British Heart3Journal, I973, 35, II78-II83.

Structural changes in the pulmonary arteriesand veins in tetralogy of Fallot

Alison Hislop and Lynne ReidFrom the Department ofExperimental Pathology, Cardiothoracic Institute, Brompton Hospital, London

The pulmonary arteries or veins from 6 children with tetralogy of Fallot have been injected with a bariumsulphate and gelatin mixture. The branching pattern of the airways, arteries, and veins was normal. At allages quantitative studies showed a decrease in total lung volume and in both pulmonary artery and vein size.In the intra-acinar region small arteries and veins were increased in number but the alveolar number was

decreased. The pulmonary arteries were relatively more muscular than normal as shown both by increasedmedial wall thickness and by extension of muscle into smaller vessels than is normal.

The altered haemodynamic conditions in congenitalheart disease affect the pulmonary vessels. Intetralogy of Fallot pulmonary artery blood flow isreduced (Dollery et al., I96I) and pressure withinthe pulmonary artery is low. In many cases flow isincreased at capillary level due to collateral circula-tion (Bing, Vandam, and Gray, 1947). Pathologicalstudies have indicated the presence of thrombi andbronchial collateral circulation (Rich, I948; Dam-mann and Ferencz, I956). Measurements of arterialwall thickness, made in uninjected material, havegiven conflicting results. Some workers report anormal wall thickness (Dammann and Ferencz,1956; Granston, I958), others a reduction (Bestand Heath, I958; Wagenvoort and Edwards, I96I).Naeye (I96I) from planimetric studies reported thateven before birth there was a reduction in area of thearterial media.Received 2 March 1973.

The normal development of the pulmonaryarteries and veins during foetal life and child-hood has recently been described using precisequantitative methods (Hislop and Reid, I972,I973a, and b). These studies provide an accuratebasis for investigation of diseased lungs. This paper

describes the results of quantitative analysis on 6cases of tetralogy of Fallot, in 5 of whom the pul-monary arteries were injected and in one the pul-monary veins.

Subjects and methodsLungs from six patients, who died either at operation or inthe postoperative period and were aged i 3 , 41, 4j, 6,and 8 years, were studied. The relevant clinical featuresare summarized in Table I, the cases being designatedby age at death. All cases had a reduced pulmonary blood

TABLE I Clinical features of cases with tetralogy of Fallot

Case Age Artery size Pulmonary Pulmonaryl Pulmonary SystemicNo. (yr) seen on x-ray artery pressure systemic flow saturation (%)

(mmHg) flow (I./min)

I I*j~ ;- 0-7:I 20 822 3i - o-6: i 8I3 4i - 0-3:1 1I7 644 6 o0-6:i 3.I 855 8* () 7/II I:1 5-8 976 441 I215 0-2:1 I*8 54

* Earlier surgical treatment (see text).+ reduced.() only slight change.

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Pulmonary vessels in tetralogy of Fallot 1179

flow and polycythaemia and in the cases in which apulmonary artery pressure had been recorded this wasalso reduced. In all a diagnosis of tetralogy of Fallot wasconfirmed at necropsy.

Cases 2 and 5 had been treated surgically previously.In Case 2 a palliative operation to relieve the obstructionto the right outflow tract led to slight clinical improve-ment. Case 5 had improved clinically after a Blalockanastomosis, which had been carried out 3 years beforedeath. Catheterization and angiography 6 months beforedeath showed that the Blalock anastomosis was stillpatent. The child died shortly after pulmonary valvo-tomy and infundibular resection.The arteries or veins were injected by the usual

departmental method with a mixture of barium sulphateand gelatin at 6o0C and pressure of Ioo cm H20. Fillingreaches to vessels IS ,um in diameter but does not pene-trate capillaries. All vessels on the arterial side of thecapillary bed are described as arteries and designated bystructure, and on the venous side as veins. The words'arteriole' and 'venule' have been avoided since theseterms have led to confusion because they were defined invarious ways. Quantitative studies included measure-ments of arteriograms and venograms, serial reconstruc-tion of branching pattern, estimation of percentage wall

thickness and of muscle extension along veins andarteries, the size of arteries accompanying airways(Davies and Reid, I970; Hislop and Reid, I970), andalso the number of arteries, veins, and alveoli in a unitarea of lung tissue (Hislop, I971).

