© 2001 American Heart Association, Inc.
Integrative Physiology |
Development of the Myocardium of the Atrioventricular Canal and the Vestibular Spine in the Human Heart
From the Department of Anatomy & Embryology (J.-S.K., A.F.M.M., W.H.L.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Pathology (S.V.), Semmelweis University Faculty of Health Sciences, Budapest, Hungary; and Cardiac Unit (R.H.A.), Institute of Child Health, University College London, London, UK.
Correspondence to Wouter H. Lamers, MD, PhD, Department of Anatomy & Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail w.h.lamers{at}amc.uva.nl
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Abstract—To establish the morphogenetic mechanisms underlying formation and separation of the atrioventricular connections, we studied the remodeling of the myocardium of the atrioventricular canal and the extracardiac mesenchymal tissue of the vestibular spine in human embryonic hearts from 4.5 to 10 weeks of development. Septation of the atrioventricular junction is brought about by downgrowth of the primary atrial septum, fusion of the endocardial cushions, and forward expansion of the vestibular spine between atrial septum and cushions. The vestibular spine subsequently myocardializes to form the ventral rim of the oval fossa. The connection of the atrioventricular canal with the atria expands evenly. In contrast, the expression patterns of creatine kinase M and GlN2, markers for the atrioventricular and interventricular junctions, respectively, show that the junction of the canal with the right ventricle forms by local growth in the inner curvature of the heart. Growth of the caudal portion of the muscular ventricular septum to make contact with the inferior endocardial cushion occurs only after the canal has expanded rightward. The atrioventricular node develops from that part of the canal myocardium that retains its continuity with the ventricular myocardium.
Key Words: atrioventricular junction • atrial vestibule • vestibular spine • tendon of Todaro • atrioventricular node
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Introduction |
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The primary heart tube loops1 and balloons2 to develop its atrial and ventricular compartments. Initially, the atria and ventricles are arranged in series, being joined via the atrioventricular canal and the interventricular foramen. Because of this, the developing right atrium at first communicates only indirectly with the putative right ventricle.3 Therefore, the establishment of a direct communication between right atrium and right ventricle requires not only physical separation of the left and right sides of the initially common atrioventricular junction but also remodeling of the canal myocardium to produce the right atrioventricular connection. Previous studies suggested that the formation of this connection might involve rightward expansion of the canal4 or, alternatively, leftward remodeling of the primary ventricular septum.5 Although simple conceptually, these hypotheses have not thus far been tested by accurate observations of the changing junctional architecture.
Some time ago, we showed that the carbohydrate epitope recognized by the GlN2 (HNK-1, Leu7) antibody was a marker for the developing interventricular myocardium.6 This allowed us to establish that the entire right-ventricular myocardium, including its inlet portion, was developed from the distal ventricular component of the primary heart tube7 and that the canal myocardium becomes sequestered as an atrial structure.7 8 We did not establish, however, which parts of the adult atrium are derived from the canal myocardium. Furthermore, we did not elucidate the formation of the right-sided part of the atrioventricular junction, nor are we aware of other studies that have addressed this issue. We have now studied the changing shape of the atrioventricular canal musculature, using the lack of expression of creatine kinase M (CKM) as its phenotypic marker.9 By combining the expression patterns of CKM and GlN2, we show that the junction of right atrium and ventricle forms concomitant with local expansion of the inner curvature of the heart. We additionally show that the canal myocardium itself eventually forms the smooth-walled vestibules of both atria, the atrioventricular node persisting as a specialized portion of this myocardium. Finally, we show that the vestibular spine, a mesenchymal mass derived from the extracardiac dorsal mesocardium, plays a pivotal role in septation of the atrial side of the developing junctions. These findings elucidate several of the developmental disturbances that underlie malformations involving the atrioventricular canal.
