The Natural History of the Ductus Arteriosus in Association with Other Congenital Heart Defects Donald E. Cassels, Saroja Bharati, Maurice Lev Perspectives in Biology and Medicine, Volume 18, Number 4, Summer 1975, pp. 541-572 (Article) Published by Johns Hopkins University Press DOI: https://doi.org/10.1353/pbm.1975.0061

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THE NATURAL HISTORY OF THE DUCTUS ARTERIOSUS IN ASSOCIATION WITH OTHER CONGENITAL HEART DEFECTS DONALD E. CASSELS, M.D.,* SAROJA BHARATI, M.D.A AND MAURICE LEV, M.D.%

I. Introduction

Subsequent to Galen's description of the ductus arteriosus in a.D. 200 [1, p. 68], there was a hiatus in anatomical observation and speculation

concerning the fetal circulation until Fallopius in 1561 [2] noted the ductus, and other descriptions followed during the sixteenth century. It remained for Harvey [3] to synthesize anatomical observations into

a concept which included blood flow and perfusion to the lung as a separate circulation. The blood flow to the periphery was thought to occur subsequent to the return of oxygenated blood from the lung to the systemic left ventricle. He remarked that the fetal circulation included

supplementary channels not present in the mature circulation. The explanation of the purpose of the fetal channels was: ". . . the heart, in its beat, forces the blood through the wide open passages from the vena cava to the aorta through the two ventricles. The right ventricle, receiving blood from its auricle, propels it through the pulmonary artery and

its continuation, called the ductus arteriosus, to the aorta. At the same time, the left ventricle contracts and sends into the aorta the blood

which, received from the beat of its auricle, has come through the foramen ovale from the vena cava."

In 1900, Gerard [4] consolidated information available into a reasonable proposal. Pohlman [5] reviewed the theories of the fetal circulation and perhaps too neatly classified these as follows:

1. Early theories suggested that mixed superior and inferior caval

?Professor of pediatrics, Pediatric Cardiology, Pritzker School of Medicine, University of Chicago. tHektoen Institute for Medical Research of Cook County Hospital, Chicago.

!Director, Congenital Heart Disease Research and Training Center, Hektoen Institute for Medical Research, Chicago; career investigator and educator, Chicago Heart Association. This investigation was supported by grant HL 07605-12 from the National Heart and Lung Institute, National Institutes of Health.

Perspectives in Biology and Medicine · Summer 1975 | 541

blood passed from the right atrium to the left, through the foramen

ovale.

2.Some believed blood passed from the left atrium to the right.

3.One proposal stated that the inferior vena cava flow was divided,

part to the right atrium and part to the left. The foramen ovale did not open into the two atria. 4.Others stated that all of the blood from the inferior vena cava

flowed to the left atrium and blood from the superior vena cava went into the right atrium. This is the current concept. 5.It was also suggested that all blood of the left ventricle went to the

head and upper extremities through the arch of the aorta and its branches, and all blood from the right ventricle went to the lungs, ductus, and descending aorta through the pulmonary artery. The aorta functioned as two parts, an upper and lower, connected by what is now called the isthmus of the aorta. This did not carry blood during fetal life. 6.One author speculated that blood flow through the superior vena cava was equal to the return through the pulmonary veins. The isthmus of the aorta carried the same amount of blood as the ductus arteriosus,

each carrying one-half the contents of the left and right ventricle. The aortic arch system in the human embryo was studied in detail by Congdon [6]. The changes in arches 1, 2, and 3 are not pertinent. The left fourth aortic root becomes a segment of the left aortic arch in the human, the usual arrangement, although there may be a right arch and rarely a persistent double arch. The controversial fifth is usually ignored, and the sixth or pulmonary arch is concerned with the pulmonary artery. The ductus arteriosus is frequently described as the terminal segment of the sixth arch inserting into the aorta. It seems likely that the ductus arises as a dorsal sprout from the aorta and a ventral sprout from the primitive pulmonary artery [7, 8].

The ductus arteriosus as an isolated essential component of the fetal circulation has facets of great interest, (a) Its function and status as a conduit and bypass for venous blood from the superior vena cava via the right ventricle to the descending aorta. The pulmonary flow component of right ventricular output is about 10-15 percent of this due to high resistance in the peripheral pulmonary vasculature. (¿>) The functional narrowing or physiological closure [9-12] within a few hours to 15 days after birth and a reversal of blood flow [13] as lower pressure develops in the pulmonary artery following expansion of the lung [14-16]. Gaseous expansion of alveoli enhances blood now regardless of the gas mixture involved [17], although an increase of oxygen further augments vasodilatation. Expansion with fluid does not. It has been suggested that diminution of pressure is related to mechanical events, that with expansion of the alveoli with breathing the vessels became uncoiled and resistance falls. However Dawes noted that there was a strong vasoconstrictive 542 J Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

element even in the nonexpanded lung and that blood flow was increased by pharmacologic agents such as acetylcholine and bradykinin

[18]. (c) Following the physiologic closure there is a gradual anatomical

obliteration of the lumen of the ductus by proliferation of intimai, subintimai, and other tissues. In the rat the ductus is unique, since it narrows or closes functionally almost as soon as the lungs expand and anatomically within a few hours. When the baby assumes an independent life, the ductus, which was

required for fetal life, becomes a form of congenital heart disease if

patency continues. Closure of the ductus arteriosus by surgery was the first heart operation [19], and the instant success of this procedure ini-

tiated the era of surgery of the heart and blood vessels.

In man the unique anatomy of the vessel facilitates closure. In contrast to the aorta and pulmonary arteries, this small vessel (the ductus) lying between the two contains little elastic tissue and is largely muscular [20, 2 1]. The smooth muscle of the media has a circular or spiral component [22], contraction would thus facilitate obliteration of the lumen rather

than shortening of the vessel. The smooth muscle cells of the wall of the ductus arteriosus have been studied in considerable detail, but there has

been no systematic comparison with the smooth muscle in other places.

Structurally and histologically nothing has been discovered to explain its remarkable sensitivity to oxygen. Molnar et al. [23] examined the ductus of fetal and newborn dogs. Sections were taken longitudinally to include adjacent pulmonary artery

and aorta and examined by the techniques of hematoxylin-eosin, elástica, trichome acid and alkaline phosphatase, adenosine-triphosphatase, adenosine-5-nucleotidase, DPN dehydrogenase, lactate and succinate dehydrogenase. In addition to the well-known structural differences there were histochemical increases in the activity of enzymes as ATP-ase

and DPN dehydrogenase. It was suggested that oxidative metabolism has an important role in functional changes in the newborn period

which are related to known constriction with increase of oxygen tension. Silva and Ikeda [24] showed that ductus media in the lamb has alternate lamellae of concentrically disposed smooth muscle cells separated

by zones containing elástica and collagen. The muscle lamellae generally

contained one or two layers of smooth muscle cells and a small amount

of collagen. Some muscle cells branched and approached cells of adjacent lamellae. Acetylcholinesterase activity was present in most of the

nerve fasciculi in the adventitia and media of the pulmonary artery,

ductus, and aorta. Small granular vesicles thought to be typical of adrenergic nerves were also present in the ductus. The smooth muscle cells

of the ductus arteriosus had no unusual ultrastructural characteristics

and were similar to the smooth muscle cells of the aorta and the pulmonary artery [25, 26].

