Raynaud's Disease and Primary Pulmonary...

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Raynaud's Disease and Primary Pulmonary Hypertension By GUILLERMO C. CELORIA, M.D., GILBERT H. FRIEDELL, M.D., AND SHELDON C. SOMMERS, M.D. PARTICULARLY since the advent of cardiac catheterization, primary pulmo- nary hypertension has been of increasing in- terest to clinicians and pathologists alike. To some it represents a pulmonary vasospastic disease, presumably of neurohumoral type, analogous to systemic essential hypertension. The occasional association of primary pulmo- nary hypertension with Raynaud's disease is thought to support this theory. Seven case reports are available in which Raynaud's disease was associated with what was considered to be primary pulmonary hypertension.'-4 The detailed findings in the case of Taft and Mallory' and that of Wade and Ball2 are of particular interest because of the scarcity of pathologic investigations in cases of Raynaud's disease with or without pulmonary hypertension. Pulmonary hypertension was confirmed by cardiac catheterization in 3 of the 7 cases, but without autopsy confirmation. One of these 3 catheterized patients (case 2 of Smith and Kroop3) has since died, and an autopsy was performed. Report of Case N. C., (A58-159). A 41-year-old white married telephone operator was in generally good health until 1951, when she noticed numbness, tingling, and blanching of all fingers up to the palm when exposed to the cold. During the previous several years she had had a cholecystectomy, a breast biopsy, and a total hysterectomy, but no history of Raynaud's phenomenon. Her symptoms grad- ually progressed so that constant warmth was necessary to prevent pain. Atrophic changes of the fingertips became evident later. In 1953 bi- lateral thoracic sympathectomies resulted in dis- appearance of symptoms except for continued blanching of her fingers on exposure to cold. Six months later, during the winter, she developed Raynaud's phenomenon in her toes and subse- quently bilateral lumbar sympathectomies were performed in 1954 with good results. From the Department of Pathology, Massachusetts Memorial Hospitals, Boston, Mass. Circulation, Volume XXII, December 1D9Q Shortly after the final syvmpathectomy she began to experience episodes of dyspnea, weakness, and dizziness. These occurred only while she was stand- ing, especially after exertion. She had numbness and tingling of the body during some of these episodes and fainted on several occasions. Blurring of vision was noted at times and scotomata were seen with some of the attacks. The exertional dyspnea became progressively more severe and in April 1956 she was first ad- mitted to this hospital. The essential clinical fea- ture included (1) a loud and "split" pulmonic second sound, (2) a blood pressure of 135/100 mm. Hg with no appreciable positional change, (3) ain enlarged right ventricle and pulmonary artery with normal-size left ventricle and left atrium seen on the roentgenogram, (4) electrocardiographic evi- dence of right ventricular hvpertrophy, and (5) reproduction 6f some of her symptoms by hyper- ventilation. Three months later, ankle edema was present. Studies of pulmonary function at this time were indicative of primary pulmonary hyper- tension. She was rehospitalized for treatment and fur- ther study in October 1956. At that time both right and left ventricular failure were found. Over the upper part of the body there were numerous telangiectases which blanched on pres- sure. Cardiac catheterization confirmed the diag- nosis of marked pulmonary hypertension with advanced right heart failure. The cardiac catheterization data included cardiac output, 3.8 L. per minute; cardiac index, 2.08 L. per minute per M.2; and arteriovenous oxygen diffusion, 7.2 vol. per cent. Oxygen saturations of the pulmonary artery, 52.3 per cent; right ven- triele, 53.9 per cent (paired sample) ; right ven- tricle, 47.3 per cent; right atrium, 45.6 per cent (paired sample); superior vena eava, 40.4 per cent; and brachial artery, 93.3 per cent. Pressures recorded in mm. Hg were right atrium 20; right ventricle 105/20; pulmonary artery, 105/40; pul- monary "capillary" 10; and systemic blood pres- sure, 130/80. These changes were interpreted by the catheteri- zation team as showing advanced right-sided heart failure from marked pulmonary hypertension. Elevated pulmonary artery pressure and normal pulmonary "capillary" pressure were considered to indicate narrowing of pulmonary arterioles, rather than an element of left-sided heart failure. A de- tailed analysis of these findings will be reported elsewhere by Chobanian et a!5 1.055 by guest on July 8, 2018 http://circ.ahajournals.org/ Downloaded from

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Raynaud's Disease and Primary Pulmonary HypertensionBy GUILLERMO C. CELORIA, M.D., GILBERT H. FRIEDELL, M.D.,

AND SHELDON C. SOMMERS, M.D.