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Materials and Methods |
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Tissue Sources, Preparation, and Staining
We studied human embryos from 4.5 weeks to 10 weeks of development. The embryos and their immunohistochemical staining were described previously.6 7 8 9 10 11 12 The ages of the embryos were estimated according to methods described by O’Rahilly and Müller.13
Three-Dimensional Reconstruction
Reconstructions were made using a computer-aided
method.14 The contours of
the atria, atrioventricular canal, ventricles, outflow tract,
endocardial tissues, vestibular spine, and CKM and GlN2 staining
pattern, as observed in serial sections of the embryos, were traced
onto acetate sheets. The vestibular spine was distinguished from the
endocardial cushions by its higher density of cells and the absence of
staining with antibody 249-9G9.
For the description of the specimens and reconstructions, we used cranial, caudal, dorsal, and ventral as indicators of orientation, with the apex of the heart always pointing ventrally. It should be noted that in the postnatal human heart, these terms correspond to superior, inferior, posterior, and anterior, respectively. For description of the atrioventricular endocardial cushions, we have retained the commonly used terms superior and inferior.
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Period Before Septation (Fifth and Sixth Weeks): Expansion of the Atrioventricular Canal
At the end of the 4th week of development, the trabecular portion of the ventricles and the atrial appendages begin to balloon from the outer curvature of the primary myocardial tube.3 In the ventricles, the original lumen of the tube remains temporarily recognizable as an area free of trabeculations in the inner curvature that is continuous with the atrioventricular canal proximally and the outflow tract distally (see Figure 15-5 in Reference 1313 ) At this stage, the canal is positioned exclusively above the inlet to the developing left ventricle.
Reconstruction of a 5-week-old heart shows the canal to be
straight and tubular
(Figure 1
). Because atria and ventricles are substantially
wider than the canal, their respective boundaries are easily
delineated. The atrioventricular canal myocardium is characterized by
its lack of CKM expression, in contrast to the ventricular
myocardium.9 The
interventricular ring expresses the GlN2
epitope.6 The area of
colocalization of the CKM-negative atrioventricular myocardium and the
GlN2-positive interventricular myocardium in the inner curvature
delineates the area of formation of the right atrioventricular
junction. This CKM-negative but GlN2-positive area occupies only about
one fifth of the atrioventricular junctional circumference.
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At 5.5 weeks, the junction of the atrioventricular canal
musculature with the atria has become wider than its ventricular
connection, so that its shape changes from a tube into a funnel
(Figures 2 and 3C), being most pronounced on the right side.
As viewed from the ventricles, the primary atrial septum is positioned
over the center of the canal
(Figure 2A, 5.5 weeks). At this stage, the vestibular spine
has penetrated the heart between the atrial connections of the caval
veins and the pulmonary vein to abut the inferior atrioventricular
cushion
(Figure 3A). The left venous valve inserts on its right side,
whereas the leading edge of the muscular primary atrial septum inserts
on a thin, finger-like extension from its cranial end
(Figures 2A [5.5 weeks] and 3C). The spine and its cranial
extension do not express the 9G9 epitope in contrast to the tissues of
the endocardial cushions
(Figures 3B and 3D12 ).
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When viewed from the atrial aspect, the atrioventricular
canal retains its position over the left ventricle
(Figure 2B
, 5.5 weeks). The muscular ventricular septum is
prominent ventrally but not yet seen separating the caudal part of the
ventricles. The developing branches of the atrioventricular conduction
bundle, however, can be distinguished as small GlN2-positive twigs in
the caudal wall of the ventricles
(Figure 2B, 5.5 weeks). The adjacent part of the GlN2 ring
belonging to the canal myocardium has widened as the precursor of the
atrioventricular node.