Perspectives in Biology and Medicine · Summer 1975 | 543

Almost all studies of the physiological mechanism of normal ductus closure have been done on animals; guinea pigs [27, 28], fetal or newborn lambs, and other species [29-31]. All studies show that the normal ductus is sensitive to oxygen tension. The exact PO2 which constricts the vessel in the fetus or human infant is not known. It may be assumed that the necessary patency in the fetus is due to a lower PO2 than would be required against an estimated pressure within the ductus of 60-70

mm Hg. Elevation of PO2 from the fetal level of 30-80 mm Hg will close

the ductus against a blood pressure within the lumen of 110 mm [32]. It is now conventional to use the partial pressure of oxygen in mil-

limeters of mercury, PO2, instead of oxygen saturation as percentage,

although measurements are closely related. The relation of PO2 to hemoglobin saturation is the well-known sigmoid oxygen-hemoglobin

dissociation curve. This is influenced by the type of hemoglobin present.

With fetal hemoglobin, which persists for several weeks, the curve is

shifted to the left, and the relation of PO2 and saturation changes [33]. In children it lies to the right of adult [34], and in cyanotic congenital heart disease the curve shifts further to the right, possibly a compensatory effect since this increases oxygen unloading [35]. More recently changes in oxygen-hemoglobin dissociation have been related to inter-

mediates of erythrocyte glycolysis, 2-3 diphosphoglycerate, and adenosine triphophate [36-38]. Although the site of the receptor

mechanism for this response is not clear, cytochrome a 3 [32] and local increase of acetylcholine [39] have been proposed. This small remnant of the embryological branchial arch system has unique features not present in other segments of the system. It is func-

tionally muscular and has a sphincter-like action which to some degree is

controlled by oxygen. Its ultimate goal is to close completely and to become "shrivelled and solidified," as Galen said [I]. But the subtleties of

the smooth muscle cells of the ductus which give the vessel its distinction have not been adequately examined. The relation of oxygen to ductus constriction has been studied in the infant both by inference and by accumulation of information from clinical and hemodynamic investigation. In the premature infant there is delayed closure [40, 41], probably immaturity of the ductus wall itself. In the second trimester the perfused human ductus does not constrict with

oxygen [42]. Constriction of the perfused fetal lamb ductus is age dependent, the maximum constriction increases with gestational age [43]. Wilson [44], however, found postmortem contraction more frequent in

the premature than in the full-term infant, a contradiction which has not

been satisfactorily explained. The normal ductus also constricts in response to catecholamines, acetylcholine, other drugs, and mechanical stimuli.

In the normal ductus, the sequence of early constrictive closure fol544 I Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

lowed by anatomical obstruction and closure postulated and explained by Gerard [4] has been repeatedly confirmed. It is tempting to ascribe nonclosure to absence of early physiological constriction. However, there is no proof that absence of early constriction prevents anatomical closure or that absence of constriction is the cause of patency. There is some evidence that intimai and subintimal proliferation begins before birth [45, 46] and that anatomic closure may be independent of constriction.

In persistent patency in the human there is a deficiency of

catecholamines in the ductus wall, especially throughout the media [47,

48], but the relationship of this observation to nonclosure is not clear. In inherited patency in the puppy, produced by mating patent ductus dogs, there is a diminished response to oxygen which suggests an abnormality of the ductus wall either in the oxygen receptor or in the muscular media [49]. In some clinical situations inability to constrict also seems important. In these cases there is an abnormally thin-walled ductus with some absence of muscular media [50].

The necessary evidence to explain patency in the human is not available.

II. Isolated Patency of the Ductus Arteriosus In humans the patent ductus is usually not a very large vessel; 10 mm in diameter is clinically significant and over 15 mm is termed giant [51]. The blood flow to the lungs may rise from about 4 liters/min per square meter to about 16 liters/min per square meter. In an average patient 30-50 percent of the systemic flow to the aorta passes through the ductus. It is common to find the pulmonary blood flow two or three times the systemic flow. Thus the overloaded pulmonary vascular system

sometimes responds by developing intimai thickening and varying degrees of obstruction at the arteriolar level and pulmonary hypertension. The study of Civin and Edwards [52] which indicated that the pulmonary vessels in the newborn had thicker arteriolar walls with an increased wall to lumen ratio gave substance to an anatomical basis for increased obstruction, resistance, and an elevated pulmonary artery pressure. Involution of vascular resistance occurs during the first 3 or 4

months. With lowering resistance pulmonary flow may increase to the

point of heart failure. In the presence of marked pulmonary hypertension in the first year or two, controversy persists whether this is due to (1) noninvolution of the newborn vascular arteriolar vessels or (2) acquisition of vascular changes due to high-pressure increased flow from the aorta-ductus-pulmonary artery shunt.

The origin of patency remains controversial. It may lie in an anatomic Perspectives in Biology and Medicine · Summer 1975 | 545

defect in the wall, or inability to respond to oxygen stimulus, or a deficient nervous component, or inability to close by proliferation of histological elements for unknown reasons. Isolated patency is recognizable and rather easily remedied surgically. It occurs about once in 2,500 in the normal population [53]. There is a female preponderance of isolated patency of about three to one. The sex distribution of the isolated patent ductus has not been ade-

quately explained. It has been reported [54] that in patency associated with maternal rubella infection, which is the only known origin or association with patency, except prematurity, this sex ratio disappears and

there is an equal incidence of female/male. The female preponderance

makes it difficult to implicate intrauterine placental problems, or infection, or postnatal pulmonary distress. Interpretation of sex-linked genetic aspects is obscured by patency in mother-son relationship and especially by patency in one of twins proven identical by available means. This usually includes an observation that the placenta is monochorionic and that blood types are identical.

III. Patency Associated with Congenital Abnormalities of the Heart Although functional closure in animals and man and isolated patency in man have been studied in great detail, patency associated with defects within the heart becomes very difficult to explain, and little information

is available. In addition to elements contributing to isolated patency

there is added abnormality of increased or decreased pressure and

blood flow within the ductus. In the cyanotic infant there may be gross abnormality of oxygen saturation, and in other lesions there may be high oxygen, high pressure, and flow in the human ductus. The purpose of this discussion is to present unique data available in

patency of the ductus arteriosus when associated with other congenital defects of the heart and to speculate on the possible causes of patency in four diverse circumstances. The material available for study of the problem is based upon over 3,800 specimens seen at the Congenital Heart Disease Research and Training Center at the Hektoen Institute. Factors which might be involved in patency of the ductus arteriosus in

complex lesions are (1) anatomical abnormality of all or any components of the ductus wall; (2) abnormality of physiologic or functional constriction which may be due to deficiency of stimulus, especially oxygen or to abnormality of receptors; (3) abnormal pressure in the pulmonary ar-

tery, aorta, or the ductus itself; pulmonary artery-diminished pressure in

pulmonary atresia, pulmonary stenosis, and complexes which contain an

obstructive element to outflow from the right ventricle; aorta-diminished

pressure at the ductus site in severe aortic stenosis or atresia or in other complexes in which pressure flow in the aorta is inhibited; (4) increased

546 J Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

or diminished oxygen saturation or PO2 in the ductus arteriosus or at either orifice.

