© 1996 American Heart Association, Inc.
Articles |
The Development of the Atrioventricular Junction in the Human Heart
From the Department of Anatomy and Embryology, University of Amsterdam, Academic Medical Center (Netherlands) and the Department of Pediatric Cardiac Morphology, National Heart and Lung Institute, London, England (R.H.A.).
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Abstract |
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Abstract The histogenesis of the separation between atrial and ventricular myocardium at the atrioventricular junction in the developing human heart has been investigated immunohistochemically by using monoclonal antibodies specific for atrioventricular cushion tissue, mesenchymal cells, atrial and ventricular myocardium, and myocardium of the primary ring. It was found that the insulation between the muscle masses of atrium and ventricle is established by the fusion of the tissues of the atrioventricular sulcus (located at the epicardial side of the junctional myocardium) with those of the atrioventricular cushions (located at the endocardial side of the junctional myocardium). This process takes place at the ventricular margin of the myocardium of the atrioventricular canal. The separation of atrial and ventricular myocardium starts at
7 weeks of development in the
anteromedial portion of the right atrioventricular
junction and is largely completed around the 12th week of development.
The only remaining myocardial continuity between atrial and
ventricular myocardium is the
atrioventricular axis of conduction. Our findings show
that the nonmuscular part of the developing leaflets of the
atrioventricular valves derives from the
atrioventricular cushions and that the tissues of the
atrioventricular groove do not contribute to the
development of these leaflets.
Key Words: accessory connections • atrioventricular junction • cushion • heart • sulcus
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussion References |
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One of the intriguing aspects of cardiac development is the manner in which the tubular embryonic myocardium, functioning initially as a fingerpump without one-way valves, eventually transforms into the complex adult four-chambered pump with a well-developed valvar apparatus and fibrous skeleton, capable of supporting two separate blood circulations after birth. In earlier studies, we have demonstrated how the processes responsible for this transformation—such as ventricular septation, the development of the atrioventricular valves, and the development of the atrioventricular conduction system—are closely related to one another.1 2 3 4 5 In this contribution, we focus on the morphological events producing the necessary insulation of the atrial from the ventricular myocardium.
It is well established that during early cardiac development the ordinary atrial myocardium is continuous with myocardium of the ventricles throughout the atrioventricular junction.2 6 7 At these stages, the physical insulation by fibrous tissue is not essential owing to the intrinsic property of slow propagation of the cardiac impulse of the atrioventricular junctional myocardium.8 In the late fetal, neonatal, and adult heart, the only remaining myocardial continuity between atrial and ventricular myocardium is the atrioventricular axis of conduction, comprising the specialized myocardium of the atrioventricular node and bundle.9 10 Myocardial atrioventricular continuities outside this main axis of conduction can occur. These (abnormal) pathways are known as accessory atrioventricular muscular connections.11 12 13 14 15 16 Although it is generally believed that these pathways reflect the incomplete insulation of the atrial from the ventricular myocardium, the histogenesis is only poorly understood. It was anticipated that a good insight into the processes that lead to the normal insulation occurring during development of the atrioventricular junctions would provide a better understanding of the histogenesis of accessory atrioventricular connections.
