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Experimentally produced malformations of the heart and great vessels in rat fetuses. Atrial and caval abnormalities

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EXPERIMENTALLY PRODUCED MALFORMATIONS
O F THE HEART AND GREAT VESSELS
I N RAT FETUSES
ATRIAL A N D CAVAL ABNORMALITIES
MAEJORIE H. FOX AND CHARLES M. GOSS
Louisiana State University School of Medicine
Department of Anatomy, New Orleans
TWELVE FIGURES
The administration of trypan blue to pregnant rats has
proved to be a valuable experimental procedure for the production of fetal cardiovascular anomalies (Wilson, '54a, '54b,
'54c, '55 ; Fox and Goss, '56 ; Richman, Thomas and Konikov,
'57). We have previously reported the high incidence of
auricular displacement in a series of fetuses recovered from
dams injected with trypan blue 8$$ days after insemination
(Fox and GOSS, '56). A subsequent study has revealed that
the incidence of this malformation drops sharply when the
dye is administered one day earlier in the gestation period.
In both series, however, almost all fetuses exhibiting appreciable auricular displacement had additional atrial or caval
malformations similar, in certain instances, to those observed
in patients with clinical congenital heart disease. Moreover,
these defects, which were associated in characteristic patterns
or syndromes, did not occur in the absence of auricular displacement. These observations lead us to postulate that one
of the primary effects of trypan blue on fetal cardiogenesis
is to occasion an early displacement of the undifferentiated
atrial chamber which results in a wide variety of secondary
aberrations.
This investigation was supported by a research p a n t from the National Heart
Institute of the National Institutes of Health, Public Health Service.
309
310
MARJORIE H. FOX AND CHARLES M. GOSS
MATERIALS AND METHODS
A total of 350 fetuses was examined. Eighty-nine were recovered from 14 dams, each of which received a single subcutaneous injection of 1 ml of a 1% aqueous solution of
Grubler’s trypan blue 8% days after insemination, 97 from 12
dams which received a similar dye injection 71/2 days after
insemination, and 164 from 14 uninjected dams. Midnight
prior t o the morning on which sperm appeared in the vaginal
smear was arbitrarily designated as the time of insemination.
A11 rats were of an isolated Long-Evans substrain. Dams
were sacrificed 18% or, more routinely, 191/2 days after insemination. Details of the techniques of preserving and dissecting the fetuses have been published previously (Fox and
Goss, ’56).
OBSERVATIONS
Atrial or caval abnormalities occurred only in fetuses recovered from dye-injected dams. Although the incidence of
these defects was higher in the 89” (30%) than in the 71/2 day
series (19%), the day of injection had very little influence on
the nature of the malformations. Anomalies in the position
or structure of the auricular appendages, terminal (proximal)
segment of the left superior vena cava, and interatrial septum
commonly occurred in fetuses of both series ; abnormalities of
the inferior or right superior venae cavae and common pulmonary vein were absent or extremely rare.
The following brief description of the normal development
of the atria and associated veins in fetal rats, based on a
series of serially sectioned normal fetuses ranging in age
from IIYz to 171/2 days, is presented to clarify the terminology
used in subsequent descriptions of the malformations and to
serve as a basis f o r their interpretation. It agrees, in all
essential details, with the descriptions of Burlingame and
Long ( ’39) and Wilson and Warkany ( ’49).
Normal structural difereiztiatiorz of the atria
I n the earliest stages of cardiac development, the future
atrium is represented by two separate, bilaterally situated
EXPERIMENTAL MALFORMATIONS O F HEART
311
primordia (Goss, '52). These unite, however, before the onset
of structural differentiation within the heart chambers. The
latter process commences about 12 days after insemination,
shortly after the convolutions of the cardiac tube bring the
chambers into their more or less definitive positions. At this
stage of development the still undivided atrium is distinctly
bilobed. The lateral lobes, forerunners of the auricular appendages, are centers of rapid expansion but the narrow
median region which is compressed ventrocephalically by the
bulbus arteriosus is a zone of relative growth stasis. The
atrium is connected to the more ventrally situated ventricle
by a short constricted channel, the atrioventricular canal.