Considering these possible contributions to persistent patency, the material available has been divided into four categories: (1) diminished pulmonary artery flow or pressure, with or without change in PO2 at the ductus level; (2) increased pulmonary flow or pressure, with or without change in PO2 in the ductus arteriosus; (3) congenital lesions with probably no significant change in pulmonary flow and with normal systemic cardiac output: (4) information on ductus peculiarities in the newborn and first few weeks (included as a separate category). It should be noted that anatomic specimens only are studied and accompanying specific hemodynamic data is not available. Persistent patency is considered to be present after 12 weeks of age, and spontaneous closure is therefore excluded in this discussion.

A. ENTITIES WITH DECREASED PULMONARY FLOW OR PRESSURE IN FETAL AND NEONATAL LIFE

1. Tetralogy of Fallot.—Tetralogy of Fallot is that condition in which there is stenosis of the outflow tract or infundibulum of the right ventricle, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. The types included in this series are both simple and com-

plicated by other cardiac complexes. All cases however have moderate to

severe infundibular stenosis.

In table 1, the occurrence of open and closed ductus is given in cases of tetralogy of Fallot according to age. In 234 cases above 3 months of age, there were 2 1 cases of patency (9 percent). Thus, there is a tendency

for the ductus to be inhibited in its normal closure as compared with the

incidence of patency in the normal population. However, the ductus

tends to be small and flow not large, and patency is seldom recognized clinically and is considered rare.

In tetralogy of Fallot, the fetal circulation may be considered to be as

follows: placental blood enters the inferior vena cava and is shunted

through the foramen ovale to the left atrium and ventricle normally and reaches the brachiocephalic region. Unaerated blood from the superior vena cava enters the right atrium and ventricle. Obstruction present in

the pulmonary circuit results in less blood going into the descending aorta via the ductus than normally. The ductus may be expected to be

smaller than normal. On the other hand a considerable amount of blood

is shunted from the right ventricle into the aorta. The amount of blood

in the aorta is increased, as is the size of the ascending and transverse

aorta.

Neonatally, the situation remains the same except the pulmonary

pressure falls. The normal aorta to pulmonary artery flow at the ductus Perspectives in Biology and Medicine · Summer 1975 | 547

level in the first 24 hours may be accentuated, but the oxygen content of the blood passing through the ductus is less than normal.

2.Double outlet right ventricle with pulmonary stenosL·.—Double outlet right ventricle in this work is considered to be that condition in which both arterial trunks emerge completely or almost completely from the

right ventricle, and there may or may not be mitral-aortic valve continuity. Only the type with subaortic ventricular septal defect (VSD) and pulmonary stenosis is considered. Table 2 shows four patencies in 17 examples. While the sample is small, the incidence of patency is higher than in tetralogy and is over 25 percent. Double outlet right ventricle resembles tetralogy of Fallot, but the aorta arises completely from the right ventricle instead straddling a ventricular septal defect. The distinction between this anatomical category and a severe tetralogy is sometimes difficult. Data obtained at cardiac catheterization and cineangiography may be similar, the differ-

ence being the position of the aorta in relation to the ventricular septum if this can be seen clearly.

The subaortic ventricular septal defect tends to give laminar flow of oxygenated blood from the left ventricle into the aorta. Thus, any aortic origin of ductus flow would tend to be relatively oxygenated and may contribute to functional closure of the ductus. Hemodynamics would depend to some extent on the severity of the pulmonary stenosis. If

severe, a low pulmonary artery pressure would increase aorta-ductus flow. However, consideration of ductus patency based upon hemodynamic information in the older age group may not apply to the

critical first month. The rather high incidence of patency is not easily explained, unless patency is an anatomical facet of the malformation.

3.Pseudotruncus .—Pseudotruncus is that condition in which there is

pulmonary atresia, and the aorta emerges over a defect of the ventricu-

lar septum either in an overriding position or completely from the right ventricle. All venous blood and all oxygenated blood eject via the aorta, probably with considerable laminar flow. A pulmonary artery is present but pulmonary valve atresia prevents blood flow from the right ventricle to the lungs. Table 3 shows that there were 29 patencies of the ductus in 34 cases

(85 percent). All oxygenated and unaerated blood enters the aorta, and the normal fetal ductus flow to the aorta through the ductus arteriosus is absent. But patency allows an aorta to pulmonary flow in fetal life and is life sustaining after birth. The ductus is a small structure and sometimes nonexistent in this

entity. It may be small from disuse in fetal life since pulmonary flow is small in nonexpanded lungs, but absence must be due to an embryological fault very early in embryonic life. The sixth branchial arches form at about the 5-mm stage. 548 J Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

If the definition of pseudotruncus does not include a patent ductus as

is sometimes done, it is tempting to include teleological considerations,

that patency persists because pulmonary artery flow is required to sustain life. However patency does not always persist. In this series there is 15 percent closure, and in the individual patient a debate ensues at 1 , 2, or 3 months whether an aortic-pulmonary artery shunt should be made sur-

gically before the ductus closes.

It may be argued that the predominance of patency is related to increased ductus flow from the aorta with lower than fetal PO2. This must

occur from the onset of respiration and includes all pulmonary blood flow except that through bronchial arteries. While the ductus flow is exclusively aortic blood flow it is relatively large, and the loud continuous

murmur is helpful in clinical diagnosis.

This is an instance where a very good case can be made for a hemodynamic basis for patency since there is mandatory flow through the ductus.

4.Pulmonary atresia with intact ventricular septum.—Pulmonary atresia with intact ventricular septum is associated with tricuspid stenosis and normal relationship of the arterial trunks. Table 4 shows that 12 cases (52 percent) had a patent ductus out of 23 cases. There is a distinct tendency for the ductus closure to be inhibited. In the pulmonary atresia complexes all venous and arterial blood flows through the aorta. The normal ductus venous blood flow is absent during fetal life. Pulmonary blood flow during the neonatal period is

through the ductus and whatever accessory bronchial vessels may be present. The anatomical situation therefore implicates pressure-flow-low PO2 in the ductus as factors contributing to a high incidence of patency. 5.Tricuspid atresia without transposition.—Tricuspid atresia without transposition is that condition in which there is absence and obstruction

of the tricuspid orifice. There is normal relationship of the great vessels and there is a ventricular septal defect of variable size. An atrial communication is necessary for survival. Table 5 shows that up to the age of 5 there were seven cases (23 percent) with patent ductus, out of 30 cases. After the age of 5, all cases had a surgical procedure and could not be evaluated. Hemodynamically this resembles pulmonary atresia, since in both entities there is absence of a normal flow through the ductus arteriosus to the aorta in fetal life. In the neonatal period all flow into the ductus from the aorta is aortic pressure-diminished PO2 blood because of complete venous admixture. Since pulmonary artery flow depends upon the size of the ventricular septal defect which gradually diminishes in size, cyanosis is a feature of the syndrome with consequent significant venous blood at the ductus lumen. This may play a role in patency, although the incidence is much less than in the pulmonary atresia syndromes. Perspectives in Biology and Medicine · Summer 1975 | 549

6. Isolated pulmonary value stenosis. —Isolated pulmonary valve stenosis

is narrowing of the pulmonary valve by partial fusion of the edges of the three cusps. It is associated with normal relationship of the pulmonary artery and aorta and intact ventricular septum. Table 6 shows only one patent ductus (3 percent) out of 35 cases, and this occurred in the 3—4-month period. While systemic cardiac output is usually normal and there is normal pulmonary artery and lung flow, there is diminished pulmonary artery pressure with augmentation of pulmonary arterial blood flow from the aorta in the newborn period with higher oxygen possibly contributing to ductus closure. Since there is such a low incidence of patency in this obstructive lesion it can also be

considered with the normal group.

