(Circulation. 1995;91:111-121.)
© 1995 American Heart Association, Inc.
Articles |
Formation of the Tricuspid Valve in the Human Heart
From the Department of Anatomy and Embryology, Academic Medical Center, University of Amsterdam (W.H.L., A.W., A.F.M.M.); the Department of Pathology, Postgraduate Medical School, Budapest (S.V.); and the Department of Paediatrics, National Heart and Lung Institute, London (R.H.A.).
Correspondence to Wouter H. Lamers, Department of Anatomy and Embryology, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, the Netherlands.
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Abstract |
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Background Some of the problems concerning the origin of the inlet component of the definitive right ventricle were resolved in a previous study in which we showed it to be derived exclusively from the embryonic right ventricle. Questions remain, however, concerning the relative contributions of endocardial cushion tissue and myocardium to the definitive valvar apparatus guarding the right atrioventricular orifice and the origin of the valvar leaflets.
Methods and Results The formation of the tricuspid valve was studied by scanning electron microscopic and immunohistochemical techniques. Concurrent with the development of the right atrioventricular connection, a myocardial ridge forms at the boundary between the atrioventricular canal and the embryonic right ventricle. It grows to become a myocardial gully that funnels atrial blood beneath the lesser curvature of the initial heart tube toward the middle of the right ventricle. Fenestrations in the floor of the gully create an additional inferior opening in the funnel, transforming its initial anterior rim into the septomarginal trabeculation. The septum formed by the fusion of the endocardial ridges of the outflow tract becomes myocardialized in its inferior portion to form, in part, the outlet septum and, in part, the supraventricular crest. The smooth atrial surface of the tricuspid valvar leaflets develops from endocardial cushion tissue. The leaflets become freely movable, however, only after delamination of the tension apparatus within the myocardium. The inferior and septal leaflets derive from the gully and the ventricular septum, their delamination being a single, continuous process. The anterosuperior leaflet forms by delamination from the developing supraventricular crest.
Conclusions The leaflets of the tricuspid valve develop equally from the endocardial cushion tissues and the myocardium. The myocardium contributing to the valve comes from two sources, the tricuspid gully complex and the developing supraventricular crest. These findings facilitate the understanding of several congenital malformations.
Key Words: ventricles • endocardium • conduction • morphogenesis • myocardium
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Introduction |
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The development of the atrioventricular valves is one of the more complex events of cardiac morphogenesis. Questions remain concerning the temporal relation of valvar development and cardiac septation,1 the relative contribution of endocardial cushion tissue and myocardium to the definitive valvar apparatus,2 3 4 and the developmental origin of the valvar leaflets.1 5 6 7 8 It is axiomatic that knowledge of details of all these aspects of morphogenesis will facilitate understanding of congenital malformations of the tricuspid valve.
Some of the problems concerning septation were resolved by our recent study9 showing that the inlet component of the definitive right ventricle was developed in its entirety from the ascending ("outlet") limb of the embryonic ventricular loop (the embryonic right ventricle). The findings and conclusions of that study were facilitated by immunohistochemical staining of sections with antibodies that specifically distinguished between the myosins of the atrium and ventricle,10 as well as identifying the myocardium surrounding the primary interventricular foramen11 and the valvar tissues. Study of the sections themselves was enhanced by the availability of a versatile computer-aided three-dimensional reconstruction program that revealed the topographical relations of the constituent parts.12 As a sequel to that study,9 we have now established that the development of the tricuspid valve is intimately associated with the process of septation. Use of the specific antibodies has shown that the tissues of both the endocardial cushions and the ventricular myocardium contribute substantially to the definitive valvar leaflets. The details of this subsequent investigation are described here.