Period of Septation (Seventh Week):
Differential Growth of the Connection of the Canal With the Right
Ventricle
In this period, the atrioventricular cushions and
outflow-tract ridges fuse to separate the left and right sides of the
heart
(Figure 2C, 6.5 to 7 weeks) and the lateral endocardial
cushions of the canal become evident. In the beginning of the 7th week,
fusion of the vestibular spine with the atrial surface of the cushions
closes the primary atrial foramen
(Figure 3E). In this process, the body of the spine expands
cranially to incorporate its spur on the free rim of the primary atrial
septum
(Figure 2A, 6 to 6.5 weeks). After closure of the primary
atrial foramen, the primary septum itself inserts on the left and
dorsal margin of the spine, with the well-developed left and right
venous valves inserting on its right-sided dorsal and ventral margins,
respectively. The tissue of the spine now contains myocytes near the
insertions of atrial septum and venous valves
(Figure 3E).
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The atrioventricular canal itself has retained its
characteristic funnel shape in this period of septation. Whereas its
connection with the atria continues to expand evenly, the expansion of
its connection with the ventricles is distinctly uneven. Marked
rightward growth is limited initially to the cranial part of the canal,
so that the circumference of the canal resembles that of a boomerang
(Figure 2A, 6 to 6.5 weeks). Toward the right ventricle, the
developing right-sided atrioventricular junction is continuous with a
myocardial gully that develops at the junction of the atrioventricular
canal and the right ventricle, funneling atrial blood toward the middle
of the right ventricle.11
Because the right side of the atrioventricular canal is covered with
epicardial tissue
(Figure 3E) whereas the gully is a purely myocardial
structure
(Figure 3F), the boundary is well-defined.
The 7th week is characterized by a pronounced caudal
expansion of both the ventricular connection of the canal and the right
ventricle
(Figures 2A through 2C, 6.5 weeks). This growth accompanies
formation of the caudal portion of the muscular ventricular septum,
which expands toward the base of the heart to become attached to the
endocardial cushions
(Figures 2 [5.5 to 6.5 weeks] and 3F). The topography of the
bundle branches parallels the newly gained prominence of the caudal
portion of the muscular septum, achieving a position on the crest of
the muscular septum at 6.5 weeks
(Figure 2B, 6.5 weeks). This positional change is accompanied
by an attenuation of the diameter of the GlN2 ring between the node and
the bifurcation of the bundle branches
(Figure 2B). Concomitant with the expansion of the
ventricular connection of the right side of the canal, the floor of the
muscular gully cavitates to form the part of the tricuspid valve lying
caudal to the right bundle branch
(Figure 2B, 6.5 weeks), permitting expansion of the initial
valvar orifice, which persists cranially.
The right-sided expansion of the atrioventricular canal is
reflected in the growth of the GlN2-positive ring
(Figure 2B, 6 to 6.5 weeks). Approximately one third of the
circumference of this ring is now also CKM-negative and occupies the
frontal instead of the original sagittal plane. This portion of the
ring, which is part of the right atrioventricular junction, is called
the right atrioventricular ring
bundle.15 The nodular
portion of the ring bundle at its junction with the ventricular septum
has increased in size but retains its position in the protruding
right-sided portion of the developing canal.
Stages Subsequent to Septation (Eighth to Tenth
Weeks): Formation of Figure 8–Shaped Atrioventricular
Junctions
Although the remodeling that accompanies septation is
complete at the end of the 7th week, the separated right and left
atrioventricular junctions do not become equal in diameter until the
end of the 8th week. Concomitant with this increasing diameter of the
right junction, the CKM-negative canal myocardium, containing the
GlN2-positive ring bundle, grows to occupy half of the circumference of
the canal
(Figure 2B). The ventricular connections of the canal
myocardium gradually assume the configuration of a figure 8, indicating
that both the separated atrioventricular junctions grow faster than the
muscular ventricular septum
(Figures 2A and 2B, 7.5 weeks). The growth of the right
junction is accompanied by an increase in size of the caudal valvar
orifice in the floor of the muscular gully
(Figure 2B, 7 to 7.5 weeks). As a result, the myocardial band
that marked the cranial border of the gully and that contains the right
bundle branch becomes prominent as the septomarginal
trabeculation.
