Pathology and Anatomy of Pulmonary Atresia and Ventricular Septal Defect

MARLENE RABINOVITCH, M.D. Department of Pediatrics

The Hospital for Sick Children and The University of Toronto School of Medicine

Toronto, Ontario

The early embryologic studies of Kramer 1 facili- tated the understanding of pathogenesis of "ex- treme" tetralogy of Fallot or pulmonary atresia with ventricular septal defect. Kramer first suggested that the outflow tract of both ventricles is the region where the conus joins the truncus and that resorp- tion and differential growth are responsible for the reduction of the conoventricular flange, making the conus shift from the extreme right toward the mid- line of the septum where it comes into alignment with the muscular portion of the interventricular septum. Coalescence of the right border of the mus- cular interventricular septum with the conal por- tion of the truncoconal septum assures that the pul- monary artery is situated above the right ventricle and the aorta is above the left ventricle. Thus de la Cruz and Da Rocha 2 suggested that unequal parti- tioning of the truncoconal septum at the expense of the pulmonary artery was responsible for the de- gree of pulmonary (infundibular) stenosis, whereas rotation of the truncus influenced the degree of aor- tic override, and the degree of fusion of the primor- dial cusps influenced the severity of valvar stenosis or atresia.

Address correspondence to Marlene Rabinovich, M.D., Divi- sion of Cardiovascular Research, The Hospital for Sick Chil- dren, 555 University Avenue, Toronto, Ontario, MSG 1XS.

EMBRYOLOGIC CONSIDERATIONS OF THE CARDIAC MALFORMATION

Van Praagh and coworkers 3 suggested that the embryologic basis for pulmonary atresia and ven- tricular septal defect (PA-VSD) was severe under- development of the subpulmonary infundibulum (subpulmonary conus). The result is that the infun- dibulum is shifted; later it hypertrophies secondary to the marked obstruction that is created by the shift. Embryologic studies of the malformation in keeshond dogs by Van Mierop and Patterson 4 sup- ported the concept of underdevelopment of the conus. Goor and coworkers s and Anderson and coworkers 6 suggested that the mechanism of under- development may be partly related to increased ab- sorption of the distal part of the infundibulum.

To address the mechanism of conotruncal fusion and the cause of abnormalities in the process, de la Cruz and associates 7 first carried out in vivo label- ing studies in chick embryos. Subsequent studies in chick embryos by Steding and Seidl s were able to demonstrate that abnormal angulation of the cono- truncal border region, created experimentally by a microfilament sling, caused the flow path to be divided unequally, resulting in conoventricular ab- normalities. This was the first suggestion that flow disturbances may be responsible for the tetralogy of Fallot malformation. Further studies by Aranega and coworkers g actually reproduced tetralogy of

Prog Pediatr Cardiol 1992, 1(1):9-17 Copyright �9 1992 by Andover Medical Publishers, Inc.

10 Progress in Pediatric Cardiology

Fallot by placing a ligature around the conal region in chick embryos at Hamburger-Hamilton Stage 17 through Stage 21.

It is important to find out how alterations in blood flow influence cellular development. In stud- ies by Kirby 1~ it has been shown that failure of mi- gration of neural crest cells is associated with cono- truncal malformations. Recent data by Icardo and Manasek u and Icardo 12 suggest that fibronectin, an extracellular matrix glycoprotein, plays a key role in cellular migration during morphogenesis of car- diac and other tissues. One can therefore speculate that alterations in flow may influence neural crest cell migration and/or cellular production of fibro- nectin and that this may be responsible for subse- quent aberrations in conus resorption or underde- velopment.

CARDIAC ANATOMICAL FEATURES In keeping with these embryologic considerations, the ventricular septal defect in PA-VSD is of the malalignment variety and, therefore, is large and rarely obstructed by membranous tissue. The aorta is overriding but usually with less dextroposition than in tetralogy of Fallot. The aortic arch is dilated and right-sided in 26-50 % of cases. Aortic valvular insufficiency may develop as a result of anular dila- tation or bacterial endocarditis. 13ha The coronary arteries are usually normal with a prominent conus branch, although anomalies include a high origin of the coronary ostia, coronary-to-pulmonary artery fistulae, and "transposition" anatomy with the right coronary artery originating from the left anterior aortic sinus and traversing the right ventricular in- fundibulum. The pulmonary infundibulum is blind- ended and may be normal in length or very short. The displaced infundibular septum may be fused to the right ventricular wall. Rarely is only an atretic valve evident; more often there is atresia of the central pulmonary artery that may extend into the branches.

