Microangiography of the Pulmonary ArterialSystem in "Hypoplastic Left Heart Syndrome"

By CRAWFORD A. GRANT, D.V.M. (Tor.), V.M.D. (Sthlm),

ANi) BEN\GT ROBERTSON, M.D.

SUMMARYMicroanigiographlic examinatioin of the pulmoniary arterial svstem in 12 n1ewborn in1-

fants with conicomitanit steniosis or atresia of the aortic anid mitral orifices showed thatthe intrapulmonary arterial pattern is inifluenced by the state of the forameni ovale. Ininifanlts with aortic atresia with a prematuirely closed foramein ovale, that is cases inwhich the left side of the heart is a cul-de-sac, there is moderate or prominent tortul-osity of the intralobular pulmonary arteries iindicatinig conigenital pulmonary hvperteni-sion. This feature is less promiinient or absent in infants with valvular insufficiency ofthe foramen ovale, regardless of the postnatal age of the patient.

Additional Indexing Words:Congenital pulmonary hyper-tensionMitral atresia Aortic sten(osis

STRIPPED of its morphogenetic and purelyclinical connotations, the term "hypoplas-

tic left heart syndrome" (HLHS) refers tocardiac malformations characterized basicallyby concomitant atresia or stenosis of the mitraland aortic orifices, with a secondary andexplicable relationship of the other anatomicfeatures to these defects.' Without compensa-tory mechanisms, the constellation of mitraland aortic obstruction implies impairment ofthe pulmonary venous return and the devel-opment of congestive pulmonary hyperten-sion. Cardiac catheterization data} as well as

morphometric observations on muscular pul-monary arteries4 > have suggested pulmonaryhypertension even in newborn infants withHLHS.

From the Department of Pediatric Pathology Karo-linska Sjukhuset, S-104 01 Stockholm 60, Sweden.

Supported in part by The Swedish MedicalResearch Council, project K70-12X-3029-01, and bythe Swedish National Association against Heart andChest Diseases.

Address for reprints: Dr. C. A. Grant, Departmentof Pathology, Karolinska Sjukhuset, S-104 01 Stock-holm 60, Sweden.

Received June 7, 1971; revision accepted for publi-cation September 17, 1971.

382

Forameni ovale M Mitral steniosisAortic atresia Ductus arteriosus

To complement our morphologic analysis ofHLHS, we have applied a microangiographictechnic for study of the intrapulmonaryarterial system. More specifically, we wereinterested in finding out whether the micro-angiographic pattern and, particularly, signsof pulmonary hypertension are influenced byintracardiac shunts potentially capable ofimproving the drainage of the more or lessblind alley formed by the left side of theheart.

MethodsMaterialThe 12 infants upon whoml this r-eport is based

form part of a largei consecutive uinselected seriesof 33 cases of HLHS. Material from four of these12 infants had been collected anid frozen someyears previously as part of another projectunrelated to HLHS. The remaininlg eight infantswere encountered more recently and withoutselection.The types of HLHS represenited in the case

series are listed in table 1. To supplement theinformation supplied in the table, it cani bepointed out that the ductus arteriosus was widelypatent throughout the series wlhereas the state ofthe foramen ovale differed considerably. Closureof the foramen ovale was noted in four inifanitsaind in tlhree of these must be considered to bepremature in view of their age. Six infanits had

Ciru-ul,aiaon, Volume XLV, February 1972

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from

PA-SYSTEM MICROANGIOGRAPHY

Survey of Microangiographic andSyndronme

Table 1

Histologic Findings in 12 Infants with the Hypoplastic Left Heart

Intralobular pulmonary vein elasticBirth Type of cardiac malformation arteries hyperplastia

Age weight Mitral Aortic Foramen Media (arteriali-Case (days) Sex (g) ostium ostium ovale Tortuosity index zation)