Partitioning of the atrium into right and left chambers
begins with the development of the septum primum in the
narrow median zone. It starts as a crescentic ridge on the
dorsocephalic wall and grows towards the atrioventricular
canal. While the septum is advancing towards the canal, two
localized thickenings are enlarging in the wall of the latter.
These are commonly designated as the dorsal and ventral
endocardial cushions and their subsequent fusion results in
the division of the canal into right and left channels. The
progressively diminishing opening between the advancing
concave margin of the septum primum and the developing
endocardial cushions is called the interatrial foramen primum.
It is completely obliterated when the septum meets and fuses
with the cushions. Before this fusion occurs, however, perforations develop in the dorsocephalic portion of the septum. The
opening formed by the coalescence of these secondary perforations is termed the interatrial foramen secundum and through
its formation the thin membranous septum acquires a concave upper margin (fig. 7).
Considerably later in development a secondary component
is added to the interatrial septum. Since the latter component
is referred to as the septum secundum in most accounts of
mammalian cardiogenesis, we shall utilize this terminology in
our subsequent descriptions although certain authors (Retzer,
'08 ; Waterston, '18 ; Burlingame and Long, '39) have ques-
312
MARJORIE H. FOX AND CHARLES M. GOSS
tioned the accuracy of this designation. It first appears as a
relatively heavy crescentic ridge just to the right of the septum
primum and interatrial foramen secundum. As its caudal,
concave margin extends progressively deeper into the lumen
of the right atrium, it gradually overlies the interatrial foramen secundum. This so-called ‘‘septum secundum” does not
become a complete partition. The aperture below its crescentic
caudal margin is termed the f orurnem ovule; the margin, itself,
forms the limbus fossae ovalis. The more caudal tip of the
latter merges with the endocardia1 cushions and septum
primum, the cephalic end blends into the dorsocephalic atrial
wall (fig, 7). uring fetal life blood passes from the right t o
the left atrium via the forumem ovule and interatrial foramen
secundum. After birth, interatrial communication is prevented by adherence and fusion of the two septa1 components.
The differentiation of the right atrium is intimately associated with the development of the sinus venosus. The primitive sinus is a composite structure formed by the confluence
of the vitelline, common cardinal, and umbilical veins. The
common cardinal veins, which represent the horns of the sinus,
are ultimately converted into the terminal (proximal) segments of the definitive right and left superior venae cavae.
Portions of the vitelline and umbilical veins are incorporated
into, or become tributaries of, the inferior vena cava. Just
prior to the onset of atrial septation the sinus occupies a midline position, caudal and dorsal to the atrium. Its two horns
open symmetrically and almost independently into the dorsal
atrial wall at opposite ends of an elongated transverse orifice.
The right horn, which receives blood from the right cardinal
veins and the developing inferior vena cava, is somewhat
larger than the left. Subsequently, the sinus shifts towards
the right, resulting in a considerable dextral extension of the
left horn. Simultaneously, that portion of the sinus which
receives the right superior vena cava shifts cranially drawing
the right extremity of the sinuatrial opening somewhat cranial
to the left. Burlingame and Long merely describe the sinal
shift as a migration of the left margin of the sinuatrial orifice
EXPERIMENTAL MALFORMATIONS O F HEART
313
to the right, past and under the advancing septum primum.
Probably in the rat, as in the human embryo (Tandler, '12;
Hamilton, Boyd and Mossman, '45),it represents a deepening
of the left sinuatrial sulcus. The shift has two important consequences. First, the left sinal horn is cut off from direct
egress into the atrium and its dextral extension drains instead
into the right sinal horn. Second, when the septum primum
fuses with the endocardia1 cushions, the sinuatrial opening is
entirely excluded from the left atrium.