Agreement exists about the different types of tissues participating in
the development of the fibrous atrioventricular
junctions. These are the atrial and ventricular
myocardium, the myocardium of the
atrioventricular canal, the
atrioventricular cushion tissue, and the tissue of the
atrioventricular groove.7 17 Controversies
exist, however, concerning the contributions of the tissues involved
and hence concerning the exact development of the
atrioventricular insulation. Two different hypotheses
have been proposed (Fig 1
). In the first,
atrioventricular insulation is held to be established
by invagination of the atrioventricular sulcus tissue
into the myocardium of the atrioventricular
canal.17 18 In this hypothesis (Fig
1b), the
atrioventricular valves develop as a result of the
invagination of the sulcus combined with a process called myocardial
undermining. In this model the cushions do not contribute to the
formation of the fibrous annulus and play only a minor role in the
formation of the leaflets of the atrioventricular
valves. In the second hypothesis (Fig 1c), sulcus tissue and
cushion
tissue both contribute to the establishment of the
atrioventricular insulation, with the
atrioventricular cushions contributing significantly to
the formation of the leaflets of the atrioventricular
valves.19 20
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In the past, adequate description of the development of cardiac structures has often been hindered by the difficulty of distinguishing the subpopulations of cells that contribute to the formation of these structures (see Reference 21). With regard to the atrioventricular junctions, the development of the fibrous skeleton and the development of the leaflets of the atrioventricular valves have been contentious topics, in part because of different interpretations of serial sections stained with classical histological dyes, such as hematoxylin-azofloxin.17 18 22 Recently, we have identified specific antibodies for the tissues participating in the insulation of the atrial and ventricular muscle masses. In addition, we report here two new monoclonal antibodies that facilitate the study of the developing human heart. Together with the antibodies used in previous studies,1 2 3 these antibodies have allowed us to test the two hypotheses of atrioventricular insulation.
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Materials and Methods |
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Tissue Sources and Preparation
Fifteen human embryos and fetuses (a minimum of two for each stage) from Carnegie Stage 14 onward were studied. Some of the embryos were also used in our studies on the spatial distribution of creatine kinase and myosin heavy chain isoforms1 2 and in our studies on the development of the conduction system.3 4 The embryos and fetuses were obtained from terminations of pregnancy at the Academic Medical Center of Amsterdam and at the Postgraduate Medical School in Budapest. The studies were approved by the respective local medical-ethical committees. The Carnegie Stage of development of the embryos was estimated by comparison of the observed external landmarks and cardiac morphology with literature data.23 No morphological abnormalities were observed in the specimens described. Embryos and isolated hearts from fetuses were fixed at room temperature in a mixture of methanol/acetone/acetic acid/water (35:35:5:25 [per volume]) for a minimum of 2 hours, dehydrated in a graded series of ethanol, cleared in chloroform, and embedded in Paraplast Plus (Monoject). The specimens were cut into 5-µm-thick serial sections and mounted on microscope slides coated with poly-L-lysine.
Immunohistochemistry
To detect the binding of the specific
monoclonal antibodies with
the respective antigens on paraplast sections, the indirect
unconjugated PAP technique was applied as described in detail
previously.1 2
Monoclonal Antibodies
The production and characterization of
anti–
-MHC
(249-5A4), anti–ß-MHC (169-1D5), and anti-GlN2 have been described
in detail in previous papers.2 3 The monoclonal
antibody
recognizing both the -MHC and ß-MHC isoform (149-23A2) was raised
against MHC extracted from atrial myocardium of adult rat
heart. Anti–Leu-7 (anti–HNK-1) was purchased from Becton Dickinson
and reacts in the human heart identical to
anti-GlN2.3 4
Anti–human desmin was purchased from Sanbio. The monoclonal
antibodies reacting specifically with the
atrioventricular cushion tissue (249-9G9), designated
anti–cushion tissue antigen (anti-CTA), and the monoclonal
antibody reacting with endothelial and mesenchymal
cells (249-5E9), designated anti–mesenchymal cell antigen
(anti-MCA), were obtained as byproducts during the procedure in
which the anti–-MHC antibody was produced.2 Because
the amount of the antibodies 249-9G9 and 249-5E9 available was limited,
extensive biochemical characterization of the antigens unfortunately
could not be performed. A single Western blot analysis, using
protein extracted from human adult ventricle, indicated that anti-MCA
recognizes a protein with an apparent molecular weight of 75 kD.
Characteristics of the antibodies used in experiments are detailed in
Table 1.
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Results |
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The Embryonic Stages
Carnegie Stages 14 and 15 (31 to 38 Days)
In the youngest specimens investigated (Carnegie Stage 14),
-MHC is expressed in both the embryonic atrial and
ventricular myocardium and in the
myocardium of the atrioventricular canal
(Fig 2a). ß-MHC, however, is expressed only in the
embryonic ventricle and in the lower part of the wall of the
atrioventricular canal (Fig 2b; see also Reference 2).
