(Circulation. 1995;91:2478-2486.)
© 1995 American Heart Association, Inc.
Articles |
Morphological Observations on the Pathogenetic Process of Transposition of the Great Arteries Induced by Retinoic Acid in Mice
From the Department of Pediatric Cardiology (H.Y., M.N., S.M-T., K.M.) and Research Division (M.M.), The Heart Institute of Japan, Tokyo, and the Department of Anatomy and Developmental Biology (H.Y.), Tokyo Women's Medical College.
Correspondence to Hiroshi Yasui, MD, Department of Anatomy and Developmental Biology, Tokyo Women's Medical College, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162, Japan.
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Abstract |
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Background The pathogenesis of complete transposition of the great arteries (TGA) is still controversial because useful animal models have not been established. We previously reported that all-trans retinoic acid induced complete TGA at a high proportion in mice. The aim of the present study was to clarify the morphogenesis of the cardiac outflow tract in the retinoic acid–treated embryos destined to develop TGA.
Methods and Results We first examined the morphology of TGA in mouse fetuses treated with retinoic acid to establish an animal model of TGA (experiment 1) and then examined the retinoic acid–treated embryonic hearts by means of ink injection and histology (experiment 2). All mouse fetuses and embryos showed visceroatrial situs solitus and d-ventricular loop. In experiment 1, among 45 embryos treated with retinoic acid 70 mg/kg at day 8.5 of gestation, 35 (78%) had TGA and 3 (6.7%) had a double-outlet right ventricle with a subpulmonary ventricular septal defect. In experiment 2, all hearts already exhibited d-loop at gestation day 8.5. At gestation day 9.5, conus swellings, composed of acellular cardiac jelly, were hypoplastic, and the conotruncal cavity was nonspiral or tubular. At gestation day 11.0, aberrant conus swellings located anteroposteriorly to give a straight orientation to the conotruncal cavity. At gestation day 12.0, side-by-side great arteries were transposed in that the aorta arose from the right ventricle and the pulmonary artery arose above the interventricular foramen.
Conclusions These results suggest that a reproducible animal model of TGA can be produced in mice by treatment with retinoic acid; that there was no loop anomaly, such as an A-loop or L-loop, in our model; and that hypoplasia of the conus swellings appears to be the primary event leading to TGA.
Key Words: morphogenesis • transposition of great vessels • arteries
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Introduction |
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Complete transposition of the great arteries (TGA) is an inborn heart defect in which the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. Despite numerous theories put forth to date, the pathogenesis of TGA is still controversial. The representative theories are as follows. The "differential conal development" theory1 2 3 4 explains that in embryos destined to develop TGA, the subaortic conus grows and the subpulmonary conus undergoes absorption. This contrasts to normal development, in which the subpulmonary conus enlarges and the subaortic conus goes through resorption. This process would bring the aorta high, anterior, and to the right and would bring the pulmonary artery low, posterior, and to the left, giving the heart the principal morphological characteristics of TGA. The "straight conotruncal septum" theory5 6 7 hypothesizes that a pair of intercalated valve swellings, ie, the precursors of the nonfacing cusps of the semilunar valves instead of the main truncus swellings, as in normal development, would interconnect with a pair of conal swellings, resulting in untwisted great arteries.
While most hypotheses were derived from observations of humans with TGA
and normal mammalian embryos, some
investigators8 9 10 11
induced TGA by experiment. From their observations, more realistic
theories were derived. While examining neutron-irradiated rat embryos
(
10% of which resulted in TGA), Okamoto8 and Okamoto
et al9 found an abnormal cardiac loop, ie, an A-loop or
L-loop, followed by an "inverted anteroposterior relationship of the
conotruncal ridge." By using the same animal model as Okamoto et al,
Asami and Koizumi10 further stressed the importance of
abnormal heart-tube looping as the cause of TGA. Recently, Pexieder et
al11 drew a similar conclusion from an observation of
mouse embryos treated with retinoic acid.
It is clear that the accuracy of a theory on the morphogenesis of an anomaly depends on the incidence of the anomaly in the animal model used. In previous reports from our group, all-trans retinoic acid was proved to induce complete TGA at a high incidence.12 13 This result prompted us to perform the present study to clarify the morphogenetic process of TGA, focusing on the changes in the mouse heart-tube looping and those of the conotruncal swellings. The first step was to determine the most efficient method of treatment and to clarify the morphology of the mouse hearts in which TGA was induced so that we could establish a good animal model of complete TGA. As the next step, we observed embryonic hearts by ink injection14 for a three-dimensional illustration of the cardiac outflow tract and by serial section for the histology to clarify the morphogenetic process.