The margins of the reconstituted sinuatrial opening protrude into the right atrium as the prominent right and left
sinal folds (vnlvulne vercosae). On the right, the folds unite
to form a single membrane which continues on the dorsocephalic atrial wall as the septum spurium; on the left, they unite
with the base of the interatrial septuni. The more caudal portion of the left fold subsequently merges with the interatrial
septum; simultaneously, the right fold is transected by the
sinus septum. The latter originates as r? ridge in the sinal wall
between the orifices of the inferior Venn c a w and the extension of the left sinal horn. When the sinus venosus is ultimately incorporated into the right a t h u n , the sinus septum
is raised up to the level of the atrial floor. I n the late fetal rat
heart, it forms a prominent muscular band that extends from
the right sinus fold to the interatrial septum (fig. 7). The
orifices of the right superior vena cava and the inferioi. vcna
cava are situated between the sinal folds to the right of the
sinus septum. The specific portion of the right sinal fold which
forms a valve f o r the inferior vena cava is designated the
Eustachian valve.
The left superior vena cava is retained as cz large systemic
vessel in the adult rat. Its terminal segment opens into the
right atrium between the interatrial septum, thc sinus septum
and functionally, this segment of the left vena cava corr(3which lies to the left of the sinus septum). Ontogenetically
and functionally, this segment of the left vena c a m corresponds to the coronary sinus of the human heart. Both are
derivatives of the dextral extension of the left sinal horn;
314
MARJORIE H. FOX AND CHARLES M. GOSS
both serve as important venous drainage channels of the heart
muscle
Small pulmonary veins can be identified as early as 12%
days after insemination. These converge to form a single
trunk which enters the left atrium just to the left of the septum
primum. This basic pattern remains unchanged throughout
most of the fetal period (figs. 9, 12). I n the adult, however,
the pulmonary veins drain into the atrium through three
separate orifices.
.
Auricular abnormalities
Although the fetuses actually comprised a graded series in
respect to the anatomical relationship of the auriculae and
great vessels, f o r the purposes of discussion wc have assigned
them to four groups characterized as follows: (a) Normal
(fig. 1). Approximately equal sized auriculae symmetrically
placed, one on each side of the major arterial trunks, partially
covering the ventrocephalic surfaces of the ventricles ; (b)
Minimal Shift (fig. 2). Almost complete auricular bilaterality
maintained, slight reduction of one auricula o r slight extension of one auricula dorsal to the major arteries; (c) Moderate
Shift (fig. 3). Major portion of one auricula shifted to contralateral side bringing segment of appendage dorsal to arterial
trunks and leaving only small lobe in normal relationship to
arteries, displaced auricula reduced in size; ( d ) Total Shift
(figs. 4, 5). Complete shift of one auricula to contralateral
side creating an impression of a single, huge, bilobed, unilateral appendage. All 164 fetuses from uninjected dams were
found to be normal. Fetuscs from dye injected dams were
distributed among all four groups : Normal, 146; Minimal
Shift, 8; Moderate Shift, 10; Total Shift, 26.
Auricular shift occurred in both directions. I n 32 fetuses
the auricular appendages were rotated in a dextral o r counterclockwise direction, in 12 the shift was towards the left and
clockwise. The data on 4 fetuses with complete left auricular
shift were incomplete, consequently these four animals are
EXPERIMENTAL MALFORMATIONS OF HEART
315
not included in table 1. Shifts in both directions were found in
fetuses from the same litter.
Abnormalities of the sirtal derivatives
The left superior vena cava terminated abnormally in 21
fetuses. The caval aberrations were almost invariably accompanied by abnormalities in the development and relationships of the three structures which normally bound its orifice
into the right atrium, viz: the Thcbesian valve, the sinus septum and the ventrocaudal se,pnent of the interatrial septum
(figs. 7,9).