EMBRYOLOGIC CONSIDERATIONS OF PULMONARY AND SYSTEMIC

COLLATERAL ARTERIES In patients with PA-VSD there is wide variability in the nature and size of communications between systemic collateral arteries and pulmonary arteries.

However, we found that specific features were pre- dictable based on embryologic considerations. During the first month of gestation, the upper lung buds are supplied by primitive pulmonary arteries that originate from the sixth aortic arch; the lower lung buds are supplied by a single pair of systemic collateral arteries that originate in the subdiaphrag- matic descending aorta. Arrest in development at this stage was observed in an infant with persistent pulmonary hypertension of the newborn, is

By the fifth week of gestation, there are many paired dorsal intersegmental (systemic collateral) arteries that communicate with a vascular plexus which develops rapidly within the lung buds. 16 As the intrapulmonary plexus joins the true central pulmonary arteries, the intersegmental arteries be- gin to involute. These intersegmental-pulmonary artery communications may persist if there is atre- sia of the pulmonary valve and associated hypopla- sia of the central pulmonary arteriesy perhaps as a result of decreased forward flow. The true bron- chial arteries are those vessels that arise from the underside of the aorta after the ninth week of gesta- tion to supply the bronchi .18 Near the time of birth, these vessels communicate with intrapulmonary ar- teries. These communications may involute post- natally or they may persist and proliferate when there is decreased forward blood flow (pulmonary atresia) late in gestation. 19

By the sixteenth week of gestation, all intra- acinar arteries are present as those arteries that are distributed alongside airways and the many addi- tional supernumerary arteries. After the sixteenth week, the intra-acinar arteries begin to form along the newly developed acini, the respiratory bronchi- oli, and the saccules (primitive alveolar ducts and alveoli).x9

PULMONARY AND SYSTEMIC COLLATERAL ANATOMY

The author and associates devised a classification of aortopulmonary connections in patients with PA-VSD based on these embryologic considera- tions and on dissections of lungs obtained at post- mortem examinations, x7 Three types of systemic collateral arteries were defined, based on their site of origin and the three different ways in which they join with pulmonary arteries. Moreover, each sys- temic collateral type had a characteristic pattern of

Pathology and Anatomy of PA-VSD 1 1

3 T Y P E S O F S C A

SCA TYPE I , INTRAPULMONARY (BRONCHJAt ARTERY BRANCH) " ANASTOMOSIS

BCA TYPE ~ (DIRECT AORTIC BRANCH)

SCA TYPE Tff (INDIRECT AORTIC BRANCH]

3 T Y P E S O F A N A S T O M O S I S

EXTRA PUt~ONAR'f

�9 HILAR ANASTOMOSIS

, EXTRAPULMONARY ANASTOMOSIS

FIGURE I. Three types of systemic collateral arteries (SCA) (direct and indirect aortopulmonary collateral arteries and bronchial collaterals) and three types of anastomosis with the pulmonary artery (PA) (hilar, intrapulmonary, and extrapulmonary). SUBCL = subclavian; AO = aorta (reprinted with permission from Rabinovitch17).

anastomosis with intrapulmonary arteries (Figure 1). "Direct" aortopulmonary collaterals are those vessels that arise directly from the descending aorta and therefore are probably derived from the primi- tive intersegmental arteries. These vessels join or are replaced at the hilum or the intrapulmonary hilar region by a vessel that is pulmonary, both histologically and by its distribution along the air- ways. This region of anastomosis is characterized by intimal proliferation of variable degrees, and it probably represents an incomplete attempt at invo- lution of the intersegmental arteries. The stenosis thus created by intimal proliferation prevents the transmission of high blood flow and pressure from the aorta to the intrapulmonary arteries, and this may protect the pulmonary vascular bed from the high systemic flow and pressure that would other- wise cause pulmonary vascular disease (Figure 2). The poststenotic pulmonary arteries are frequently very tortuous and dilated, suggesting the presence of pulmonary vascular disease, but, in fact, this is rarely seen. 17"2~ Usually these vessels join with intrapulmonary arteries inside the lung, and they can be traced back to central pulmonary arteries,

creating a dual circulation. In some cases, however, they form the sole blood supply to a segment or to subsegments of lung, and their ligation at the time of surgery can lead to pulmonary infarction (Figure 3).

