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Transposition of the great vessels and other cardiovascular abnormalities in rat fetuses induced by trypan blue.

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Transposition
of the Great Vessels and Other
Cardiovascular Abnormalities in R a t
Fetuses Induced by Trypan Blue ’
I. W. MONIE, EVA TAKACS AND J. WARKANY
Department of Anatomy, University of California Medical Center,
San Francisco, California, and the Children’s Hospital Research
Foundation and the Department of Pediatrics,
University of Cincinnati, Cincinnati, Ohio
ABSTRACT
Complete and p a r t i d transposition of the great vessels, dextrocardia,
and absence or stenosis of the tricuspid or mitral valves were encountered singly or
in combination in rat fetuses from mothers injected with trypan blue solution subcutaneously on the 8th or 9th day of gestation. Hearts with transposition of the great
vessels were usually characterized by shortness of the aorta and pulmonary trunk,
cranial location of the aortic valve, displacement of the coronary arteries, and a channel
or “track” extending from the cranial portion (infundibulum) of the right ventricle
to the commencement of the transposed pulmonary trunk. Inadequate expansion of
the atrioventricular ring about the 12th or 13th day of gestation possibly leads to
deformity of the atrioventricular cushions and to absence or stenosis of the tricuspid
or mitral valves. Sinuosity of the truncus arteriosus seen in many 13th day and older
embryos of the trypan blue series is considered a significant factor in the development of transposition of the great vessels.
Transposition of the great vessels occurs
in about 12% of cases of human congenital heart disease which come to autopsy
(Keith et al., ’58). In complete transposition the aorta and pulmonary trunk arise
from the right and left ventricles respectively, and pass cranially more or less parallel to one another. Other forms of transposition include partial transposition in
which both great arteries arise from the
right ventricle, and “corrected” transposition in which the aorta and pulmonary
trunk spring from the proper ventricles,
but the former vessel lies ventrosinistrally
to the latter.
Transposition is often accompanied by
ventricular or atrial septa1 defect or by
patency of the ductus arteriosus; in addition, the coronary arteries are usually displaced and the ventricular septum lacks its
membranous portion and is entirely muscular (Lev. ’53). In about 7% of human
hearts with transposition the tricuspid
valve is absent; on the other hand, almost
30% of cases of absence of the tricuspid
valve are accompanied by transposition
Various hypotheses have been advanced
to account for this malformation. Thus,
Rokitansky (1875) attributed it to abANAT. REC., 156: 175-190.
normal convexity of the proximal truncobulbar septum and its incorrect fusion
with the ventricular septum while Pernkopf and Wirtinger ( ’ 3 3 ) incriminated
abnormal spiralling of the entire truncobulbar septum following faulty rotation of
the developing heart tube. Shaner (’51),
however, concluded from a study of pig
embryos that tardy descent of the aorticopulmonic septum and its delayed fusion
with the bulbar cushions (ridges) after
they had undergone rotation was the key
factor in the causation of transposition.
Keith (’09), on the other hand, attributed transposition to abnormal absorption
of the bulbus cordis whereas Lev and
Saphir (’45) blamed maldevelopment of
the bulbus cordis and the presence of an
abnormal bulbar cushion. On somewhat
similar lines, de la Cruz and da Rocha (’56)
have stressed the importance of a combination of abnormality of the conoventricular flange (bulboventricular spur), the
truncoconal ridges, and the primordia of
the aortic and pulmonary valves as factors
1
Supported by U. S. Public Health Service grants
HE-07029.HD-00419 and. HD-00502.
The term “transposition” hereafter will refer to
transposition of the great vessels unless otherwise
stated.
2
175
176
I. W. MONIE, EVA TAKACS AND J. WARKANY
producing this abnormality. Recently, the
significance of the truncobulbar region in
the development of transposition has been
shown by Le Douarin ('61) who x-irradiated this part in the chick embryo and obtained abnormal spiralling of the contained septum while Rychter ('62) has
produced transposition in the chick by
temporarily applying a microclip around
the bulbus cordis.
Spitzer ( ' 2 3 ) , using a phylogenetic approach, attempted to explain transposition
principally on the emergence of reptilian
characteristics in the mammalian embryo.
He suggested that a n aorta arose from the
right ventricle as in certain reptiles while
that from the left ventricle was suppressed; this, accompanied by altered location of the ventricular septum, supposedly
resuIted in the pulmonary trunk springing
from the left ventricle. Initially, this view
received considerable support (Abbott, '36;
Harris and Farber, '39) although it was
known that mammals most likely evolved
from a pre-reptilian ancestor lacking the
cardiovascular peculiarites of modern reptiles (Goodrich, '30) ; also, no reptilian
characteristics have ever been observed
in developing mamalian hearts. Evidence
against Spitzer's concept has been summarized recently by Shaner ('62).