PARTICULARLY since the advent ofcardiac catheterization, primary pulmo-

nary hypertension has been of increasing in-terest to clinicians and pathologists alike. Tosome it represents a pulmonary vasospasticdisease, presumably of neurohumoral type,analogous to systemic essential hypertension.The occasional association of primary pulmo-nary hypertension with Raynaud's disease isthought to support this theory.

Seven case reports are available in whichRaynaud's disease was associated with whatwas considered to be primary pulmonaryhypertension.'-4 The detailed findings in thecase of Taft and Mallory' and that of Wadeand Ball2 are of particular interest becauseof the scarcity of pathologic investigations incases of Raynaud's disease with or withoutpulmonary hypertension.Pulmonary hypertension was confirmed by

cardiac catheterization in 3 of the 7 cases,but without autopsy confirmation. One ofthese 3 catheterized patients (case 2 of Smithand Kroop3) has since died, and an autopsywas performed.

Report of CaseN. C., (A58-159). A 41-year-old white married

telephone operator was in generally good healthuntil 1951, when she noticed numbness, tingling,and blanching of all fingers up to the palm whenexposed to the cold. During the previous severalyears she had had a cholecystectomy, a breastbiopsy, and a total hysterectomy, but no historyof Raynaud's phenomenon. Her symptoms grad-ually progressed so that constant warmth wasnecessary to prevent pain. Atrophic changes ofthe fingertips became evident later. In 1953 bi-lateral thoracic sympathectomies resulted in dis-appearance of symptoms except for continuedblanching of her fingers on exposure to cold. Sixmonths later, during the winter, she developedRaynaud's phenomenon in her toes and subse-quently bilateral lumbar sympathectomies wereperformed in 1954 with good results.

From the Department of Pathology, MassachusettsMemorial Hospitals, Boston, Mass.

Circulation, Volume XXII, December 1D9Q

Shortly after the final syvmpathectomy she beganto experience episodes of dyspnea, weakness, anddizziness. These occurred only while she was stand-ing, especially after exertion. She had numbnessand tingling of the body during some of theseepisodes and fainted on several occasions. Blurringof vision was noted at times and scotomata wereseen with some of the attacks.The exertional dyspnea became progressively

more severe and in April 1956 she was first ad-mitted to this hospital. The essential clinical fea-ture included (1) a loud and "split" pulmonicsecond sound, (2) a blood pressure of 135/100 mm.Hg with no appreciable positional change, (3) ainenlarged right ventricle and pulmonary artery withnormal-size left ventricle and left atrium seen onthe roentgenogram, (4) electrocardiographic evi-dence of right ventricular hvpertrophy, and (5)reproduction 6f some of her symptoms by hyper-ventilation. Three months later, ankle edema waspresent. Studies of pulmonary function at thistime were indicative of primary pulmonary hyper-tension.

She was rehospitalized for treatment and fur-ther study in October 1956. At that time bothright and left ventricular failure were found.Over the upper part of the body there werenumerous telangiectases which blanched on pres-sure. Cardiac catheterization confirmed the diag-nosis of marked pulmonary hypertension withadvanced right heart failure.

The cardiac catheterization data included cardiacoutput, 3.8 L. per minute; cardiac index, 2.08 L.per minute per M.2; and arteriovenous oxygendiffusion, 7.2 vol. per cent. Oxygen saturations ofthe pulmonary artery, 52.3 per cent; right ven-triele, 53.9 per cent (paired sample) ; right ven-tricle, 47.3 per cent; right atrium, 45.6 per cent(paired sample); superior vena eava, 40.4 percent; and brachial artery, 93.3 per cent. Pressuresrecorded in mm. Hg were right atrium 20; rightventricle 105/20; pulmonary artery, 105/40; pul-monary "capillary" 10; and systemic blood pres-sure, 130/80.