At this stage, the myocardial continuity between atrium and ventricle
throughout the atrioventricular junctions is most
clearly illustrated by the expression of -MHC. The lower part of the
right portion of the atrioventricular canal is
characterized by the expression of GlN2/Leu-7 (Fig
2c).3 4
This part of the wall of the right atrioventricular
canal belongs to the "primary ring" of myocardium
that surrounds the primary interventricular foramen and
will partly develop into atrioventricular conduction
tissue3 (see also Fig 3). Most of the
myocardium of the wall of the
atrioventricular canal, joining the atrial and
ventricular muscle masses, is sandwiched between the tissue
of the atrioventricular groove encircling the
atrioventricular canal completely on the epicardial
side and the tissue of the (anterosuperior and
posteroinferior) atrioventricular
cushions on the endocardial side (Fig 2d). A small area of the
internal
relief of the atrioventricular canal is not covered
with cushion material since, at this stage, the right and left lateral
atrioventricular cushions have yet to be formed. Hence,
in this area the endocardium is in direct contact with
myocardium (Fig 2e through 2h).
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The configuration of the respective structures and tissues at Stage 15 (data not shown) closely resembles that of Stage 14. An important feature of the late Carnegie Stage 15 heart (36 to 38 days)2 3 is the fusion of the posteroinferior and anterosuperior atrioventricular cushions and the appearance of the lateral atrioventricular cushions.
A schematic representation of the
structure of the right
atrioventricular junction in hearts of Stages 14 and 15
is given in Fig 4a.
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Carnegie Stages 17
Through 19 (42 to 51 Days)
Except for the expression of -MHC,
which has become virtually
restricted to the atria and the wall of the
atrioventricular canal (Fig 5a and 5b),
the hearts examined at Stages 17 through 19 do not show any changes in
the expression patterns of the antigens studied when compared with the
hearts at Stages 14 and 15. The lower part of the
atrioventricular canal characteristically expresses
both cardiac MHC isoforms (Fig 5a through 5c) and, at the right
side
only, GlN2/Leu-7/HNK-1 (Figs 3
and 5d).The
atrioventricular sulcus tissue is still separated from
CTA-expressing endocardial cushion tissue (Fig 5f) by
atrioventricular junctional myocardium.
However, compared with the younger hearts, the shape of the
atrioventricular junction has changed. This change in
morphology is due to the outward expansion of the
ventricular myocardium, leading to the bulging
of the "shoulders" of the ventricular free wall (see
Fig 4b).
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At this stage, the lateral atrioventricular
cushions
have become prominent mesenchymal structures. The left lateral cushion
contributes to the formation of the mural leaflet of the mitral valve,
while the right lateral cushion (Fig 5a through 5f) contributes
to the
formation of the inferior leaflet of the tricuspid
valve.5 The stainings with anti–ß-MHC (Fig
5c) and
anti-CTA (Fig 5f) clearly demonstrate that, at this stage, the
developing leaflets of the atrioventricular valves are
partly mesenchymal and, due to the delamination of the valvar tissue
from the ventricular muscle mass (see also Reference 5),
partly muscular in composition.
Carnegie Stages 20 Through
23 (52 to 60 days)
An interruption of the continuity between atrial and
ventricular muscle masses is detected for the first time in
the anterior aspect of the right atrioventricular
junction in the heart of an embryo at Carnegie Stage 20 (Fig 6a
through
6d). Elsewhere in this heart, the atrial and
ventricular muscle masses are still continuous.
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In two later embryonic specimens (Stages 22 and 23, 56 to 60 days), the separation has extended somewhat more to the lateral portion of the right atrioventricular junction (not shown). When the right atrioventricular junction is followed toward the atrioventricular nodal area, the amount of nonmuscular material separating atrium from ventricle decreases, and the muscle masses are still continuous at the posterolateral portion of the right atrioventricular junction. Furthermore, atrioventricular continuity is still observed in the left atrioventricular junctions.