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Methods |
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Embryos
The embryos used for this study were obtained from terminations of pregnancy performed for medical reasons at the Academic Medical Center in Amsterdam or at the Postgraduate Medical School in Budapest, or were taken from the collection held at the Royal Brompton National Heart and Lung Hospital in London. The studies of the tissues obtained 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.13 No morphological abnormalities were observed in any of the specimens described. The hearts of 16 embryos, with a gestational age ranging from 4.5 to 16 weeks, were fixed in situ (up to 7 weeks) or after dissection from the thorax, in a mixture of methanol : acetone : acetic acid : water (35:35:5:25 by volume). They were processed for immunohistochemical staining as described previously.9 10 11 14 The hearts of 16 additional embryos were dissected from the thorax and fixed in 4% formaldehyde solution freshly prepared from paraformaldehyde and diluted in 0.1 mol/L phosphate buffer (pH 7.4). After fixation, all hearts were found to be in a moderately contracted condition. In a number of formaldehyde-fixed specimens, the lateral wall of the right atrium and right ventricle was trimmed away under a dissecting microscope. Other specimens were left intact during the first steps of preparation. Fixation in formaldehyde for 1 to 5 hours was followed by immersion in 4% glutaraldehyde for several hours to days in a refrigerator and eventually in 1% buffered OsO4 for 1 to 2 hours. After fixation, the specimens were critical-point-dried, sputter-coated with gold, and examined in a scanning electron microscope (Philips 500). After the first recordings, the specimens were further dissected, sputter-coated once more, and reinvestigated. This approach revealed the topographical anatomy of the small embryonic hearts. A number of intact specimens were processed for embedding in epoxy resin, having been oriented carefully under a dissecting microscope. Serial sections were cut at 1-µm thickness and stained with toluidine blue. Other specimens were fixed in 4% formaldehyde, cut at 10-µm thickness, and stained with Masson's trichrome technique. The diameters of the hearts prepared for scanning electron microscopy were 35% to 40% smaller than those of specimens embedded in plastic or paraffin. This difference reflects the drying procedure.
Monoclonal Antibodies
The monoclonal antibody that demarcates
the junction between the
proximal and distal segments of the ventricular component of the heart
tube (the "primary ring") was raised against a protein extract of
the ganglion nodosum of chickens and has been designated
anti-GlN2.15 Its staining pattern in human embryonic
hearts has been detailed elsewhere.9 11 The
characterization of the staining pattern of monoclonal antibodies
against the atrial (
) and ventricular (ß) isoforms of myosin heavy
chain and against the M isoform of creatine kinase in human embryonic
hearts has also been described previously.10 14 The
antigen to tissues of the endocardial cushions and ridges that is
recognized by the fourth monoclonal antibody used in this study has not
been characterized because of its limited availability. In histological
sections, nonetheless, this antibody reacts only with the tissue of the
endocardial cushions and ridges and, in older embryos, with the valvar
structures. A fifth monoclonal antibody specifically recognizes
connective tissue cells in histological sections. Anti–human desmin
antibodies were obtained from Monosan, Sanbio. Binding of the
antibodies to the antigens in the sections was visualized with the
indirect unconjugated peroxidase-antiperoxidase technique. Finally,
some of the sections were stained with alcian blue to reveal the
glucosaminoglycans in the endocardial cushion tissues.
Three-dimensional Reconstruction
The topography of the
myocardium and endocardial cushions
surrounding the developing tricuspid valve was studied in
three-dimensional reconstructions. The contours of the compact
myocardium and the endocardial cushions as observed in serially
incubated sections of the embryos were traced onto acetate sheets by
use of a projection microscope and a camera lucida. Computer
reconstructions were made with a computer-aided method of
reconstruction.9 12 Microdissections of the
reconstructions that revealed the topographical relations of the
internal structures were generated by graphically removing the
structures intervening between the observer and the zone of interest.
For ease of understanding, the ventricular trabeculations were excluded
from the reconstructions. The schematic drawings were subsequently made
with the help of a medical artist.