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Meanwhile, the vestibular spine has become muscularized to
become the major myocardial constituent of the base of the atrial
septum. Myocardialization spreads from 2 sites, namely, the insertion
of the primary atrial septum and of the venous valves
(Figures 3G and 3H). Both expand so that at 8 weeks, the
vestibular spine is largely muscular. Two weeks later, these myocytes
express relatively high levels of CKM. A nonmyocardial component
containing cells that abundantly express 
-smooth muscle actin
remains present between the myocardializing foci throughout the length
of the spine
(Figures 4H and 5). This structure persists as Todaro’s
tendon, which runs from the sinus septum to insert in the central
fibrous body, the latter now formed from the fused endocardial
cushions.
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By 10 weeks, the atrioventricular canal myocardium itself
has become sequestered within the atria as the smooth-walled vestibules
of the tricuspid and mitral valves
(Figures 4A, 4C, and 5). The primary atrial septum is
continuous with the left, dorsal side of the bulky, myocardialized,
vestibular spine
(Figures 4A, 4C, and 5). The spine, in turn, rests cranially
on the central fibrous body
(Figure 4C) and caudally on the canal myocardium
(Figures 4A and 5). As a result of the differential growth in
the atrioventricular connection, the medial part of the canal has
become wedged beneath the spine
(Figures 4A, 4B, and 5). It remains folded, nonetheless,
around that part of the developing central fibrous body derived from
the inferior endocardial cushion
(Figure 4E, compare with Figure 6), with the coronary sinus
draining into the right atrium between the spine and the vestibule
(Figures 4A, 4B, and 5).
The atrioventricular node persists as the apical portion of
the infolded canal musculature
(Figures 4 and 5), with its caudal, or inferior,
extension16 representing the
continuity of nodal tissue with the adjacent part of the canal. The
transitional cells of the node are formed in part from the
myocardialized spine. The node itself continues cranially as the
penetrating atrioventricular bundle of His. The boundary is marked by
the transition of the -myosin heavy chain–positive
(Figure 4E), CKM-negative
(Figure 4G) canal myocardium into the ß-myosin heavy
chain–positive (not shown) and CKM-positive
(Figure 4G) myocardium of the bundle. This transition from
CKM-negative to CKM-positive myocardium coincides with the junction of
the node with the bundle of His at the end of the 8th week but is
positioned distally in the bundle in younger embryos
(Figure 2B).9 The
myocytes in the bundle of His also lose their GlN2 expression
(Figures 4F and 5).
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Discussion |
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The atrioventricular canal is usually perceived as a simple tube connecting the septating atria and ventricles. Instead, we have shown that its pattern of growth is complex, with marked differences in the evolution of its atrial and ventricular connections.
Formation of the Right Atrioventricular
Connection
Initially, the orifice of the canal is positioned
exclusively above the developing left ventricle. The temporally
distinct pattern of growth of the ventricular connections of the canal
musculature and the increasing proportion of the circumference of the
canal possessing a CKM-negative but GlN2-positive phenotype shows that
the right-sided part of the junction forms as the result of a local
expansion of myocardium with phenotypic features shared by both the
atrioventricular and the interventricular junctional myocardia. Only
after the canal has expanded rightward does the caudal portion of the
muscular ventricular septum rise to make contact with the inferior
endocardial cushion. This last process completes muscular ventricular
septation, ensuring that blood crossing the right atrioventricular
junction enters exclusively to the right ventricle.
The growth of the morphologically right ventricle, a
structure barely identifiable at 4 weeks of development yet the same
size as the morphologically left ventricle by 7 weeks, corresponds
temporally with the rightward expansion of the atrioventricular canal.