ResultsAll lungs were reduced in volume for age, to agreater amount in the older cases.

Branching patternArteriograms (Fig. i) showed a normal branchingpattern of the main arterial pathways but an in-creased density of background haze of small vessels.In Cases i and 3 filled bronchial vessels could bediscerned on the arteriogram. Measurement of themain pulmonary artery pathways showed them to bereduced in diameter for age (Fig. 2). The decrease indiameter was greater at the hilum than the peri-phery and the difference increased with age. Thegradient from hilum to periphery was reduced in all

FIG. I Arteriogramof the right lung of Case 5 afterarterial injection with a bariun sulphateand gelatin suspension. The main arterial pathways are decreased in size for age and the back-ground haze is abnormally dense.

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xi8o Alison Hislop and Lynne Reid

cases. The one venogram (Case 6) showed similarchanges in veins to those in the arteries.

Dissection and serial reconstruction in Cases 4,5, and 6 confirmed that the pre- and intra-acinararterial, venous, and airway branching pattern wasnormal, though the size of the vessels was muchreduced.

TetralogyofFallot

*-v 1 yro0-o 34yro---o 4 'yr*-. 6 yrm m 8 yr

Normol----- 10 mth

o-----o S yr

0 25 50 75 100Distance from hilum (0/o)

FIG. 2 Measurements on arteriograms of the dia-meter of the main arterial pathway to the upper andlower lobe in 5 cases of tetralogy of Fallot and 2

normal lungs. The former all show a reduction indiameter.

Vessels and alveoli per unit area of lungIn all cases the total number of alveoli per squarecentimetre of lung section was reduced by com-parison with normal lungs of similar age (Table 2).The alveoli were thus larger than normal - a slightdegree of emphysema. Since the total lung volumewas also reduced there probably was a reduced totalnumber of alveoli.

TABLE 2 Number ofarteries and alveoli in one squarecentimetre of lung tissue and the ratio of alveoli toarteries

Case Age Alveolilcm2 Arteries/cm2 Ratio alveolilNo. (yr) arteries

I AL I0,541 336 31372 3j* 7,462 23I 19-953 4i 8,644 374 23.II4 6 7,25I 347 20-895 8* 7,3I3 330 22-I6

Normalio mth I2,418 287 43.264 yr 9,529 233 40-85 yr 9,I23 195 46.8Io yr 8,580 I79 47 9

* Earlier surgical treatment (see text).

The number of arteries, less than 200 [Lm exter-nal diameter in a square centimetre, was counted.These vessels are in the alveolar region and avail-able for gas transfer, but those less than i6o stm inlumen diameter are not seen as separate lines on thearteriogram (Millard, I965). The number was in-creased in all but Case 2, the increase being mostpronounced in vessels less than 75 tLm externaldiameter. When related to the reduced alveolarnumber there is a relative increase in arteries in allcases (Table 2).

In the one case where the veins had been in-jected, the concentration of veins per unit area oflung was similar to the normal but when related toalveolar number was increased, particularly thoseveins below 75 ,um. It is unlikely that this increase insmall vessels represented an increase in bronchialcollateral ones, since there was little increase inbronchial artery size, and cross filling was only seenin the central part of the lung not at the periphery.

Structure of vesselsThe structural changes in the arteries in 5 cases aresummarized in Table 3. In all 5 cases, in vessels

10-

9.

8-

7.

6-

5E

4-

-

E,! 2 -

I,

c. _

I -

E0

iS 8 -

7 -

5-

3,

2-

0*

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Pulmonary vessels in tetralogy of Fallot II8I

TABLE 3 Summary of structural changes in arteries in cases with tetralogy of Fallot

Case No. and age (yr)Arteriograms I, I 2 2, 3** 3, 44 4, 6 5, 8*

Pattern N N N N NLumen diameter

Wall structure

% wall thickness t t (t) t IIMuscle extension into small vessels N t N t IMuscle extension into acinus N ; N (I)Diameter of arteries with airwaysStructure of arteries with airways N ; N NRight ventricular muscle t t t t t

N = Normal.t = Increase in size or muscle.= Decrease in size or muscle.

