lII' n nd .....mody..mi<find;nl .in..... of""n1l"ol.. . nd . ..ial ..p..ld<f<eta nd ""len' d '" a"<riow<. Clr<.IIJ'i<»I,11 , ,15~II 66 (1918)

_ 33 _

16. H , ..". D . n a L. Rela' "", bel_• •" .."Mal <1"'.10' i. ,I>< , moll ""l_ ,,, aru:tie •• nd immod "" .."""iMity of pulmonazy h~pe"••~on rollo"i'l <lo.u.. of "".,ri­cular and . " i.1><fIul <\<ro:«•. Clm"',;"'. 11 . 1 1 67· 1 17~ (19SJj)

17. Hu m . D . " a L Elfo:«. o. ,he , iltit ",. 'ride.pul_", .."",Ia,u .. , . d ...."" idbodin o r ,he .., or.._ '0••nd "'"""'" rrom . "m..lo'ed hilh ol' it_ . T1>o<~~.

:Ill; :14.28ustn18. S nw'~. p, G, I. A MITCH'~_. M. 1. P!,oltnorw'y h~pe....."'" d... ' 0 ob"''''''io.

of ,he in'",puimooary ", i• •. """~~. :I(I: 106- IIJ 096S)

19. H...",. D .... AL .... 1"""""Y ",oo-«<I",i", di...... CIrr./alion. ~ : 242_248(1%61

20. Ba.~~.o, O . "" ho logy of 'he ......,. or ,he pul"",..1)' . i"",lo, ion , A r<lJ l '" 6/Iwl",.<t/ M «Ik Uo<. S6, 211 ( 193S)

21. G"'~""'N. A. S. Morpholof:icaI."..&Iion< of ,he pul"",..1)' . ....i.. in ""'IO.i,.,"""" di....... p,~,6/'~ 1.,';/0" ~IM«J;cu.- 01 CkH:qo , 21 , 116 ( 1958)

22. H 'A"'. D . & B"",. 1'. V. The lu.a modi. of ,he . ......... .r'he I..". i. pu l"",.al)'hypell< . ..on. J"",,,,,' 01 ""i0oi011' 004 8o<:'<tiolotr" 76; 165· 174 ( 1958)

21. WAG'~'-'OOII'. C . A . V..«oo. !ri<:lion .nd medial h)..."rophy i. pul"",.ol)' h~pe"... ,ion. C;', . laIioto, :I; Sl l ·S46 ( 1960 )

24. WAG'~'-'OOII' . C. A. H AL The p.alhology of lbt puln>ona l)' ,""",Ia,u.. , Sprinefi<1d.lil., Thoma,. 1964. p. 172

2S. WAG<N'-'OOIIT. C . A . The motpholOl)' or ..ltai.......ull.. le~o• • i . pul mona",hy..........on, J"",,,,,' 01 ""/001011' """ 80<:,.,;,,/00:, . 78 ; lOl·SII ( 1959 )

26. SolOn. N. H AL 1'\11_ 1)' h~pet".oo. " ith hep.a' ie . i'rh.... . &-11i&!< H",,'Jo"""'. 30 ; 17S·178 (1%8)

27. NAYI, R. l. " h i...", " pu lmona", hj-pe...,,,"'" ,,;oh <:o<,i"i.1 por1,1 h~pe,·

..n,ion, 0 ••,,_ivc " ody of , i. <a C;" . /a,ioto, zz; 376-1114 (1%8)

28. HEA'H. D . H AL .... ,""""'''' ,""",la, .,.. i. 0 d". orte, ,o"o-pul""",ol)' 0.0'

"""""i, for fou , yen /tt lll&!< H"'Tt , ,,,,,,,,,I . 1 1; 18l-196 ( 1959)

29 S"'-D."'A. M . E. n E,peri""otal . " ...... h)..." ••• ion . nd .,,,,,,Ia, di.....in ..la,,,,,, '0 ""Iyey,h<m". A",m'""" ,,,,,,,,,,I ofI'a'holotr" 81 , 9J 5·981 ( 1%8)

)0 1laowN. C. H . & HU' ''''N. C. V. PuI"""",1)' "",o-"""Iu.i... d i....., L<J",,'. 1 ; 61·65 (1%6)

)1 H"'TH . D & Eow...... J. E. Con~aun'ion of .""ie ti.... or pulmo• • 1)' ..un~in idk•.,.,hic pul""",.1)' hype"",.ion, C;"o/a' ''''' . 1 1; S9-62 (1960)

l2- FULTON, R. M. U AL V••""",lo, weiih' i. ca nl iac hype""'l'h~. &-#;,/0 H",,''"",,,,,I.14; 41 3-420(1912)

ll- Woo<>. P. l'\l1mona", hype ......on "'ith <p«;aJ ..r...... to the ,""""",'ricI"",f....' on, (;;,;&!< H"", J"",,,,,'. 10: 117-110 (19181

)4, SRn·R"D. J, T."- aL, C1i.","I. p!ly<io\of:i....1and 1'"'001"..... """,0."''''''' i" p.ali.nts"'ith idiopatbie pulmonal)' hype......... &-11/'" H"". J"",,,,,I. 19: 10 (I.m

l5. W'm.... W, L.. l ., " .... h i"",,,, pol""""'", hype"••, ion . nd R. yna ud ·, phenom·enon, """..port .nd "'""" of ,he li....""" . A" hi.., . , 1. ,..",,1 Md ;''-. 114,811·8 )0 (1964)