3 Months of Development
At the beginning of the third month of gestation
atrioventricular discontinuity is, in addition to the
discontinuity observed in the right side, now also observed in the
posterior region of the left atrioventricular junction
(Fig 7). The developing leaflets at this stage still
consist partly of ventricular (ie, ß-MHC–expressing)
myocytes and partly of cushion-derived (ie, CTA-positive)
mesenchymal cells.
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At the end of the third month of gestation, the
atrioventricular valves have obtained their mature
morphology, more or less (Fig 8). CTA is expressed in
the leaflets of the atrioventricular and
arterial valves as well as in the central fibrous body.
Only a few myocardial cells can still be detected within the leaflets
of the atrioventricular valves at this stage (Fig 8a,
8d, and 8e). At both the left and right
atrioventricular junctions, the atrial
myocardium and ventricular
myocardium are now almost completely separated due to the
fusion of the tissues of the atrioventricular sulcus
and cushions. In most areas, nonetheless, the atrial
myocardium and ventricular
myocardium are still in very close proximity, and isolated
muscular atrioventricular connections can still be
observed. At the right atrioventricular junction, the
area of fusion of the CTA-expressing, cushion-derived tissue and
the tissue of the sulcus is located at the ventricular
margin of the right atrioventricular ring. Although the
ring no longer expresses GlN2/Leu-7, it remains easily distinguishable
from its surroundings by its peculiar myocardial
arrangement.3 24 25 The location of the
zone of fusion
between sulcus tissue and cushion-derived tissue within the left
atrioventricular junction seems to be much deeper than
the zone of fusion in the right atrioventricular
junction. This is due to the fact that, in addition to the outward
growth of the ventricular wall, a prominent
ventricular thickening has developed toward the luminal
side in the left ventricle. This development is schematically depicted
in Fig 9.
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4 Months of Development
At
this fetal stage, the atrial and ventricular muscle
masses at the right atrioventricular junction are
separated from each other by a well-formed thick layer of
connective tissue (Fig 10a and 10c). The
leaflets of
the atrioventricular valves and the central fibrous
body still express CTA (Fig 10b and 10d). At
the parietal margin of the
right atrioventricular junction, the insertion of the
anterosuperior leaflet of the tricuspid valve is located at the
ventricular side of the right
atrioventricular ring (Fig 10d). The valvar tissue is
in continuity with the sulcus tissue, which remains confined to the
epicardial side of the atrioventricular ring. At the
left atrioventricular junction, the separation between
atrial and ventricular muscle masses is as yet not so
clear, and occasionally strands of myocardium continue to
cross the presumptive line of fusion between sulcus and cushion
tissue.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussion References |
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The Development of the Atrioventricular Junction in the Normal Heart
We have studied the morphogenesis of the tissues producing atrioventricular insulation in the human heart by using specific antibodies reacting with atrial and ventricular myocardium, the myocardium of the atrioventricular canal, the atrioventricular cushion tissue, and mesenchymal cells in the atrioventricular sulcus. The data presented demonstrate unambiguously that the separation of the atrial and ventricular muscle masses is associated with "fusion" of the tissues of the atrioventricular sulcus with the atrioventricular cushions. The interruption of the atrioventricular continuity, ie, the line of fusion of the nonmyocardial tissues, lies at the ventricular margin of the atrioventricular junctional myocardium. As a consequence, the entire embryonic atrioventricular junctional myocardium, as defined by its specific pattern of gene expression, extensively described in previous papers,1 2 3 4 26 becomes incorporated into the definitive atrium. The atrioventricular axis of conduction tissue persists as the only muscular atrioventricular continuity in the healthy adult human heart as a result of the lack of fusion of the tissues of the atrioventricular sulcus and the dorsal atrioventricular cushion.
On the basis of the material
studied, we conclude that the process of
separation of atrial and ventricular myocardium
starts at 7 weeks of development at the anteromedial portion of the
right atrioventricular junction. This is much earlier
than suggested in 1939 by Odgers,19 who argued that the
atrioventricular junctional myocardium
becomes interrupted for the first time at 4 months of development.