The vessel was completely transposed in 16 fetuses and
drained directly into the cephalolateral portion of the left
atrium. Sinal folds were present in the right atrium of these
animals, but four lacked a sinus septum and in three the
caudal segment of the interatrial septum was also missing.
Among the 12 fetuses in which both sinus septum and Thebesian valve were represented, in one they bounded a large
interatrial aperture, in three they bordered a very small interatrial aperture, and in 8 they were so shortened and fused to
each other and the interatrial septum that not even a minute
probe could be forced between them (fig. 8).
The left superior vena cava drained into both atria in two
fetuses, the openings being separated by a short segment of
intact vessel which ran across the dorsal surface of the left
atrium. The orifice in the right atrium was normal in respect
to size, position and valvular covering; that in the left atrium
was an oval, unguarded opening in the cephalolateral wall
(fig.9).
I n three fetuses the left superior vena cava did not drain
directly into either atrium. I n one it joined the inferior vena
cava just before the latter terminated in the right atrium.
The cavae were not separated by a sinus septum but prominent sinal folds projected into the atrial chamber. I n the two
remaining fetuses, all three venae cavae terminated in a common antechamber (sinus venosus) which communicated with
316
MARJORIE H. FOX A N D CHARLES M. GOSS
the right atrium (fig.10). Neither animal had a sinus septum
and the sinal folds were poorly developed.
A t times it was impossible to delimit precisely the left superior vena cava from the adjacent atrium because the vessel
gradually flared out and became grossly expanded as it approached the heart (fig. 6). Marked terminal expansion
seemed to be associated with caval transposition for it was
noted seven times when the left superior vena cava terminated
in the left atrium and only once when it drained into the right.
Abwmna1itie.s of the interatrial septum
Septum primum. The septum primum was structurally abnormal in 13 fetuses. I n 6 the interatrial foramen primum had
not been obliterated (fig. lo), in 6 the interatrial foramen
sccundum was not present (fig. ll), and in one specimen both
of these defects occurred. All fetuses with patent interatrial
Eoramcn primum had a single, common atrioventricular valve.
Six had, in addition, a large defect in the upper portion of the
interventricular septum ; the seventh had only one ventricle.
The intact primary septum of at least 6 fetuses can be attributed to a lack of secondary perforation since these animals
lacked a septum secundum. The seventh fetus had a normal
septum secundum, consequently the possibility of premature
fusion of the two components of the interatrial septum and
obliteration of the interatrial foramen secundum must also be
considered.
Marked degrees of atrial shift caused the septum primum
to have a more transverse than cephalocaudal orientation and
failure of the septum secundum to develop frequently made
the interatrial foramen secundum appear exceptionally large,
but in all fetuses, other than those detailed above, the septum
primum was structurally normal.
Septum securcdum. The secondary component of the interatrial septum was lacking in 30 fetuses and in these animals
the atria were very incompletely separated by the thin, membranous, crescentic septum primum (figs. 8, 9, 10, 12). In
EXPERIMENTAL MALFORMATIONS O F HEART
317
fetuses with a normal septum secundum, there was appreciable
individual variation in the extent to which the latter overlapped the septum primum, and as a consequence the interatrial foramen ranged from an opening of considerable size
down to a narrow slit. I n most specimens the closure of the
foramen had been half to three-quarters accomplished.
Five fetuses were of particular interest in that although
they lacked a normal septum secundum they had one or more
aberrant atrial septa. In three of these animals an aberrant
septum occurred at the point where a dextroposed left auricle
or left superior vena cava (fig. 9) was situated dorsal to the
arterial trunks. I n the fourth fetus an aberrant septum projected caudally into the left atrium immediately adjacent to
the septum primum thereby partially covering the interatrial
foramen secundum. Although investigation proved that it was
merely a deep infolding of the atrial wall, its gross appearance was such that had it been situated on the right of the
septum primum it undoubtedly would have been classified as
a normal but shallow septum secundum. Three secondary
septa projected into the right atrium of the fifth fetus. Conceivably, the best developed of these might be interpreted as
an abortive septum secundum, but the two remaining ridges
merely served as incomplete partitions between the main atrial
cavity and a small left-lying auricular extension.