36. ClwltIA. G, C. .. AL, R.....od· . di......nd po-im.o'Y pol"""""" hy".,..tHion.CI<-nd4'''''.22 , J05~·)059 (1%01

37. GU>.TN.... H. I'. ET AL H.l.ur•• ""h die primir ,,",~ulit<n Fo..... o.,Cor I'\I I""""," ?S<Io",;,..;,,1w "",,;,;";,,1>< W""Iw""IoTIII. 9S ; 1179--1 189: 1695-!107 (1968)

REFERENCES 3S

l8. G... " K . ET M . P,iml.. ,",1.011", pulmo.... Hyp<rtoni<. Zrl''''htlfi 1"' K.-rIs­la~ff.." hM"",59: 8t>S-U l (l 9701

19. SntW '''IG'''''''KL, H. ET ' L Pri mA", pol""""," Hypoton;" bei<i<ben jUn,...n F..""n ,fku,,,1,;, "",;;,ioinh< W~;f', 94, ~l"4lS (1969)

40 s",~u"".... W . ET AL TI>o .If""', of an in'..""",,o, info,",," of """pi""ph,i""on I'Iil"""",,,, and .,,,.nU< ........,..,,,*,,,0<, ";,h ond wi,hou, propraoolol I"""t:ea' "",n' in dos'. EA.rop«J. J"",,,,, 1 4 f'M'~Y, 10 ; l4~ (1910)

41. G' H' , K. &< G. ... .. . E. Errao" ,"..n ei"" , klini>Ch-''''<!e'''''''''''i<e!l<n S,..di.,om Prob"m de, primi, .., kull",n polmonolen Hypen ono< , &11_.""'><11< _" ,.niseI,;, Wom.M<lvif ' . 100, 21~·2 1$7 (19701

42, G""", ,,, R . F. IT .... I'Illmonary h,penen.""': indi.Od",,' a:>d '0«"" ••ri.bilit,1<lah"" '0 .."",la: """"oily. A_ rl",. H.." J"""",', 66 : I·J (I96J l

4J, K u , J, M , ET ' L Ful.i "" .nd tbe pol"""",,,, <i...,Ia, ion , 11Jl>rox. U ; 249.261 (1911)

44. K u . J. M . Of AL. M. " <><iI. in ,he lun, . of .... f<don C""alrNia>p«lalNlix«<d• .A"",k~" J"",..14 f'~lltoIoty, ~ I : 1031 ·1044 (1961)

4~. H• • • I5ON, C. V. E• .,.timen,., I'Iilmonary .n«;"";k""'• . J"""",I of f'~'~Y

~""&<,"'IoIot-Y, 60 : l:S9.293 (1"" Sl

46. Bo'N"", P, j , I'Illmnnary ."",;"";k""', ond co, 1'Ii"""""", do< to '«urre"tthrombo<mhDli,"" 0,-,.1.,10<1, 10 : J4J·J61 (I9~)

41. B" ~'Jl", p, j , Throm bo-embnli<: prima", ""Imona", or..,;"";"""'i•. &",>11H..,I J"""",' , I~ : 93. 100 ( 1954)

48. 1""",.,., T , V , ET .... MHlo rmal ~btiooly>i. in '.mili.1 pulmonary h,_ n.ion.A_ 1nl. J"",,,,,I of Mrdk i..., M : ~· 1 4 ( I91J)

49. N..yt, R, L. 1'Il1"""",,,, le.i "", in .y" . mi< ",le""i•. D'~"" of 11.< 0..". 44:J74-lllO (l 96 l )

SO T", u. , E. &< L,~"",o1Iho . C. Pulmon. ", hYPOn<n,,,,,, jn .~,«mO< ,dero~., A_ Itof'l.< R"'-"",'k /)j'~"" • .10, ) 9OMO(I (1911)

SI. SLA~A. R. U At. HyPOt« " ,"," on<ti<:lk pul"""",;", p, imiti""<tlupu' ~",thCmll t<".

d".....i".. f'm~ """"'0" . 1S: % 1--%411967)

S2. GA.""a, D. L . .,. AL. I'IlI""""-'} hy_"""n in rll<uma,ojd an h, itis: r<pon of..... wj,h int imal ",le,,,,;, of ,be 1'Ii1""""-,,, a nd d;,i'al a"", ie, . $,,,,,,,,, MrdicalJ"",,,,,', z: I ~ J·I SS ( 1937)

S) , B. 'IJ$TI '~. H. Peti. " etit i. nodo>a limit<d '0 ,he pul_", <i"",Ia,""' . A_''''.J"",,,,,I of N'ltoInn, J I : 8J1-!1l1 (19~l l

Sol, CLA_~. K. P. &< Gu" . j , C. H, o<"",.,.;. < pulmon.", a,,<, ;' ;' . A"", ,,,",, J",",,",of Di~~, of Cl/I/d,..., 118 : 718·724 (19691

SI , A¥IAOO, D , M, TI>o lun, <;r<ulatjon. O. ford &< f ranklun. Perpmon. 1965.