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Methods |
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We kept Jcl:ICR mice (females, 8 to 10 weeks of age; males, >10 weeks of age) in a clean rack under 12-hour light-dark conditions. Food (CE-2, CLEA) and tap water were given ad libitum. To set up matings, females were checked by vaginal smear before darkness (6 to 7 PM), and those in proestrus were placed with males in individual cages. The midnight after the mating day was defined as day 0.0 of gestation. The morning after mating, the females were checked for the presence of vaginal plugs (plug day is equal to gestation day 0).
Experiment 1: Effect of Retinoic Acid on Fetal Growth and Gross
Morphology
The stage of treatment was determined by use of the data
from
our preliminary study.12 13 Pregnant females were
injected
with all-trans retinoic acid (Sigma Chemical Co) at a dose of 40, 60,
or 70 mg/kg dissolved in 0.1 mL IP dimethyl sulfoxide at gestation day
8.5. Control mice received the solvent only. At gestation day 17.5,
fetuses were delivered by caesarean section, weighed, perfused with
physiological saline through the apex of the left ventricles, and fixed
with 2% glutaraldehyde solution.15 The fetuses were
examined for morphology of the cardiovascular system under a
stereomicroscope. Body weight was expressed as mean±SD. A univariate
ANOVA with Scheffé's procedure was used for statistical
analysis. To clarify the spatial relation between the two semilunar
valves of the hearts in the retinoic acid–treated fetuses, we measured
the angle between the line that passes through the center of the two
semilunar valves and the one that passes through the posterior edge of
the two AV valves in 56 hearts with TGA, 17 hearts with double-outlet
right ventricle, and 13 normal hearts, as illustrated in Fig 1
.
Double-outlet right ventricle was defined as a heart
defect in which one of the great arteries and >50% of the other arose
from the right ventricle.
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Experiment 2: Morphogenesis of TGA
On the basis of the
results of experiment 1, all-trans retinoic
acid 70 mg/kg was injected into dams at gestation day 8.5 for the study
of TGA morphogenesis. Control dams received no treatment. Embryos were
taken from the dams at gestation days 9.0 through 12.5 at 12-hour
intervals and observed by the following methods. (1) Ink injection.
Approximately 2 µL india ink was injected into the embryo slowly
through a glass pipette inserted into the umbilical vein. The embryo
was perfusion-fixed with Carnoy's solution, dehydrated with 95% and
absolute ethanol, cleared in benzene, and observed under a
stereomicroscope. (2) Histology. The embryo was perfusion-fixed with
4% paraformaldehyde in PBS, embedded in paraffin, sectioned in the
frontal plane at 5 µm, and stained with hematoxylin and eosin.
Table 1 shows the number of observed embryos at each
stage. Each component of a developing heart was expressed by the
nomenclature of Van Mierop et al6 with some modifications:
the entire ascending limb of the heart tube, the bulbus cordis, was
practically divided into three parts, and the proximal, mid, and distal
thirds were designated the primitive right ventricle, the conus cordis,
and the truncus arteriosus, respectively; the combined region of the
conus cordis and truncus arteriosus was designated the conotruncus (Fig
2).
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Results |
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Experiment 1: Effect of Retinoic Acid on Fetal Growth and Gross Morphology
All treated fetuses showed visceroatrial situs solitus and d-ventricular loop. Tables 2
and 3
summarize the effect of all-trans retinoic acid on the growth of
fetuses and the cardiovascular system.
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Transposition of Great
Arteries
This anomaly was induced in 35 (78%) of 45 embryos treated
with
retinoic acid 70 mg/kg, among which 18 hearts (49%) had an intact
ventricular septum (Fig 3). In hearts with TGA from 101
total fetuses, 45 (44.5%) had an intact ventricular septum and 56
(55.5%) had a subpulmonary ventricular septal defect. All hearts with
TGA had a complete infundibulum beneath the aortic valve. While
pulmonary valve–mitral valve fibrous continuity was found in 99 hearts
with TGA, 2 hearts with TGA and a subpulmonary ventricular septal
defect had subpulmonary infundibulum. The pulmonary valve was normal
except for in 1 heart, which had pulmonary atresia and ventricular
septal defect. The aortic valve was located in a range between right
and anterior relative to the pulmonary valve (Fig 1
).