Iwterrelatiomhips betweert rnalf orinatiorts
Almost without exception, the structural and positional defects appeared as patterns or complexes rather than isolated
phenomena (table 1). Analysis of these patterns reveals a
number of relatively consistent associations between certain
of the components.
Aside from the fetus exhibiting pattern Q, all structural
modifications of the atria and venae cavae were accompanied
by some degree of auricular displacement. Minimal auricular
shift, however, was not incompatible with normal atrial development and 5 of the 8 fetuses in this category had the normal
pattern ( A ) . This pattern appeared once with moderate shift
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EXPERIMENTBL MALFORMATIONS OF HEART
319
but never with total shift. Fetuses with total auricular displacement tended toward absence of a normal septum secundum (21), malpositioning of the left superior vena cava (12)
but normal development of the septum primum (16). As a
result of these three trends 15 of the 22 fetuses in this category
developed patterns B, F or M. Absence of a normal septum
secundum (8) or transposition of the left superior vena cava
(6) also occurred in the 10 fetuses with moderate auricular
shift but, in addition, half of the animals in this category of
shift had a malformed septum primum.
With three exceptions (patterns G, J" and Q ) , malpositioning of the left superior vena cava was accompanied by appreciable auricular shift. No other specific malformation appeared essential for caval abnormality. It occurred when
septum primum was normal (10) or defective (11)and when
septum secundum was normal ( 5 ) , aberrant (2) or absent (14).
Variations of the two components of the interatrial septum
showed no clear interrelationship. I n 10 fetuses both components were abnormal, in 8 both were normal, in 3 only the
septum primum was abnormal and in the remaining 20 animals
only the septum secundum was affected. Although patent
interatrial foramen primum and intact septum primum each
occurred once with a normally terminating left superior vena
cava, in all other instances they were associated with caval
abnormality and usually accompanied by appreciable auricular shift.
The development of the septum secundum was very closely
correlated with the degree of auricular displacement. With
one exception (pattern A) a normal septum developed only
when auricular displacement was absent (1), minimal (7) or
accompanied by transposition of the left superior vena cava
(2: patterns E and J ) . On the other hand, complete absence
of a normal septum secundum was consistently accompanied
by moderate (8) or total (21) auricular shift.
Aberrant secondary atrial septa were found in the absence
of a normal septum secundum and, in at least 4 instances, at
points where the atrium or auriculae were compressed by over-
320
MARJORIE H. FOX AND CHARLES M. GOSS
lying arterial trunks. Their presence did not seem to be
correlated with any particular degree of auricular shift nor
with an aberrant termination of the left superior vena cava.
DISCUSSION
Three aspects of the data, when considered collectively,
strongly suggest that one of the primary effects of maternal
trypan blue injections on fetal cardiogenesis is to cause an
abnormal looping of the cardiac tube which results in a lateral
displacement and rotation of the atrial chamber prior to its
differentiation.
First, the auriculae were anatomically malpositioned in 40
fetuses recovered from trypan blue injected dams. Further,
in most of the fetuses with moderate or total auricular shift
the cephalic end of the septum primum deviated markedly towards one side causing the entire septum to have a visible tilt.
These two aberrations afford concrete morphological evidence
of an atrial displacement during some stage of cardiogcnesis.
Second, 29 of the 32 fetuses in which total or moderate atrial
displacement indicated an appreciable departure from the
normal atriobulbar relationship lacked the secondary component of the interatrial septum. Further, in four of these
animals secondary septa had developed in aberrant sites where
the atria or auriculae were compressed by the arterial trunks.