The patent ductus arteriosus can serve as a spe- cial type of direct aortopulmonary collateral ar- tery. It may supply the pulmonary confluence, but it can also supply a single lung by anastomosis with a hilar vessel that is pulmonary in its histology and branching pattern. 22 If the ductus closes after birth, the sequelae will be those associated with an absent pulmonary artery, namely generalized hypoplasia of the intrapulmonary arteries. If the ductus con- stricts, the lung will be protected from pulmonary vascular disease. If it remains patent, this complica- tion will be likely. The Division of Cardiovascular Surgery at The Hospital for Sick Children has suc- cessfully banded an arterial ductus serving as a col- lateral artery in a two-year-old child; the subse- quent regression of mild vascular disease (medial hypertrophy of muscular arteries) has been docu- mented (Figure 4). Another infant showed ad- vanced pulmonary vascular changes of intimal pro- liferation, but in association with pulmonary venous obstruction. The likelihood of pulmonary vascular disease in a child with ductal supply to a lung is dependent, therefore, on age and the degree of stenosis.

The next type of systemic collateral artery has been called an indirect aortopulmonary collateral, because it is a tributary of a major aortic branch, for example, subclavian, internal mammary, inter- costal, or coronary artery. These vessels probably form later in gestation since they rarely are associ- ated with direct aortopulmonary collaterals. They usually join the central extrapulmonary arteries, as seen in the unusual coronary artery-to-pulmonary artery fistula, 23 or these "indirect" aortopulmonary collaterals can fan out over the pleural surface of the lung as small, multiple branches. They also can have a stenosis associated with anastomosis.

The bronchial artery branches are true bronchial arteries that form another type of systemic collat- eral artery; they form anastomoses with intrapul- monary arteries, usually in the periphery of the lung. The distal vessels are usually normal in archi- tecture but they may be quite small, and the anasto- motic network which develops mainly after birth can be extensive and profuse (Figure 5).

12 Progress in Pediatric Cardiology

FIGURE 2. The site of anastomosis between a direct aortopulmonary collateral artery and a pulmonary artery at the hilum. There is marked occlusive intimal hyperplasia. (Movat stain, original magnification X 50.)

GROWTH OF THE CENTRAL AND PERIPHERAL PULMONARY ARTERIES

In the surgical repair of PA-VSD there are two im- portant questions:

1. Can the central pulmonary arteries be recon- structed to supply most of the lungs or at least the equivalent bronchopulmonary segments of one good lung?

2, Can their growth be enhanced by palliative sur-

gery using conduits or systemic-to-pulmonary artery shunts with or without unifocalization of collateral vessels/

It is certain that adequate flow is mandatory. 24'25 In some patients with technically adequate shunts, however, growth of the pulmonary arteries is not achieved and intrinsic factors related to the compo- sition of the vessel wall may play a role. Following observations by Rosenberg and coworkers, 26 it was

FIGURE 3. (,4,) Features in a patient with PA-VSD. Direct aortic branches become pulmonary arteries to right upper lobe, right lower lobe, and left lower lobe. There are no intrapuhnonary anastomoses between branches of these vessels and branches from the pulmonary arteries of the right middle or left upper lobe. (B) The postmortem arteriogram of the right lung (c = collateral artery to right upper lobe; p = pulmonary artery to right middle lobe; s = poststenotic sinusoidal dilatation of collateral branch to right lower lobe). (C) Postmortem arteriogram of left lung (c ~ collateral branch to left lower lobe; p = pulmonary artery to left upper lobe and lingula).

A IY

,..

~TIONS

,S

13

14 Progress in Pediatric Cardiology

A

FIGURE 4. (A) Cineangiogram taken from a two- year-old patient with PA-VSD and left-sided ductus arteriosus to the left lung. (B) Photomicrograph of the vascular bed shows evidence of medial hypertrophy of the pulmonary arteries. (C) Regression of medial hy- pertrophy is observed following banding of the ductus (arrows denote medial muscular coat). (Movat stain, original magnification X 320.) C

found that patients with tetralogy of Fallot may have decreased pulmonary artery elastin, and this connective tissue component may be critical for vascular growth .27 Minute full-thickness sections of pulmonary arteries were obtained from infants at the time of surgical placement of a systemic-to- pulmonary artery shunt. Using quantitative mor- phometric analysis of electron photomicrographs of the arterial wall, the proportion of elastin, colla- gen, smooth muscle, and ground substance in the media was calculated. The growth of the pulmo- nary arteries was then measured by two-dimen- sional echocardiography at the time of the shunt operation and again 7-27 months afterward. A direct correlation between pulmonary arterial

growth and the proportion of elastin in the media of the vessel wall was shown.