B. ENTITIES WITH INCREASED PULMONARY FLOW

1.Atrial septal defect, secundum type.—In this condition there is a defect

in the fossa ovalis and a persistent communication between the right and left atrium. This may be small or large, and occasionally so large that there is almost a common atrium.

In table 7 it is seen that there were eight (28 percent) instances of patency above 3 months of age and 20 examples of closure. The fetal blood flow of the inferior vena cava blood to the left atrium

which is well oxygenated by the placental contribution is reversed after birth. The right ventricle and pulmonary artery now have increased blood flow with increased oxygen. If the pulmonary artery pressure is high there is flow through the ductus to the aorta. But since this pressure falls quickly as respiration is established, aortic oxygenated blood can enter the ductus. The immediate influence on the ductus is not clear, and flow in either direction would tend to cause constriction.

It is of considerable interest that patency prevails through 8 weeks, and there are no instances of closure in the first month. The immediate

effect of oxygen is thus not apparent. This defect is usually quite benign, easily identified in the older ages, and repaired by surgery with a low risk. 2.Atrial septal defect, primum type.—In this condition there is a defect in the lower portion of the atrial septum. It is almost always associated with

a cleft aortic leaflet of the mitral valve.

Table 8 shows that there were only two instances of patency (7 percent) and 27 instances of closure. It can be argued that the mitral insufficiency increases the flow of arterial blood into the right atrium, ventricle, pulmonary artery, and ductus, and this elevated PO2

influences ductus closure. Regardless of hemodynamic considerations, in these small samples patency is less frequent in this lesion, similar but more complex than the isolated atrial septal defect.

550 I Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

3.Isolated ventricular septal defect.—Table 9 shows 26 cases of patency (22 percent) and 93 cases of closure of the ductus. In a study of 1,368 instances of heart disease in the first year of life it was noted that in the category of left to right shunts without an element of obstruction and without cyanosis isolated ventricular septal defect was the most frequent

single anomaly. This represented 23.3 percent of those with heart dis-

ease and confirms the general clinical experience. With expansion of the lung after birth a pressure gradient develops between the left systemic ventricle and right pulmonary ventricle. The blood flow or shunt between the ventricles may be small with a small

defect or large with a large defect. The relative value of the aortic and

pulmonary artery pressure will depend both on the size of the defect

and the resistance of the pulmonary vascular bed. A very large shunt so that the pulmonary flow is two or three times the systemic flow may itself increase pulmonary artery pressure. Since the pulmonary blood flow is already large and has increased oxygen saturation and the aortic flow is fully saturated, it is surprising that there is 22 percent persistent patency of the ductus arteriosus. The

factors involved in this persistent patency are not clear, since pulmonary artery blood has increased oxygenation and aortic blood no diminution in oxygen. There is no abnormality of sex distribution in the patency group. Any ductus blood flow into the lung tends to increase further an

already augmented flow. Speculation would include increased pressure and flow as possible mitigation toward patency. Patency in the presence of increased pulmonary flow is even more

evident when an atrial septal defect is combined with a ventricular septal defect.

The influence of this defect on patency is contrasted with that in atrial

septal defect and in the combined lesions in the following section (table 9).

4.Atrial septal defect and ventricular septal defect. —Table 10 shows 15 cases of patency (37 percent) and 26 cases of closure. There is a distinct tendency toward inhibition of closure of the ductus. This group is smaller than the isolated ASD or VSD. But the combina-

tion, each of which leads to increased pulmonary flow of blood with increased oxygen tension, has an increased incidence of patency. While this hemodynamic status is present after pulmonary ventilation

is well established, this may not be so when respiratory effort and venti-

lation is depressed for any reason. It is possible that during this period when cardiac output and aortic pressure is depressed right to left hypoxic blood could flow through the ductus and inhibit constriction. The three defects are compared in more detail. In a comparison of ASD, VSD, and ASD-VSD combined, the complexity of patency of the ductus arteriosus when associated with other defects is shown in relation

to the simple defects of the atrial septum (ASD), of the ventricular sepPerspectives in Biology and Medicine · Summer 1975 | 55 1

tum (VSD), and when these occur together. These defects are the tradi-

tional oxygenated blood to venous blood shunts, commonly referred to

as left to right shunts. All three categories produce arterialization of pulmonary artery blood, as seen in the unnumbered table. ClosurePatency(%) Patent ASD ...................... VSD ...................... ASD and VSD .............

209 8326 2615

34 23 36

Of the three categories, ASD is a low pressure flow with increased volume in the pulmonary artery and lungs, often twice normal. But the association of ASD and VSD in the same patient has the greatest

percentage of patency. Possibly this is related to an increased volume and pressure of the pulmonary blood flow, since the left ventricle pressure may be about 100 mm Hg and the right ventricle normally about 30 mm Hg. If the ventricular septal defect is large the combined large flow

tends to be reflected as increased pulmonary artery pressure which may reach systemic levels.

In both the VSD category and in ASD and VSD the left to right shunt

occurs with increased pressure, and the pulmonary artery pressure tends to be high. This could lead to right to left shunt at the ductus level

of venous plus shunted arterialized blood and ductus constriction.

But it is of interest that in the ASD category, where there is increased

flow but not pressure, patency occurs more frequently than in the VSD complex. These contrasting hemodynamic situations illustrate the difficulties of applying simple hemodynamic-oxygen data to patency. 5. Common atrioventricular orifice.—In common atrioventricular orifice

there is a single orifice and common valve for the mitral and tricuspid

valves. In the complete type this is associated with a combined atrial and ventricular septal defect. In the incomplete type there is valvular tissue on the summit of the ventricular septum connecting the anterior and posterior bridging leaflets. Table 1 1 shows 12 instances of patency and 51 instances of closure of the ductus (19 percent). There is some tendency toward inhibition of closure of the ductus.

During fetal life the alteration in the fetal circulation is related to the presence or absence of mitral and tricuspid insufficiency and subaortic stenosis. Where mitral insufficiency and subaortic stenosis are present,

the left ventricular ejection fraction would be reduced and aortic outflow and pressure less. Neonatally these factors are reinforced by an increased left to right 552 I Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

shunt through the combined septal defect and increased pulmonary artery flow and possibly ductus flow. Whatever the net effect of the grossly abnormal hemodynamics is, patency occurs in about 20 percent of material available. Pulmonary vascular disease occurs early in this group, presumably because of increased flow and pressure in the pulmonary artery system. The relation of high vascular resistance to patency is not known. 6. Total anomalous pulmonary venous drainage into the systemic venous circuit.—Table 12 shows that there are eight patencies (16 percent) and 40 closures of the ductus. There is a slight tendency for inhibition of closure of the ductus.

In fetal life it is estimated that only about 10 percent of the output of

the right ventricle contributes to pulmonary blood flow. Therefore pulmonary venous drainage into the left atrium should not be important in the fetal hemodynamic economy.