According to Burlingame and Long (’39), Retzer (’08) and
Watcrslon ( W ) ,who have studied cardiogenesis in rat, pig
and human embryos, respectively, this is exactly what might
be anticipated if the median atrial zone, and consequently the
septum primum, was shifted lateral t o the bulbus and truncus
arteriosus during early cardiac development. These authors
claim that the secondary component of the interatrial septum,
the so-called “ septum secundum” is not an independently
growing duplicate of the septum primum but is merely a deep
fold of the atrial wall formed by expansion of the atria on
either side of the compressing bulbus and truncus. Presumably if this site of compression were shifted, the secondary
component of the septum would not form in its accustomed
EXPERIMENTAL MALFORMATIONS OF HEART
321
place and an aberrant septum could form. It is interesting
that the above authors’ concept of the genesis of the “septum
secundum, ” derived from studies of normal development, receives experimental confirmation from our data.
Third, in 13 of the 26 fetuses in which displacement of the
auriculae indicated a marked atrial dextroposition, the left
vena cava, a derivative of the left sinal horn drained into the
left atrium. Concomitantly, in all but one instance, the opening of the left sinal horn into the right atrium, which normally
serves as the orifice of the left superior vena cava, was reduced
or entirely obliterated by an approximation of the septum
primum to the sinus septum. These twin defects clearly demonstrate that the septum primum had transected the sinuatrial opening leaving all or part of the left sinal horn associated with the left atrium. Theoretically, two developmental
aberrations, inhibition of sinal migration or dextroposition of
the septum primurn, might lead to a transection of the sinuatrial opening. While we can not, at present, rule out the
possibility of an inhibition of sinal migration, it is significant
that whenever there was evidence that the septum primum
had completely transected the sinuatrial opening and fused
with the endocardial cushions, there was also a visible dextral
deviation of the auriculae.
Not only do the data indicate that the primitive atrium was
frequently displaced in respect to the bulbus and sinus venousus, but they suggest that in certain fetuses an abnormal
atrioventricular relationship also prevailed. Six fetuses had
a trilogy of defects consisting of retention of the interatrial
foramen primum, common atrioventricular valve, and high
interventricular septa1 defect. This syndrome could have resulted from an abnormal atrioventricular relationship which
caused a malalignment of the endocardial cushions and prevented their fusion with each other and the atrial and ventricular septa.
Since auricular displacement was the only defect which
consistently accompanied transposition of the left superior
vena cava, absence of a normal “septum secundum,” and
322
MARJORIE H. FOX AND CHARLES M. QOSS
retention of the interatrial foramen primum (table l), these
aberrations appear to result directly from atrial displacement.
The remaining malformations, with one exception, also were
consistently associated with auricular displacement but additional morphogenetic factors may have contributed to their
pathogenesis. Imperforate septum primum or terminal expansion of the left superior vena cava (non-regression of the left
sinal horn a ) rarely occurred without transposition of the latter
vessel; in both fetuses with complete lack of sinal incorporation the septum primum had failed to fuse with the endocardial cushions (pattern N ) ; the sinus septum failed t o form only
when the left superior vena cava terminated abnormally.
Imperforate septum primum, persistent common atrioventricular ostium, and persistent and abnormally terminating
left superior vena cava associated with diminution of the
Thebesian valve are well recognized, although not particularly
common, human cardiovascular malformations. I n trypan
blue-exposed rat fetuses anatomically similar malformations
appear to result from an early atrial displacement. Since
auricular shift offers a fairly reliable index of such displacement, it is unfortunate that the anatomical relationship of the
auricular appendages to the great vessels is not routinely meritioned in clinical reports of autopsy findings. A careful investigation of this relationship during autopsy might reveal
evidence of atrial displacement in instances of human cardiac
malformations and thereby demonstrate a basic morphogenetic
similarity between clinical and experimentally produced defects.