These changes were interpreted by the catheteri-zation team as showing advanced right-sided heartfailure from marked pulmonary hypertension.Elevated pulmonary artery pressure and normalpulmonary "capillary" pressure were considered toindicate narrowing of pulmonary arterioles, ratherthan an element of left-sided heart failure. A de-tailed analysis of these findings will be reportedelsewhere by Chobanian et a!5

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CE106EROIAA, FRIEDE1AL, SOMEAIUES

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Figure 1 rigure 3A sin all musculaer artery is seen? with extreme NW ma of the wall is seen in this small muscultrno rrowing of the lumen, cellular in.tmal prolifera arter iatlelition to itiman(l cellutlar proliferationtion, and fibrosis. The inner elastic lamina is frayed) {-zZ f7 e;<Pele t R eea dflb osi s. Mallsfsonz trichrRomne.and in some areas is disrupted. Verhoeff-vanGieson.

Figure 2High-power viri of tnall musculair artery oai theight and its arteriolar branch on the left showcscellular intimal 1rolif'rration in both e'ssels withnarrowing of their 11Minva. Yerhoeff- ran Gieson.

Skini tid muscle biopsies were reported to showdoe(lelice of seleroderiia or otlier collagen dis-

ease. No clinieal or radiologic evidence of seler o-

deumKia (levelolped liter in hier course. She was dignitalized, g-iven iereuriald diuretics, and dischargedxwith the clinical, diagnoses of primary pulimonaryhypertension antd Raynaud's dlsease.The platient was subsequently hospitalized on 3

oecasions for trieatrimerit of ecardiac failure. l)uring

the last of these, in l)Deeliber 1 95S, she died aftera prolonged pleriod of hypotension. An-1 auatopsy

was perfori-ed 6 lourl s after death.

(Oi gross exammination there wa\tts Ceyanosis of theface aniid of the fing-ertips. Over the faice andt'hest niultiple sma1ll dairk red-blue areas resem-blihun telangieeta ses were seen. The skin on allfillgers was smiiootli aud shin)v, and the fingelrnailson 1both lblands were shiot and roug)-h. There wasslighlt peripheral edemtia.

TIn the right )leurall eavity 300 ml. of yellow-pink watery fluid were founi, aid the lung aip-peared eollapsed. A few fibrous adhesions wereIlso noted betweeni the IoNer lobe anid the posteriorparietbl pleurai. The left plleural eavity was oblit-erated hr dense ftibrous adhe,;sions that somiiewhatconlstricted the lung-.

There werie aln estimiiated 400 iiil. of thiin, straw-(olored fluid iii the pericairdial caivity. The hear-tweighed 410 G(i3. and wa-is enlarged, due prililarilyto diiatation and some hypertrophy of the r-ightatriutni aMid venifitrlle. The ventriele measured 0.7ciii. in thickniess, com)ipared to norimial tlhickness of0.4 cmii. The pulmtionary aritery waVfs dilated andsiowmedl soni e athlieroseler osis.

Te'lle riglht lung- weighed 210 Gin,. anid the left190 Giat. Tlhey aippeared nega-tive, exeept for a]smi1all amouii ofpi0nk iniueoidI imiaterial in soIme ofthe bronchli. r11111.v?was miioder-ate di.lata-tion of the)ulimonaIry arteria-l branches and the largest showedthickening- of thleir xx a-ils anid scatttered yellowishirntiirnal plaques.The othier organs appeaired ne(1o,gatixe, except for

an al)l)arent telangiectatsis of the jejunumn.Micro,scoeopic sections of botlh luiigs showed slight

septal flbrosis in somiie regions, dilhatattion of a fewailveoli with rupture of so11w otf the septa, and illildSupbjleural fibrosis, but no priniiary parenchyrmialdise,ase. In tIme lung, the primary disease process

