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THIS STUDY OF TETRALOGY OF FALLOT was undertaken to determine to what extent this malformation complex could be explained
as a morphologic response of the heart to the physical forces resulting from an abnormal blood flow and blood pressure pattern. The
defining features of tetralogy of Fallot (TF) used in this study are
shown in Text-figure 1, which views the base of the heart from below. These features include: a high ventricular septal defect (VSD)
through which the aortic valve protrudes to be positioned over the
ventrictular septum, obstruction in the right ventricular outflow tract
at either the infundibtulum or at the pulmonary valve, and right ventricular hypertrophy.
The classic explanation of the genesis of this malformation is the
malseptation hypothesis,' which holds that the conus arteriosus is
une(jually divided, yielding a small infundibulum, and is incompletely
divided in its inferior aspect, yielding a membranous VSD. More
recently, the infundibular hypoplasia hypothesis 2 has proposed that
the infundibulum is uinderdeveloped in all its dimensions and that
From the Department of Pathologv, The Johns Hopkins University School of Medicine
158
American Journal
of Pathology
Normal
Tetralogy
of
Fallot
TETRALOGY OF FALLOT
-Right Lateral
A-P
Normal
159
|L
L
R
Tetralogy
of
Fallot
L
R
TEXT-FIG 2-Diagram of ventricular ejection pathways in the A-P and lateral planes.
normal human embryo. Bottom-proposed alteration in TF.
Top-a
160
American Journal
of Pathology
The clinical records and autopsy findings for each patienit were reviewed. The
patient's age at surgery and at death were noted. The heart was examined with
particular attention to the structure of the aortic and pulmonary valves, the interventricular septum and the infundibular portion of the right ventricle. Measurements were made of right and left ventricular free wall thickness and the
diameters of the "os" of the infundibulum, the pulmonary valve, the main pulmonary artery, the ventricular septal defect, the aortic valve and the ascending
aorta. The degree of aortic overriding was estimated. The position of the ventricular septal defect, position of the crista supraventricularis and the relative
right and left ventricular chamber volumes were noted. Associated cardiovascular abnormalities and noncardiovascular malformations were recorded.
Results
4(5%)
AORTIC
76 (99%)
STENOTIC
TRICUSPID
2(3%)
BICUSPID
43(56%)
UNICUSPID
9(11%)
DOMED
5(6%)
ATRETIC
12(16%)
ABSENT
2(3%)
1(1%)
TETRALOGY OF FALLOT
161
Bicuspid
Unicuspid
Domed
Atresia
4
1
9
4
162
American Journal
of Pathology
55% NO SEPARATIONi
called fibrous infundibular stenosis. Many cases did not show this endocardial thickening, and these represent so-called muscular infundibular stenosis. In some cases the narrowing of the infundibulum was
localized to the opening or os of the infundibulum, while in others the
narrowing was diffuse along the entire length of the infundibulum.
In still other cases the infundibulum was only slightly narrowed, and
the obstruction to right ventricular oufflow was localized to the pulmonary valve. This was particularly noticeable in cases with domed
pulmonary valves.
There was right ventricular hypertrophy in all cases of TF. In virtuLally
all these cases the right and left ventricular free wall thicknesses were
equal. Similar findings were seen in isolated VSD. Right ventricular
hypertrophy was also present and often marked in cases of pure PS.
Significant malformations of the great vessels were frequently present (22%) in the 77 cases of TF (Table 2). The malformations included: right sided aortic arch (15 cases), vascular ring (1 case) and
absent left pulmonary artery (1 case). Other minor deviations from
normal development of the great vessels included patent ductus
arteriosus (6 cases) and aberrent origin of one subclavian artery (4
cases). Significant great vessel malformations were not present in the
TETRALOGY OF FALLOT
.DINf
DSMALLEST
OPV
RV OUTFLOW
NORMAL
PURE
PULMONARY
STENOSIS
163
0.9
0.7
3.9
4.9
4.6
1.3
ISOLATED VSD
1.0
TEXT-FIG 5-Schematic and quantitative comparison of the diameters of the infundibulum and pulmonary valve (Dinf/Diw) and of the aortic valve and the smallest right
ventricular outflow tract (DAv/Ds.iailest RV outflow) for the normal heart, TF, pure PS
and isolated VSD.