Although we observed that the process of fusion between the tissues of
the atrioventricular sulcus and
atrioventricular cushions is largely completed around
the 12th week of development, in all the fetal hearts we studied, at
the line of fusion between sulcus and atrioventricular
cushion tissue, isolated strands of cardiomyocytes were
observed that were possibly connecting the atrial with the
ventricular muscle mass. Interestingly, examination of
serial sections of neonatal human hearts, previously described in a
study on the distribution of myosin heavy chain
isoforms,25 revealed that these isolated strands of
cardiomyocytes can still be observed in these otherwise
normal hearts (Fig 11).
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It is noteworthy that the
atrioventricular insulation
at the right side develops and "matures" first during
development, but that the left-sided fibrous annulus is better
developed in the adult heart.27 The ontogenesis of the
atrioventricular junction is schematically depicted in
Table 2.
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Accessory Atrioventricular
Connections
Our description of the formation of the fibrous insulating
tissues
offers new insights on the possible morphogenesis of parietal accessory
atrioventricular muscular connections. It seems
possible that atrioventricular connections may persist
into adult life as a result of an incomplete fusion of sulcus and
cushion tissue (Fig 12b). Incomplete fusion would well
account for the intimate relationship of the muscular connections to
the fibrous annulus supporting the leaflets of the mitral
valve.28 It is also of interest to note that in the
right-sided atrioventricular junction, parietal
accessory atrioventricular connections with special
histological characteristics have been
described,11 15 classified previously as
"parietal
specialized accessory atrioventricular muscle
bundles."12 These connections are almost certainly
related to the specialized ring tissue.
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Considering the development of
the fibrous annulus, as described above,
it is unlikely that the parietal accessory
atrioventricular bundles located subepicardially and
"crossing" the adipose part of the fibrous annulus (Fig
12c) at
the epicardial aspect (ie, through the sulcus tissue) do present
persisting embryonic atrioventricular connections,
since they are not located in the area of the embryonic junctional
myocardium. Moreover, as these bundles are not observed in
the sulcus tissue of embryonic hearts, the data presented in
this paper indicate that they have to be "acquired" during fetal
and/or postnatal life.
Formation of the Leaflets of the
Atrioventricular Valves
Our study lends no support to the concept that
ingrowth of the
tissue of the atrioventricular sulcus produces the
larger component of the mesenchymal portion of the leaflets of the
atrioventricular valves. This concept was derived from
studies of serial sections stained with classical
histological dyes. In these studies, structures within
the sections were discriminated on the basis of their morphological
appearance, using terms like "poorly staining appearance" and
"more readily stainable."22 It was stated that the
insulation of the atrial and ventricular muscle masses
became established by simple invagination of the extracardiac
atrioventricular sulcus tissue17 18 (see
Fig 1). The material contribution of the
atrioventricular cushion tissue to the formation of the
fibrous skeleton and the atrioventricular valvar
leaflets was thought to be very
small.6 17 18 29 Our
results, in contrast, show that the leaflets of the valves derive
equally from the atrioventricular cushions and
myocardium.5 By means of the antibody reacting
specifically with the cushions in the early stages, we were able to
follow their fate as development proceeded. Moreover, we have not been
able to confirm the presence of remnants of the cushions in the apical
part of the parietal leaflet of the tricuspid valve, the so-called
"noduli albini," mentioned for the first time by Bernays in 1876
(see Reference 19) and reiterated more than a century later by
others.17 18 Our results, therefore, support the more
classical accounts, which accorded for a more important role of the
cushions in the formation of the fibrous annulus and
valves.19 20 21 30
Thus, our immunohistochemical results show convincingly that no true
inward growth of atrioventricular sulcus tissue takes
place. The impression of active invagination of the
atrioventricular groove is given by three closely
related processes (Fig 4). The first is the thickening of the
ventricular free wall. This process takes place around the
fifth week of development. The second is the bulging of the shoulder of
the free wall of the ventricle, which gives rise to the formation of
the "shark-teeth"–shaped appearance of the
atrioventricular groove (Fig 4b). The third process is
the increase in the mass of the sulcus tissue "filling up" the
atrioventricular groove. This occurs around the sixth
week of gestation. The insulation between atrial myocardium
and ventricular myocardium is established by
fusion of the tissues of the atrioventricular sulcus
and the atrioventricular cushion (Fig 4c).