Bremer ('28) proposed that the blood
streams ejected from the developing right
and left ventricles influenced truncobulbar
septation and, consequently, alteration in
the course of one or both streams might
result in transposition or other abnormality of the great vessels. The importance of
such streams in normal and abnormal
cardiac development in man (De Vries and
Saunders, '62) and chick (Jaffee, '65) has
been discussed recently. From a later study
of a n early human embryo Bremer ('42)
concluded that other factors, increased
flexion of the heart tube and altered disposition of the sinusoids in the heart wall,
might also be of importance in producing
transposed great vessels.
Difficulty i n determining the fundamental cause of transposition has been due
largely to the lack of mammalian embryos
which show this abnormality in the early
stages of formation. However, it has been
shown that x-irradiation (Wilson et al.,
'53) and trypan blue (Wilson, '55) can
each produce transposition in rat young
and consequently valuable tools have been
provided for studying this malformation.
Studies on trypan blue as a cardiovascular
teratogen have been reported also by Fox
and Goss ('56, '57, '58), Christie ('61),
Wegener ('61), Smith ('63), and Inoue
('64).
Since none of the hypotheses yet advanced to explain transposition of the
great vessels seems entirely satisfactory,
it was decided to study the development
of this abnormality in rat fetuses from
mothers injected with trypan blue solution
during early pregnancy. In addition to
obtaining transposition of the great vessels, dextrocardia, and abnormalities of
the tricuspid and mitral valves were often
eiicountered (fig. 1). The apparent causes
of these different malformations and their
possible interrelationships will be considered.
MATERIALS AND METHODS
Pregnant rats of a Long-Evans substrain were injected subcutaneously with
1 cm3 of 1 % trypan blue in 0.8% saline
on either the 8th or 9th day of gestati0n.j
Fetuses were removed from control and
trypan blue injected mothers from the
11th to 22nd day of pregnancy and some
newborns were collected i n addition. A
total of 226 experimental and 48 control
young were examined (table l ) , prepared
for histological study, serially sectioned at
8-10 p, and stained with hematoxylin and
eosin. Wax plate reconstructions were
made of hearts from 40 experimental and
9 control fetuses.
Since interest was focused mainly on
transposition of the great vessels a n attempt was made to select for detailed study
fetuses which on inspection appeared to
have this abnormality; this bias, however,
relates only to older fetuses in which the
aorta and the pulmonary trunk were separate and readily distinguishable.
3Obtained from Rockland Farms. New Citv. N. Y.
Both before and during gestation rats were fed Purina
Laboratory Chow, Ralston Purina Company, St. Louis,
Missouri.
4 Trypan blue (Direct blue 14) CI 23850; Matheson,
Coleman and Bell.
5Day of finding sperm in the vagina is considered
the first day of pregnancy.
177
TRANSPOSITION O F GREAT VESSELS
NORMAL
T R A N S POSIT!ON
LV
RV
T R l C U S P l D VALVE
ABSENCE
0
OF GREAT VESSELS
RV
\ LV
@
.__-
P
Fig. 1 Normal and abnormal hearts from rat fetuses late in pregnancy. The left anterior vena cava terminates in the right atrium in the same manner as, the coronary sinus
in man. The ductus arteriosus connects the pulmonary trunk with the aorta.
Key: A, aorta; L, left anterior vena cava; LA, left atrium; LV, left ventricle; P, pulmonary trunk; PC, posterior vena cava; R, right anterior vena cava; RA, right atrium;
RV, right ventricle.
TABLE 1
Rat embryos sectioned
Trypan blue
injected on
8th day
Trypan blue
injected on
9th day
11
11
15
31
7
7
0
0
0
0
0
5
5
6
5
18
11
10
16
16
21
16
7
10
9
17
20
49
18
17
16
16
21
16
7
15
14
81
145
226
12
13
14
15
16
17
18
19
20
21
22 1
Total
1
Total
Day of
gestation
EgEi
Controls
5
4
4
4
6
4
3
3
4
3
4
4
48
Includes some newborn.
RESULTS
Embryos from trypan blue injected
mothers were generally smaller than those
Of
Of the
age and Of the 226
examined, 76 (30.0% ) showed abnormalities of the heart and great vessels,e
sepa-
rately or in Combination; the principal
cardiovascular abnormalities observed in
embryos from the 13th to 22nd day are
6 The types of cardiovascular abnormalities obtained
with injection of trypan blue on !he Sth da,y of gestation were similar to those following lnjectlon on the
9th day.
178
I. W. MONIE, EVA TAKACS AND J. WARKANY
0
.*
r=
%.i
xl
a“$
M
shown in table 2. Of the anomalies encountered i n other systems, anophthalmia
and microphthalmia (left eye - 11; right
eye - 7) were the most frequent. Exencephaly and diaphragmatic hernia each
occurred twice while spina bifida, hydrocephaly, absence of the left lobe of the
thyroid gland, and esophageal atresia were
each observed once. These malformations
showed no particular relationship to any of
the accompanying cardiovascular abnormalities except esophageal atresia which
was associated with a double aorta. No instance of absence of the spleen was encountered.