In patients with PA-VSD the variability of the systemic collateral blood supply must be consid- ered in respect to peripheral pulmonary arterial growth. Blood supply may be inadequate because of deficient branching or because of severe stenoses both at the hilum and distally. Further obstruction of flow can result from thromboses, which are more likely with severe polycythemia or vascular dis- ease, particularly if a surgical shunt has been placed into a limited area of pulmonary blood supply, zS In lungs obtained at postmortem examination from patients with PA-VSD, morphometric studies were performed to assess the size, number, and muscu-

Pathology and Anatomy of PA-VSD 15

A

i~, !

PULMONARY ARTERY

BRONCHIAL ARTERY

B -~...'---~.-----~.~ P UI.. M O N A R y ARTERY

FIGURE 5. (A) Normal relationship of the normal pulmonary arteries to airways and bronchial arteries. In the left lung the arteries are drawn in front of the bron- chi to avoid obscuring their structural features. (B) Some of the features dissected in a patient who had PA-VSD. The bronchial arteries to both lungs are enlarged. hz the right lung and the left upper lobe, the axial pulmonary arteries are severely hypoplastic; in the left lower lobe and lingula the diameters of the axial pulmo- nary arteries are nearly normal. Large anastomoses with bronchial arteries are seen. (C) Dissection of the vessels in the left lower lobe shows large anastomoses (a) between branches of a bronchial artery (b) and a pulmonary artery (p). (D) The postmortem arteriogram shows a large anastomosis (a) between a bronchial arterial branch and a pulmonary artery in the left lower lobe. On the right the axial arteries are hypoplastic. The dense backgroud haze is the result of filling of the enlarged bronchial arteries (reprinted with permission from RabinovitchZT).

16 Progress in Pediatric Cardiology

larity of peripheral pulmonary arteries. 17 There was great variability, but in all cases the arteries were small when compared to their accompanying air- ways. Moreover, the absolute number of arteries usually was decreased in keeping with a subnormal number of alveoli. These features may limit the increase in pulmonary blood flow with exercise. Since vascular development of the lung occurs mostly in the first two years of life, these data sug- gest that early surgical correction would be prefer- able, all other factors considered.

MECHANISM OF PROGRESSIVE OCCLUSION OF COLLATERAL ARTERIES

Mult ipleaortopulmonary collateral arteries may be large and relatively unobstructed at birth, causing severe congestive heart failure. However, the site of anastomosis almost invariably continues to be- come more obstructed over time with progressive cyanosis. The mechanism of progressive occlusion is not well-understood. It may be related to turbu- lence at the site of anastomosis or to an intrinsic "program" of endothelial and smooth muscle cells similar to that which was described in relationship to intimal proliferation in the late gestation ductus arteriosus. In endothelial and smooth muscle cells cultured from the ductus arteriosus, developmen- tally regulated changes in the production of extra- cellular matrix components were observed.

Ductus arteriosus endothelial cells produce 10 times more hyaluronan than cells from the pulmo- nary artery or aorta, and ductus smooth muscle cells produce twice as much fibronectin as cells from those at other vascular sites. In three-dimensional collagen gels, it was demonstrated that smooth muscle cells from the ductus were more migratory than those from the aorta; this was directly related to their capacity to produce more fibronectin. 3~ There was also an association between increased production of fibronectin and increased production of a specific hyaluronan-binding protein, facilitat- ing their migration, especially through a hyal- uronan-rich matrix such as that produced by en- dothelial cells. 2~176 Similar alterations in specific extracellular matrix components may govern inti- mal proliferation at the collateral-pulmonary ar- tery anastomotic site.

REFERENCES 1. Krarner TC: The partitioning of the truncus and

conus and the formation of the membranous portion of the interventricular septum in the human heart. Am ] Anat 1942; 71:343-370.

2. de la Cruz MV, Da Rocha JP: An ontogenetic theory for the explanation of congenital malformations in- volving the truncus and conus. Am Heart ] 1956; 51: 782-805.

3. Van Praagh R, Van Praagh S, Nebesar RA, et al: Tetralogy of Fallot: Underdevelopment of the pul- monary infundibulum and its sequelae. Am ] Cardiol 1970; 26:25-33.

4. Van Mierop LHS, Patterson DF: The pathogenesis of spontaneously occurring anomalies of the ventricu- lar outflow tract in Keeshond dogs: Embryologic studies. Birth Defects 1978; 14:361-375.

5. Goor DA, Dische R, Lillehei CW: The conotruncus: I. Its normal inversion and conal absorption. Circu- lation 1972; 36:375-384.

6. Anderson RH, Wilkinson JL, Arnold R, et al: Mor- phogenesis of bulboventricular malformations: I. Consideration of embryogenesis in the normal heart. Br Heart ] 1974; 36:242-255.