\6, A"AOO, D , M . N""""" ;"ft..-, on ,he NI"""",'} .;"",Ia'''''' : ;nc:eaO<d in'ra·<..n;.1 I"<"" 'c. "".." idi". .nd bmyl ium i'laIMy'f-S<!o...ird<"'rr', A« m . fIN' Xj>Tri""",'rllr f'ol~l, fPof""",,,,,,knlo6lr, 240; 446-112 (1961)

S7. Bur, P. V. &< HEA"', D. 1"...."...wjon of ,he .ppea rance' of """U pulmo..", blood""""I, in . n;mal., C_IaIlo<l R,~m., , ; :!9)·294 (1961 )

~, WAOIN""""T, C. A. 8< W""' N""""' , N. The l'Iiimona", va",ulatutc in norma l..ttk .t ",0"""' .' diff<t<nt .t<'. f'o't.%tin ..rot'"'", 4 (J) : 2M·27J (1969)

)9, TvL", w. S, Of AL, Modem fun<tioon.1 mo,ph"lt,o of the <Qui"" IU"I. £q«i",a...l

V"""""'yJ"",,,,,I, :l() ) ; 1·12 (l~1Ol

60. MelA""KLl~, R, F . IT a... " " LKIy of the ....t>ero>s p"l",o.,..y ar te", in va. """""",mal•. A ...rin>w J...,.,.,j qf A",,'om~. 101 , 149- IS9 ( 1961)

61. Me lAooHu N, R. F. n a l, SHt>ero>s PHI""",",,, a..'omy in ..noH' animal• • nd man.J"""",I qf ,Iw A",.,.;"Q" M.J;<QI Anot';",ioo, 17~ , 694-697 (19611

62. l.u>Yo, T. C., Jr . R.opon... '0 by po><ia of pIllmo..", . n ",ial " rip< in a non-a QLlOOU!ba' h, Jour",,1 of ApplmI PI>~..,q y , 18 , S66-SM (1970)

63. Me M..... ", G . "d",..li... and i"'Pf"'nali",,: a ....min. , M nJt<.:1 J"",,,,,I ofA. " ",·110, 2 : 16 (1964)

64. G a ..~a..<>, M. J, oil I'INo:<. " . P"'''H.ize<l ..,..,..,1. in a" hma . &-itl>ll M Hlt<.:1Jou,,,,,I, 1 : S6J ( 1967)

6.1. \la~', J, R. 11>< "'..... and fa .. of ..ooacli... I>onnon<. in ,he <i"'HIa"on. &-/1/>11Jou ,..1of f loa ,-..lotfY, ;1$: 1O'J-1ol2 ( 19691

M . GUI!, C. N . M. ..hol i"" of ....,.Cl;.... hormo..... hy the I"n,. A",,,,,,,loloU ,:19: 6.1~J2 (19711

61. G,n l5,C, N , IT Al . Pl.lmo..ry."nc' '''''of S-byd"",y' ",ptam;"" . nd norepj""phrinohef"", 'nd .1'1<, ea .-d""'HI""",",,, by.,... in "",n. 0"","""" Re_ rrIo, 30: 666-674.(1912)

63. N a"", H. '" G'u ... C. N. EIf«, of balo1ho"" and ni,,,,,,, o . id< on removal of""..p;""pt,,,,,,, from ,... pHI""",",,, <i","lal""'. A"," "',loiogy, 39: S79-l-W (191))

69. P" ""A '--, "' . S. 11>< """''''Hi"" of .""i..tio" of tyPe J "'""""""nd J roII<• . lw,Pone•• R.. od, Br<athin.: H. nnl ·B...... «ntoH'", ' l""J'Ofi" m, London, OI"",hill,1970, p, S9

70. GH' , A , IT AL. E!lpo.imon' al re,"I" of ..sal blo<l: in <ard"'PHI""",",,, d,......10.. Porte,. R., 0<1 . Ilru,bin" H<rinl · Ik'<.... «nto.."" .ympoo;""" London. Cb",·<hill, 1910. pp. l lS-n6.

71. h Ell , E, Pr ima", . nd <h",";,: 'hrombo<mbol;': pul""","",, bypo".n.""'. A.,loiogy,2.1 , SSI -S14 (l 9n )

12. WOOD, P. Di...... of ,....a" and ci"",Ia,Oon, LorKIon. Eyr< oil Spoll i. _ ,1968, ch . 18 .nd 19

1). B""'",", S. G. Pri ma", p"l""",a", bypon<H' '''''. Mod<," """"'1''' of <Q..JIo",,,,utordl_ s<, 36 : 67·12 (19671

74, G<:x>vw'N, J. F. .,. aL. O6h'...'; .... PHI",,",",!, b»><.1<n..on and thromboembohsm.&-It/>II MHlk ol J"",,,,,t , I ; 701·711 (l 96l )

1.1. K " H'NaO~l , B, Et aL. L"hypo".n' ioH p"l",,","i,. " . ""n,;<II<" "" " throm bo­.mbol..... ": ',od< chn..... do cilk] ob" "... ,,,,,,," 5d...I",I..-1I< _1,1.1",11<W,.,,,,,,,,,,t,-;),. 9H, U II· I320 U\l631

