Persistent ductus arteriosus: probably primary congenital

British Heart Journal, 1977, 39, 610-618

Persistent ductus arteriosus: most probablya primary congenital malformationADRIANA C. GITTENBERGER-DE GROOT

From Department of Anatomy and Embryology, University of Leiden, Leiden, The Netherlands

This study was undertaken in an attempt to determini whether there is a distinct histological difference betweenthe human normally closing ductus arteriosus and a pe.rsistent ductus arteriosus. The microscopical investigationwas done in 42 specimens ofhuman ductus arteriosusfrom subjects ranging in agefrom 12 hours afterprematuredelivery to 32 years. The ducts derivedfrom hearts with various congenital malformations, in some of whichpatency of the ductus was essentialfor survival, as well asfrom hearts without other congenital malformations.Because no histological differences werefound between the isolatedpatent ductus arteriosus and those associatedwith other congenital heart anomalies, the specimers were classified according to age. Stages of a normalanatomical closing process were not encountered in patients over 4 months of age with a patent duct. Youngermaterial showed either a histologically normal stage ofanatomical closure or an abnormality ofthe ductus wall.This abnormal histology is mainly characterised by an aberrant distribution of elastic material, the most

conspicuous feature being a thick, wavy, unfragmenteI subendothelial elastic lamina. In respect of the questionas to whether the observed histological abnormality forms part of a primary anomaly of the ductus arteriosusor is secondary to the prolonged patency, it appears that most of the evidence provides support for the viewthat a primary anatomical defect of the ductus wall is responsible for persistence qf the ductus arteriosus.

The human ductus arteriosus has been the subjectof many studies, but most of these investigationsconcerned normal anatomical closure (e.g. Jagerand Wollenman, 1942; Danesino et al., 1955;Bakker, 1962; HofEmann, 1964; Desligneres andLarroche, 1970) or physiological closure (e.g.Eldridge and Hultgren, 1955; Adams and Lind,1957; Rudolph et al., 1961). Many studies have alsobeen based on animal material (e.g. Sciacca andCondorelli, 1960; Hoefsmit, 1967; Hornblad,1969; Broccoli and Carinci, 1973). The mono-graph by Cassels (1973) entitled The DuctusArteriosus provides an abundance of information onthe human ductus arteriosus, covering a great manyfields of interest and giving a good review of theliterature. There is, however, sparse material pub-lished on the histology of persistent ductus arterio-sus. Some comments are given by Bakker (1962),Desligneres and Larroche (1970), and Cassels et al.(1975). With respect to the pathogenesis of thepersistent type, Cassels et al. (1975) think it reasoni-able to conclude that in some groups of heart mal.-formations the haemodynamic oxygen tension playsa significant role in the patency of the duct,Received for publication 8 November 1976

whereas in others its persistent function as an openvessel is probably a facet of the congenital heartdisease complex and related chiefly to an anomalyof the wall. The anomaly could be located at severalsites in the ductus. Cassels and Moore (1973)mention that in persistent patency in man there is adeficiency of catecholamines in the duct. In addi-tion, there might be an anomaly of the smoothmuscle or oxygen receptors (Cassels et al., 1975).The question of whether persistent ductus

arteriosus might be caused by an underlying ab-normality of the ductus wall became especially im-portant after the influence of the prostaglandinsand their inhibitors on the closing process of theductus became known. These drugs might be usedin infants with diseases in which either closure orpatency of the ductus arteriosus could be life-saving (Sharpe and Larsson, 1975; Sharpe et al.,1975; Friedman et al., 1976; Heymann et al., 1976;Nadas, 1976; Olley et al., 1976; Moulaert et al.,1977).The aim of the study reported here was to deter-

mine whether there is a pronounced histologicaldifference between the normally closing humanductus arteriosus and a persistent ductus arteriosus.