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Acknowledgments |
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This work was supported by grant 90-066 of the Netherlands Heart Foundation. The authors gratefully acknowledge A.A. van Horssen for his informative drawings and C. Gravemeijer for excellent photography.
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Footnotes |
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Reprint requests to Andy Wessels, PhD, Department of Cell Biology and Anatomy, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425-2204. E-mail andy_wessels@smtpgw.musc.edu.
Received March 22, 1995; accepted August 30, 1995.
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D. P. Kolditz, M. C.E.F. Wijffels, N. A. Blom, A. van der Laarse, N. D. Hahurij, H. Lie-Venema, R. R. Markwald, R. E. Poelmann, M. J. Schalij, and A. C. Gittenberger-de Groot Epicardium-Derived Cells in Development of Annulus Fibrosis and Persistence of Accessory Pathways Circulation, March 25, 2008; 117(12): 1508 - 1517. [Abstract] [Full Text] [PDF]
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D. M. Stroud, V. Gaussin, J. B.E. Burch, C. Yu, Y. Mishina, M. D. Schneider, G. I. Fishman, and G. E. Morley Abnormal Conduction and Morphology in the Atrioventricular Node of Mice With Atrioventricular Canal Targeted Deletion of Alk3/Bmpr1a Receptor Circulation, November 27, 2007; 116(22): 2535 - 2543. [Abstract] [Full Text] [PDF]
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D. P. Kolditz, M. C.E.F. Wijffels, N. A. Blom, A. van der Laarse, R. R. Markwald, M. J. Schalij, and A. C. Gittenberger-de Groot Persistence of Functional Atrioventricular Accessory Pathways in Postseptated Embryonic Avian Hearts: Implications for Morphogenesis and Functional Maturation of the Cardiac Conduction System Circulation, January 2, 2007; 115(1): 17 - 26. [Abstract] [Full Text] [PDF]
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V. Gaussin, G. E. Morley, L. Cox, A. Zwijsen, K. M. Vance, L. Emile, Y. Tian, J. Liu, C. Hong, D. Myers, et al. Alk3/Bmpr1a Receptor Is Required for Development of the Atrioventricular Canal Into Valves and Annulus Fibrosus Circ. Res., August 5, 2005; 97(3): 219 - 226. [Abstract] [Full Text] [PDF]
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 J. S. Lawton, S. P. Deshpande, P. B. Zanaboni, and R. J. Damiano Jr Spontaneous Atrioventricular Groove Disruption During Off-Pump Coronary Artery Bypass Grafting Ann. Thorac. Surg., January 1, 2005; 79(1): 339 - 341. [Abstract] [Full Text] [PDF]
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F. J. de Lange, A. F.M. Moorman, R. H. Anderson, J. Manner, A. T. Soufan, C. d. G.-d. Vries, M. D. Schneider, S. Webb, M. J.B. van den Hoff, and V. M. Christoffels Lineage and Morphogenetic Analysis of the Cardiac Valves Circ. Res., September 17, 2004; 95(6): 645 - 654. [Abstract] [Full Text] [PDF]
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E. J. Armstrong and J. Bischoff Heart Valve Development: Endothelial Cell Signaling and Differentiation Circ. Res., September 3, 2004; 95(5): 459 - 470. [Abstract] [Full Text] [PDF]
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 F. Nicolini, C. Beghi, C. Muscari, A. Agostinelli, A. M. Budillon, I. Spaggiari, and T. Gherli Myocardial protection in adult cardiac surgery: current options and future challenges Eur. J. Cardiothorac. Surg., December 1, 2003; 24(6): 986 - 993. [Abstract] [Full Text] [PDF]
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 A. Wessels and D. Sedmera Developmental anatomy of the heart: a tale of mice and man Physiol Genomics, November 11, 2003; 15(3): 165 - 176. [Abstract] [Full Text] [PDF]