7. de la Cruz MV, Sanchez Gomez C, Arteaga MM, et al: Experimental study of the development of the truncus and conus in the chick embryo. JAnat 1977; 123:661-686.

8. Steding G, Seidl W: Contribution to the develop- ment of the heart. Part II. Morphogenesis of congeni- tal heart. Part II. Morphogenesis of congenital heart disease. ] Thorac Cardiovasc Surg 1981; 29:1-16.

9. Aranega A, Egea J, Alvarez L, et al: Tetralogy of Fallot produced in chick embryos by mechanical in- terference with cardiogenesis. Anat Rec 1985; 213: 560-565.

10. Kirby M: Cardiac morphogenesis: Recent research advances. Pediatr Res 1987; 21:219-224.

11. Icardo JM, Manasek FJ: Fibronectin distribution dur- ing early chick embryo heart development. Dev Biol 1983; 95:19-30.

12. Icardo JM: Distribution of fibronectin during the morphogenesis of the truncus. Anat Embryo11985; 171:193-200.

13. Bharati S, Paul MH, Idriss F, et al: The surgical anat- omy of pulmonary atresia and ventricular septal de- fect: Pseudotruncus. ] Thorac Cardiovasc Surg 1975; 69:713-721.

14. McGoon MD, Fulton RE, Davis GD, et al: Systemic collateral and pulmonary artery stenosis in patients with congenital pulmonary valve atresia and ventric-

�9 ular septal defect. Circulation 1977; 56:473-479. 15. Goldstein JD, Rabinovitch M, Van Praagh R, et al:

Pathology and Anatomy of PA-VSD 1 7

Unusual vascular anomalies causing persistent pul- monary hypertension in a newborn. Am J Cardiol 1979; 43:962-968.

16. Congdon ED: Transformation of the aortic arch sys- tem during development of the human embryo. Con- trib Embryol 1922; 154:47-119.

17. Rabinovitch M, Herrera-de Leon V, Castaneda AR, et al: Growth and development of the pulmonary vascular bed in patients with tetralogy of Fallot with or without pulmonary atresia. Circulation 1981; 64: 1234-1249.

18. Boyden EA: The time lag in the development of the bronchial arteries. Anat Rec 1970; 16:611-614.

19. Hislop A, Reid LM: Intrapulmonary arterial devel- opment during fetal life: Branching pattern and structure.i Thorax 1973; 28:129-135.

20. Thiene Gi Frescura D, Bini RM, et ah Histology of pulmonary arterial supply in pulmonary atresia and ventricula~" septal defect. Circulation 1979; 60:1066- 1074.

21. Haworth SG, Macartney FJ: Growth and develop- ment of the pulmonary circulation in pulmonary atresia with ventricular septal defect and major aor- topulmonary collaterals. Br Heart J 1980; 44:14-23.

22. Freedom RM, Moes CAF, Pelach A, et al: Bilateral ductus arteriosus (or remnant) in congenital heart disease: An analysis of 27 patients. Am J Cardiol 1984; 53:884-891.

23. Liao PK, Edwards ED, Julsrud PR, et ah Pulmonary blood supply in patients with pulmonary atresia and

ventricular septal defect. JAm Coll Cardio11985; 6: 1343-1350.

24. Gill CC, Moodies DS, McGoon DC: Staged surgical management of pulmonary atresia with diminutive pulmonary arteries. J Cardiovasc Thorac Surg 1977; 73:436-452.

25. Kirklin JW, Bargeron LMJ, Pacifico AD: The en- largement of small pulmonary arteries by prelimi- nary palliative operations. Circulation 1977; 56: 612-617.

26. Rosenberg HC, Williams WG, Trusler GA, et al: Structural composition of central pulmonary arter- ies: Growth potential following surgical shunts. J Thorac Cardiovasc Surg 1987; 94:498-503.

27. Farrar JF, Bloomfield J, Reve RDK: The structure and composition of the pulmonary circulation in congen- ital heart disease. J Pathol Bacterio11965; 90:97-105.

28. Newfeld EA, Waldman JD, Paul MH, et al: Pulmo- nary vascular diseases after systemic-pulmonary ar- terial shunt operations. Am ] Cardio11977; 39:715- 720.

29. Boudreau N, Rabinovitch M: Developmentally reg- ulated changes in extracellular matrix in endothelial and smooth muscle cells in the ductus arteriosus may be related to intimal proliferation. Lab Invest 1991; 64:187-199.

30. Boudreau N, Rabinovitch M: Fibronectin, hyaluro- nan, and a hyaluronan binding protein contribute to increased ductus arteriosus smooth muscle cell migration. Dev Biol 1991; 143: 235-247.