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Persistent ductus arteriosus

Table Material

Group Case Code Age Heart Sex Intima Internal Subendothdial Amount RemarksNo. No.* anomalies cushions elastic elastic lamina ofelastic

lamina material

1 5673 2 d - d + + - - Prem. 32 wkI < 2 5816 3 d - & + + - - Prem. 35 wk

3 3609 12 h - - + - - Prem. 36 wk (Fig. 5)4 0 h - + + + + - 5407-'61 (Fig. 8)5 3786 8 h T d + + - -6 3630 10 h T + + - -7 1080 12 h P d + + - -8 3966 1 d L 9 + + - -9 2602 1 d T d + + - -10 301 1 d - ? + + - -

II 11 4314 2d L d ++ + - -12 3057 2 d L + + + - - (Fig. 1, 2, 3a)13 2060 2 d - 9 + + - - 2 dissecting aneurysm14 3629 3 d - 9 ++ + - -15 3967 4 d L 9 ++ + - -16 3644 5 d L d + + + - -17 3049 6 d L + + + - -18 2782 6 d T + + + + - - Almost closed (Fig. 3b)19 1901 8 d T + + + - -20 4166 9 d - 9 ++ + + - -21 4396 14 d - ? + + + + - -22 2587 17 d T +++ + + + Fig. 723 5452 1 m L 9 +++ + -

24 5670 1km L d + + + -

25 2780 1km T +++ + - - Almost closed (Fig. 4)26 1538 2 m L - - - + + + Fig. 627 2648 2 m L 9 + + +28 1405 2 m - + + + + - - Almost closed

F29 3900 4 mth VSD 9 + + +30 1039 4 mth T d + + + + +31 2663 4mth - ? - - + +++32 15 4j mth P & + + + +33 5783 7 mth VSD + ±+ +34 2278 8 mth T ++± + + - Fig. 935 792 11 mth VSD 9 ++ + +

IV 36 1830 13 mth P + + + + + Thromb. in trunc. pulm.37 2 y OAVC 9 + + + + 3104-'6138 3 y OAVC ? + + + + 10142-'5839 2425 4 y - ? Pul+ + + - - Aln'ost closed (Fig. 11)

Ao+ + + + - Patent (Fig. 11)40 3645 5 y - 9 + + + - Fig. 1041 2642 6 y - 9 + + + -42 2574 32y - a + + + -

*Code No. as in the collection of the Laboratory for Anatomy and Embryology, Leiden; T, transposition without ventricular septal defect;P, pulmonary atresia; L, left hypoplastic heart; VSD, ventricular septal defect; OAVC, ostium atrioventriculare commune; -, no othercongenital heart anomalies.Intima cushions: - not present (Fig. 5. 6); + not very distinct (Fig. 10); + + obvious (Fig. 1, 2, 8, 9); + + + very obvious (Fig. 7).Internal elastic lamina: present +, absent-.Subendothelial elastic lamina: present +, absent-.Amount of elastic material: - normal; + slightly more fine fibres (Fig. 7); + + and + + + elastic lamellae present (Fig. 6).Cases 4, 37, and 38 were kindly put at our disposal by Dr. P. M. Bakker, Leyenburg Hospital, The Hague, and cases 1 and 2 by Dr. A. J.M. G. Moulaert, Wilhelmina Children's Hospital, Utrecht.

The question of whether any abnormal histologicalpicture found in the wall of a persistent ductusshould be considered part of a primary defect ormerely a consequence of prolonged patency is alsodiscussed.

Patients and methods

The material consisted of 42 specimens of humanductus arteriosus from subjects ranging in age from12 hours after premature delivery to 32 years(Table). These ducts derived from hearts with aorticatresia, pulmonary atresia, transposition without a

ventricular septal defect (all anomalies in whichpatency of the ductus is essential for survival), ven-tricular septal defect, and ostium atrioventricularecommune, as well as from cases without further con-genital heart anomalies. In most of the specimenspost-mortem angiocardiography had been per-formed before anatomical and histological pre-paration, to show the presence or absence ofanatomical patency. According to the publishedreports (Moss et al., 1963), in full-term infantsfunctional closure normally takes place 10 to 15hours after birth. Anatomical closure takes muchlonger, i.e. 1 week to 3 months (Cassels, 1973). On

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Adriana C. Gittenberger-de Groot

Fig. 1 Transversesection of a ductusarteriosus showingcharacteristics of aclosing process whichstarted normally. Case12, aged 2 days.(Weigert elastic stain.x 8.)Fig. 2 Detail of Fig.1. In the inner third ofthe media there aremucoid lakes borderingthe fragmented internalelastic lamina and theintimal cushions.(x32.)Fig. 3 (a) Detail ofthe wall of a ductusarteriosus. Mucoid lakesand cytolytic necrosisare present in the innerthird of the media.Same case as Fig. 1and 2 (H. E.x 32.) (b) Detail of awall showing a largearea of cytolyticnecrosis. Case 18, aged6 days. (H. E.x 32.)Fig. 4 Transversesection of an almostclosed ductus arteriosus.Postnatal intimalproliferation iscompletely devoid ofelastic material. Case25, aged 1V months.(Weigert elastic stain.x 14.)