()= Only slight change.* Earlier surgical treatment (see text).

greater than 200 Ftm external diameter the thicknessof the muscle coat was higher than normal for thesame age, particularly in the 2 cases where surgicalattempt had been made to increase the flow.Though increased, the wall thickness was less thanis normal at birth so there had been some normalpostnatal regression. All cases, in vessels below200 ,tm, showed the normal relative increase in per-centage wall thickness, but, when compared withnormal children, these vessels were not abnormallythick, except in Case 5 (Hislop and Reid, 1973a).

Wall thickness measured both in injected anduninjected veins was normal.

Population counting of the small arteries showedthat in Cases 2, 4, and 5 there was an abnormal ex-tension of muscle into smaller vessels (Cases 2 and5 had surgical treatment). In Cases i and 3 the dis-tribution of muscle in small vessels was normal.Measurements were made of the diameter and

structure of arteries accompanying terminal andrespiratory bronchioli, alveolar ducts, and alveoli.In each case at all levels the arteries were sub-stantially smaller in diameter than normal. In Cases2 and 4 muscle distribution in the vessels within theacinus was normal; in Cases I and 3 a reductionwas found in the number and extension of musculararteries and in Case 5 a slight increase in muscleextension. The differences, shown in Fig. 3, are notgreat and could lie within the limits of individualvariation.

In the 2 cases that had been treated surgically thechanges were similar throughout the lung ex-amined. In Case 2 there was some intimal thicken-

Alveoli Alveolar Respiratory Terminalducts bronchioli bronchiolus

A- _ _ _ ___

TetralogyOf Fhiot

-,O,mm l&yr31yr

_~l 4i yr

6 yr

8 yr

Normal10 mth5 yr10 yr

FIG. 3 Diagram illustrating the extension of musclein the walls of small arteries within the acinus, for 5cases of tetralogy ofFallot and 3 normal lungs.

ing in medium-sized arteries and in Case 5 consider-able intimal thickening in both arteries and veinsand some thrombotic lesions. There was no evi-dence of thrombosis or intimal thickening in theother 4 cases.

DiscussionThe precise quantitative methods used in this studyhave established the presence of new structuralfeatures in the pulmonary circulation in tetralogyof Fallot.

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II82 Alison Hislop and Lynne Reid

Structural changes

In this group of 6 cases of tetralogy of Fallot the agerange was I3 months to 8 years. Despite this, thepathological changes in the pulmonary circulationwere similar in all, in contrast to lungs from infantswith ventricular septal defect where structuralchanges vary widely from case to case (Hislop, I97I).The lungs in all cases were reduced in volume,

and the blood vessels, both arteries and veins, werereduced in size probably to a greater degree thanwas lung volume. The degree of hypoplasia in-creased with age even after operation.Though the vessels were small, the branching

pattem of arteries and veins, both pre- and intra-acinar, was normal. Normally the pre-acinar arterialbranching is complete by the i6th week of gestation(Hislop and Reid, I972), intra-acinar branchingoccurring during later foetal life and childhood(Hislop and Reid, I973a). In the lung, develop-ment of the circulation is under strong genetic con-trol, since before birth flow is so small that growth isnot in response to functional demand. Reduced flowin these cases not only had not prevented multi-plication of arteries during foetal life or childhoodbut vessels beyond the alveolar ducts were increasedin number, particularly arteries. This was demon-strated by the dense background haze and thenumber of arteries within a unit area of lung. Theintra-acinar region has responded to the reducedflow by excessive multiplication.The increase in the small arteries that are pre-

capillary in position may lead to a larger area forblood-gas exchange and will tend to reduce therate of flow; both these factors may increase thechance of oxygenation within the lung. A perplexingfact is that though the intra-acinar arteries are in-creased the post-acinar venous system is still hypo-plastic. Perhaps flow is the important factor for veinsize.