Postnatally however, this lesion is the prototype of left to right shunts, since the total pulmonary flow of oxygenated blood returns to the right atrium, and the venous circulation is highly oxygenated as expected since it represents complete admixture of all venous blood, and all the pulmonary blood flow is not as oxygenated blood. There must be some

return to the left heart for survival, and this normally occurs through an

atrial septal defect. An example of the hemodynamics in this complex is shown in a female aged 14 days. Ordinarily the ductus would be closed at least functionally. There was a high pressure large flow into the pulmonary artery and a

right to left shunt through the ductus arteriosus into the descending

aorta.

The systemic oxygen determinations were left atrium 67 percent; femoral artery 71 percent; right innominate vein before the anomalous pulmonary venous flow into the superior vena cava 50 percent, after the

junction of the anomalous vessel to the cava 93 percent; right atrium 79 percent; right ventricle 76 percent; pulmonary artery and presumably ductus 78 percent. But the pulmonary artery pressure was 85/40 and the femoral artery

60/40 in the presence of a very mild coarctation. The difference between

right and left atrial saturation must represent straining and sampling

since a large shunt to the left atrium was apparent in the cineangiogram. This ductus was widely patent at 14 days. If the information is applicable to day 1 or 2, the ductus blood oxygenation is only slightly elevated above the fetal level of about 60 percent. Likewise, the ductus was under high systemic pressure. The relatively low oxygen and the high pressure

in the pulmonary artery may be hemodynamic elements contributing to

patency. But closure of the ductus is the rule in this complex since in this report there is only 16 percent patency. Perspectives in Biology and Medicine · Summer 1975 I 553

The origin of patency is not clear, since in the anatomical complex

patency has the lowest incidence in the increased flow category. It is possible that hemodynamic abnormalities do not play an important role

and that patency is an incidental part of the complex.

7.Simple complete transposition without ventricular septal defect.—In this condition, the aorta emerges from the right ventricle and the pulmonary from the left, but the architecture of the heart is otherwise relatively

little disturbed. Mixing occurs at the atrial level through a defect. A patent ductus would be advantageous.

Table 13 shows that there are 10 patencies (23 percent) and 34 closures in this condition. Therefore there is a tendency for inhibition of

closure of the ductus.

Probably the fetal circulation is not greatly altered by transposition of

the aorta and pulmonary artery.

However, neonatally, the aorta and systemic circulation perfuse chiefly venous blood, alternated more or less by arterial blood from the left atrium through variable shunts, usually an atrial septal defect. When

the pulmonary vascular resistance promptly falls with the onset of respiration there is low pressure-low PO2 blood flow into the pulmonary

artery, but the high pressure aortic flow arises from the right or venous

ventricle and the aortic-pulmonary flow through the ductus is low PO2 blood. If the physiology of this ductus resembles that of the normal vessel and retains response to oxygen, patency could be expected in a higher percentage of instances. 8.Simple complete transposition with ventricular septal defect. —Table 14 shows 20 cases of patency (43 percent) and 27 cases of closure of the ductus in this entity. There is a marked tendency for inhibition of closure of the ductus.

The transposition categories, with and without VSD, show a striking influence of a VSD on patency of the ductus arteriosus or the association

of patency when a VSD is present. These entities are similar in number, 44 without VSD and 47 with VSD.

However, when a VSD is added to the transposition complex the incidence of patency nearly doubles, rising from 23 to 43 percent. This is somewhat similar to the categories of ASD and VSD. There are few patencies in ASD (7 percent), more in isolated VSD (22 percent), but when the lesions are combined the incidence rises to 37 percent in a series of 41.

It could be suggested that if increased pulmonary artery flow is augmented by increased pressure from a systemic ventricle through a VSD the hemodynamics of the ductus is influenced toward patency, especially

if the flow, as in this category, contains venous blood of lower PO2.

9.Complete transposition with tricuspid atresia. —In this entity, the pulmonary trunk emerges from the large left ventricular chamber, while the aorta emerges from the small right ventricle. 554 I Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

Table 15 shows four cases of patency (36 percent) and seven cases of

closure. Although the number of cases is small, there is a distinct tendency for the inhibition of closure of the ductus, either from subtle hemodynamic-oxygen reasons or because of abnormality of the ductus

wall, and hence may be part of the syndrome ofcongenital abnormality of the heart.

While this category is composed of a small series, the hemodynamics are of great interest. As in the simple tricuspid atresia complex, the

normal fetal and neonatal flow to the right ventricle is prohibited by a

closed tricuspid orifice. But flow to the pulmonary artery is normal or increased since this arises from the left ventricle due to the transposed arteries. The aortic flow varies with the size of the VSD, since this vessel

arises from a small right ventricle whose only inflow is through the VSD.

Thus, both great vessels have the same mixed veno-arterial blood and the only difference is pressure-flow in relation to the ductus arteriosus. The lesion is uncommon and survival is limited.

10. Taussig-Bing complex. —The Taussig-Bing complex is defined as that condition in which the aorta emerges completely from the right ventricle, while the pulmonary trunk emerges either from the right

ventricle adjacent to a ventricular septal defect or the pulmonary trunk overrides the defect. This assumes that pulmonary stenosis is not present.

Table 16 shows that there were 18 cases of patency (55 percent) and

15 cases of closure of the ductus. There is thus a dramatic tendency for the ductus to be inhibited in its closure, and it is the only pathological state in which patency predominates, except pseudotruncus.

Considering the anatomical peculiarities of this complex, several

hemodynamic facets are obvious as possibly contributing to the unusu-

ally high incidence of patency. (1) Pulmonary artery blood flow is increased by direct association with a systemic pressure ventricle; (2) the flow pressure is high, depending upon the pulmonary vascular resistance; and (3) pulmonary blood flow is highly oxygenated, with a high PO2. A diagnostic feature of the Taussig-Bing complex is that pulmonary artery blood has an increased oxygen saturation compared with any other blood sample obtainable, except left atrium or left ventricle. In this complex the ductus arteriosus tends to be large. While it is tempting to ascribe this to elevated pressure-flow from the pulmonary artery, this blood is arterialized and the ductus response to PO2 is to constrict. If the flow through the ductus early is aorta to pulmonary artery, this has a lower PO2 since the aorta arises from the right or venous ventricle.

But a dilated thin-walled ductus may be an abnormal ductus and unable to close either by constriction or subintimal proliferation. Patency of the ductus arteriosus would then be a facet of the anatomical com-

plex, and it is possible that high pressure distension is deleterious. Perspectives in Biology and Medicine · Summer 1975 | 555

An example of Taussig-Bing physiology in a small 4-kg infant who was 6 months of age: he had a hematocrit of 55 percent, a moderate

polycythemia. The right ventricle pressure was 110/11 mm Hg pressure with 75 percent saturation, the pulmonary artery pressure 110/20 mm Hg and blood with 83 percent oxygen saturation.

On the left side, the left ventricular pressure was 95/10 with 95 per-

cent saturation, but the aorta had 110/60 pressure with 75 percent saturation. The ductus was closed.