Abbreviations used in thle figures: a: adventitia; cn: cytolytic necrosis; i: intima cushions; iel: internal elastic lamina;m: media; ml: mucoid lakes; p: postnatal intimal proliferation; sel: subendothelial elastic lamina.

the basis of these data it seems justified to concludethat persistent ductus arteriosus exists at least in allcases where the ductus arteriosus remains patent in

infants older than 3 months.All specimens were sectioned serially and studied

microscopically. The plane of section was eitherlongitudinal or transverse. In some cases the ductuswas, after cleaving, sectioned in both planes. Aftersectioning, the material was fixed in alcohol-

glycerin for staining with haematoxylin-eosin,azan, Weigert, and van Gieson elastic tissue stains,or resorcin-fuchsin-iron haematoxylin-picric acid-thiazin red (standardised method of Hoefsmit,1967).

Attention was paid to the characteristics of thenormal anatomical closing process of the humanductus arteriosus, which is described by severalauthors, e.g. Jager and Wollenman (1942), Bakker

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(1962), Desligneres and Larroche (1970). Werelated our findings to the very thoroughly docu-mented study done by Bakker (1962) on the normalclosing process. The most characteristic features ofthe normally closing ductus (Fig. 1-4), whichresembles most a muscular artery, are: (1) intimalcushions protruding into the lumen of the ductus;(2) splitting and fragmentation of the underlyinginternal elastic lamina (Fig. 2); (3) a media con-taining little elastic material; (4) a large amount ofmucoid substance very often concentrated inmucoid lakes, mostly in the inner third of the media.In addition, in the later stages we see the occurrenceof (5) cytolytic necrosis (Fig. 3 a, b); and (6) post-natal intimal proliferations on top of the intimalcushions, clearly recognisable by the absence ofelastic material (Fig. 4).The amount and distribution of smooth-muscle

cells and fibrous and elastic tissue was also takeninto account. The elastic tissue proved to be of greatimportance for our study.

Results

Since no histological differences could be detectedbetween the isolated patent ductus arteriosus andthe patent ductus associated with other congenitalheart malformations, the specimens were classifiedaccording to age (Table). On the basis ofthe findingsin the reports concerning the time of anatomicalclosure of the ductus arteriosus, 4 age-groups weredistinguished, as follows.

GROUP 1Three ducts of prematurely born infants, with agestational period of 32, 35, and 36 weeks, who hadlived for 2 days, 3 days, and 12 hours, respectively.The first 2 cases (cases 1 and 2) showed histo-

logically a stage of anatomical closing processnormally begun, in accordance with their age (2 and3 days after delivery). The ductus of the infant wholived for 12 hours (case 3) did not show the above-mentioned characteristics of the normal closingprocess in that there were no intimal cushions ormucoid lakes, and the internal elastic laminabordered the lumen (Fig. 5).

GROUP IIFifteen ducts, ranging in age from immediatelyafter full-term delivery to 1 week.

Except in cases 4 and 13, the structure ofthe ductuswall indicated a normal closing process. In one case(case 18) the ductus was almost closed. Case 13showed the general characteristics of a normalclosing ductus but also two large dissectinganeurysms in the wall. Case 4 showed a peculiar

histological anomaly which is described in the nextgroup.

GROUP IIITen cases, ranging in age from 8 days to 2 months.Five of these ducts (cases 19, 20, 21, 23, 24) werepatent, showing stages of an anatomical closingprocess normally begun. Two (cases 25 and 28) arealmost closed, showing only a very small slit-likelumen, and 3 (cases 22, 26, and 27) were patent,showing an abnormality of the wall. One specimenin the last group (case 26) showed a wall structureresembling an elastic artery rather than a muscularartery (Fig. 6). In this case the elastic lamellae of theaorta and pulmonary artery continued into theductus wall except in a small central part of themedia, whereas normally about two-thirds of theelastic lamellae merge into the adventitia of theductus and the remaining lamellae form theinternal elastic lamina (Fig. 5). In the remaining 2cases (cases 22 and 27) and in case 4 of group II,the histological structure of the wall did not differgreatly from the picture shown by a normallyclosing ductus at first sight, but on closer inspectionthere was a remarkable feature: a conspicuous wavyunfragmented subendothelial elastic lamina (Fig.7 and 8) over most of the intimal cushions and merg-ing into the normal internal elastic lamina of theduct where no intimal cushions were present.