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Double-Outlet Right Ventricle
In embryos treated
with retinoic acid, double-outlet right
ventricle occurred in 11% (10 of 88) at a dose of 40 mg/kg, 16% (17
of 109) at 60 mg/kg, and 11% (5 of 45) at 70 mg/kg. Ventricular septal
defect was classified as subpulmonary in 18 cases, subaortic in 11,
doubly committed in 1, and noncommitted in 2.16
Subpulmonary ventricular septal defect was found in 70% (7 of 10) at a
dose of 40 mg/kg, 47% (8 of 17) at 60 mg/kg, and 60% (3 of 5) at 70
mg/kg. Of 18 hearts with a double-outlet right ventricle and a
subpulmonary ventricular septal defect, 8 (44%) had subaortic
infundibulum and pulmonary valve–mitral valve fibrous continuity,
suggesting a close relation between the hearts in this group and those
with TGA.
Other Findings
Cardiac defects other than
TGA and double-outlet right ventricle
included truncus arteriosus communis (2 cases); tetralogy of Fallot (1
case); isolated ventricular septal defect (39 cases); and aortic
atresia, mitral atresia, and rudimentary left ventricle with a normal
relation between the great arteries (1 case) (Table 3). In the
retinoic
acid–treated hearts, we found hypoplasia of the nonfacing aortic cusp,
ranging from mild hypoplasia to complete absence (bicuspid aortic
valve). The frequency and severity of hypoplasia in hearts with TGA did
not differ from that in hearts without TGA (data not shown). Aortic
arch anomaly, ie, interruption of the aortic arch (type
B)17 or aberrant origin of the right subclavian artery,
was found in 57 (24%) of the total cases (Table 4).
Twenty-four (24%) of the embryos with TGA had interruption of the
aortic arch, and of these 24, aberrant origin of the right subclavian
artery coexisted in 4 cases. Eleven embryos (34%) with double-outlet
right ventricles, 15 (38%) with ventricular septal defects, and 4
(6%) with normal hearts had an aortic arch anomaly.
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Experiment 2: Morphogenesis of TGA
Common findings for each
stage derived from ink injection and
histology are described below and focus on the conotruncal morphology.
At all stages examined, including gestation day 8.5 (Fig 4),
all hearts had d-loop and situs solitus. The AV
cushion appeared to be similar between the control and retinoic
acid–treated groups on all gestational days.
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Gestation Day
9.0 to 10.0
Control mice. A pair of bulky swellings,
composed of
acellular cardiac jelly, were observed at the conus cordis,
contributing to the spiral conotruncal cavity (Figs 5A, left; 6A, left;
and 6B, left). The truncus swellings were
less bulky and grew slower than the conus swellings. Mesenchymal cells
appeared in the conus swellings at gestation day 9.5 to 10.0.
Retinoic acid–treated group. The conus swellings were hypoplastic and divided into multiple segments, and the conotruncal cavity was nonspiral or tubular (Figs 5, right; 6A, right; and 6B, right). The truncus swellings were similar to those in control mice. The appearance of the mesenchymal cells in the conus swellings was first observed at gestation day 10.0 to 10.5, which suggests a delay in the endothelial-mesenchymal transformation in this group.
Gestation Day 10.5 to 11.5
Control mice. The conotruncal swellings grew further
with the increase in mesenchymal cells (Figs 5B, right; 7A, right; 7B,
right; and 7C, right). The cavity in the conotruncus
appeared as a thin tape twisted 90° clockwise at its midpoint. The
aortopulmonary septum in various stages of advancement in each mouse
was aligned with the bulging truncus swellings. The aortic arch system
was mature in that the third, fourth, and sixth arch arteries were
predominant.
Retinoic acid–treated group. Aberrant conus swellings, though still hypoplastic compared with control mice, grew in the ventral and dorsal positions to give a straight orientation to the conotruncus (Figs 5B, right; 7A, right; 7B, right; and 7C, right). The length of the conus cordis was similar to that in the control mice. Aortopulmonary septation was delayed compared with control mice.
Gestation Day 12.0 to 12.5
Control mice. The aorta originated to the posterior
from the left ventricle and coursed toward the fourth aortic arch; the
pulmonary artery arose from the right ventricle and coursed toward the
sixth aortic arch (Figs 5C, left; 8A, left; 8B, left; and 8C,
left). The free wall of the conus cordis beneath the
pulmonary valve primordia was slightly longer than that beneath the
aortic valve primordia. The left-sided pulmonary channel was in a
relatively cranial position at the level of the semilunar
primordia.