This can be correlated with congenital malformations such as straddling
tricuspid valve, in which the size of the right ventricle corresponds
with the proportion of the right junction connected to it. Indeed, the
formation of the right junction is intimately linked with the
development of the tricuspid valve. Concomitant with expansion of the
ventricle, there is delamination of a muscular gully from the
ventricular
trabeculations.11 This gully
guides atrial blood to the cranial part of the ventricle (see Figure 1
in Reference 1111 ). The tricuspid orifice is initially formed cranially,
with its margins demarcated by the rim of the gully containing the
right bundle branch, and by the fusing ridges of the outflow tract.
Only after 6.5 weeks of development is the caudal orifice of the valve
developed in the floor of the gully, the septomarginal trabeculation
demarcating the junction of these developmental components of the
definitive valve.
Fate of the Canal Myocardium and Location of
the Atrioventricular Node
The definitive fibro-fatty atrioventricular junction is
formed at the site where the canal myocardium itself initially made
contact with the ventricular
myocardium.7 8
Hence, the initial myocardium of the canal is sequestered as an atrial
structure, forming the smooth-walled atrial vestibules. The
atrioventricular node, along with its caudal
extension,16 is also an
integral part of the right atrial vestibule. This is because the node
is no more than the only part of the canal, which retains its muscular
continuity with ventricular myocardium
(Figure 6). Accordingly, the node retains the slow
conduction, which initially characterizes all of the canal
myocardium.17 During
formation of the node, the canal myocardium thickens but does not
increase in length, in accordance with its very low mitotic
activity.18 The canal itself
remains folded around the central fibrous body, the structure that
develops locally from the endocardial
cushions.19 The atrial
margin of the node is apposed to the myocardialized vestibular spine,
containing the tendon of Todaro. Its ventricular margin is continuous
with the GlN2-positive ring remaining on the crest of the muscular
ventricular septum as the bundle of His. The slowly conducting
component derived from canal
musculature17 is
characterized by a lack of expression of CKM. In contrast, the rapidly
conducting ventricular components of the conduction axis are
distinguished from the surrounding working myocardium by their high
expression of CKM. This high expression is initially confined to the
bundle branches and trabeculations, expanding into the bundle only
between 8 and 10 weeks of development
(Figure 2). It remains to be established whether the
increased CKM expression reflects maturation concomitant with an
increase in velocity of conduction.
Vestibular Spine Functions as an Anchor in
Atrial Septation
On its atrial side, the septation of the expanding
canal is achieved by the downgrowth of the primary septum. It is growth
of the vestibular spine, nonetheless, that completes atrial septation.
This mass of extracardiac mesenchymal tissue, first described by
His,20 penetrates the heart
via the caudal hiatus in the myocardial wall of the atrium, the
so-called dorsal mesocardium. It then becomes wedged between the
primary atrial septum dorsally, and the fused endocardial cushions
ventrally. Its development is linked topographically with that of the
pulmonary
vein.12 21 The
mesenchymal tissue of the spine and its spur on the rim of the primary
atrial septum share some structural and biochemical properties with the
cushions.22 23
But unlike endocardial tissue, spinal tissue does not express the 9G9
epitope.12 Furthermore, the
vestibular spine and its spur share a common
origin,24 and both become
myocardialized. These findings suggest that the primary atrial foramen
is closed as a result of cranial expansion of the body of the spine
over the endocardial
cushions,25 26
its finger-like cranial extension serving as a conduit. Indeed, this
extension is often absent in animal models with persistence of the
primary atrial
foramen.27 28
Therefore, the role of the vestibular spine during septation of the
venous pole of the heart is remarkably similar to that of the
aorto-pulmonary septum, derived from the neural crest, in the arterial
pole of the heart, all the more because the spine also serves as a
conduit for migration of cells from the neural
crest.29 The
myocardialization of the spine also resembles that found occurring
within the outflow tract concomitant with formation of the subpulmonary
infundibulum.30 It starts
near the sites of insertion of the primary atrial septum and the venous
valves on the spine, largely replacing the mesenchymal component (the
mesenchymal caps in Figure 12 of Reference 3131 ) with myocardium and
covering the atrial aspect of the atrioventricular node to form part of
the so-called transitional
cells.31 32 The
center of the spine (the mesodermal core in Figure 12 of Reference 3131 ),
in contrast, does not myocardialize but remains as the tendon of
Todaro.