76. Y II , P. N . Prima", pIlh-nonar y h)-pon.,,~on : r<pon of . i, ......nd revie", of lit...•tu" . An"" b 01 1. " , ,,,,1M:d;c;"" 49: l 1Js-II6' (19S8)

n. Gc u " , • . H. P. HAufuo. 01<, pt iml, ","''' ull''H pIllmonal<H Hypon on" in do,$oh_i<. 1961.1910: E;nle;tunl . 5</0 •• ,::<;"", _,:;,.;,,'" W,.,J....",,t,-,, , . lOll21016-2144 ( 1 ~7())

18, w"' ,P. & A. a, ,, , , U , Primll..... k" lI .. Hyponon " in do. s<h",. i•. 50*....·"',,.'"_ 1:;";'1<'" W""""",",t,-;f ' . l OO , 21.7-2lS11 (191(1)

79. Bv. ..u , F , IT At. D<r V<rla. f dc, oM".k" ... p"lmonaleH . n or.. I" n HyP<T1<" ' '''''.S ,h",'::<;"'" _h;,,;"'" Woc"'wl<h: lfi . l OO : 146-1 4.! ( 1910)

8(l, N a",. , F , & BU~l~A~~, A. The..".. "nd !'NI""" do• • hron ;"""n Co. Pulmonale,5<10 •• •::<;"", _;,m"'" W _ ns<lorifi , 100 : U S-14l (191(1)

U FERENCEs

~ l. RlVI" , ' . L, H~pe""n~on . ",\r " llopuhno""i... primi,i"". SNo...,'",i,,'" mrdo'zi. U</o<W"""'""'"'f', l OO , 143_14l(1910)

~2. SANG'A , K . n AL L ·_ )1\Ort>iq...dd·h~pe"",,<ion."",,,110 puh".,...i... d'",i&itl<....<ul.i.... Sd<...;",urlo< _,;.ur<Io< Wo</w:= "'ift , . , 1252-12ll (J%8)

8J. B'''''''ANN , K . n AL. Priml ... pulmo..1o H~pe"on" . V"IK....II.,.,.. <I., 0.",,,,­G,,,II,,IK.f'r" K"ul>,ojf"'~_nr. )8 , 134 (1912)

84. H"",•• W. ET AL _h'u"I<" ;,;I><,d"Zw»n..... d<'p'iml' ...<kuli"''' HYP<>Ion".V,,"" ...I' _nr'" dTr o._r" G,,,II"""ft r" im><T< "'N i,i•• 15 ; 436 (l%9l

IS. HAG" , W. .-r ' L Priml, <kull ... pul""""" Hyperton" u.-.:l Appeh"u..I<,. "'N i, l.oiJrIw: /(Ii. ik, 66: 386-390(1911)

16, Voos, H. &< H...... H. Ep;<Io"';"lo&i<..-.:I Klioik <10, pti.....' ... .. ul."'u pu1moni",OHYI'<fton., : .io !l<ri<h' ul><, 42 Fill., Z<ir"""ft rUT KUi,!tntjfor" lutnr. !IV : 887(19 10)

87. s,..,.., H. .-r .L. Priml ... pul""",,1< Hyperton it : .i" 8<i,~ ru, Hi uft" . i' "od""iololl", V"""...n•..,..,, <In' n..,,,,,,,,&"""""f' f'" I........ "'N h i. , 75 : 4J9 (1%9)

88. K. ,N..... F, hi....., pul""",,1< Hype" . ". """ w......' Z,jt~,ift fll' i. ",,, "''''i,i"""" ih" G""'t</W", so; 4~ 1 -I56 (1%9)

89. K. ,N..... F. Pulmonal. Hn .."oni• . w......, mnIi,;oiw.. W"""""""'ift. 110: 6J 1-6J4(197(1)

90. BLAN<U ' , R. 0., z"i,f.k,,,, im "' blu f de, pri....., ....kull...n pul"""",," Hype, ·'on". Sth...,i,,,i,,'" mnIi'i"irrlw W"""'''''''''''ft . 100 : 21~7·2I S8 (19101

91, "' " .p;demi< of pulmonary h~pe""n"o" (Edi'ori.ol), U'f«', 2 : 2~2 (1911)

92. K• • V" " , 0 , .-r .t. DO. Wi,l;un, von Ami""",. aul di. Hino<lymomik .... k" i..."u.-.:l ".,..." K ...i.louf, I><i i,Y, Dorr<ichu"1 om Hu"d , "'U""ylt-StIlmmkIHr,'rA"'hi , jiff.~i_"I<11r p",IwIog" "",J P""'-'<%f", 264: J89--<lO~ (1%91

9). T~'~H"", K, ET 'L. Haemo<lynamic .lfee" of i"'prc'.... n 00 ,he pul"""",•• .-.:1 'Y'",,,,ic eirrulo'ioo. Pfiiil"r A,d ,;, r" di, " mml< Phl'w1orw <I.. M",,,,,".uotJ... T""', JU, llG-ln (I'm)

94. W""'~.-a>Rr, C. A. Th< p.o 'hoh>jy or pulmona". ""oo-o«l... i"" d....... Vi",4a...A,,"-' , Ab" iI""" of. P"'iu>Iotfi,,.. A"" ',,,,* .od Hirt%fi<, )«I ; 69-19 (974)

9~. Hu rK D. or AI.. TI>< <lru<'u'" or 'I>< pulmonary 'ru"k ., ~ilf<",n' ' 8<'< . od io """"of ""I""""". hy......n~on a od pulmona". , .."",i., )"",,,,,1 of p",lu>J,yy ood __'moIoty, 77 : ...)-1:16 119'w)