Control embryos. In 11th day control
embryos the heart was a n S-shaped tube
consisting of sinus venosus, primitive
atrium, primitive ventricle, bulbus cordis
(conus arteriosus) and truncus arteriosus.
The bulbus ’ lay to the right of and usually
somewhat dorsal to the ventricle while the
truncus swept craniodorsally in a sinuous
manner to give origin to the first. and occasionally to the second, branchial (aortic)
arch arteries.
On the 12th day the ventricle was more
caudally situated with the primitive atrium
expanding to the right. The truncus was
generally similar to that of the previous
day but, in some embryos, the two truncobulbar cushions were beginning to form;
the latter spiralled through about 90”. The
second, third and fourth branchial arch
arteries were now discernible, and the
common pulmonary vein usually entered
the left horn of the sinus venosus.
With the establishment of the septum
primum and the interventricular septum
on the 13th day, the four heart chambers
became recognizable, the primitive ventricle forming the left ventricle and the
bulbus cordis the right ventricle. The dorsal and ventral atrioventricular cushions
were now apparent (fig. 5c) although not
always in contact and each atrium communicated either with the left ventricle
only or with the ventricle of its own side.
The truncus now ascended obliquely from
the heart (fig. 2a) and the truncobulbar
cushions showed increased spiralling which
in one embryo amounted to about 225”.
The third, four, and sixth branchial arch
7The term “bulbus” or “bulb” refers to the bulbus
cardis; likewise “truncus” refers to truncus artenosus.
TRANSPOSITION O F GREAT VESSELS
NORMAL
EXF E R I M E N T A L
179
E XPERl MENTA L
I ZTU
DAY
I 4TH
DAY
15'"
DAY
Fig. 2 Wax-plate reconstructions of normal and abnormal rat embryo hearts from the
13th, 14th and 15th day of gestation. Each is shown from the front (left) and from the
left side (right). The controls were normal in appearance.
13th day: ( a ) control; ( b ) and ( c ) sinuous truncus.
14th day: ( d ) control; ( e ) and ( f ) sinuous undivided truncus accompanied by absence
of the tricuspid valve. In ( e ) the left atrium is small and lies dorsal to the right atrium;
i n ( f ) the right ventricle is cranially located.
15th day: ( g ) control; ( h ) the right ventricle is cranially situated, the pulmonary trunk
lies dorsal to the aorta, and the right and left atria open into the left ventricle; ( i ) absence of tricuspid valve, cranial location of right ventricle, and dextrocardia.
In ( c ) , ( e ) and ( f ) spiralling of the truncobulbar cushions was slight or absent.
Key: B, bulbus cordis; D, ductus arteriosus; T, truncus arteriosus; V, primitive ventricle.
Rest of key as in figure 1.
arteries were present and the pulmonary
arteries appearing.
By the 14th day the foramen secundum
was apparent in the septum primum, the
pulmonary trunk was separating from the
aorta, and portions of the branchial arch
arteries were regressing; also, the right
umbilical vein was disappearing and the
left umbilical vein enlarging. The aorta
now ascended almost vertically from the
heart (fig. 2d) while the partially separated pulmonary trunk swept directly dorsally to be continuous with the left ductus
arteriosus.
On the 15th day the atrioventricular
cushions were fused and the pulmonary
trunk, almost completely separated, passed
around the left side of the aorta (fig. 2g).
The interventricular foramen was still patent and the ventricles had become pyriform in shape. The septum secundum was
recognizable.
By the 16th day, part of the dorsal atrioventricular cushions had advanced into the
interventricular foramen and the ascending aorta, communicating with the left
ventricle through the former, increasing in
caliber. The aortic and pulmonary valves
180
I. W . MONIE, EVA TAKACS AND J. WARKANY
were now distinguishable, the former lying
caudal to the latter; the left coronary artery was usually discernible.
On the 17th day the margins of the interventricular foramen were opposed, the
right coronary artery recognizable, and the
right aorta and right ductus arteriosus disappearing. The configuration of the heart
and great vessels remained generally the
same for the rest of gestation (fig. 3a).
The left umbilical artery disappeared about
the 19th day.
Embryos f r o m t r y p a n blue
injected mothers
11th a n d 12th d a y embryos. Generally,
the hearts of 11th day embryos resembled
those of the corresponding controls. Cardiac abnormality was difficult to assess as
even the controls vaned considerably in
NORMAL
shape, nevertheless, in one embryo the position of the ventricle suggested beginning
dextrocardia.