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 A. F. M. MOORMAN and V. M. CHRISTOFFELS Cardiac Chamber Formation: Development, Genes, and Evolution Physiol Rev, October 1, 2003; 83(4): 1223 - 1267. [Abstract] [Full Text] [PDF]
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 R. H Anderson, S. Webb, N. A Brown, W. Lamers, and A. Moorman Development of the heart: (2) Septation of the atriums and ventricles Heart, August 1, 2003; 89(8): 949 - 958. [Full Text] [PDF]
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A. Moorman, S. Webb, N. A Brown, W. Lamers, and R. H Anderson DEVELOPMENT OF THE HEART: (1) FORMATION OF THE CARDIAC CHAMBERS AND ARTERIAL TRUNKS Heart, July 1, 2003; 89(7): 806 - 814. [Full Text] [PDF]
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 D. Sedmera, P. Kucera, and E. Raddatz Developmental changes in cardiac recovery from anoxia-reoxygenation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2002; 283(2): R379 - R388. [Abstract] [Full Text] [PDF]
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 S. W. Kubalak, D. R. Hutson, K. K. Scott, and R. A. Shannon Elevated transforming growth factor {beta}2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor {alpha} knockout embryos Development, January 2, 2002; 129(3): 733 - 746. [Abstract] [Full Text] [PDF]
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M. L. Kirby Getting to the Heart of Cardiac Morphogenesis Circ. Res., March 2, 2001; 88(4): 370 - 372. [Full Text] [PDF]
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J.-S. Kim, S. Viragh, A. F. M. Moorman, R. H. Anderson, and W. H. Lamers Development of the Myocardium of the Atrioventricular Canal and the Vestibular Spine in the Human Heart Circ. Res., March 2, 2001; 88(4): 395 - 402. [Abstract] [Full Text] [PDF]
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 A. S. Boyer, W. T. Finch, and R. B. Runyan Trichloroethylene Inhibits Development of Embryonic Heart Valve Precursors in Vitro Toxicol. Sci., January 1, 2000; 53(1): 109 - 117. [Abstract] [Full Text] [PDF]
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H. Sun, E. O. Velipasaoglu, D. E. Wu, H. A. Kopelen, W. A. Zoghbi, W. H. Spencer III, and D. S. Khoury Simultaneous Multisite Mapping of the Right and the Left Atrial Septum in the Canine Intact Beating Heart Circulation, July 20, 1999; 100(3): 312 - 319. [Abstract] [Full Text] [PDF]
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 P. W. Oosthoek, A. C. Wenink, L. J. Wisse, and A. C. Gittenberger-de Groot Development of the papillary muscles of the mitral valve: morphogenetic background of parachute-like asymmetric mitral valves and other mitral valve anomalies J. Thorac. Cardiovasc. Surg., July 1, 1998; 116(1): 36 - 40. [Abstract] [Full Text]
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A. C. Gittenberger-de Groot, M.-P. F.M. Vrancken Peeters, M. M.T. Mentink, R. G. Gourdie, and R. E. Poelmann Epicardium-Derived Cells Contribute a Novel Population to the Myocardial Wall and the Atrioventricular Cushions Circ. Res., June 1, 1998; 82(10): 1043 - 1052. [Abstract] [Full Text] [PDF]
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A. F.M. Moorman, F. de Jong, M. M.F.J. Denyn, and W. H. Lamers Development of the Cardiac Conduction System Circ. Res., April 6, 1998; 82(6): 629 - 644. [Full Text] [PDF]
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S. Webb, N. A. Brown, and R. H. Anderson Formation of the Atrioventricular Septal Structures in the Normal Mouse Circ. Res., April 6, 1998; 82(6): 645 - 656. [Abstract] [Full Text] [PDF]
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 W. M. Keyes and E. J. Sanders Regulation of apoptosis in the endocardial cushions of the developing chick heart Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1348 - C1360. [Abstract] [Full Text] [PDF]
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