cases
of
aortic
arch.
pure
PS and in only
case
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American Journal
of Pathology
6-
5-
4-
i
a
QZ
3-
a
I
I,
0-1
1-2
5-10
YEARS
TEXT-FIG 6-The degree of right ventricular outflow obstruction (DAv/Drn,aII est ltV
outflow ) plotted against the patient's age at death on a logarithmic scale with SD indicated.
Normal ratio is 0.9. Right ventricular outflow tract is smaller than normal at birth and
becomes even smaller with age.
TETRALOGY OF FALLOT
165
2.0-
1.5-
1.0
0.5
0-1
1-2
YEARS
TEXT-FIG 7-The degree of infundibular stenosis in the right ventricular outflow tract
(Dinf/Dt ) plotted against the patient's age at death on a logarithmic scale with SD
indicated. The normal ratio is 1.2; ratios less than 1.0 indicate infundibular stenosis,
which is not present at birth but appears in the first months of life and progresses.
early life, and that stenosis of the infundibulum develops in the first
months of life.
Discussion
166
American Journal
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Pathology
the VSD in TF,5 and Lev 6 has described the muscle band which separates the aorta from the triscuspid valve as a second parietal band
of the crista supraventricularis. Both the malseptation hypothesis and
the infundibular hypoplasia hypothesis predict that the VSD would be
membranous in position. This is not so in 45% of the cases in this
series.
passes
com-
munication and maintains its patency. As blood flows through the VSD
into the aorta, the aorta would tend to undergo relative migration to
the right to a position over the ventricular septum. This relative migration of the aorta, viewed from the right ventricular aspect, might
occur behind the crista supraventricularis, which would yield a
membranous VSD as in 55% of our cases of TF. Alternatively, the migration might occur into the developing crista, separating the muscle
fibers of that structure and resulting in an intracristal VSD as shown
in Text-figure 4.
The presence of frequent great vessel malformations in cases of TF
(Table 2) supports the proposal of rearranged outflow streams during
early embryonic life. A rearrangement of the ventricular outflow
streams would tend to result in an unusual pattern of blood flow in
the developing aortic arches. This would favor persistance of unusual aortic arches and would result in great vessel malformations.
The comparison of the diameters of the infundibulum and pulmonary valve and the aortic valve and the smallest RV oufflow tract diameter in TF plotted against the patient's age reveals two important
facts. The first is that the right ventricular outflow tract is small at
Table 2-Major Great Vessel Malformations in Tetralogy of Fallot
15
1
1
17/77 (22%)
TETRALOGY OF FALLOT
167
birth when compared to the aorta. The second fact is that, although
the entire right ventricular outflow tract is smaller than normal,
localized infundibular stenosis is not present at birth, when compared
to the degree of pulmonary valve stenosis, but develops in the first
months of life.