In 12th day embryos the hearts were
usually similar to those of the controls but
in one the atrioventricular canal appeared
narrow while in another the common pulmonary vein terminated in the right horn
of the sinus venosus indicating possible
inversion of the atria (fig. 5a). In several
embryos the appearance of the branchial
arch arteries was delayed.
13th, 14th a n d 15th d a y embryos. In
8 of the 11 wax-plate reconstructions made
of hearts from the 84 embryos of this
group the truncus still followed a sinuous
path especially where the right or left
atrioventricular channel was absent. In
the latter instance, the bulbus or the right
ventricle usually lay cranially and one or
TRANSPOSITION
RA
LV
0
Fig. 3 ( a ) Normal rat fetal heart on 21st day. ( b - f ) Complete transposition of the
great vessels in hearts from the 18th to 22nd day of gestation accompanied by: persistent
interventricular foramen ( b ) ; closed interventricular foramen ( c ) ; absence of tricuspid
valve ( d ) ; and absence of tricuspid valve and dextrocardia (e). In ( f ) there is partial
transposition in which both aorta and pulmonary trunk arise from the right ventricle;
also, the aorta lies ventral and sinistral to the pulmonary trunk. The picture is ahnost
that of “corrected” transposition.
Figures in parentheses indicate the distance from the aortic valve to the aortic arch
expressed as a percentage of the distance from the posterior caval opening to the aortic arch.
Key as in figure 1.
TRANSPOSITION O F GREAT VESSELS
181
Fig. 4 Portions of wax-plate reconstructions of ( a ) normal and ( b ) abnormal hearts
of 14th day embryos. Each shows the relationship of the truncobulbar outflow tract to
the interventricular septum and to the ventricles. The truncobulbar cushions are shown
(coarse stipple) and septation is incomplete. In ( a ) the entrance to the aorta ( A ) lies
dorsally and that to the pulmonary trunk ventrally; the latter overlies the right ventricle.
Only a small crescentic portion of the left ventricle (LV) is visible between the upper edge
of the ventricular septum (IVS) and the left truncobulbar cushion. In ( b ) the tricuspid
valve is absent and the truncus so sinistrally placed that its lumen straddles the free edge
of the ventricular septum. Truncobulbar septation is retarded and there is only slight
spiralling of the cushions. The pulmonary trunk occupies the dorsal portion of the truncus
and, consequently, it almost entirely overlies the left ventricle; the aorta is ventrally 10cated and mostly overlies the right ventricle.
The bifid ventral atriovenlricular cushion is shown in black in (b). A portion of the
dorsal atrioventricular cushion ( D ) is seen in contact with the free edge of the ventricular
septum i n both (a) and (b).
Rest of key as in figure 1.
other atrium was enlarged and displaced
(fig. 2b,c,e,f). In three embryos the region
of the truncobulbar junction was so sinistrally placed that it communicated with
both the left and right ventricles (fig. 4b).
In several 15th day embryos separation
of the aortic and pulmonary trunks was
delayed and in these the truncobulbar
cushions showed only minimal spiralling
or none at all; in such embryos, the pulmonary trunk lay mostly dorsal and somewhat caudal to the aorta (fig. 2h).
Absence of the tricuspid valve was observed in 12 embryos while in two embryos
with inversion of the ventricles the tricuspid valve proper was absent in one and
the mitral valve proper was missing i n the
other; in addition, one embryo showed tricuspid stenosis. Where the tricuspid or
mitral valve was absent the dorsal and
ventral atrioventricular cushions were usually large and misshapen; the latter cushion was especially affected and frequently
was bipartite or horse-shoe-shaped so that
it partly encircled its dorsal counterpart
(fig. 5d).
Where the tricuspid or mitral valve was
absent the corresponding atrium was usually distended but occasionally it was small
and the opposite atrium enlarged; in some
instances one atrium lay cranial to the
other and the ventricles were displaced
(fig. 2h,i). In two 14th day embryos both
the tricuspid and mitral valves opened into
the left ventricle as in some 12th day control embryos.
Dextrocardia was noted in eight embryos and in one of these it was accompanied by inversion of the ventricles and
absence of the mitral valve proper; in four
others the tricuspid valve was absent. The
three remaining embryos of this group
were examples of: isolated dextrocardia,
8 In this paper “absence of the tricuspid (or mitral)
valve” means that neither the ostium nor the valve
leaflets were pmesent.
I. W . MONIE, EVA TAKACS AND J. WARKANY
Fig. 5 ( a ) Beginning inversion of the atria i n a 12th day experimental embryo
common pulmonary vein opens into the right horn of the sinus veaosus. x 65.
111
which the
( b ) Inversion of the ventricles in a 13th day experimental embryo; the atria are normally
placed. Cushions are visible within the truncus. X 35.
x
( c ) 13th day control embryo showing disposition of chambers and atrioventricular cushions.
42.