If the data was approximated at days 1, 2, or 3 when the ductus almost closes functionally, the high pulmonary artery PO2 may play a role. If the pulmonary vascular resistance fell quickly from fetal levels and ductus flow was from aorta to pulmonary artery with low PO2 blood, latent patency would be enhanced. This discussion considers factors involved in the physiology of the normal ductus. But if ductus wall abnormality is significant in the incidence of patency, then this anatomical aspect of the problem is accentuated in the Taussig-Bing complex. C. ENTITIES WITH NORMAL PULMONARY FLOW IN FETAL AND NEONATAL LIFE

There is a group of conditions in which there is neither increased nor

decreased pulmonary flow as compared with the normal, in fetal life or neonatally. These are aortic stenosis (table 17), paraductal (adult) coarctation (table 18), origin of a coronary from the pulmonary (table 19), and idiopathic hypertrophy with fibroelastosis (table 20). In all of these the ductus arteriosus after birth should have a normal flow from the aorta with a normal PO2. The data shows little inhibition of closure of the

ductus. The exceptions are three instances of patency in 52 specimens of aortic stenosis and two patencies in 41 adult coarctation. In Ebstein's disease (table 21) there is no diminution of closure of the ductus arteriosus. In fetal life in this condition aerated blood from the

placenta passes as usual into the left atrium through the foramen ovale. Unaerated blood from the superior vena cava enters the right atrium, and there may be some shunt to the left atrium if there is some obstruction of the outflow from the right ventricle. Regardless of the hemodynamics which may vary with the severity of the anomalies present, there is no instance of persistent patency after 12 weeks of age in Ebstein's anomaly. IV. Small, Closed, or Absent Ductus Arteriosus There were no instances of abnormal ductus in normal pulmonary artery flow. While there was one instance of Ebstein's anomaly, this also 556 I Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

included pulmonary atresia which places this in the decreased lung flow category.

There were 17 examples in the category of decreased pulmonary flow as shown in table 22. While the numbers are too few to establish a

pattern, smallness (about 1 mm) occurs more frequently than expected. Speculation suggests that this might be related to diminished pressure and flow through the ductus in fetal life. Table 23 shows the status in the category of increased flow. However,

in three of eight examples the complex included an element of pulmonary stenosis, leaving only four instances of abnormal ductus in the increased flow category. It is of interest that there is an example of closed or absent ductus in Taussig-Bing, where there is over 60 percent patency.

Table 24 shows the abnormal ductus in other complexes. Of great interest is the absence of the ductus in one instance. Absence cannot be

related to abnormal hemodynamics and is an embryological abnormality related to formation of the sixth aortic arch at about 5 mm. V. Conclusion

The defect related to~the origin of patency of the ductus arteriosus as an isolated anomaly of the cardiovascular system is not well understood. The unique status of the smooth muscle cells of the media in their

response to oxygen has not been explained, and probably has been inadequately studied. It is not even clear that deficiency of contraction of the ductus in response to increased oxygen tension after onset of respiration is the major component of persistent patency. The elegant studies

on ductus contraction and closure in normal newborn animal or infant

are not necessarily applicable to the problem of patency which may be related to an anatomical abnormality of the ductus wall. This could include a deficiency of smooth muscle, of oxygen receptors, or of

catecholamines or acetylcholine. There would appear to be increasing evidence that this is so, and as studies of inherited patency in poodles progress this question may be brought to a conclusion.

The problem of patency as an isolated anomaly, although complex, appears simple when patency in association with congenital malforma-

tions of the. heart is considered. The problem of abnormal fetal hemodynamics and ductus flow as an influence on ductus growth is one facet of ductus hemodynamics. This is a possible determinant or contribution to patency or closure if associated with (1) diminished ductus flow in the presence of obstruction to pulmonary artery flow present in

different forms of pulmonary stenosis, (2) increased flow in the pulmo-

nary artery and presumably ductus when associated with intracardiac lesions as a ventricular defect which increases pulmonary artery flow. In addition, many of the complex multiple anomalies of the heart are asPerspectives in Biology and Medicine · Summer 1975 | 557

sociated with cyanosis, and diminished oxygen tension in ductus blood

which should tend to influence patency if the media smooth muscle is normal and responsive. In the entities considered the hemodynamics and PO2 values are fairly well known as a consequence of many studies by cardiac catheterization and cineangiocardiography in many patients. In most instances the data

discussed indicates a higher frequency of patency than generally thought. For instance, in tetralogy of Fallot it is the stated belief of many clinicians that patency is infrequent and unusual. This large group of 234 has an incidence of 9 percent. There are other anatomical complexes with quite a high incidence of

patency, especially the pseudotruncus and Taussig-Bing categories. It

seems reasonable to conclude that in some categories the hemodynamic-

oxygen tension plays a significant role in patency, but that in some persistent function of the ductus as an open vessel it is probably a facet of the congenital heart disease complex and related chiefly to an

anomaly of the ductus wall. Identification of these groups will require further correlation with hemodynamic studies in early infancy. REFERENCES

1.Galen. In: J. C. Dalton. Doctrines of the circulation. Philadelphia: Lea's, 1884.

2.G. Fallopius. Observationes anatomicae. Francofurti apud haeredes An-

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3.W. Harvey. Anatomical studies on the motion of the heart and blood.

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6.E. C. Congdon. Transformation of the aortic arch system during the development of the human embryo. Contrib. Embryol., 14:47, 1927. 7.F. Keibel and F. P. Mall. Human embryology. Vol. 2. Philadelphia: Lippincott, 1912.

8.G. S. Huntington. Anat. Rec, 17:165, 1919-1920.

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11.G. V. R. Born, G. S. Dawes, J. C. Mott, and B. R. Rennick. J. Physiol. (Lond.), 132:304, 1956.

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14.R. A. Arcilla, W. Oh, J. Lind, and W. Blankenship. Acta Paediatr. Scand., 55:615, 1966.

15.H. M. Rudolph, P. A. M. Auld, R.J. Golinko, and M. H. Paul. Pediatrics, 28:28, 1961.

16.G. C. Emmanouilides, A. J. Moss, E. R. Duffie, and F. H. Adams. J. Pediatr., 65:327, 1964.

558 J Donald E. Cassels, Saroja Bharati, and Maurice Lev · Patent Ductus Arteriosus

17.S. Cassin, G. S. Dawes, J. C. Mott, B. B. Ross, and L. B. Strang. J. Physiol. (Lond.), 171:61, 1964.

18.A. G. M. Campbell, G. S. Dawes, A. P. Fishman, and A. L. Hyman. J. Physiol. (Lond.), 181:47, 1965. 19.R. E. Gross and J. P. Hubbard. J. Am. Med. Assoc, 112:729, 1939.

20.C. Langer. Z. Ges. Arztl., 13:328, 1857.

21.F. Walkoff. Das gewebe des ductus arteriosus und die obliteration. Dieselben Ztschn. Med. Leipz. Heidele, 3, R: 109, 1869. 22.H. Von Hayek. Z. Anat. Entwicklungsgesch., 105:15, 1935. 23.J. J. Molnar, E. Mesel, R. J. Golinko, and A. M. Rudolph. J. Histochem. Cytochem., 10:667, 1962. 24.D. G. Silva and M. Ikeda. J. Ultrastruct. Res., 345:358, 1971. 25.K. C. Richardson. Am. J. Anat., 114:173, 1964. 26.L. S. Van Orden, F. E. Bloom, R. J. Barrnett, and N. J. Giarman. J. Pharm. Exp. Ther., 154:185, 1966.

27.J. Barcroft, J. A. Kennedy, and M. F. Mason. J. Physiol. (Lond.), 92:1, 1938.

28.J. A. Kennedy and S. L. Clark. Anat. Rec, 79:349, 1941. 29.E. C. Amoroso, G. S. Dawes, and J. C. Mott. Br. Heart. J., 20:92, 1958.