GROUP IVFourteen cases, ranging in age from 4 months to 32years. All these ducts had a histologically abnormalwall. Ten (see Table) showed, as the most strikingfeature, the unfragmented wavy subendothelialelastic lamina (Fig. 9 and 10). In general, the intimalcushions were not very pronounced and the in-ternal elastic lamina underneath them was often notfragmented (Fig. 10). In 7 of these cases there wasno increase in the amount of elastic material in theintima or media compared with the normallyclosing ductus, and 3 showed a media and intimawith slightly more elastic material than normal. It isnot possible, however, to count the elastic lamellaeas in elastic arteries. In 3 other cases, the ductshowed a pronounced increase in the amount ofelastic tissue with countable elastic lamellae, onlythe central part of the media containing slightly lesselastic material. In 2 (cases 30 and 36) a few notvery prominent intimal cushions were also present,and these again showed the subendothelial elasticlamina. The third case (case 31) bore a strongresemblance to case 26 in group III, looking morelike an elastic than a muscular artery. No intimalcushions or internal elastic lamina were present, buta subendothelial elastic lamina was discernible. The

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fourteenth case (case 39) was remarkable in that thepulmonary end of the ductus was almost closed,showing all of the features of a normal closingprocess, whereas the aortic end was widely patentand showed the subendothelial elastic lamina (Fig.11).

Discussion

In all cases with a patent ductus at an age of 4months or older (group IV) the wall showed a histo-

logical picture which differed from that seen duringthe normal closing process. In the age group from1 week to 2 months (group III) the wall structureeither reflected a normal closing process or showedan abnormality. The same holds for groups I andII.On the basis of published data (Cassels, 1973), it

seems justified from a clinical point of view tospeak of persistent ductus arteriosus in all cases ofpatent ductus in infants older than 3 months.Since these cases-always show an abnormal histo-

Fig. 5 Section showingductus arteriosus andadjacent great arteries.No characteristicfeatures of the onset ofthe anatomical closingprocess are present. Themerging of the greaterpart of the elasticlamellae of the adjacentelastic arteries into theadventitia of the ductusarteriosus (-) isclearly visible, theremainder forming theinternal elastic lamina.Case 3, prem. 36 weeks,lived 12 hours.(Weigert elastic stain.x 13-5.)Fig. 6 Detail of atransverse section of aductus arteriosusshowing aortification.In the intima and theouter part of the mediamany countable elasticlamellae are present.No subendothelial elasticlamina is seen. Case 26,2 months. (Weigertelastic stain. x 32.)Fig. 7 Transversesection of a ductusarteriosus, showing asubendothelial elasticlamina on top of theintimal cushions. Intimaand media containslightly more than thenormal amount ofelastic material. Case22, aged 17 days.(Weigert elastic stain.x28.)

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logy, the histologist (e.g. the present author) will beinclined to define persistent ductus arteriosus on thebasis of this abnormality. The clinician, however,will encounter difficulties ifhe does this, because theabnormal histology is not restricted to patients olderthan 3 months. This raises the problem of how todifferentiate clinically between persistent ductusand 'simple' prolonged patency in infantsyounger than 3 months. The pharmacological treat-ment of prolonged patency might throw some lighton this problem. It is conceivable that a persistentductus arteriosus with an abnormal histology of thewall, would not react to certain drugs, e.g. indo-

methacin, which induce closure in cases of 'simple'prolonged patency. If this working hypothesisshould prove to be correct, the term persistentductus arteriosus could be used for all cases ofpatent ductus in patients over 3 months of age andyounger infants who do not react to, for example,indomethacin. Heymann et al. (1976) mentionedthat one of 15 cases of prolonged patency in pre-mature infants did not react to indomethacin.Histological investigation of such ducts mightreveal an abnormality. Further investigations arerequired to elucidate this problem.The 3 premature ducts studied did not provide