( d ) 13th day experimental embryo with absence of the tricuspid valve, displaced
deformation of the ventral atrioventricular cushion. X 42.
atria and
Key; AT, primitive atrium; D, dorsal atrioventricular cushion; LA, left atrium; LV, left ventricle; PV, common pulmonary vein; RA, right atrium; RV, right ventricle; T, truncus artenosus;
V, ventral atrioventricular cushion; X, anatomical left ventricle; Y, anatomical right ventricle (bulbus cordis).
TRANSPOSITION O F GREAT VESSELS
complete situs inversus, and partial situs
inversus.
16th a n d 17th d a y embryos, Of 32 embryos, 14 showed delayed separation of the
aorta and pulmonary trunk accompanied
by patency of the interventricular foramen. In one 16th day embryo the aortic
and pulmonary valves lay in the same
transverse plane, and a similar arrangement was found in a 17th day embryo in
which the right ventricle was displaced
cranially and the aorta and the pulmonary
trunk were shorter than in the controls.
18th to 2 2 n d d a y embryos a n d n e w borns. Excluding patency of the interventricular foramen, the most frequent cardiovascular abnormalities in the 73 embryos
of this age group were: transposition of
the great vessels ( 2 0 ) , dextrocardia ( 7 ) ,
and absence of the tricuspid valve (7).
Of the 20 embryos with transposition
(table 2 ) , the aorta arose from the right
ventricle and the pulmonary trunk from
the left ventricle, in ten. In the remainder,
either the aorta ( 2 ) or the pulmonary
trunk (5) overrode the ventricular septum,
while in three both the aorta and the pulmonary trunk arose from the right ventricle, the former vessel being ventral and
sinistral to the latter (fig. 3f). Where the
pulmonary trunk overrode the ventricular
septum it always lay dorsal to the aorta.
In 17 of the 20 embryos with transposition the interventricular foramen was patent, sometimes widely so, and in two there
was a ventricular septal defect in addition;
the latter abnormality also occurred in one
embryo i n which the interventricular foramen was closed. A n atrial septal defect
was seen twice in association with transposition being accompanied in one embryo
by pulmonary stenosis and in the other by
absence of the tricuspid valve.
Transposition of the great vessels was
associated with absence of the tricuspid
valve in four embryos, once with tricuspid
stenosis, twice with absence of the mitral
valve, and once with mitral stenosis. Dextrocardia accompanied transposition in
three embryos in which there was also
absence of the tricuspid valve ( 2 ) or tricuspid stenosis.
In one 18th day and one 20th day fetus
with transposition, both the tricuspid and
mitral valves opened into the left ventricle
183
and the right ventricle was reduced i n
size.
I n many fetuses, both those with and
without transposition, the time of appearance of the coronary arteries was delayed.
I n the presence of transposition the coronary arteries were often abnormally located although usually retaining the same
general relationship to the pulmonary
trunk as in the controls; in some instances,
however, they arose normally then followed a bizarre course. In one 22nd day
fetus with transposition a single coronary
artery was present.
In all fetuses with transposition the
aortic valve lay either on the same level
as the pulmonary valve or cranial to it and
the normal relationship (aortic valve caudal to pulmonary valve) was not seen; in
such embryos both the ascending aorta
and pulmonary trunk seemed shortened
(fig. 3b-f). Also, where the great vessels
were transposed the heart was often markedly rotated to the left or right and the
atria displaced i n a n extreme fashion. In
fetuses with both transposition and absence or stenosis of the tricuspid valve,
cranial displacement of the right ventricle
was marked (fig. 3d, e ) .
Several embryos with transposition
showed a channel or “ t r a c k extending
from the cranial end of the right ventricle
towards the origin of the pulmonary trunk
(figs. 6c and 7b, e ) ; in some instances, it
communicated with the left ventricle. The
path of this “ t r a c k and the course of the
pulmonary trunk together formed a curving line which swept around the ascending
aorta in the same manner as the pulmonary trunk in the controls.
Absence of the tricuspid valve occurred
in 7 of the 73 fetuses of this group (18 to
22 days fetal age) and in four was associated with transposition; in two of the
fetuses with the latter abnormality there
was also dextrocardia. Absence of the
mitral valve occurred twice and in both
instances was associated with transposition. Tricuspid stenosis was also encountered twice and was accompanied by transposition and dextrocardia once; mitral
stenosis occurred twice and was associated
with transposition once.
Dextrocardia also occurred in 7 of the
73 fetuses of this group. In two, it was
184
Fig. 6
X 16.
1. W. MONIE, EVA TAKACS AND J. WARKANY
( a ) Great vessels and heart of normal 22nd day embryo; pulmonary valves are shown.
( b ) A more caudal section of the previous embryo showing the aortic valves and infundibulum
of the right ventricle. X 16.