Nomenclature
The boundaries and names of the cardiac segments
used in this
contribution are as used in our previous study,9 except
that the proximal segment of the ventricular component of the heart
tube (the descending limb or inlet) is now described as the embryonic
left ventricle, while the distal segment (the ascending limb or outlet)
will be called the embryonic right ventricle. The expression of GlN2 in
the myocytes surrounding the primary interventricular foramen is used
to delineate the boundary between the embryonic ventricles. In addition
to its typical double-layered appearance, the myocardium of the
atrioventricular canal is also delineated by the pattern of expression
of myosin heavy chains and the M isoform of creatine kinase. The
junction between the embryonic right ventricle and the outflow or
arterial segment is defined by the absence of muscular trabeculations
within the outflow segment. The parietal endocardial ridge of the
outflow segment is positioned at its right and posterior side, while
the septal endocardial ridge is situated leftward and anterior. For
orientation, the diaphragmatic surface of the embryonic heart is
considered to be horizontal and the plane of the atrioventricular
orifices is considered to be vertical.
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Formation of the Right Ventricular Inlet (Carnegie Stage 15 to 17: 35 to 44 Days of Development)
Septation of the ventricles occurs during Carnegie stages 15 to 20, that is, between 5 and 7.5 weeks of gestation. Before septation, the atrioventricular canal is positioned entirely over the embryonic left ventricle, which, in turn, has direct access to the embryonic right ventricle through the primary interventricular foramen. The right atrium, therefore, has access to the right ventricle only via the cavity of the left ventricle, although the walls are continuous in the roof of the primary interventricular communication. Hence, the right atrioventricular junction must develop from part of the myocardial wall of the atrioventricular canal together with the surroundings of the primary interventricular foramen. Using an antibody that identifies the myocardial cells surrounding the primary interventricular foramen,11 we were able to define the myocardial remodeling of the lesser curvature of the ventricular loop that accompanies the formation of the right atrioventricular connection.9 Concurrent with the development of the right atrioventricular connection, a ridge forms from the ventricular myocardium that, internally, marks the boundary between the initial atrioventricular canal and the developing right ventricle (Figs 1A
and 2). Inferiorly, the ridge merges
with the ventricular trabeculations and the crest of the ventricular
septum. The pattern of staining with GlN2 maps this site as the
primordium of the right bundle branch of the ventricular conduction
system (not shown in the present figures but described previously
in detail11 ). Superiorly, the ridge becomes effaced as it
approaches the myocardium in the lesser curvature that separates the
atrioventricular canal from the outflow segment.
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, tricuspid gully complex.
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Accompanying the
extensive anterior and superior growth of the right
ventricle occurring in week 6, the myocardial ridge enlarges to form a
thin myocardial shelf that guards the inferior margin of the developing
right atrioventricular connection (Fig 3). Posteriorly,
the shelf is continuous with the wall of the expanded atrioventricular
canal, whereas medially, it is continuous with the crest of the
ventricular septum. Anteriorly, it extends medially to just beyond the
point of branching of the primordium of the atrioventricular (His)
bundle into the right bundle branch (Fig 3B, 3C,
and 3J) and laterally
to the lesser curvature of the heart tube (Fig 3B and
3D). The shelf
becomes more prominent during the 17th stage, when it becomes a
myocardial gully that funnels atrial blood beneath the myocardium of
the lesser curvature toward the middle of the cavity of the developing
right ventricle.
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, ring of GlN2-positive cardiomyocytes. Other abbreviations
as in previous figures.