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Fig. 8 Transversesection of a ductusarteriosus. The lumenis bordered by a

subendothelial elasticlamina. Case 4, 0 hours.(van Gieson elasticstain x 28.)Fig. 9 Detail of atransverse section of aductus arteriosus,showing the wavyunfragmented sub-endothelial elasticlamina on top of anintimal cushion. Case 34,aged 8 months.(Weigert elastic stain.x28.)Fig. 10 Transversesection of a ductusarteriosus. The intimalcushions are not verypronounced and theinternal elastic laminais not fragmented.Bordering the lumen,there is a subendothelialelastic lamina. Case 40,aged 5 years. (Weigertelastic stain. x 28.)Fig. 11. Section of aductus arteriosus. Thepulmonary end (*) isalmost closed, whereasthe aortic end is patent,showing the subendo-thelial elastic lamina.Case 39, aged 4 years.(Weigert elastic stain.x14.)

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enough information to draw conclusions on theoften prolonged patency of the ductus of pre-maturely born infants. As already mentioned, twoof the specimens show that the closing process hadbegun normally. In the third no features of ana-tomical closure are present, but the wall does notshow any other abnormalities. Though the prob-lem of prolonged patency of the ductus in pre-mature infants has been discussed in many publica-tions (Rudolph et al., 1961; Danilowicz et al., 1966;Girling and Hallidie-Smith, 1971; Benjamin andWiegenstein, 1972; Kitterman et al., 1972;Friedman et al., 1976; Heymann et al., 1976;Nadas, 1976), I have undertaken a more detailedstudy with emphasis on the morphological aspects,which is now in progress.The majority of the cases with an abnormal

histology of the ductus wall show a pronouncedwavy unfragmented subendothelial elastic lamina.Mucoid lakes may occur, but cytolytic necrosis israrely encountered. There is usually no obviousincrease in the amount of elastic material, so thatsuperficially the wall does not differ greatly fromthat of a normally closing duct. This may accountfor the fact that some of the authors who studiedcases with persistent ductus arteriosus state that thewall structure does not differ distinctly from that ofa normally closing ductus (Wielinga, 1959; Bakker,1962).To the best of our knowledge, Jager and Wollen-

man (1942) are the only authors to mention the sub-endothelial elastic lamina, but they did not pay anyfurther attention to this phenomenon. The fact thatthe subendothelial elastic lamina has not been des-cribed more often is in all probability explained by

a b c

the lack, in the past, of histological studies in largeseries of persistent ductus arteriosus.Mucoid lakes and cytolytic necrosis are also en-

countered during the normal closing process of theductus arteriosus, but their significance is notknown. Cytolytic necrosis is characterised by loss ofnuclei (Fig. 3b); the accompanying increase ofcollagen fibres found by Schlatmann (1973) inaortic walls, was not seen in the present material.

Desligneres and Larroche (1970), who investi-gated 9 cases of patent ductus arteriosus in infancyas well as a large series of normal ducts, encountered'more and thicker elastic fibres than usual' in themedia for two cases of 'pathologic' ductus arteriosusand of one normal duct. Bakker (1962) also mentionsan increase in the amount of elastic material in thewall of some specimens ofpatent ductus; he uses theterm aortification to indicate this increase. A similarterm, aorticisation, is used by Hutchins andBannayan (1971) to indicate the development ofendocardial fibroelastosis after myocardial infarc-tion. This process, in which the endocardium isthickened and elastic lamellae appear, takes one totwo years.

In our material we encountered in some ductsslightly more very fine elastic fibres than are foundin normal closure (Table, Fig. 7). However, on afew occasions we saw a ductus wall with true elasticlamellae (Table; Fig. 6). For these cases, whichconstitute a very small minority, the term aortifica-tion can be used, indicating that the ductus wallresembles an elastic rather than a muscular artery.However, it should be stressed that we prefer to usethe term only descriptively and regardless of thecause and time of development of the anomaly,

d

f~

Fig. 12 Distribution of elasticmaterial in an elastic artery andin various types of patentductus arteriosus: (a) elasticartery; (b) ductus arteriosuswithout intimal cushions; (c)

!i ;, ductus showing characteristics ofo 9 ~normally begun closing

process; (d) persistent ductus-i ~-;:I arteriosus with subendothelial- ~ elastic lamina and obvious

intimal cushions, in some placesshowing a slight increase in theamount of elastic material in theintima and media; (e) persistent

-_a- ductus arteriosus as in (d), butintimal cushions not very distinct

- and internal elastic lamina notfragmented; (f, g) persistentductus arteriosus with

g aortification of the wall.