% , W,wON.-a>Rf, C. A, Of AL, Elf"" of lul.i... on pulmona". a"", it< and ""i". of ,heW, 1lou<OA, 29: S22·!211 (1974)

'I. STtrnusG.o, W, Of AL. v" , I<ichrnd< U"..""",,U", ;,;1><, d;' Wi,h "" _on Amino­"", No,ad",nalin, A",ph<to", ;n und Ephtdrin . uf d., H' mody..",ik "'" I"""""uod 1Ioi"." K ,.;. I.u~ .0 Hund<". Z>""""'ft r" XTri*"ffo<",h""", 60, 7H2(I'll)

98. STVHUNG••, W. or .L. 0., Ein"u" ei"., N·Alk,I ;',,,,,,, . ul d;' Wi,l;u".....Amph<tomi", aul dO. Himod)'narnik .... 8'''''''" uod ~~ ... " K...lslaul... Am ..i·,"ilt.'.""'~""S,11 : 342·346 11'11)

A N NEX I

CLASSIF ICATION OF CHRONIC COR PULMONA LEACCORDI NG TO CAUSATIVE DISEASES ·

The di.ea ses that may cause chronic pulmonary heart disease are li'tedbelow, classified into broad etiological groups.

t. Diseases primar ily atr<:<ting air passages of t.... lung and the alveoli

1.1 Chronic bronchitis with generalized airway, obstruction withor without emph~sema

1.2 Bronchial asthma

1.3 Emphysema without bronchitis or a'thma

1.4 Pulmonary fibrosis, with '" withou t emph~ma, due to :(0) Tube...:ulo.i.(Il) Pneumoconiosis(c) Bronchi..,tasis(<I) Other pulmonary inf.., tion.(e) RadiationU) Mucoviscidosi,

I.S Pulmonary granu!omata and infiltration,(0) Sarcoidosis(Il) Chronic diffuse interstit ial fibrosi,(c) Berylliosis(<I) Eosinophilic grannloma or hi'tiocytosis(c) Malignant infi ltration(f) Scleroderma(g) Disseminated lupus eryt....mato'u'(h ) Derm.tom~ositis

(i) AI~lar microlithiasis

1.6 Pulmonary resection

1.7 Congenital cystic disease of the lung,

L8 High-altitude hypo,ia

• ,,-, WHO T..-.' ......' So,.... "" 211.,.. , , ..........,.. w HO ...... ConvooI<to< ..O " ...kCO<~ • • ,'...

_ 38 _

ANNEX I

2. Di",a"" prim.rily . ffecting the movements of lhe thorac;c, c.ge

2.1 K~ ph05COl io,j. and olher thoracic deformil ie.

2.2 Thor. copla. ty

2.3 Pleural fibr",i.

2.4 Chronlc ....u'omu5C\ll.r >ve. kn",,~.g. , poliomyelili.

2.5 Obc<i. y wi'h al....,I", h~p<>'o'on';l"'i,,n

2.6 Idiopalhic alveolar hypoven. ilalion

3. Di""a,,,, primarily affecting .he pulmonary vaoculalure

3.1 Primary affections of lhe arterial wall(a) Primary pulmonary h~perlen,ion

(6) Polyarterili. nodo,"(c) Other arteri l;,

3.2 Thrombotic di"'rders(a ) Primary pulmnnary lhrombo.i.(6) Sidle cell anaemia

3.3 Emboli. m

(a) Embolism from lhrombosi. oUI.ide lhe lunll'(6) Schi.lo",mia.i. (bilharzia.i.)(c) Malignant emboli'm(d) Olhe, emboli. m

3.4 Pre", ure on main pulmonary aneri.. and vein. by media.tinaltumours, aneury.m, gra nulnma, or fihr"" i•.

ANNEX 1

DIAGNOSIS OF PULMONARY HYPERTENSIONBY DI RECT MEASUREME NT

I. c . t.........t"'" or tM ""tmo,..., arter,

Th~ onl, valid method of determining th~ pr~ssure in th~ artery "calhe1~rization of that artery. Th~ usefulness of the indirect m~thod. i.limited.

The introduction of \h~ " ft oat ~ calh~ter ( I) has greatly .implifiwth~ direct m~asur~m~nt of I h~ pressure in th~ pulmonary arl~ry. Mor~

recently, the introduclion of th~ Swan·Gan. cath~ter ha. mad~ possibl~

Ih~ rapid d~termination of the pr~ssur~ in the right caviti.... of th~ h~art

and in th~ pulmonary art~ry, togeth~r wilh lhe " capillary ~ p.... 'ure(wedge pr~ssure) (2, J). Th~ cath~ter has Iwo IUbes and a balloon al lhetip; Ih~ ca th~tor i. introduoed into the right atrium without radioSl'opiccontrol, and the balloon i, then inftatw and is drawn by th~ blood ftowtoward. th~ periphery of th~ pulmonary circulalion, wh~re th~ capillarypr~ssure can be measured.

2. Normal pulmomary art~rial pr<S'IUr ~ at rest

The figures giv~R in the report of th~ WHO hpen Committee onChronic Cor Pulmonal~ (4) may he regarded as valid. The mean pressurein the pulmonary artory does not normally ~x=d l~ mm Hg when th~

.ubject i, at rest in a lying posilion. This value is littl~ alfeciN by ageand n~v~r e.ceeds 20 mm Hg. Hypen ension i. definitely pr=nl if Ihepressure uceeds 25 mm Hg.