The pathogenetic mechanism of TF we propose explains these
findings. The infundibular pulmonary portion of the divided right
ventricular ejection stream is less than normal. This decreased relative
flow through the infundibulum results, at birth, in a small infundibulum
which is not yet more stenotic than the pulmonary valve. During the
first few months of life, the infundibulum participates in the generalized right ventricular hypertrophy. In addition to a stenotic malformed
pulmonary valve, this increasing muscle mass in an already small
infundibulum causes increasing resistance to right ventricular ejection during systole. This progressively increasing resistance to infundibular blood flow in the presence of an alternative route for right ventricular ejection, the VSD, leads to a decreasing relative size of or
failure of growth of the infundibular lumen. Finally, at the point of
stenosis (the os of the infundibulum), there is variable fibroelastic
proliferation of the endocardium. Occasionally this fibroelastic endocardial proliferation is exuberant and results in valvuloid formation
(Figures 1-5). The morphology of these changes in this variant of
TF (fibrous infundibular stenosis) is identical to that seen in other
situations in which boundary layer separation could be expected to
occur and permits intimal cell proliferation at a point of absent shear
effect. Similar proliferations are encountered in coarctation of the
aorta 8 and in some instances of aortic valve insufficiency.9
Several clinical, cardiac catheterization and pathologic observations
support the view that infundibular stenosis is a postnatally acquired
lesion related to decreasing relative blood flow through the infulndibulum. Patients with TF usually are not severely cyanotic at birth but
become so, progressively, in the first months of life.10 Levin et al 11
have demonstrated, by cardiac catheterization, that shunts in TF are
bidirectional in early life. Several patients have now been reported1 215'
in which a VSD without infundibular stenosis was found by cardiac
catheterization in early life, and classic TF was demonstrated in later
life. In addition, several patients have been reported in which atresia
of the right ventricular outflow tract has developed following systemic-to-pulmonary artery anastomosis for TF.10- 1 In this situation the
extracardiac shunt would increase resistance to pulmonary artery
blood flow throuigh the infundibulum.2" This decreasing flow through
168
American Journal
of Pathology
TETRALOGY OF FALLOT
169
3.
4.
5.
6.
7.
8.
9.
0.
1]1.
1]2.
13.
14.
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American Journal
of Pathology
15. Watson H, Lowe KG: Functionial adaptations of the right ventricular outflow tract in congenital heart disease. Br Heart J 27:408-412, 1965
16. Fabricius J, Hansen P, Lindeneg 0: Pulmonary atresia developing after a
shunt operation for Fallot's tetralogy. 13r Heart J 23:556-560, 1961
17. Sabiston D, Corniell W, Criley J, Neill C, Ross, R, Bahnison H: The diagnosis and surgical correction of total obstruction of the r-ight ventricle:
an acquired condition developing after systemic arteiy-pulmonary artery
anastomosis for tetralogy of Fallot. J Thorac Cardiovasc Suig 48:577-587,
1964
18. Frater R, Rudolph A, Hoffman J: Acquiired pulmonary atresia in tetralogy
of Fallot with functioning Blalock-Tauissig shunt. Thorax 21:457-458, 1966
19. Mizuno A, Sato F, Hasegawa T, Tsuizuki M, Furuse A, Kotoda T, Saigusa
M: Acquired obstruction of the right ventricular outflow tract in tetralogy
of Fallot after Blalock-Taussig anastomosis. Jap Heart J 11:113-119, 1970
20. Rockoff SD, Bilbert J: Functional ptulmonary atresia: a cause of alngiocardiographic misinte r-pretation in tetralogy of Fallot. Am J Roentgenol
94:85-91, 1965
21. Zaret B, Conti CR: Infundibular pulmonic sten;osis with intact ventricular
septum in the adult. Johns Hopkins Med J 132:50-60, 1973
22. Case Records of the Massachusetts General Hospital. N Engl J Med 280:
714-721, 1969
23. De Vries PA, Saundei-s JBCM: Developmenit of the venitr-icles anid spir al
outflow tract in the human heart: a contribution to the development of the
human heart from age group IX to age group XV. Contrib Embryol Carnegie Inst Wash 37:87-114, 1962
24. Maron 13j, Hutehinis GM: Trtuncus arteriosus malformationi in a hutman
embryo. Am J Anoat 134:167-174, 1972
Fig 3-Early stages of intimal proliferation in the os of the infundibulum. The pulmonary valve is above and the right ventricle below (VVG, x 40).
Fig 4-Valvuloid from heart shown in Figure 2. There are calcium deposits in the core
of the proliferated intimal tissue. (VVG x 20).
Fig 5-Valvuloid which has reattached to the endocardium at its downstream end, at
the top. Its gross appearance resembled that seen in Figure 1. (VVG, x 30).
American Journal
of Pathology
[End of Article]