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because no relation between the duration of thepatency and the amount of elastic material has beenestablished. Fig. 12 gives a schematic representa-tion of the distribution of elastic material in thevarious types of ductus wall structure.A remarkable case is the one in which the pul-

monary end of the ductus is almost closed, whereasthe aortic end is patent and shows the subendo-thelial elastic lamina. The phenomenon of diver-gent behaviour of the aortic and the pulmonary endsof the ductus has been described (e.g. Bakker,1962; Cassels, 1973). Cassels (1973: p. 311) stateson the basis of his interpretation of studies done byCongdon (1922) and Keibel and Mall (1912), thatthis may have a developmental cause, since theductus (6th branchial artery) originates from aventral and a dorsal sprout; Cassels was of theopinion that 'the factors related to closure mayaffect the dorsal and the ventral sprout differently,allowing one or the other to remain open, theopposite segment closing normally'.As to the question of whether the histological

abnormality of the wall in persistent ductus arterio-sus is secondary to the prolonged patency or part ofa primary anomaly, a few points should be takeninto consideration.As indicated by the material studied (Table),

there is no direct relation between age (i.e. theduration of the patency) on the one hand and theoccurrence of the subendothelial elastic lamina aswell as the amount of elastic material in the ductuswall, on the other hand. (The fact that we did notfind many cases with an abnormal histology at avery early age will be dealt with later.) Further-more, no relation was found between the presenceof a subendothelial elastic lamina and the amountof elastic material in the intima and media. There-fore, the occurrence of a postnatal reaction of theductus wall resembling the process described byHutchins and Bannayan (1971), in which elasticlamellae are deposited in the endocardium over aperiod of one or two years after a myocardial in-farction, seems improbable when cases with per-sistent ductus arteriosus of different ages are com-pared.The altered haemodynamic situation in serious

congenital heart malformations is apparently notadequate to maintain the patency of the duct. Thecases with a patent ductus arteriosus associatedwith other congenital heart malformations areevenly distributed over the material. All too often,the ductus closes even in cases where patencywould have meant survival. Another factor, e.g. aprimary anomaly, must play a role. The fact thatin isolated persistent ductus arteriosus, which isnecessarily a primary defect, the same histological

picture is found as in persistent ductus arteriosusin combination with other heart malformations, alsosuggests the existence of a primary abnormality.The phenomenon that the anomaly can be re-

stricted to one of the two sprouts from which theductus originates (Cassels, 1973: p. 31 1) can be inter-preted as support for the hypothesis of a primarydefect of the ductus wall. Otherwise, we would haveto accept that the two original components of theductus are still differentiated, showing different re-actions, a long time after the development of theductus as a homogeneous structure.

In the present material only two young cases showthe abnormal histology. One (case 4) is a neonatewho died during delivery, and the other (case 22)lived 17 days. If a primary defect were involved, onewould expect to find the abnormality evenly dis-tributed over the different age-groups. However,this study was done on necropsy material, andprobably there are very young infants with theanomaly who are still alive. Patients with solitarypersistent ductus arteriosus do not as a rule die im-mediately after birth, and when it occurs in associa-tion with other congenital heart malformations itmay prolong survival. Therefore, the fact that wedid not find more cases showing a histologically ab-normal ductus at a very early age does not neces-sarily mean that the difference in wall structure is aconsequence of the prolonged patency.From the above points, we can summarise as

follows: (a) no relation between the duration ofthe patency and the amount or distribution of theelastic material, (b) altered haemodynamic situationinadequate to maintain patency, (c) the samehistology in isolated persistent ductus arteriosusas when associated with other heart malformations,(d) one end of the ductus closing normally, theother end remaining patent, showing an abnor-mality, and (e) an abnormal histology in a neonatedying during delivery. From this we concludethat in all probability the aberrant distribution ofelastic material, with the presence of a subendo-thelial elastic lamina as its most striking aspect,forms part of a primary anatomical defect of theductus wall resulting in a persistent ductus arteri-osus.

The author thanks Dr. P. M. Bakker and Dr.A. J. M. G. Moulaert for putting material at herdisposal.

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Persistent ductus arteriosus: probably primary congenital