( c ) Transposition of great vessels in a 19th day experimental embryo. The pulmonary trunk
lies dorsal to the aortic valve two cusps of which are seen. X 24.
( d ) A more caudal section of the heart of the previous embryo showing the pulmonary trunk arising mostly from the left ventricle. The interventricular foramen is open. x 24.
Key: A, aorta; C , “track” or channel; I, infundibulum; P, pulmonray trunk.
Rest of key as in figure 5.
T R A N S P O S I T I O N O F GREAT VESSELS
185
Following their study of 18% and 19%
accompanied by absence of the tricuspid
valve alone, and in one by the same ab- day rat fetuses obtained from mothers innormality and transposition. Dextrocardia jected with trypan blue, Fox and Goss ('57)
was also encountered as part of complete considered that the primary cause of carsitus inversus in one embryo and as an diovascular malformations induced by this
isolated event in another. In two fetuses agent was abnormal looping of the heart
with dextrocardia the left, and in three the tube which eventually led to displacement
and rotation of the primitive atrium; this
right, descending aorta was present; in
suggestion has received support from both
two others there was a double aorta.
Christie ('61) and Smith ('63).
Other cardiovascular abnormalities obAbnormal looping of the heart tube,
served in this group of fetuses, singly or except for that associated with beginning
in combination, were : persistent truncus dextrocardia, was difficult to determine in
arteriosus (5) ; pulmonary stenosis (3); 1l t h day experimental embryos because
atrial septa1 defect (2); and single coro- of the variations in heart shape observed
nary artery ( 2 ) . Pulmonary stenosis was in controls of similar age. However, apalways accompanied by stenosis or absence parent inversion of the atria and narrowof the ductus arteriosus. A single pulmo- ness of the atrioventricular canal were
nary artery, an aortic valve with four distinguishable on the 12th day, and by
cusps, stenosis of the left duct of Cuvier the 13th day abnormalities of the atrio(left common cardinal vein), and stenosis ventricular channels and truncal sinuosity
of the right anterior vena cava each OC- were readily recognized. Although the lastcurred once.
mentioned was seen in some 11th and
Cardiovascular abnormalities observed 12th day control embryos, it was never
in litter mates were dissimilar except in observed in those of 13 days and older.
the case of three pairs of embryos. Abnormal looping of the heart tube reHowever, even then the malformations sulting in inversion of the ventricles, how(inversion of ventricles, both atria com- ever, was recognized in some 13th day
municating with the left ventricle, and and older embryos from trypan blue
transposition of the great vessels) although treated mothers.
similar were not identical; frequently, abDextrocardia was noted in 15 embryos
normal embryos were accompanied by one from the 13th to 22nd day of gestation
or more apparently normal litter mates. and in one was associated with inverOnly a few embryos in each litter, how- sion of the ventricles; mirror-image dexever, were subjected to detailed examina- trocardia was seen in only two fetuses.
tion.
In seven of the fetuses dextrocardia was
accompanied by absence of the tricuspid
COMMENTS
valve and in one transposition was presEmbryos from mothers injected with ent in addition. The frequent association
trypan blue were usually smaller than con- of absence of the tricuspid valve with
trol embryos of corresponding age indicat- dextrocardia suggests that hearts with the
ing that this teratogen, like many others, former malformation may be inclined to
retards fetal growth in general; next to rotate to the right possibly as a result of
abnormalities of the heart and great ves- change in atrial or ventricular size.
sels those of the eye and nervous system
Absence or stenosis of the tricuspid or
were the most frequent.
mitral valves in many 13th, 14th and
The commonest malformations of the 15th day embryos perhaps results from
cardiovascular system (table 2) were trans- inadequate expansion of the atrioventricposition of the great vessels, absence or ular ring which leads, in turn, to deforstenosis of the tricuspid or mitral valves mation of the dorsal and ventral atrioaccompanied by atrial or ventricular dis- ventricular cushions. Fox and Goss ('57)
placement, and dextrocardia, findings also observed similar valvular abnormaliwhich generally agree with those of others ties in rat fetuses as a result of trypan
who have employed the same teratogen in blue while Haring ('60) has reported them
as a teratogenic effect of carbon dioxide.
rats.
186
I. W. MONIE, EVA TAKACS AND J. WARKANY
In the present study the ventral atrioventricular cushion was usually thrust around
its dorsal counterpart and often seemed
bipartite (fig. 5d). Sometimes one or both
atrioventricular cushions appeared larger
than those in the corresponding controls,
a finding also noted occasionally with respect to the truncobulbar cushions.
Failure of the atrioventricular ring to
expand adequately apparently results in
both atria continuing to discharge into
the left ventricle, a s in controls of the
12th day, or to absence or stenosis of the
tricuspid or mitral valve. The former
valve was more often affected than the
latter and it seemed as if the valve on
the same side as the bulbus was more
prone to malformation. Indeed, it is possible that some examples of apparent
mitral valve abnormality in the older fetuses may actually be instances of tricuspid valve abnormality associated with
inverted ventricles; one such example was
encountered in this study. While inversion of the ventricles is easily recognized
when the bulbus is a distinct structure, it
is less readily apparent in older fetuses.