A 57 1 M 3890 Stenosis Atresia Patent + 0A 169 1 F 3770 Stenosis Atresia Closed ++ 0.19 +A 174 2 M 3080 Stenosis Atresia Inicomplete 0 0.19 0

valveA 175 2 M 3160 Stenosis Stenosis Practically + 0.23 0

closedA 39 3 F 3275 Atresia Atresia Floppy valve 0 0A 147 3 M 3800 Stenosis Atresia Floppy valve + - 0A 172 3 F 3300 Atresia Atresia Incomplete 0 0.15 0

valveA 143 6 F 4210 Steniosis Atresia Patent + 0A 181 6 F 2340 Steniosis Atresia* Practically ++ 0.19 +

closedA 191 7 M 3840 Stenosis Atresia Patent, ++ 0.17 0

thickenedvalve

A 5 10 M 3710 Stenosis Atresia Incomplete + 0valve

A 171 40 M 2910 Stenosis Atresia Closed, +++ +minorfenestrations

*Surgery at the age of 5 days with aortic valvulotomy and atrial septostomy.

distinct morphologic evidence of valvular insuffi-ciency at the foramen ovale; in three the valvewas apparently normally formed but was inade-quate to cover the extremely dilated interatrialcommunication, and in three it was greatlyoverdimensioned, thickened, and floppy to suchan extent that it prolapsed to the right of theinteratrial septum (fig. 1). In another infant, thevalve of the foramen ovale was greatly thickenedbut was not overdimensioned or prolapsed. In theremaining infant the foramen ovale was patentand covered from the left by an apparentlynormal valve. The interventricular septum wasintact in all cases. No examples of anomalouspulmonary venous return were encountered in theseries.

TechnicThe pulmonary arterial tree of one or both

lungs was injected with a 7.5 to 10% aqueoussuspension of fine barium sulfate (Micropaque)at a pressure of 60 to 80 mm Hg. The injectiontime was at least 15 min; longer periods ofinjection do not enhance the contrast filling of thespecimen. After injection, the lungs were fixed in10% neutral formalin. Frontal slices of the lungs, 2to 3 mm thick, were then cut and radiographed.Circulation, Volume XLV, February 1972

Representative slices were selected for microangi-ography, embedded in a 1:4 mixture of yellowbeeswax and paraffin (Fibrowax), and cut in1,000 to 1,500-,u thick blocks which were thenstereomicroangiographed with a technic describedin detail elsewhere.6

Tortuosity of intralobular pulmonary arterieswas taken as angiographic evidence of pulmonaryhypertension.7 The degree of arterial tortuositywas expressed in a four-grade scale from 0 to+++ (fig. 2). Previous microangiographic stud-ies8' 9 of the intrapulmonary arterial pattern of thenormal late fetal, neonatal, and infantile lungserved as a basis for comparison with the presentseries.The lungs were also studied histologically in

routine paraffin sections, stained with Weigert'selastic tissue stain, and counterstained with vanGieson's stain. In the cases from which non-injected blocks of pulmonary tissue were availablefor histologic examination, the media index ofmuscular pulmonary arteries was determinedmorphometrically according to the principlesoutlined by Wagenvoort.10To avoid bias, grading of arterial tortuosity in

the microangiograms and evaluation of thehistologic slides were done without access to

383

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from

GRANT, ROBERTSON

Figure 1

Case A 147. Floppy valve of the foramen ovale. Seen from the rig/ht atriumn (A), the excessiveand thickened valvtlutle tissue has prolapsed toward the observer. The interatrial communica-tion formed in this mianner can be better appreciated in B which displays the same valve fromthe left atrium. Note the stenotic miitial orifice (arrow).

detailspatient.

of cardiac morphology and age of the

Results

Microangiographic Findings

Some degree of tortuosity characterized theintralobular pulmonary arteries in nine infantswith HLHS. This feature was particularlyprominent (+++) in the oldest infant of theseries (age, 40 days) in whom at autopsythe foramen ovale was closed except for minorfenestrations. Tortiiosity of intrapiulmonaryarteries was moderately prominent (++) intwo infants in whom the foramen ovale was

prematurely closed, and in one infant inwhom the patent foramen ovale was coveredwith a thickened but seemingly competentvalve. Slight (+) tortuosity of intralobularpulmonary arteries was recorded in one infantin whom the foramen ovale was practicallycompletely closed at 2 days of age and in fourinfants with patency or valvular insufficiencyof the foramen ovale. In the remaining threeinfants in the series, all with valvular insuffi-ciency of the foramen ovale, the microangio-graphic pattern of the pulmonary arterial sys-

tem was interpreted as normal (table 1; fig. 2).In one case (A 5), the number of

bronchopulmonary arteries in the circumhilarportion of the lung was slightly increased.There was no evidence of abnormal arterialbronchopulmonary anastomoses in the caseseries.