In all the cases of tetralogy of Fallot the arterialwall thickness was increased. This was not the ex-pected result since previous authors have reported anormal or low wall thickness (Danmann and Fer-encz, I956; Naeye, I96I) which they believed to berelated to the low flow (Nadas, I963). The greatestincrease in muscle was in those cases where anattempted correction had been made, and the re-sultant higher pressure and flow may explain thefurther increase in these two cases, though in onlyone (Case 5) were the haemodynamic conditionsrestored to near normal. Ferencz (I960) and Daoud,Kaplan, and Helmsworth (I966) have demonstratedan increase in wall thickness after surgical correc-tion but only in cases where the flow became greaterthan normal. In all our cases the increased wall

thickness still represented a drop in wall thicknesssince birth, suggesting either an arrest in loss ofmuscle or a secondary increase, the latter almostcertainly in the corrected casesThough the arteries in these cases are more

muscular than normal when judged by size, eitherby wall thickness or extension of muscle into smallvessels, muscle does not extend further to the peri-phery of the acinus than normal, i.e. the normalnon-muscular arterial pattern characteristic ofchildhood (Hislop and Reid, I973a) is found withinthe acinus. The extension is not seen because thevessels within the acinus are small. The extension ofmuscle into small arteries may be to maintain thenormal muscular distribution within the acinus.The pulmonary veins show the same pattern of

change as the arteries. We have shown a reduction invein size, whereas Wagenvoort (I970) considered theveins to be dilated. In the present study though ithas also been possible to demonstrate an increase innumber of small veins in the acinar region, venousstructure seemed normal.The pre-acinar arteries and veins seem to have

responded to the abnormal haemodynamic situa-tion by changes in size and structure, as have theintra-acinar arteries and veins which have also in-creased in number.

Clinical considerationsIn Cases 2 and 5 palliative surgery had been carriedout; in the former the clinical changes were small,but in the latter considerable improvement hadoccurred. The increase in flow known to have beenproduced in Case 5 had not led to any lessening ofvessel hypoplasia and had probably been detri-mental in that greater muscle hypertrophy andintimal thickening with thrombosis were also pre-sent. In Case 2 with less increase in flow there wasless muscle hypertrophy but still signs of intimalthickening. In these cases the intimal and throm-botic changes seem to be the result of increasedflow rather than of decreased, as previously reported(Rich, 1948). All in this series had polycythaemia.The general metabolic rate of children with

tetralogy of Fallot is below normal (Bing et al.,I947), and the children are usually small for age.This was so in the present series and in addition thelungs were abnormally small for the size of thechild. On the chest radiograph, measurements oflung length and width were made and comparedwith the normal centiles of radiographic growth thathave recently been prepared for children of 6 yearsand over (Simon et al., I972). In both features thetwo cases over 6 years were close to the 3rd centile.By extrapolating the normal centiles it seems that

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Pulmonary vessels in tetralogy of Fallot 1183

the younger cases were also at this level. These chil-dren were also close to the 3rd centile for height.In the normal the lung surface area has a linear re-lation to the body surface area (Dunnill, I962). Theemphysematous alveoli decrease surface area evenfurther. Reduced blood flow increases distensibilityand in these cases this may have contributed to theemphysema.

We are grateful to Dr. M. Joseph, Dr. R. Gibson, Mr.M. Paneth, Mr. W. P. Cleland, and Dr. K. F. W. Hinsonof the Brompton Hospital, and to Dr. A. G. Leathamand Mr. C. Drew of St. George's Hospital for allowing usto study these specimens. Dr. G. Simon has helped withinterpretation of the radiographs and angiograms andDr. S. Godfrey with the catheter studies.

This study was supported by the Research Committeeof the Board of Governors of the Brompton Hospital andis part of the work accepted for the degree of Ph.D.London University. Dr. Hislop is currently supportedby the British Heart Foundation.