Between Carnegie stages 15 and 17, the lumen of the
atrioventricular canal is occupied centrally by a large posteroinferior
and a somewhat smaller anterosuperior endocardial cushion. The
posteroinferior cushion rests on the developing muscular ventricular
septum but does not extend beyond the site of bifurcation of the
developing ventricular conduction tissue as identified by the location
of GlN2-positive tissues. A small right lateral endocardial cushion is
seen that is continuous anteriorly with the parietal endocardial ridge
of the outflow segment (Fig 2A
). This lateral cushion ends
posteroinferiorly as a spur on the myocardial ridge demarcating the
junction of the atrioventricular canal with the right ventricle (Fig
2A
through 2C and 2F). The superior portion of the lateral cushion is
apposed to the anterosuperior cushion (Fig 2A). Toward the end
of week
6, the funnel-like right atrioventricular connection is guarded
medially by the posteroinferior endocardial cushion inferiorly and by
the anterosuperior endocardial cushion superiorly, while it is guarded
laterally by the musculature of the atrioventricular canal inferiorly
and by the right lateral cushion superiorly (Fig 3D).
Formation of the Valvar Components (Carnegie Stages 18 to 20: 45 to
52 Days of Development)
The ventricles continue to increase in size
apically during week 7
of development. With this increase in ventricular size, the orifice of
the developing tricuspid valve appears to move toward the ventricular
base (compare Fig 1A and 1C). A conical group of
trabeculations, with
its apex attached to the anteroinferior boundary of the tricuspid gully
and its base to the free lateral wall of the right ventricle (Fig
1B),
condenses to form the primordium of the anterior papillary muscle. The
myocardial gully itself is also seen to be connected to the ventricular
wall by numerous trabeculations (Fig 1C). The floor of the
myocardial
gully becomes fenestrated (Fig 4H), creating, in
addition to the existing anterior ventricular orifice, an inferior
orifice for the tricuspid funnel (Fig 4I through 4K). Between
these two
outlets, the band of myocardium forming the anterior free border of the
myocardial gully and containing the right bundle branch becomes
recognizable as the developing septomarginal trabeculation.
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During this
seventh week, fusion occurs (Fig 4C and 4D) of
those
portions of the right lateral and anterosuperior endocardial cushions
initially seen in apposition beneath the lesser curvature (Figs
2A and 3D). As a result, the parietal
endocardial ridge of the outflow segment
appears to split beneath the lesser curvature into the right lateral
cushion laterally and into the anterosuperior cushion medially. The
parietal and septal endocardial ridges themselves also begin to fuse to
form the septum of the outflow segment (Fig 1C through 1E), but
in
addition, they expand in an apical direction, particularly during week
8 (compare Fig 1D and 1G). This apical growth of
the fused ridges
proceeds anteriorly to the right lateral cushion and the adjacent part
of the anterosuperior cushion. These structures, therefore, while
retaining their position near the lesser curvature, come to lie on the
posteroinferior (atrial) aspect of the newly formed outlet
("conus"16 17 ) septum (Fig
5). The
intraventricular part of this outlet septum, in consequence, becomes
plastered onto the myocardium of the lesser curvature (the
ventriculoinfundibular fold18 ) to form the anterosuperior
wall of the tricuspid funnel (Fig 1C, 1E, and
1F). Shortly after
fusing, the newly formed outlet septum and the adjacent part of the
right lateral cushion become populated with myocytes that grow in from
the neighboring myocardium (Fig 5). The upper part of this
myocardialized segment of the endocardial ridges forms the outlet
component of the muscular ventricular septum that separates the
subaortic from the subpulmonary outlet.19 The lower,
intraventricular, part of the myocardializing structure is continuous,
via its contribution from the right lateral endocardial cushion, with
the lateral wall of the right ventricle (Fig 1C,
1E, and 1F). Because
all the blood coming from the right atrium passes beneath its leading
edge, it can now be identified as the supraventricular crest (Fig
1G).
Subsequent to these changes, the interventricular foramen and the
bifurcation of the ventricular conduction system are the landmarks of
the junction of the muscular ventricular septum with the endocardial
cushions and with the developing supraventricular crest (Fig 5D
through
5I). At the point of closure of the foramen, the tricuspid valve
remains in a primitive stage of formation. The subsequent development
of its leaflets occurs in the stage of early fetal life.
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, areas
of myocardialization of endocardial tissue. Other abbreviations as in
previous figures.