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RAYNAUD 'S DISEASE

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Figure 4 Figure 5Splittingq of thle last fibers is seen in the UpiJCt .Vecr)oth inig arteritis with th rombosis is seen in thispar-t o* this miediuim-sized miuscula,r arterqy, wfheueas medium-siued muscuila-ir artery app?roximately 500the eclastic fibers elisctere in the inner anld outer micronis in diamete)r. The wall is intiltrateel pri-laminar are ra)(-ither wriniled. Cellutlar intimal pro- manilaU by neutrophils. There is relatively littleliferationt uld narrown of the lumen are also j)ro7ile attira e change such as that depicted inseenI. Ver-hoeffr-1 GieSon. smaller muscutlar arteries. Ifematoxylin and rosin.

appeared to be vasculair, affectin all branches ofthe arterial, and to a lesser extent the \'QilouS,pulmonairy tree.

There w -as miarked aitherosclerosis of the largerarteries, witlh eccentricna-trrowing of the lumnens inthe vicinitv of subintiiua-il )laiques. Oil-red-O stainisfor fat show-ed al)n(dliant lipid in these plaques atndelsewhere in the subintimaz-l tissue. No proliferatiollof endotheliail cells w,as apparent. There w%ias sliglhthypertrophy of the muscular mnedia, and elasticfibers were wrinkled aind fragmnented in somneairteries.

Trhe mnuseul;ir a-irteries, ranging frotmi 1.00 to 1,000miciron'sI in (liamiieter, also showed marked change,but of a differenit type. Below 250 to 300 inicronsii diamieter, the m-nost proominent finding was aRmiiarked cellular intimiial proliferation wvith extreimienarrowing or occlusion of the lumiiens (figs. I to 3).These h-perplastie cells stained with the Verhoeff-van Gieson stain like smnooth mnuscle.6 Slig,ht in-timial fibr'osis was associaited in some instances,hut the proliferativ-e cha-inge predomninated.

In the inuseular arteries that exceeded 300 ni-eronis in diameter, solnie lhyperplasia of endothelialcells wa$s a-tlso seen, and inoderate edemna of mnanyof these eells wavs noted. The most characteristicintimal ethange however, was an eccentric fibrosisof slight to imioderate degree (fig. 4).The miedia of muscular arteries of all sizes was

g,enerally thickened, primwarily by an increase insimooth imiusele buit to somiie extent by fibrosis. Theelastic lamiinae of iimedimai and sn-iall arteries wasoften wrinkled, thickened, and occasionallv frag-imiented. Edema of the adventitia was evident in

Circulation, Volume XXII, December 1960

miiost of the inuscular arteries of smiall ta ad miedium1size.

Acute arteritis wais nloted in sever-al musculararI'ter'ies that ra,nred froimi 2.50 to 500 milicrons indiameter. These arterial wvalls showed focal ne-erosis with neutiophils infiltrating all layers of thewall anid tlhe, adjacent conneetive tissue. In sonieof these vessels thromuibi w-ere pr-esent, a few ofwlhielh showed early peripher-al organization (fig.a). A throinibus, possibly of emibolic origin, wasals,o noted in oiuc section in smnall muscularartery of about 100 mnicrons in diamneter but hemethere was no apparent arteritis.

In the arterioles the iiiarked intimnal cellularproliferationi (fig. 63) was also )resent and thearteriolar luniens were either malrkedlv narrowedor occluded. In sonie arterioles, particularly thosenear the parent arteries, smooth muscle persistedin the media while in others the wall contained aninereased aimount of relativelv acellular tissue thatstained like fibrous tissue with the Verhoeff-vanGiesoln stain.

Elsewhere dilated arterioles with thinned wa,illswere noted.6 Small veins slhowed moderate toiniarked s5ubintimtml acelluilar fibrous tlhiekening, b1)tin conitrast to arterioles had no endothelial pr-o-liferation (fig. 7). Larger veins also had fibrousthickening of their walls and in addition sonieatheroselerotic changes.