Histologic Findings

Routine sections from the lungs showed noparenchymatous lesions except congestionand, in some cases, intraalveolar edema andhemorrhage. Muscular and transitional pul-monary arteries, as well as pulmonary arteri-oles were primarily interpreted as normal infive and as unduly thick-walled in seven cases.However, in only one instance (A 175) wasthis latter impression corroborated by anabnormally high media index (0.23). In theother cases in which morphometry of themuscular pulmonary arteries was done, themedia index ranged between 0.15 and 0.19,that is, within normal limits for the perinatallung.1' Intimal fibrosis and thrombotic orplexiform lesions were not observed.

Circulation, Volume XLV, February 1972

384

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from

PA-SYSTEM MICROANGIOGRAPHY

Figure 2

Microangiographic pattern of the intrapulmonary arterial system in HLHS. (A) Case A 39.Normal intrapulmonary arterial pattern scaling down from elastic-transitional branches atupper left to muscular intralobular branches. No appreciable arterial tortuosity. Moderatedegree of alveolar capillary filling; x 13.

(B) Case A 171. Cornesponding segment of the intrapulmonary arterial tree with prominenttortuosity (+++) of the peripheral muscular branches. In this field there is virtually no fillingof alveolar capillaries (an inconstant finding in pulmonary-artery-injected specimens from casesof pulmonary hypertension); X 13.

The normal pattern in A was found in a 4-day-old infant with mitral and aortic atresia butwith an incompetent floppy valve of the foramen ovale which could permit a decompressiveleft-to-right shunt. The hypertensive pattern in B was obtained fiom a 40-day-old infant withmitral stenosis, aortic atresia, and a closed foramen ovale.

In three cases the intrapulmonary veinshad elastic hyperplasia with arterializationas defined by Wagenvoort,12 that is, condensa-tion of medial elastic fibers into distinctinternal and external elastic laminae. Nochanges of this type were noted in thepulmonary veins in the other nine infants(table 1; fig. 3).Circu/laton, Volume XLV, February 1972

Discussion

The HLHS, in our view, is basically a defectinvolving the mitral and aortic orifices. Inthese cases the right heart is invariably dilatedand hypertrophied, the ductus arteriosus ispatent and wide and the ascending aorta verynarrow. The thickness and the degree offibroelastosis of the left ventricle depend upon

385

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from

GRANT, ROBERTSON

*;.:V;

,,,

I....II.r~:,:

Figure 3

Histologic appearance of pulmonary vascular changes in HLHS. (A) Case A 175. Undulythick-walled muscular pulmonary artery in infant with mitral stenosis, aortic stenosis, andclosed foramen ovale. Media index of muscular pulmonary arteries 0.23. Age 2 days. Elastin-van Gieson; X 550. (B) Case A181. Elastic hyperplasia in small septal pulmonary vein. Thevein is "arterialized," that is, there are well-differentiated internal and external elastic laminaeenclosing the media. Case of mitral stenosis,days. Elastin-van Gieson; X 210.

whether this ventricle is a cul-de-sac or hasanother outlet, that is, has a ventricular septaldefect, in addition to the partially or whollyclosed valvular orifices. The same conditionsapply to the left atrium; here the volume andwall thickness depend upon the flow throughthe gaping open or closing foramen ovale.'

In the present series, the interventricularseptum was consistently intact, and the onlyvisible potential intracardiac shunt was pro-vided at the atrial level, by valvular insuffi-ciency of the foramen ovale. The morphologicprerequisite for an interatrial shunt is easilyrecognized when there is incomplete coveringof the foramen ovale, due to either underde-velopment of the valve or dilatation of theforamen. The pathway is less obvious whenthere is an overdimensioned, floppy valve. In

aortic atresia, and closed foramen ovale. Age, 5

the latter condition, the interatrial left-to-rightshunt seems to be facilitated by herniation ofthe abnormal valve through the foramen ovaleas noted by Kanjuh and associates.'.3The presence of a cardiac septal defect does

not necessarily imply a shunt mechanism.However, in view of the hemodynamic situa-tion in HLHS, an interatrial left-to-right shuntseems highly probable in infants with valvularinsufficiency of the foramen ovale. Such ashunt would no doubt enhance the pulmo-nary venous drainage and hence reduce therisk of pulmonary hypertension. Our micro-angiographic findings suggest that this in factis the case; tortuosity of intralobular pulmo-nary arteries was absent or only slightlydeveloped in those infants in whom an