Formation of Freely Movable Valvar Leaflets (8 to 16 Weeks of
Development)
Coincident with a coarsening of trabeculations, the
ventricular
cavity expands alongside and behind the tricuspid funnel
(compare Fig 1C, 1F, and 1H). In
consequence, the developing tricuspid
valve becomes a more distinct entity, with the anterior papillary
muscle and the septomarginal trabeculation becoming increasingly
well-defined structures (Fig 1I and 1K). At the
same time, the inferior
orifice of the tricuspid funnel gradually widens (Fig 1J and
1L).
It is delamination from the underlying myocardium
during weeks 8
through 12 that characterizes formation and liberation of the valvar
leaflets. The inferior leaflet is formed in this fashion from the
lateral and inferior wall of the myocardial gully. The site of the
anterior papillary muscle identifies the position of the anterolateral
boundary of the gully and, hence, the anterior boundary of the inferior
leaflet. Its atrial aspect is covered by tissue derived from the
expanding lateral endocardial cushion. After the delamination of the
inferior leaflet, which is completed in week 8 (Figs 1H and
5D through
5I), the ventricular cavity continues to expand into the muscular
ventricular septum beneath the posteroinferior endocardial cushion.
This delamination heralds the formation of the septal (medial) leaflet
of the valve, a process that commences inferiorly in week 9 and
progresses in an anterosuperior direction (Fig 6B and
C). The delamination occurs within the myocardium, but
the newly formed septal leaflet retains the tissue of the
posteroinferior endocardial cushion on its atrial aspect, with the
myocardial tissue forming its ventricular aspect (Fig 6E and
6F).
Delamination does not reach the medial papillary muscle until week 10,
some time after this muscle has become identifiable at the medial
margin of the anterosuperior leaflet (Fig 6A). The process of
delamination proceeds only to the site of the right bundle branch and,
hence, involves only myocardium covered by the posteroinferior
endocardial cushion.
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The anterosuperior leaflet is formed from the
supraventricular crest,
which, as already described, develops from the intraventricular part of
the muscularized outlet septum and carries portions of the right
lateral cushion and the anterosuperior cushion on its atrial aspect
(Fig 5). As with the other two leaflets, further development
proceeds
by a superior continuation of the delamination of the lateral wall of
the myocardial gully into the myocardium of the supraventricular crest
(Fig 5C; compare Fig 1G and 1J).
The anterosuperior leaflet becomes a
well-defined and freely movable structure by week 11. Its medial margin
is then supported by the medial papillary muscle, and its lateral
margin is tethered by the anterior papillary muscle.
The endocardial
cushion tissue and the myocardium contribute about
equally to the freely movable valvar leaflets (Fig 6). The
endocardial
cushion tissue provides the smooth endocardial lining on the atrial
side of the leaflets. The myocardial origin of the ventricular aspect
of the leaflets guarantees their continuity with the ventricular
trabeculations and, with maturation, becomes the tension apparatus,
transforming into fibrous tissue during month 4 of development. The
anterior papillary muscle, nonetheless, is first identified at 7 weeks.
The medial papillary muscle is developed from the medial (septal)
margin of the fused and myocardialized endocardial ridges and is
separate from the developing septal leaflet. Only when the septal
leaflet is completely delaminated at 12 weeks does it develop its
commissure with the anterosuperior leaflet. The posterior papillary
muscle complex remains ill defined, even at this stage.