The location of the spine also accounts for the purported formation of the secondary septum of the atrium. Shown in many textbooks as a complete muscular partition, the cranial margin of this purported septum is no more than a deep infolding between the systemic and pulmonary venous sinuses. Its ventro-caudal margin, forming the ventral rim of the oval fossa, in contrast, is a true septal structure. It is derived from the myocardialized vestibular spine, with the venous valves attached to its right atrial margin and the tendon of Todaro extending through its core.
Implications for Cardiac Malformations
Congenital malformations
(Figure 7), as explained by embryologists, are often
considered to arise from developmental arrest. Our analysis of the
development of the junctions elucidates the pathogenesis of several
well-known malformations of this region. The spine, atrioventricular
canal myocardium, and endocardial cushions are all crucial in
development of the atrioventricular junctions and their environs. The
spine closes the primary atrial foramen and the canal myocardium forms
the atrial vestibules, whereas the endocardial cushions form the smooth
atrial aspect of the atrioventricular valvar
leaflets11 along with the
central fibrous
body.19
As previously argued,7 persistence of the situation existing before septation (in other words, absence of the remodeling of the inner curvature to establish the right atrioventricular connection) leads to double-inlet left ventricle. Normal expansion of the atrial connections of the canal but failure of expansion of its ventricular connections results in tricuspid atresia of the classic type, which is closely related to double-inlet left ventricle. In this malformation, the smooth myocardial floor of the blind-ending atrium represents the vestibule or, in other words, the canal myocardium. This condition resembles the heart in the 6th week of development. The normal closure of the primary atrial foramen and relatively normal position of the atrioventricular node33 indicate that development of the vestibular spine is normal in the setting of tricuspid atresia. Incomplete expansion of the ventricular connections of the canal musculature produces overriding and straddling of the tricuspid valve, intermediate between double-inlet and the normal heart.34 Significantly, the tricuspid valve overrides the caudal part of the muscular ventricular septum, this being the part of the septum that is last to form. In Ebstein malformation, the development of the junctional myocardium is almost certainly normal. The valvar complex, however, fails to delaminate properly from the ventricular trabeculations, with failure of sculpting of the papillary muscle from the trabeculations.35 Possibly as a consequence, the caudal postpapillary opening of the valve does not develop in the floor of the muscular gully.11
The atrioventricular cushions themselves can fail to fuse to different degrees. Clefting of the aortic leaflet of the mitral valve is an example of partial fusion. Because the primary atrial foramen is closed and the muscular junction is normally separated, it can be considered an isolated malformation. Failure of fusion of the atrioventricular cushions, however, can also be seen together with a common atrioventricular junction and deficient atrioventricular septation. However, in this situation, as seen in the embryo at 7 weeks, the aorta has yet to be transferred to the left ventricle. In most definitive examples with atrioventricular septal defect, in contrast, the aorta is exclusively connected within the left ventricle. Thus, atrioventricular septal defect coexisting with common atrioventricular junction is much more than simple arrested development. In mouse models, incomplete fusion of the cushions and persistence of the primary atrial foramen also occur in conjunction with double-inlet left ventricle. These combinations are usually associated with deficient development of the vestibular spine.27 28 The malformations seen in mice and humans, therefore, suggest that the spine is needed not only for the closure of the primary atrial foramen but also for proper morphogenesis of the adjacent atrioventricular canal.
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Acknowledgments |
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J.-S.K. was supported by the Korean Research Foundation and R.H.A. by the British Heart Foundation. I.E.M. Kos prepared the drawings. We thank Dr D. Franco for critical reading of the manuscript.
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Footnotes |
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Original received September 29, 2000; revision received January 4, 2001; accepted January 4, 2001.
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References |
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