30.F. E. Coughlin and G. S. Husson. Am. J. Dis. Child., 100:531, 1960.

31.N. B. Everett and R.J.Johnson. Anat. Rec, 110:103, 1951.

32.F. S. Fay. Am. J. Physiol., 221:470, 1971.

33.D. W. Allen, J. Wyman, Jr., and C. A. Smith. J. Biol. Chem., 203:81, 1953. 34.M. Morse, D. E. Cassels, and M. Holder. J. Clin. Invest., 29:1091, 1950. 35. ----------.J. Clin. Invest., 29:1098, 1950. 36.C. Bauer. Respir. Physiol., 10:10, 1970.

37.R. Benesch and R. E. Benesch. Biochem. Biophys. Res. Commun., 26:162, 1967.

38.A. Chanutin and R. R. Curnish. Arch. Biochem. Biophys., 121:96, 1967.

39.I. Oberhansli-Weiss, M. A. Heyman, A. M. Rudolph, and K. L. Melmon. Pediatr. Res., 6:693, 1972.

40.M. L. Powell. Med. J. Anat., 2:58, 1963.

41.D. Danielowicz, A. M. Rudolph, and J. I. E. Hoffman. Pediatrics, 37:74, 1966.

42.D. M. McMurphy and L. O. Boreus. Am. J. Obstet. Gynecol., 109:937, 1971.

43.D. M. McMurphy, M. A. Heyman, A. M. Rudolph, and K. L. Melmon. Pediatr. Res., 6:231, 1972.

44.R. R. Wilson. Br. Med. J, 1:810, 1958. 45.A. Sciacca and M. Condorelli. Bibl. Cardiol., 10 (suppl), 1960 46.M. Jones, M. W. Barrow, and M. W. Wheat. Surgery, 66:891, 1969. 47.T. Brundin, K. A. Norberg, and S. Soderlund. Scand. J. Thorac Cardiovasc. Surg., 5:16, 1971. 48.D. E. Cassels and R. Y. Moore. Chest, 63:727, 1973.

49.D. H. Knight, D. F. Patterson, and J. Melbin. Circulation, 47: 127, 1973.

50.P. H. Benavides, J. E. Vela, and G. Monroy. Arch. Inst. Cardiol. Mex., 26:332, 1956.

51.H. N. Oldham, Jr., N. P. Collins, G. E. Pierce, D. C Sabiston, Jr., and A.

Blalock. J. Thorac. Cardiovasc. Surg., 47:331, 1964. 52.W. H. Civin and J. E. Edwards. Arch. Pathol., 51:192, 1951.

53.D. E. Cassels. The ductus arteriosus. Springfield, 111.: Thomas, 1973.

54.L.J. Krovetz and H. E. Warden. Dis. Chest, 42:46, 1962.

Perspectives in Biology and Medicine · Summer 1975 ¡ 559

CT) O

Total over 12 wk

15yr ...... 16yr ...... 17yr ...... 18yr ...... 19yr ...... 20yr ...... Over 20 yr.

13-14 yr. . .

12-13 yr. . .

11-12 yr. . .

10-11 yr. . .

9-10 yr. . .

1-2 yr___ 2-3 yr.... 3-4 yr. ... 4-5 yr ___ 5-6 yr. . . . 6-7 yr. . . . 7-8 yr. . . . 8-9 yr. ...

Stillborn. . . 0-4 wk ___ 4-8 wk.... 8-12 wk... 3-4 mo ___ 4-5 mo... . 5-6 mo ___ 6-9 mo ___ 9-12 mo...

Age

11

1

' i

1 1 1

"2

4 23 2

Male

10

3 13 3 1

Female

Ofen Ductus

10 6 12 6 7 9 6 5 1 3 7 3 2 1 4 4 3 3 3 14

6 1 1 9 1 1 6

Male

3 1 13

Female

Closed Doctos

Tetralogy of Fallot

TABLE 1

Male

Female

Open Doctos

MaleFemale

Closed Ductus

Double Outlet Right Ventricle with Pulmonary Stenosis

TABLE 2

13

13 6 3 1 1 3 1 1 4

16

19 4 1 5 1 1 3 1 2 1

Female

Open Ductus Male

TABLE 3

Male

Female

Closed Ductus

Pseudotruncus

2

Total over 12 wk

17yr ....... 18yr ....... 19yr ....... 20yr ....... Above 20 yr.

16yr .......

12-13 yr. . . . 13-14 yr. . . . 15yr .......

10-11 yr ____ 11-12 yr ____

3-4 yr ..... 4-5 yr ..... 5-6 yr ..... 6-7 yr ..... 7-8 yr ..... 8-9 yr ..... 9-10 yr ____

1-2 yr ..... 2-3 yr .....

Stillborn. . . . 0-4 wk ..... 4-8 wk ..... 8-12 wk. . . . 3-4 mo ..... 4-5 mo ..... 5-6 mo ..... 6-9 mo ..... 9-12 mo....

Ace

37 4 3

Male

2 2

"i

28 2 3 1

Female

Male

Female

Closed Ductus Male

Female

Ofen Ductus Male

Female

Closed Ductus

Tricuspid Atresia without Transposition

Pulmonary Atresia with intact Ventricular Septum

Open Ductus

TABLE 5

TABLE 4

Male

Female

Open Ductus

Male

Female

Closed Ductus

Isolated Pulmonary Stenosis

TABLE 6

Ut s? NO

Total over 12 wk

Over 20 yr.

19yr ...... 20JT ......

9-10 yr. . . 10-11 yr. . . 11-12 yr. . . 12-13 yr. . . 13-14 yr. . . 15yr ...... 16yr ...... 17yr ...... 18yr ......

8-9 yr. ...

4r-5 yr ___ 5H5yr. ... 6-7 yr. . . . 7-8 yr. . . .

3-4 yr. ...

1-2 yr. . . . 2-3 yr. . . .

Stillborn. . . 0-4 wk ___ 4-8 wk.... 8-12 wk. . . 3-4 mo ___ 4-5 mo ___ 5-6 mo ___ 6-9 mo.... 9-12 mo...

Age

3 21 1 2 1

Male

"i "2

2 19 3 1

Female

Open Ductus Male

Female

Closed Ducxus

Atrial Septal Defect, Secundum Type

TABLE 7

Male

Female

Open Ductus Male

Female

Closed Ductus

Prlmum Type

Atrial Septal Defect,

TABLE 8

12

1

"2

2 20 4

Male

14

1 1 1 1 3 1

"i

3 20 11 4 1

Female

Open Ductus

Male

14

Female

Closed Ductus

Ventricular Septal Defect

TABLE 9

CJi s> US

Total over 12 wk

Above 20 yr.

20yr .......

6-7 yr ..... 7-8 yr ..... 8-9 yr ..... 9-10 yr ___ 10-11 yr ___ 11-12 yr.... 12-13 yr. . . . 13-14 yr.... 15yr ....... 16yr ....... 17yr ....... 18yr ....... 19yr .......

5-6 yr .....

2-3 yr ..... 3-4 yr ..... 4-5 yr .....

1-2 yr .....

0-4 wk ..... 4-8 wk ..... 8-12 wk. . . . 3-4 mo ..... 4-5 mo ..... 5-6 mo ..... 6-9 mo ..... 9-12 mo....

Stillborn. . . .