Slight to nmoderate hyaline corlonary arteriolo-sclerosis and slight interstitial mnyoeardial edeinaand fibr:osis xwere present. In the -spleen, pancreas,and liver there was slight to immoderate hyalinethickening of arterioles with narrowing of their

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1CELORIA, FTRIE)EDLL, SoAINIjIERS

Figure 6 Figure 7Ma rkedl narrowing o'f small arteriolar liutt by Iwo simill rcins4 with ccllarl4f fit) rOsis of theirct"llular proliferation iS ne i'1 in this hligJh-powcerhjphotomaicro1]raph. Werhoeff 'an Gieson. Icoll4 , are ' n1l crn r)i f)f t//f,

o444(1. jI(4a4ceac iflptOn. i (Ils. ord Massontr1ichr Iomr. fl'8fl{}S l tt#C fls0 l '(.iI-.9s.

Iiimnens. In larger arter ioles and smiiall muscularaLrterlies tlher-e werel, inalinn, slight hy'pe plasmof endothelialI cells 4d11(1 of lilediail smiiootlh n iasciccells and frlying of adveittitial collagen.

Only nnniniil intimnal pl)olifer-ationlt and li.alinea rtel'ioloseleo-isi evxixted iii the kidnexvs an(l otlherorgans, except for the skini. Here ther-e wasmlloderate hyaline arteriohlar tlhiekening as well asbotlh celbila r endothelin1 hyperpla sia and medialhypertrophiy of smnall muselarall,1-teries. Sectionlscould not he obtained fr-omn digital vessels,.

DiscussionSmiiith 41(1 Kroool)3 iln their cases 1 an(il 3,

itoted marke( p)ulinonary arteriolar seleiLos1is.Fromn tlheir ])hotoii icrograp)hs there wouldalso ap)pear to hav\7e been extenisive inivolve-utieit of smyial llnmuscular ar teries. The su.b-intin-l- thiekeni.nos- of the arterial and1 acrte-r iolar wav(ills appeared to l)e relatively acelulz1arill echaracter. Taft anid M11lalloryl also placedthe lesion primarily iii the arterioles and dr'ewa parallel between tlhe chlanoges in thcse ves-sels and those in 'rapidly progressive neph-roselerosis.'' The thickenied arterioles wererelatively acellular, and ito areas of necriosiswere inoted.

In tlheir autopsied case, Wade and Ba12found the mnajor ehange to be in the smallermuiscular arteries, ranging from 80 to 250microns in diameter. The lumens of these ves-sels were reuceed by a concentric intimnalfibrosis or fibroelastosis characteristically un-

LlrrO(Ilnl)allicI n' imuflalllnnalIt)oolrx' inlfilt ratioll or-degeneraition of thie mtedia or adveoi-titia. Rirereeelt blit l1o10remote tlirollnbi w0vere nioted. Aniatrial septal (lefect 2 by, 1.5 em. in greatestdliinelliolls wvals present inl th-iis case and al-tflonlgh it iwas considered by the authorsmerelv asi ani inc(idenital findling it could ha-vealtere(d pulmonar (laiarnisenc"iouglh to ae-count for thie morpholog-ie finding]is. Sinilar1a'viscular chicanges were n-ioted ini t-he} (ligitalarteries, panireas. and klidne-ys. whereas afoeal fibrin-oid arteritis wass Iote(l ini the ad-renal g(lands and a mild celullar a,rteritis wvasse,eni ini the liver. Some of the prominlentarterial lesions in their (ea1s-e were thiought toresemble thie changes Hin slerodlera, whereasotler lesiolns sillallic'ted )olartrleritis.The mait pilnmornary lesioni in the presen-t

ease was vascular also inivolvingi (chiefly thesmnall muscuilar arteries aniid ar terioles. Tncjontrast to the pi-eviously reported (eas;ies,however, these viessels were occluded by theproliferationi of enidothelial (cell, a ehangeniot observed elsewhere in the body. TIn pre-v\ious eas;es thle thickenling of pulmonary vas-cular walls was du1e to aln in.crease in rela-tivelyaeVllular fibrous or filbroelastie tissuie.Tf the same uniderlying disease process ispresent inl our easse as in those of Taft andMalloryvl Smnith anid Kroop,3 and WVade and

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RAYNAUD'S DISEASE

Ball,2 and if cellular proliferation precedesfibrosis as in other vascular disorders, thenin our case the cellular endothelial prolifera-tion in the small muscular arteries and arte-rioles would represent earlier changes thanpreviously described.The necrotizing arteritis restricted to the

muscular pulmonary arteries from 250 to 500microns in diameter is interpreted as an acuteresponse to a high degree of pulmonary hyper-tension proximal to the major point of ob-struction to pulmonary arterial blood flow,namely in the distal arteries and proximalarterioles. Thrombosis in these vessels isthought to be secondary to the arteritis. Arte-ritis was not found in other organs.