The ~ capillary ~ pres'ure i. of the ord~r of 6---9 mm Hg and may ~v~n

reach 12 mm (5); this pressure, too, seem. liul~ alfectw by age. Th~ m~an

" capillary ~ pressure giv~, a good indication of the mean 1~f1 alrial pressureprovided that it does not e.."""d 25 mm Hg (6).

Great ,tress ha, bttn laid in recent y~a", on the vallle of Ih~ ~nd·

diastolic pressure of Ih~ pulmonary anery as an indicator of capillarypressure and/or ~nd-diastolic pressure of the left ventricle ; it is oftenbelieved Ihal there i. no pres,ure gradi~nt in th~ pulmona ry vaSl'ular bedat th~ ~nd of Ih~ diastol~. Ho_ ver, this oo~pl is nol valid in a numberof dinical oondition" particularly Ih~ pulmonary vaocular diseases (7),The a ppearance of a grad;ent hetw""n Ihe mean f'T"'.ure of the pulmonar y

- "' -

ANNEX 2 "artery and the mean capillary pressure, on lhe other hand, indicates anincrease in vascular re>i'lance.

Wh.n th. ha.modynamic ••amination i' conducted in th. 'landingposition, there are diff.ren... in pre>sure and perfusion in diff.rent partsof the lung, and Ih. ~ pulmonary " pre>'nre i$ the pre..'nre m.a'uTe<l in thepulmonary trun k"

3. Norm. 1 pulmOOlary . rt....lal I'«""'re "" effort

Some forms of pulmonary hypertension are lat. nt and become apparemonly when ther. is an increase in blood 1101'1' , It is therefore important toknow Ihe re..pon.. of the nonoal pulmonar~ cireulation to .ffort.

Most of lh. mea,uremen" report. d in the liltrature have been carriedout in Ih. lying position .nd show th.t Ih. mean pulmonary arterialpressure ri... proportion.tel~ less than the c.rdi.c output.

For an oulput of 20 li're.. or more. the mean pulmonary arte rialpr."ure doe' not normally exceed 30 mm Hg. and the capillary preuurerem.ins below 20mm "g (S). In athl.I.... for an output of 25 lilres ormore, the m. aU p.....ure in the pulmon.ry . rt. ry m. y re.ch 3S mm " S.Th. pros,ure gradiem (j>A'--P"r iocr.a.., On .1T0rt (S). lu older people(61 -S3 y.ars) the values observ.d are higher (PA~ _ up 10 SO mm Hg),bul as in younger subjoots Ih. vascular r.sistance is low (8-10); Ih. m••npulmonary pre.., ures on effort of middle-aged subjects differ only slightlyfrom lhose of youuS subjects {Il I.

Th. re i' liule infonoation on the evolulion of pulmonary arterypressure during ex.rci .. in Ih. seared or "anding position,; in onc serieshowever, the Par during exercise carried oul on the bicyd••rgomet.rdid nol ••..,.,d 30 mm Hg for oUlputs up 10 15 litre.. (121. Th. relationshipappears 10 be curvilin.ar, flallening oul beforelhe highest Outpul i, reache<!.The lota l pulmon.ry v. scular re,i"ance decre.....

The validily of the mea,urement or M capillary ~ pr.ssure on effortis 'till come.led . and only very few m.asuremeuts have been made ofleft .trial pressure on effort in man and .ven in animal.; it i, pos,ibl.that Ihi, p.....ure decrease, sliShtly (13). In general. therefor•• the questionof the .volulion of vascular re,i'lal>Ce of the lung during effort rem.in,open to discu"ion ; however. the fall in re>islance i, certainly less Ihanw.s aettpted a fe.... ye.rs ago (14).

The m.thodology employed affect, Ihe ""ults obtained; pulmonaryarterial pressure tends 10 decrease during prolong.d effort althe same level(5), .nd th. repetition of .,.rcise tests also lead' to low.r val"" (15).

• l'A~ ~ , '" ""',~, .""',",1'.., __ "'__,

PR'MARY PULMONARY KY PERTE SsrON

Th. re i. no doubt that mOre information n«d. to be oblain.d on tbeyariou. pressu"," and th. resi.tan..... in the l....r circulation under d.arlyd.fin.d . ..rci.. conditions.

4, M""""n" _ of ""_"",,, . ry hyp«t....iIKI

Th. mechanisms of pulmonary hyportonsion may nry greatly d.pondingon th. und.rlying di..a... It is normal tn distinguish precapillary hypor_I.nsion (which ind udes primary pulmonary hyport.nsion) from the po,t·capillary hyport.nsion. ahhough th.... forms .re occasionally mi..d :po5lcapillary hyportension (e.g" mitral stenosis) may be complicated byprecapillary hyport.n.ion, whil. precapillary hyport.n.ion may includ'a postcapillary component ("g.• th. strongly contested role of diastolichyport.nsion of th. left ventricle in chronic pulmonary di..ases) (16-18).