SUMMARY
1. In experiments utilizing the technique of maternal trypan
blue injection for the production of congenital cardiovascular
anomalies 350 hearts of 18l,h or 19lh day old rat fetuses were
dissected and examined for malformations of the atria and
venae cavae. Of these fetuses, 89 were recovered from dams
injected with a 1%trypan blue solution 8% days after insemination, 97 from dams injected 7% days after insemination,
and 164 from control, uninjected dams.
EXPERIMENTAL MALFORMATIONS O F HEART
323
2. One or more atrial or caval abnormalities, in certain instances anatomically similar to human cardiovascular defects,
were found in 30% of the fetuses in the 8y2 day series and in
19% of the 7v2 day series, but none in fetuses from uninjected
dams.
3. The most commonly observed malformations were auricular displacement, absence of the ‘ ‘ septum secundum, ” and
transposition of the left superior vena cava associated with
reduction or occlusion of its normal orifice in the right atrium.
Abnormalities of the septum primum or additional defects
of the sinus venosus derivatives occurred less frequently.
4. The malformations did not occur at random but were
associated in characteristic patterns or syndromes, one component of which was almost invariably auricular displacement.
5. On this basis we suggest that most of the observed defects
resulted directly or indirectly from normal cardiogenic p r o o
esses operating subsequent t o an early atrial displacement.
ACKNOWLEDGMENT
We are indebted to Mi-. Don Alvarado of the Department of
Illustration, Louisiana State University School of Medicine,
for the preparation of the drawings presented in this paper.
LITERATURE CITED
P., AND J. LONG 1939 The development of the heart i n the rat.
BURLINGANE,
U. Calif. Publ. Zool., 4 3 : 249-320.
Fox, M., AND C. Goss 1956 Experimental production of a syndrome of eongenital cardiovascular defects in rats. Anat. Rec., 124: 189-208.
GOSS,
C. 1952 Development of the median coordinated ventricle from the lateral
hearts i n rat embryos with three to six somites. Anat. Rec., 112:
761-796.
HAMILTON,W., J. BOYD
AND H. MOSSMAN 1945 Human Embryology. Williams
and Wilkins Co., Baltimore.
RETZER,R. 1908 Some results of recent investigations on the mammalian heart.
Anat. Rec., 2 : 149-155.
RICHMAN,s., w. THOMASAND N. KONIKOV 1957 Survival of rats with induced
congenital cardiovascular anomalies. AMA Arch. of Path., 63: 4 3 4 8 .
TANDLER,
J. 1912 The development of the heart in Manual of Human Embryology. Ed. by F. Keibel and F. Mall. J. B. Lippincott Co., Philadelphia and London. Vol. 11,Chap. X V I I I , 534-570.
324
MARJORIE H. FOX AND CHARLES M. GOSS
WATERSTON,D. 1918 The development of the heart i n man. Trans. Roy. SOC.
Edinburgh, 58: 257-302.
WILSON,J. 1954a Influence on the offspring of altered physiological states
during pregnancy in the rat. Ann. Tu’. Y. Acad. Sci., 57: 517-525.
1954b Congenital malformations produced by injecting azo blue into
pregnant rats. Proc. SOC. Exp. Biol. and Med., 85: 319-322.
1954c Withdrawal of claim that azo blue causes congenital malformations. Ibid., 87: l.
1955 Tcratogenic activity of several azo dyes chemically related t o
trypan blue. Anat. Rec., 188: 313-333.
WILSON,J., AND J. WARKANY1949 Aortic-arch and cardiac anomalies in the
offspring of vitamin A deficient rats. Am. J. Anat., 85: 113-156.