Retinoic acid–treated group. The right-sided aorta originated from the right ventricle and ran toward the fourth aortic arch; the left-sided pulmonary artery arose above the interventricular foramen18 and coursed toward the sixth aortic arch (Figs 5C, right; 8A, right; 8B, right; and 8C, right). The size of the conal free wall was almost identical between the subaortic and subpulmonary area. The right-sided aortic channel was located in a relatively cranial position. In some hearts, the right intercalated valve swelling was hypoplastic or absent.
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Discussion |
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There has been some confusion over the definition of TGA. Thus, many cases of TGA in the experimental models reported thus far may actually be cases of double-outlet right ventricle. The widely accepted definition given in the previous sections enabled us to distinguish clearly between TGA and double-outlet right ventricle.
Our method, ie, injection with retinoic acid 70 mg/kg at gestation day 8.5, induced complete TGA in 76% (34 of 45) of the mice. Moreover, 3 hearts from the group of mice treated with retinoic acid had double-outlet right ventricles with subpulmonary ventricular septal defects. Hence, 82% (37 of 45) of the treated hearts had TGA-type morphology in that the aorta arose from the right ventricle and the pulmonary artery from the left ventricle or above the ventricular septal defect. Thus, this method gives a highly useful and reliable animal model for the study of the morphogenetic process of TGA.
Our observation of retinoic acid–treated mouse embryos revealed hypoplastic conus swellings without spirality 0.5 to 1.5 days after injection, when the conus swellings were composed of acellular cardiac jelly. A pair of aberrant conus swellings grew and were aligned with the truncus swellings 2 to 3 days after injection, giving rise to the straight conotruncal septum. These facts suggest that the exogenous retinoic acid perturbed the normal production of extracellular matrix in the conus cordis, eventually leading to the formation of the aberrant conus swellings. In this study, the heart tube contained a d-loop in all embryos examined, including those at gestation day 8.5, at the time of treatment with retinoic acid. Therefore, hypoplasia of the conus swellings was the primary morphological change and may play a key role in the pathogenesis of TGA in our model.
On the other hand, Pexieder et al11 treated mouse embryos with retinoic acid at gestation days 7.0 and 8.0 and thus produced TGA in 63.4% of the embryos treated. They observed an A-loop and an L-loop at gestation day 10, followed by hypoplastic conus swellings at gestation day 11. Because the abnormal heart-tube looping was the primary change in their model, they concluded that TGA is a loop anomaly. Since the heart-tube looping takes place at gestation day 7.5 to 8.5 in mice, it is quite reasonable that their treatment affected the heart-tube looping, producing anomalously looped hearts. Nevertheless, considering the striking similarity of the conotruncal morphology, the two models may share the same morphogenetic cascade involving the conotruncus, entering it from different points.
In the normal development of mammal and chick embryos, conotruncal swellings and the AV cushion are formed by the accumulation of extracellular matrix and mesenchymal cell migration into the cardiac jelly.19 20 21 Retinoic acid is known to regulate cellular growth, differentiation, and morphogenesis,22 23 which would be related to retinoic acid–induced malformations,24 25 26 27 28 29 and to modulate the production and accumulation of extracellular matrix by regulating transforming growth factor.30 Moreover, members of the transforming growth factor family are expressed in the myocardium of the outflow tract of mouse embryos at gestation day 9.5 to 10.5.31
From these facts, we could postulate the possibility that the exogenous retinoic acid in our model disturbs the actions of intrinsic retinoic acid, including those mediated by transforming growth factor, on the conus cordis, leading to reduced volume of extracellular matrix. In addition, hypoplastic extracellular matrix, which may have an abnormal molecular composition, may suppress the transport of chemical inducers that are thought to stimulate endocardial-mesenchymal transformation or mesenchymal migration,21 further intensifying hypoplasia of the conus swellings. It is also possible that exogenous retinoic acid directly degrades the extracellular matrix. However, the reason that the exogenous retinoic acid left the AV cushions unaffected needs to be clarified.
While hypoplasia of the conus swellings caused the model animals to deviate from normal cardiogenesis, the abnormal conus swellings seen at later stages seem to be the precursor to the straight conotruncal septum that is essential for formation of TGA. These abnormal conus swellings may be different from those developing in the normal control mice, considering their aberrant locations and suppressed and delayed development. Therefore, further examination should determine the formation process and constituents of the abnormal conus swellings.
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Acknowledgments |
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This work was supported by an open research grant from The Japan Research Promotion Society for Cardiovascular Diseases. We thank Keiko Komatsu for histological procedures, Akira Miyama for photographs, and Dr Masahiko Ando for review of the manuscript.
Received August 2, 1994; revision received October 26, 1994; accepted November 26, 1994.
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