In chronic disease. of the pulmonary parenchyma_the principalcauses of pulmnnary hypertension -the role of the destruction of th.Ya",utar bed is still d.batabl•• but the contribution of alv.olar hypo.iais universally accepted, The concept of a hyporkin.'ic condition in thesediseases ha. been abandoned; in the chronic conditions (• .g., afler pn.umo­nectomy and in congenita l cardiopalh ie, with I.n·to-right shunt) a v.ryhigh out put may occasionally be accompanied by normal pulmonarypressure (19).

5. Primary ""Imnnary hyp«t....ioa

The pr."ures recorded in the pulmonary artery are often very high­high.r than those observed in chronic lung disease. Hyport. nsion isestablish.d rairly rapidly and prog....... in a ,hort tim• . _t i. not a ffect. dby the inhalation of n.ygen (20). The " capillary W pressure i, generallynormal (20.21 ).

Th. vascular resistance is very bigh, increasing still more on .ffort,and the cardiac out put is poorly adjusted (21).

REF ERENCES

I. G.~""",,~, r . Un< micro'«hniq"" d" ca,M«,;""" cardiaq"" droi, pra';cable." H' du malado san. <on,,,,,,. ,a<!io>scop;q"", O m l"*"",. SI, IU-I92 (I%IH

1, Sw.~, H. J. C, l:f ~L. Ca,M'er;za'ion oflll< n ;n man wi'. use of a fInw.<l ireclNballoo n lipp«! ca,M'er, N... &g-k",d Jo, 1 of Md;"w. 283: 447-<lJI (1970)

J. B",.o~, G , A, M""",,,,men' of pulmonary -.. press"'" b)' 'M ~ow direclNSwan-G.... call...'er. c.srd;,,,.,,Mk., h _ r<h. 6 : 7411-7:» (1971)

4, WH O r « hnic.al Re""n Serie•• No. 2lJ, 1%1 (Re",," of 'M WHO hpen Cnrn·mill.. on OIronlc O>r P"lInonale)

•

"I:

I' :i ~l ... ~l::; ~. ~ .~ ,i: ~"i! _~ 1 li _~s ~ ! st • 0 ~ O;- :- .il. ~ ~ ~. ~ s '" .. .-

a ; :q ~ ~~ ~ P .g ~ ~'~ U ~ ~ 1 4 J! ~'. ! - " . , . - -:. '5 1: ~ 11 ;.; ... :;.- .. --,' -- ~ ~ ~,- 1 ,f! So;J - e ~ e " ~ .s _ 'a .;: .2.!t .S ......:] '0 ~ ;: ~ ~~ ~ ~i el ..l _~ 1 !:;'~ a ~ .!! ~~ ~~ • • o ,,~ - -'- ~';:;~'.'l~ 1lo_ ,1/;; -; c ~ ii ; ·s jl: ~~ "2 '~ ,.!! :;. ~ _ e S

~ l Eh -: H, 'l;e, ,~ Il i g ~ M ~~i ,~ ~ ~ a• !~'i':';: -~ j llo • .!! i ~ 0-': ]e ,,- - ~ s.,g !~~ e i~ i "' ,~ il. -,g ~ ..l! 3 "'. ;:;~ 1 -5,iiJ~ _~~! i ~ '" o~~ ~ ~ h !~-, ' l h ~;;: ~ '\/"'"~,~ & ~ ; _. 5 ~ ~ "'~ ,Il j u: 2 ~. r.: '- ;i.-;:; ~ ,-~ ~ ~ ~ e .~~ i!'P <'lI ... '= X ~ .~~§:;. ~ ~~~

! ° 1 2! ., 1$ ~. ~~ ~~ ~ .... nv a ~ .. .!! ~ ',- § e Y-',s~-:~s e e e s "' ;; ~ 5 ,~ _ 6 l!':"~ ~ "' ~ "o ,,;:; 'l!B:;;:_' I; ~* ~ K_5 "' . ,a .~ .... '~,> .. ,..: .. s s •. _l!'.!! · a ~

l~ -- ~ - e e 'l! c " "1; e ... ." \1'; ' l: I" .-

1 ~-,. ~;::~~ _§o ' I;--!<=n s s ~l~-!~ ;';-Il_I: .~ ,~~

~ "c.] <~E ,,,, ~ to :~ q ~ 1'': h l[ ~ ~ ~1 '~ ~ H ~i I ;,;, '"i'o.!' _£;.;.~~ ] 'Q~i~ ~1i h': ;-.sJ5gEL"i;<l;- l_5 i

~ ~ ,~ l~, § ; i i, i ~fU ~~j['\I ],ii~lt~iJ~!i~~g.uc " ,- - £ ~ ,,_ .,,"d " - J, -I - -;el l'"z ~ ",~~i. "" .!llt S ~ a l=~ :Z :~ 1: Ea "~..i _~ ~ l! ~ ~~-~ i ~ ~~ ~ " <1 _ • ..: ~ - -~ ..i ~ ..i ~ ~ ,e ..: l=;<l~ !~t~~'ii~~S~_~