PLATES
ADDRE V I ATTONS
AO, Aorta
Aber. Sept., Aberrant septunl
AV Valve, Common atrioventricular
valve
F.OV., Foramen ovalc
I A F 11, Interntrial for:mmen sccundurn
I.V.C., Inferior Venn rnva
PV, Puluionnry vein
R A; LA, Right and left atria
RAA; TIAA, Right 2nd left auricular
appendages
R.S.; L.S. folds, Right and left sinal
folds
R.S.V.C.; L.S.V.C., Right and left
superior veiiae cavae
Sept. I, Septum primum
Sept. 11, ' ' Septum seauriduni ' '
Sept. Sp., Srptum spurium
S. Sept., Sinus septum
S. Ven., Sinus vrnosus
TCV, Tricuspid valve
PLATE 1
EXPLANATION @F FIGURES
1
2
Heart and major arteries of control r a t fetus 19% days after insemination
showing normal size and position of auricular appendages. The proximal
segment of the transpurelit left superior vena cava overlies tllc pulmonary
and systemic arches. x 12.
Heart and major arteries of trypan blue-exposed fetus with minimal auricular shift towards the right. Note the alight reduction in size of the left
:iuricula. x 12.
3
Heart of fctal rat showing moderate auricular shift towards the right. Note
small lobe of left auricula to left of aorta. X 12.
4 Heart of fetal rat showing total auricular shift. Note that the auriculae are
both displaced t o the right and rotated in a counterclockwise direction. x 12.
5
Heart of fetal rat in which the auricular are completely shifted to the left
and rotated in a clockwise direction. X 12.
6
Atrial region of fetus with moderate right auricular displacement and trans
position of the left superior vena cava. Note the small lcft-lying auricular
lobr and the terminal expansion of the left superior Venn envn which has hem
cut off close to its junction with the left atrium. x 12.
326
EXPEHIXIEST.iL hlALYOKMATIONS OF €IE:AI<T
X1RSORTF. H . POL A K D CH.\RLEB M. COBS
PLATE 1
PLATE 2
EXPI.AN.4T'ION OF FIGlJRES
7a,b
Interior of right atrium of control rat fetus 19% clays a f t e r insemination.
X 13.
Ss,b
Interior of right atrium of fetus with transposed left superior vvna eavtt.
Note lack of septum secundum and approximation of scpturn primum to
sinus septum resulting in a diminution of the Thebesian valve :ind ohliteration of the orifice of left sinal horn. X 13.
9a,b
Interior of atria of fetus with right auricular shift. Notc that caudal
extremity of left sinal fold merges with the scptum primnm in the region of
the sinus septum. In addition to t h r iiormal orifice of the left superior vena
c a m in thc right atrium the vesscl has a xeconclary opening in the left
atrium. An aberrant septum projrrts into the l r f t atrium close t o the
latter orifice. X 13.
328
PLATE 2
EXPERIMENTAL XILFORMATIONB OF HEART
> l A X . J O H I l i & I . FOX A N I ) C'HARIJES Y . ( i 0 8 S
I
329
PLATE 3
EXPLANATION OF FIGURES
10a,b Interior of atria of fetus in which yiiius venosus is rctairied as an antechamber to the right atrium. h’ote t h a t sinal folds d o not project into
cavity of right atrium. Dotted arrow passes from right t o left atrium
through patent interstrial foramen prirnum. Atria also communicate via
large interatrial foramen secundum. X 13.
Ila,b
Interior of right atrium of fetus in which the interatrial foramen secuiidum
is lacking. The left superior vena eava is transposed :uid the opening of
the left sin:il hor11 into the right atrium is minute. X 13.
12a,b Intcrior of a t r i a i n fetus with complete auricular shift to loft. Notc
crescentic septum primum and complete absence of septum secundum. L e f t
superior veiiii cava ran be seen passing dorsal to left atrium in its course
to the right atrium; pulmonary vein enters left atrium in its normal position. X 13.
330
PLATE 3
12 B
331
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vessels, experimentale, fetuses, malformations, atrial, heart, abnormalities, rat, producer, cava, great
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