Circulafnon, Volume XLV, February 1972

386

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from

PA-SYSTEM MICROANGIOGRAPHY

interatrial shunt could be assumed on morpho-logic grounds. Conversely, infants in whomthe foramen ovale had closed or had aseemingly competent valve had moderate orprominent tortuosity of intralobular pulmo-nary arteries, an indication of more advancedpulmonary hypertension. Arterial tortuositvwas particularly prominent in the oldest infantin the series, but was otherwise unrelated tothe age of the patients.

Practically complete closure of the foramenovale by 2 days of age also characterized oursingle case of mitral and aortic stenosis (A175). In this infant, drainage of the small buthypertrophied and fibroelastic left atriumthrough the stenotic valvular orifices wasobviously sufficient to prevent the develop-ment of even moderate tortuosity of intralobu-lar pulmonary arteries. However, the mediaindex of muscular pulmonary arteries wasincreased in the noninjected lobe of the samespecimen, a finding suggesting pulmonarvhypertension. The microangiographic andmorphometric findings are thus contradictoryin this particular infant for unknown reasons.

In this study we were primarily concernedwith the pulmonary arterial pattern but theelastic hyperplasia with arterialization ofpulmonary veins seen in the histologic sectionsprovides a further morphologic hint of conges-tive pulmonary hypertension, at least ininfants with a foramen ovale which had closedor had a competent valve.To judge from our microangiographic find-

ings, then, pulmonary hypertension is adependent phenomenon witlhin the frameworkof HLHS and is associated with sealing off ofthe left heart by closure of the foramen ovale.This concept has not clearly emerged fromprevious functional and morphologic studiesof the HLHS. For example, Sinha andassociates2 specifically mentioned the state ofthe foramen ovale-"practically closed"-foronly one of the three infants in whom theyobtained a significant left-to-right pressuregradient between the atria. Moreover, theclinical data of Krovetz and associates. forinfants with aortic atresia and mitral stenosisindicated a pulmonary artery mean pressureCirculation, Volume XLV, February 1972

equal to, or exceeding, systemic artery meanpressure regardless of whether the foramenovale was described as being closed, probepatent, or having a large opening. Wagen-voort and Edwards,4 in reporting an increaseof medial thickness in muscular pulmonaryarteries in some perinatal cases of HLHS, donot consider the state of the foramen ovale.Naeye, even for newborn infants, as indicat-infants in his HLHS series as having "a patentforamen ovale or other type of interatrialdefect which permitted the shunt of pulmo-nary venous flow into the right atrium." It isdifficult to reconcile this ease of outfloxv fromthe left atrium with the uniform increase inrelative pulmonary arterial mass reported byNaeye, even for newborn infants, as indicat-ing congenital pulmonary hypertension.

Intracardiac left-to-right shunt is not theonly possible egress from the pulmonaryvenous system in mitral or aortic atresia.Pulmonary venous drainage to the superiorvena cava by means of a levoatriocardinalvein14-1 has been recognized in a few cases ofHLHS, as well as myocardial sinusoidsserving as a shunt between the left ventricleand the sinus coronarius.13 17-1" Bronchialveins emptying into the azygos system couldprovide an additional route for the pulmonaryveins emptying into the arygos system couldThe angiographic methods used in the presentstudy do not, however, permit the analysis ofcollateral venous pathways. Therefore, amicrophlebographic study of the lungs inHLHS has been initiated; preliminary resultssuggest an increase of pulmonary systemicvenous collaterals in cases with prematurelyclosed foramen ovale.