% ~~ x~ # ol ~~ ~ i a ~ ~~~ ~ O 'E : ~ t <T!-~ -i" l ~~~ '< ~ !'lI -e , "' O i J - -~ » a , -_ '" ", 5 ;z ~ " :I: Ill ] - ~ x , i".: .'-. '- <f <l! ~" ~~ "' J5,; ''''1i ~ "' ': ] · 'll · ~'' 8 · - u.l '~ ': ·~" ! = '~ i ~ ~~1l, 'I:~ i ~ .s ~ -a!·~ "·~ il~ ~f '; \I~t .~~ ~$ ~ ~ ~~:l1 h ~ _M~ P ~ ~ g ~ ~ =h h § '" ~~ ~.'l P h q l<t:1:_0: :I: ~ ~ w ~ o r ;- .. ~ " t/55 ~ " <:'>;"'~0: ~ Cl l!.Il~ ... 'll Cla~", ~"';,; ": ob ,,: $! = ~ ~ ~::::~t: ~~~N

,

~,

~z

~~>z>"~3;/

~<>~

~cz~

"a~•

fo'-;;!' ·';.i 2-'2'2 ·';~C~;;';e -%: f .~ -e ~ .s a ", ",j :§! e ~ ,~ 1i.fi~ .0 _ ;, 1 _ ~ 'll l! :!O s " ~ ~ :;: <> ~

~ ~ -~ i ~ :l! .?> ~ '". ~ ~ ; § f :~ : ~• l.l ., ~ ~ --' i! ." ~ ! , ~ . _ ~::> s e:lil§ ..... __ ... Il~f! I: ~"' ~ _ ~ .§g'QEliiS. -ElI II "' ~ O ~ ' '' Eg ~"E! e II S::>:g __ '0 i! ,5 ,d it '2'2:~gl. _f> :I; ..l! . ::~ ~ U 3' ~ ~ ~-"- ... ~ i! ;;~ _· ~ o ~ t: _ ", .;,_"!O ~ '2 II ,'; ;>. " .= ", ." e .~ JI 0 ill Eo - .8 • -2 " /i ~ ',0 ,":< % 'll " ~oi.s,· <Cis ~ j :ii ::> ~ s I ~ ~.5. ~ ::;: H i ~ ~ '0:a _" "" ~ 1: e I JI ~ 'E ~ ~ - . ~ JI ;;; _. e-~ ;:ijl! z <I; - 'a "j' :;'- ';; _~ ~ " 2" 'f~::> d u '0 '5 ,lI .!l -" _~ z " ~ i a~ ~. ,lI... . i 3 ;; E f ~ ao .. l3~il""c'o -~ c

~~~ -~ ]¥l ~ ] ~ ~ ~~ _~ H ~,~~u~.. .: ... Cl .t El lil ..... u .a ll; Cl Q ~ ,JI ·'i _a .d i 1l,,1l , _~ 5 sc « j" ',§ e n~~6:;l! 'i~

' - J/ " ;;~ ~ .b .0"' ·- ~ ~ .. ~", o. ,l " -~ ~ ':: - -1l .:l ] ::>. l ,0 . ~ :: _~ JI .. s .. , ?;' "

~ ~ hi ~ il ; ~ U~ 8 ff~ i I ! ~ ~ ~ ~ H ~~ ::;:'f; i 'o i 'O l Lo: g o ~n'o O: 'o 2 ~ 'o l! i :e ,q~ ~ ~

~Hlnh£~"8 ~nH Hilsj~lHWI"J~ ot. ~ ,q ,,~ = ~ . .t. z ~": Ii: 't 0: :: is ..,'~ '' _.~ j . t.[

~. 8~ 5~ g ~ 'i~ii! ~,~'§ j,.; ~~.%~~~.,;:~~ 1 ~ ,~=~~ 0; j ]' -l. ~ i:i !f "':ji . a 0 ~ 0 . ~,~ ~ e f <: 'a .! ~ I ::;: '2 i>: g el ,, 8 8 t ~ ~ :.: ' ~ o.;~ ::;:~ z ::;: O: .~ :I: ):I: ~ ,~ .:l ~ !l ol 'E ::;: C ..l i -e:.€ .,; '0 :1: .1 ..l '~ o; ~ <i f:l:£ 0 '0 :':0 o: !::'. 0 o~ 0~ 0; '0 O: C z 'l; ... C U~I5 I!l I!lI!lI!lI!lI5I5 I!l I!l Q I!lI5 I5 is Q I!l

<i~ f,;~,.," 1 -~ ~ i

u~0;11'1" ., "

ill~ ~ I

HI..'l!j

I,"·~~.) ,.,q~Il"j'l;I_ i,11­jilt'1' --,

I

•I

ANNU 3 "Dr J. A, Will. """"i... Prof. ....... Dopan"",", or V" . rinary Seo."",. ColI.~ of AJri­

cull"ral.nd U fo Sei<1>o:o>. Uni....''"'~ of Wi.co,,,in. Madi""". Wise.• USA

Or p, Wi",. De;>o r1men' of In" mal Modici.... Modicol P<>Iy<l inic. Uni..nily of Zllridl.S" ill< , lond

WHO Mc",",;'"

Or S, H...oo. Modicol Offioer. Cord'"""""I.. Di....... World H• • I,h Orp.nizo'ion.Go"'''''. S""' ll< r lond ( SKTr' . 'l)

Or V. Khoteho,OUI'O'I. Modl",l 0fIic<,. N",,-Commu"icabl. Di....... World H..UnOrp n"" ""' . Go"'''''. Swill<rlond

Or T. Su. ...r. AClinl Cho.f. Cordio"""",ta, Di....... World H..ltn Or;anization.Gono"". S""ill<,lond