Absence or stenosis of the tricuspid or
mitral valve leads eventually to reduction
in size, or virtual absence, of the corrcsponding ventricle and, in older fetuses,
only one ventricle may be recognizable.
Shaner (’49) observed malformed atrioventricular cushions in young pig embryos which he related to abnormalities of
the tricuspid and initral valves and to
aortic and pulmonary stenosis in older
fetuses. These findings are supported by
those of Fox and Goss (’57) who also
noted that atrioventricular valve abnormalities and pulmonary stenosis frequently occurred together in rat fetuses
from mothers injected with trypan blue.
In the present investigation, pulmonary
stenosis was observed in only three fetuses and was unaccompanied by abnormality of either the tricuspid or mitral
valve. In a study of rat young from
PGA-deficient mothers (Monie and Nelson,
’63) pulmonary stenosis was observed in
8% and was not associated with abnormality of the atrioventricular cushions or
valves; it is therefore probable that pulmonary stenosis may arise by more than
one mechanism.
The examples of transposition of the
great vessels encountered showed some
or all of the following features: ( 1 )
shortened ascending aorta and pulmonary
trunk; ( 2 ) location of the aortic valve at
a level similar or cranial to that of the
pulmonary valve; ( 3 ) rotation or relocation of the coronary arteries; and ( 4 ) a
channel or “track,” sometjmes incomplete,
extending from the cranial portion of the
right ventricle to the commencement of
the transposed pulmonary trunk.
An important factor in the causation of
transposition in these fetuses may be retarded development of the truncus which
leads to prolongation of its sinuous stage,
and to reduction in its length as well as
that of its derivatives, While it is probable that these disturbances may result
from cellular damage by trypan blue directly or indirectly, it is also possible that
retardation of thoracic growth limits the
space available for the enlarging heart
and delays change in truncal shape.
Truncal sinuosity and shortening are
probably responsible for the sinistral location of the truncus (and cranial portion
of the bulbus) observed in some 14th and
15th day embryos i n which the lumen of
that structure lay over the cranial edge
of the ventricular septum (fig. 4b). As a
consequence of this, eithcr from derotation or from altered bloodflow, spiralling
of the truncobulbar cushions is minimal
or absent which leads to the dorsally
placed pulmonary trunk communicating
directly with the left ventricle while the
ventrally located aorta retains its connecFig. 7 (a,b, c ) Transposition of the great
vessels in a 21st day experimental embryo in
which the interventricular foramen is open. The
sections are sequential and show the pulmonary
trunk dorsal to the aorta and having a more
caudal level of origin. In ( a ) the left coronary
artery and portions of the aortic valve cusps are
visible. In ( b ) a “track” or channel extends
from the right to the left ventricle; it is also apparent in (c). X 20.
(d, e, f ) Transposition of the great vessels in
a 22nd day experimental embryo i n which the
interventricular foramen is closed, The sections
are sequential. In ( e ) a “track” extends from the
right to the left ventricle. x 20.
Key: DC, left duct of Cuvier; F, interventricular
foramen; LCA, left coronary artery.
Rest of key as in figures 5 and 6.
TRANSPOSITION O F GREAT VESSELS
187
P-
188
I. W. MONIE, EVA TAKACS AND J. WARKANY
tion with the right ventricle; the essential
elements for complete transposition are
now present. Conceivably, where truncal
displacement is less marked partial transposition ensues.
Apparently, a further consequence of
the changes just described is that the
cranial portion of the bulbus, which normally forms the infundibulum of the right
ventricle, is drawn around the left side of
the aorta and its lumen encroached on
by the caudal end of the aorticopulmonic
septum. In complete transposition traces
of the infundibular channel may be seen
as a “track passing from the right ventricle towards the commencement of the
transposed pulmonary trunk [fig. 6c) ;
sometimes, however, an actual channel is
present which communicates with the left
ventricle and i t is possible that should
this persist a ventricular septa1 defect will
result (fig. 7b, e).
Undue persistence of the bulboventricular spur (conoventricular flange) has
been suggested as a factor of importance
in transposition and other cardiovascular
abnormalities, yet, in the fetuses of this
study, it did not appear to play a significant role in this regard. Frequently, it
was much less evident in abnormal hearts
than in those of corresponding controls
and it is possible that undue sinistral location of the truncus hastens its disappearance. Such findings may seem to
conflict with those of Rychter (’62) who
considered that transposition, produced in
chick embryos by application of a microclip to the bulbus, is due to restriction of
the morphogenetic movements of that
structure. However, the effect of trauma
on a small portion of an otherwise normal heart cannot be compared with the
action of a teratogen affecting the entire
heart even if certain portions of it may be
less severely disturbed than others; the
situations are dissimilar even if the resulting malformations resemble one another.