References1. ERIKSSON BO, GRANT CA: What is the

"hypoplastic left heart syndrome"? Proc AssEurop Paediat Cardiol 6: 29, 1970

2. SINHA SN, RUSNAK SL, SO-AMMERS HM, COLE RB,MUSTER AJ, PAUL MH: Hypoplastic leftventricle syndrome: Analysis of thirty auitopsycases in infants with surgical considerations.Amer J Cardiol 21: 166, 1968

3. KROVETZ LJ, ROWE RD, SCHEIBLER GL: Hemo-dynamics of aortic valve atresia. Circullation42: 953, 1970

387

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from

GRANT, ROBERTSON

4. WAGENVOORT CA, EDWARDS JE: The pulmonaryarterial tree in aortic atresia with intactventricular septum. Lab Invest 10: 924,1961

5. NAEYE RL: Perinatal vascular changes associatedwith underdevelopment of the left heart. AmeiJ Path 41: 287, 1962

6. ROBERTSON B: The intrapulmonary arterialpattern in normal infancy and in transpositionof the great arteries. Acta Paediat Scand(suppl) 184: 1968

7. DOYLE AE, GOODWIN JF, HARRISON CV,STEINER RE: Pulmonary vascular patterns inpulmonary hypertension. Brit Heart J 19: 353,1957

8. ROBERTSON B: The normal intrapulmonarvarterial pattern of the human late fetal andneonatal lung. A microangiographic and histo-logic study. Acta Paediat Scand 56: 249.1967

9. ROBEuRTSON B: The normal intrapulmonarvarterial pattern in infancy and early childhood:A micro-angiographic and histological study.Acta Path Microbiol Scand 71: 481, 1967

10. WVAGENVOORT CA: Vasoconstriction and medialhypertrophy in pulmonary hypertension. Circu-lation 22: 535, 1960

11. WAGENVOORT CA, NEUFELD HN, EDWARDS JE:The structure of the pulmonary arterial tree infetal and early postnatal life. Lab Invest 10:751, 1961

12. WAGENVOORT CA: Morphologic changes inintrapulmonary veins. Human Path 1: 205,1970

13. KANJUH VI, ELIOT RS, EDWARDS JE: Coexistent

mitral and aortic valvular atresia: A pathologicstudy of 14 cases. Amer J Cardiol 15: 61 1.1965

14. LUCAS RV JR, LESTER RG, LILLEHEI CW,EDWARDS JE: Mitral atresia with levoatriocar-dinal vein: A form of congenital puilmlonaryvenous obstruction. Amler J Cardiol 9: 607,1962

15. SHONE JD, EDWARDS JE: Mitral atresia associatedwith pulmonarv venous anomalies. Brit Heart J26: 241, 1964

16. HUN-T CE, RAO S, MOLLER JH, EDWARDS JE:Anomalous pulmonary vein serving as collater-al channel in aortic stenosis with hypoplasticleft ventricle and endocardial fibroelastosis.Chest 57: 185, 1970

17. BELLET S, GOULEY BA: Congenital heart diseasewith multiple cardiac anomalies: Report of acase showing aortic atresia, fibrous scar inmyocardium and embryonal sinusoidal remains.Amer J Med Sci 183: 458, 1932

18. RAGHIB C, BLOEMENDAAL RD, KANJUH VI,EDWARDS JE: Aortic atresia and prematureclosure of the foramen ovale: Myocardialsinusoids and coronary arteriovenous fistulaserving as outflow channel. Amer Heart J 70:476, 1965

19. PETERSON CR, BRAMWIT DN, CRAIG DE, JONESRC: Aortic valvular atresia and prematureclosure of the foramen ovale: Case report withclinical, angiographic, and autopsy findings. jThorac Cardiovasc Surg 58: 79, 1969

20. SPOLVERINI LM, BARBIERI D: uber dieangeborenen Herzfehler: Anatomischpatolo-gische Studie. Jahrb Kinderh 56: 472, 1902

Circulation, Volume XLV, February 1972

388

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from

CRAWFORD A. GRANT and BENGT ROBERTSONHeart Syndrome"

Microangiography of the Pulmonary Arterial System in "Hypoplastic Left

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1972 American Heart Association, Inc. All rights reserved.

75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TXCirculation

doi: 10.1161/01.CIR.45.2.3821972;45:382-388Circulation. 

http://circ.ahajournals.org/content/45/2/382located on the World Wide Web at:

The online version of this article, along with updated information and services, is

  http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer

of the Web page under Services. Further information about this process is available in thewhich permission is being requested is located, click Request Permissions in the middle columnClearance Center, not the Editorial Office. Once the online version of the published article for

can be obtained via RightsLink, a service of the CopyrightCirculationoriginally published in Requests for permissions to reproduce figures, tables, or portions of articlesPermissions:

by guest on October 4, 2017

http://circ.ahajournals.org/D

ownloaded from