ReferencesBest, P. V., and Heath, D. (1958). Pulmonary thrombosis in

cyanotic congenital heart disease without pulmonaryhypertension. J7ournal of Pathology and Bacteriology, 75,28I.

Bing, R. J., Vandam, L. D., and Gray, F. D. (I947). Physio-logical studies in congenital heart disease. II. Results ofpre-operative studies in patients with tetralogy of Fallot.Bulletin of theJohns Hopkins Hospital, 8o, I2I.

Dammann, J. F., and Ferencz, C. (1956). The significance ofthe pulmonary vascular bed in congenital heart disease.I. Normal lungs. II. Malformations of the heart in whichthere is pulmonary stenosis. American HeartJournal, 52, 7.

Daoud, G., Kaplan, S., and Helmsworth, J. A. (I966).Tetralogy of Fallot and pulmonary hypertension. Compli-cation after systemic-to-pulmonary anastomosis. AmericanJournal of Diseases of Children, III, I66.

Davies, G., and Reid, L. (I970). Growth of the alveoli andpulmonary arteries in childhood. Thorax, 25, 669.

Dollery, C. T., West, J. B., Wilcken, D. E. L., and Hugh-Jones, P. (I96I). A comparison of the pulmonary bloodflow between left and right lungs on normal subjects andpatients with congenital heart disease. Circulation, 24, 6I7.

Dunnill, M. S., (I962). Postnatal growth of the lung. Thorax,17, 329.

Ferencz, C. (I960). The pulmonary vascular bed in tetralogyof Failot. II. Changes following a systemic - pulmonaryarterial anastomosis. Bulletin of the Johns Hopkins Hos-pital, io6, ioo.

Granston, A. S. (I958). Morphologic alterations of the pul-monary arteries in congenital heart disease. Proceedings ofthe Institute of Medicine of Chicago, 22, i i6.

Hislop, A. (197I). The fetal and childhood development of thepulmonary circulation and its disturbance in certain typesof congenital heart disease. Ph.D. Thesis, University ofLondon.

Hislop, A., and Reid, L. (I970). New pathological findings inemphysema of childhood: I. Polyalveolar lobe with em-physema. Thorax, 25, 682.

Hislop, A., and Reid, L. (1972). Intra-pulmonary arterialdevelopment during fetal life - branching pattern andstructure. Yournal of Anatomy, 113, 35.

Hislop, A., and Reid, L. (I973a). Pulmonary arterial develop-ment during childhood: branching pattern and structure.Thorax, 28, 129.

Hislop, A., and Reid, L. (I973b). Fetal and childhood de-velopment of the intrapulmonary veins in man - branchingpattern and structure. Thorax, 28, 3I3.

Millard, F. J. C. (I965). The development and the electro-cardiographic diagnosis of right ventricular hypertrophyin chronic lung disease. M.D. Thesis, University ofLondon.

Nadas, A. S. (I963). Paediatric Cardiology, 2nd ed. Saunders,Philadelphia.

Naeye, R. L. (I96I). Perinatal changes in the pulmonaryvascular bed with stenosis and atresia of the pulmonicvalve. American Heart Journal, 6i, 586.

Rich, A. R. (I948). A hitherto unrecognized tendency to thedevelopment of widespread pulmonary vascular obstruc-tion in patients with congenital pulmonary stenosis(tetralogy of Fallot). Bulletin of the Johns Hopkins Hos-pital, 82, 389.

Simon, G., Reid, L., Tanner, J. M., Goldstein, H., andBenjamin, B. (I972). Growth of radiologically determinedheart diameter, lung width, and lung length from 5-I9years, with standards for clinical use. Archives of Diseasein Childhood, 47, 373.

Wagenvoort, C. A. (I970). Morphologic changes in intra-pulmonary veins. Human Pathology, I, 205.

Wagenvoort, C. A., and Edwards, J. E. (I96I). The pulmonaryarterial tree in pulmonic atresia. Archives of Pathology, 71,646.

Requests for reprints to Professor Lynne Reid, Depart-ment of Experimental Pathology, Cardiothoracic Insti-tute, Brompton Hospital, London SW3 6HP.

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