Thus, rather than being in conflict, these
observations seem to suggest that similar
abnormalities may arise through different
mechanisms.
No atavistic trends (Spitzer, ’23) were
seen in any of the embryos examined and
delayed descent of the truncal component
Qf the truncobulbar septum, as described
in Pig embryos (Shaner, ’51), was not
observed; admittedly, in the latter, difference in species and in rate of development may play a significant role. Abnormal location of sinuses in the developing
heart wall as described by Bremer (’42)
in a young human embryo were not recognized, although the illustrations of that
author suggest that the heart he described
might have had some degree of truncal
sinuosity.
Of 20 fetuses with transposition of the
great vessels, four (20% ) showed absence of the tricuspid valve; the same
four embryos represented more than half
of all the fetuses ( 7 ) with absence of the
tricuspid valve in this particular age
group. In man a similar relationship is
usually found between these two anomalies.
It is possible that in early development
a sinuous truncus remaining closely applied to the heart may limit expansion of
the atrioventricular ring and lead to abnormality of the tricuspid or mitral
valves; the appearance of some wax-plate
reconstructions of abnormal hearts suggests such an effect. On the other hand,
trypan blue may directly damage cells of
the atrioventricular region and disturb
their development.
The relatively high frequency of transposition associated with absence of the
tricuspid valve may result from the
smaller and often cranially located right
ventricle in the latter instance predisposing to sinistral location of the truncus and
to the events apparently ensuing from
this. In fetuses where both transposition
and absence of the tricuspid valve were
present, the aorta appeared shorter and
the aortic valve more cranially placed
than in transposition alone.
In regard to the sex incidence of transposition of the great vessels, the findings
of the present study resemble those in
man; out of 35 rat fetuses with this
malformation 20 (57% ) were males and
15 (43%) were females; no reason for
this distribution was apparent.
In addition to complete and partial
transposition, instances of the aorta overriding the dorsal portion of the ventric9
Includes dissected but unsectioned fetuses
TRANSPOSITION O F GREAT VESSELS
Ular septum in association with a normally arising pulmonary trunk were
encountered. It is possible that this
abnormality arose from inhibition of the
remodelling of the ventral atrioventricular
cushion which normally occurs about the
15th or 16th day of gestation and which
permits the aorta to communicate directly
with the left ventricle.
Although many teratogens are known
to affect cardiovascular development, only
x-irradiation and trypan blue have been
shown to produce transposition of the
great vessels in quantity and consistently.
In rat young from PGA-deficient mothers
(Baird et al., '54; Monie and Nelson, '63)
transposition is rarely encountered, although this may be partly explained by
the frequency of incomplete aorticopulmoiiic septation and the fact that transposition cannot be diagnosed with certainty unless this septum is virtually
complete. On the other hand, abnonnalities of the branchial arch arteries and
their derivatives resulting from trypan
blue generally resemble those produced by
other teratogens. The frequency of transposition with trypan blue and to a lesser
extent with x-irradiation has suggested
some degree of specificity of action in the
case of these teratogens.
Trypan blue has been observed to interfere with cardiogenesis and cellular activity in the somatic mesoderm (Mulherkar,
'60; Stkphan and Sutter, '61) of the chick
embryo, and to cause damage to the septal myocardium (Wegener, '61) in fetal
rats. Smith ('63), on the other hand, has
described changes in the myoepicardial
cells of rat embryos following use of the
same teratogen, which he considers lead
to increased glycogen storage, myocardial
thinning, and to reduction in the amount
of cardiac jelly. In the present study, decrease in the quantity of cardiac jelly was
not apparent nor was thinning of the
myocardium a marked feature except in
resorbing embryos. Such differences may
be due to the influence of genetic factors,
to the chemical nature of the teratogen,
and to variation in dose and time of administration.
The type of abnormality resulting from
teratogenic action must also be related to
genetic background as transposition of the
189
great vessels and other cardiovascular abnormalities apparently are more readily
produced in rats of the Long-Evans strain
than in others,
Genetic factors most likely account for
the different types of abnormalities seen
in litter mates following subjection of the
mother to a teratogenic agent although
conceivably slightly different rates of development and perhaps variations in uterine blood supply also play a role.
All of the cardiovascular abnormalities
encountered in the rat fetuses of this
study have their counterpart in man and
conceivably the mechanisms involved in
their formation may be similar.
ACKNOWLEDGMENTS
Gratitude is expressed to Dr. R. C . Armstrong and Mr. J. Morgan for assistance
with the histological aspects of this study
and to Mr. J. Maeno for his outstanding
skill in the making of wax-plate reconstructions.
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