This patient suffered basically from a wide-spread disorder of the arteries and arterioleswith marked exacerbation of vascular diseasein the lungs. The morphologic findings are inpart compatible with the hypothesis of Smithand Kroop3 that the pulmonary hypertensionis secondary to a recurrent arterial spasmsimilar to that causing the peripheral mani-festations of Raynaud's disease. The muscularhypertrophy of the media, the occasionallyobserved concentric arrangement of smoothmuscle nuclei, and the wrinkling of the elasticmembranes of the small muscular arteriesfurnish morphologic evidence of vasospasm.These findings, however, may to some degreealso represent compensatory changes in re-sponse to increased intravascular pressure.Complete resolution of the etiology of thepulmonary vascular changes in these cases,therefore, must await further studies.

SummaryA case of Raynaud's disease with autopsy

is reported in which the clinical picture wasdominated by pulmonary hypertension ap-parently unassociated with any significantpulmonary parenchymal disease. Microscop-ically cellular intimal proliferation of small

pulmonary muscular arteries and arterioleswas the most characteristic lesion. In severalproximal medium-sized muscular arteriesthere was necrotizing arteritis with thrombusformation. Similar vascular lesions were notfound in other organs, although generalizedarteriosclerosis and arterioloselerosis werepresent. The pulmonary vascular changes arethought to represent a local exacerbation ofgeneralized vascular disease, but a specificetiology was not apparent.

Summario in InterlinguaEs reportate un caso de morbo de Raynaud con

necropsia, in que le tableau clinic esseva dominateper hypertension pulmonar apparentemente non-as-sociate con significative morbo pulmono-parenchymal.Microscopicamente, le proliferation cellular del in-tima in le arterias e le arteriolas del musculo pul-monar esseva le lesion le plus characteristic. Inplure arterias muscular proximal de dimensiones in-termediari, arteritis necrotisante con formation dethrombos esseva constatate. In altere organos nullesimile lesiones vascular esseva trovate, ben quearterio- e arterioloselerosis generalisate esseva pre-sente. Es opinate que le alterationes pulmono-vas-cular representa un exacerbation local de generalisatemorbo vascular, sed nulle etiologia specific essevaapparente.

References1. TAFT, E. B., AND MALLORY, G. K.: Primary

pulmonary vascular sclerosis. Arch. Path. 42:630, 1946.

2. WADE, G., AND BALL, J.: Unexplained pulmonaryhypertension. Quart. J. Med. 26, 83, 1957.

3. SMITH, W. M., AND KROOP, I. G.: Raynaud 'sdisease in primary pulmonary hypertension.J.A.M.A. 165: 1245, 1957.

4. SCHUMACHER, E. E., JR.: Cor pulmonale inassociation with Raynaud's disease. Report ofa case with sympathectomy. Henry Ford Hosp.Bull. 5: 256, 1957.

5. CHOBANIAN, A. V., HALPERIN, M., AND HOLLANDER,W.: The mechanism of effort syncope in pri-mary pulmonary hypertension. In preparation.

6. HEATH, D., AND EDWARDS, J. E.: The pathologyof hypertensive pulmonary vascular disease. Adescription of 6 grades of structural changesin the pulmonary arteries with special referenceto congenital cardiac septal defects. Circulation18: 533, 1958.

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SOMMERSGUILLERMO C. CELORIA, GILBERT H. FRIEDELL and SHELDON C.

Raynaud's Disease and Primary Pulmonary Hypertension

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1960 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.22.6.1055

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