Age

TABLE 10

1 20 6 2 1

Male

11

1 23 6 2 5 1 2 1

Female

Open Ductus Male

Female

Closed Ductus

Defect

Atrial Septal Defect and Ventricular Septal

Male

10

Female

Male Female

Closed Ductus

20 3 1 2 1

Male

1

"2

13 2

Female

Open Ductus

Male

Female

Closed Ductus

Venous Drainage

Open Ductus

Total Anomalous Pulmonary

Combined Complete and Incomplete Types

TABLE 12

Common Atrioventricular Orifice,

TABLE 11

Ut Ui »fr.

Total over 12 wk

Above 20 JT.

18yr ....... 19yr ....... 20yr .......

9-10 yr. . . . 10-11 yr ____ 11-12 jr. . . . 12-13 yr. . . . 13-14 yr. . . . 15yr ....... 16yr ....... 17yr .......

8-9 yr .....

2-3 yr ..... 3-4 yr ..... 4-5 yr ..... 5-6 yr ..... 6-7 yr ..... 7-8 yr .....

1-2 yr .....

Stillborn. . . . 0-4 wk ..... 4-8 wk ..... 8-12 wk.... 3-4 mo ..... 4-5 mo ..... 5-6 mo ..... 6-9 mo ..... 9-12 mo....

Age

68 13 3 1 2

Male

20 8 2 2

Female

Male Female

Closed Ductus

12

10 13 2 2 2 1 2 2

Male Female

Open Ductus Male

Female

Closed Ductus

Ventricular Septal Defect

out Ventricular Septal Defect

Open Ductus

TABLE 14

Simple Complete Transposition with

TABLE 13

Simple Complete transposition with-

TABLE 15

11 6 1

Male

Female

Open Ductus

Male

Female

Closed Ductus

Complete Transposition with Tricuspid Atresia

Ut s> Ut

Total over 12 wk

Above 20 yr.

18yr ....... 19yr ....... 20yr .......

12-13 yr ____ 13-14 yr. . . . 15yr ....... 16yr ....... 17yr .......

11-12 yr. . . .

10-11 yr. . . .

8-9 yr ..... 9-10 yr. . . .

5-6 JT ..... 6-7 yr ..... 7-8 yr .....

3-4 yr ..... 4-5 JT .....

1-2 yr ..... 2-3 yr .....

Stillborn. . . . 0-4 wk ..... 4-8 wk ..... 8-12 wk.... 3-4 mo ..... 4-5 mo ..... 5-6 mo ..... 6-9 mo ..... 9-12 mo....

Age

Male

12

Female

Male

Female

Closed Ductus Male

Female

Open Ductus

1 19

Male

Female

Closed Ductus

Aortic Stenosis

Taussig-Bing Complex

Open Ductus

TABLE 17

TABLE 16

Male

Female

Open Ductus

Male

Female

Closed Ductus

Paraductal (Adult) Coarctation

TABLE 18

Ut s> s>

Above 20 yr.

20yr .......

19yr .......

9-10 yr. . . . 10-11 yr. ... 11-12 yr ___ 12-13 yr___ 13-14 yr. . . . 15yr ....... 16yr ....... 17yr ....... 18yr .......

8-9 yr .....

1-2 yr ..... 2-3 yr ..... 3-4 yr ..... 4-5 yr ..... 5-6 JT ..... 6-7 yr ..... 7-8 yr .....

Stillborn. . . . 0-4 wk ..... 4-8 wk ..... 8-12 wk.... 3-4 mo ..... 4-5 mo ..... 5-6 mo ..... 6-9 mo ..... 9-12 mo....

Age

Male

Female

Male

Female

Closed Ductus Male

Female

Open Ductus Male Female

Closed Ductus Male

Female

Open Ductus

Male

Female

Closed Ductus

Ebstein's Disease

Idiopathic Hypertrophy with Fibroelastosis

Origin of Coronary Artery from Pulmonary Artery

Open Ductus

TABLE 21

TABLE 20

TABLE 19

TABLE 22 Abnormal Ductus in Decreased Pulmonary Flow

Te tea logy Age

M

DORV with PS M

Pseudo-

T.S. with

?.?. without Teaks-

Pun Puluonaiv

TSUNCUS

P. At.

position

Stenosis

M

M

M

Small Ductus

Stillbirth (premature) ..... Stillbirth (full term) ....... Newborn up to 48 hr. . . 1 Closed or Absent Ductus

Stillbirth (premature) . Stillbirth (full term)... Newborn up to 48 hr.. Note.—Small ductus in one tricuspid stenosis with absent right ventricle; one pulmonary atresia with tricuspid insufficiency; and one pulmonary atresia with Ebstein's. Closedor absent ductus in one stillbirth tricuspid atresia

with complete transposition with pulmonary stenosis; one newborn complete transposition with common atrio-

ventricular orifice with pulmonary atresia; and one newborn common atrioventricular' orifice with pulmonary stenosis. DORV with PS = double outlet right ventricle with pulmonary stenosis; TS with P. At. = tricuspid stenosis with pulmonary atresia; T.A. without Transposition — tricuspid atresia without transposition.

I 567

Ut s? OO

M

M

PDA

Prihum

PDA

M

AND

AND

M

CAVO

ASD,

M

* Complete A-V orifice with small ductus in tetralogy of Fallot. T Complete transposition with pulmonary stenosis. t Complete A-V orifice with absent ductus in comí common atrium with pulmonary stenosis.

Small Ductus

M

Coaect.

Transit.

CT

M

?.?.

with

'" [" [ ......... ¿i ./ " '' ..... j'

Closed or Absent Ductus

M

VSD, AND PDATAPVD

Stillbirth (full term) .......................... Newborn up to 48 hr ..................... ij ..

(premature) .

Stillbirth

(premature) ...... Stillbirth (full term) Newborn up to 48 hr

Stillbirth

Age

VSD

asd

Abnormal Ductus in Increased Pulmonary Flow

TABLE 23

M

CT with N. Arch with VSD

M

M

M

CT withS.V. with N. ArchIncreased withoutTaussig- Pulmonary VSDBing Flow

Ut s> «5

M~~F M

F

Insufficiency

with Tricuspid

Pulmonary Atresia

I Absent ductus in complete transposition with pulmonary atresia with complete A-V onfice.

* Small ductus in unusual tricuspid stenosis with absent pulmonary valve and pulmonary Sow.

Stillbirth (premature) . Stillbirth (full term) . . Newborn up to 48 hr.

Stillbirth (premature) . Stillbirth (full term) . . Newborn up to 48 hr.

Age

Premature Closure or Narrowing op Foramen Ovale M

Small Ductus

M

Hypoplasia of Aorta

Closed or Absent Ductus

Mitral Atresia Complex

it

M

CAVO F

position with

Complete Trans-

Abnormal Ductus in Other Complexes Not Included in Discussion

TABLE 24

Unusual Tri-

M

F

cuspid Atresia and Stenosis

Appendix TABLE Al

Pulmonary Stenosis Included in Group a as Diminished Pulmonary Blood Flow After 12 Weeks (PS in Group A)

_ Ducts

Observed_ , P of

------------

------------------------ Ei- expected??? = Pulmonary Blood Flow (PBF)

Open Closed Total pected

Group A, diminished PBF .............. 74 313 387 Group B, increased PBF ................ 123 340 463 GroupC, normal PBF ................. 5 156 161 Total .............................. 202

809 1011

(%)P

77 96.10N.S.