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Developmental Origin of the Leaflets of the Tricuspid Valve
Before septation, the right atrium has access to the right ventricle only via the cavity of the left ventricle. The formation of the tricuspid valve, therefore, occurs in two phases. The first phase involves the development of the connection of the right atrium with the right ventricle, whereas the second phase involves the formation of the valvar leaflets with their tension apparatus. In a previous study, we showed how the formation of the right atrioventricular connection itself is dependent on the remodeling of the embryonic interventricular junction that accompanies the process of cardiac septation.9 In the present study, we have established that the leaflets of the tricuspid valve develop more or less equally from two components, namely, the ventricular musculature and the endocardial tissues of the atrioventricular canal and the outflow segment. Furthermore, the valve was found to develop from two building blocks, the so-called tricuspid gully complex and the fused ridges that divide the outflow segment.2 16
Tricuspid Gully
The remodeling of the tissues of the
right atrioventricular
junction produces a myocardial gully that guards the inferior portion
of the ventricular inlet and directs atrial blood toward the middle of
the right ventricle. Staining with the GlN2 antibody reveals that the
precursor of the right bundle branch demarcates the position of the
anterior free boundary of this gully, while the simultaneous
development of the anterior papillary muscle complex marks its
anterolateral free boundary. As early as week 6 of development,
therefore, the anterior ledge of this tricuspid gully can be identified
as the precursor of the septomarginal trabeculation. Two points should
be made concerning this configuration. First, the gully originally has
only an anterior ventricular orifice pointing toward the developing
outflow tracts. A new inferior orifice develops in the floor of the
gully during week 7. Interestingly, separate anterior and inferior
valvar orifices can persist as characteristic morphological features of
the so-called double-orifice tricuspid valve.20 Second,
when the septomarginal trabeculation becomes prominent with the
appearance of the inferior ventricular orifice, it is attached
relatively high on the septum. Only gradually does it descend toward
the apex to attain its definitive position around week 10.
Our analysis shows that the inferior and septal (medial) leaflets of the tricuspid valve develop from the tricuspid gully. The inferior and lateral myocardial wall of the gully, together with the right lateral endocardial cushion, form the inferior leaflet, while the septal leaflet is formed from the muscular ventricular septum together with the posteroinferior endocardial cushion. From the stance of the myocardial delamination, the formation of these leaflets is a single and continuous process, with the formation of the septal leaflet following temporally on that of the inferior leaflet. The precise mechanism of delamination with the myocardium remains to be established, but it may very well be similar to that underscoring the expansion of the ventricular cavity elsewhere, namely, by expansion of preexisting intertrabecular spaces.2 Such spaces already exist in the stage 15 embryo, not only between the ventricular trabeculations but also between the crest and the stem of the ventricular septum.
Endocardial Ridges of the Outflow
Segment
In the early embryonic heart, the myocardium of the lesser
curvature (the ventriculoinfundibular fold18 ) separates
the inlet and outlet components of the right ventricle superiorly.
Toward week 7 of development, these components become additionally
separated by a frontally oriented partition that arises as a result of
the fusion of the endocardial ridges of the outflow
segment.17 21 The lower (conal) portion of these
ridges,
together with the adjacent part of the right lateral cushion, becomes
transformed in its greatest part into myocardium. Although the
advancement of a dynamic process such as ingrowth of cardiomyocytes
from the surrounding myocardium into endocardial cushion tissue can
only be inferred from the analysis of a temporal series of staged
embryonic hearts, several facts support our conclusions concerning
myocardialization. First, the myocardial tissue separating the
subaortic and subpulmonary portions of the outflow segment are derived
from the tissues formed by fusion of the endocardial ridges. Second,
the myocardialization of the endocardial ridges starts well before
their fusion, as shown immunohistochemically by colocalization of
slender myocardial cells and endocardial tissue (Fig 4). Third,
throughout this period, the endocardial cushion tissue retains a
thickness of 
0.1 mm (compare Figs 4 and 6)
and decreases in size
only relatively as a result of the pronounced growth of the ventricular
myocardium.22 The upper part of this newly formed
myocardium is incorporated to form the outlet component of the muscular
ventricular septum. The lowermost, intraventricular, part is interposed
between the tricuspid gully and the subpulmonary part of the outflow
segment and contributes both to the supraventricular crest and to the
anterosuperior leaflet of the tricuspid valve.
Our study shows, therefore, that the anterosuperior leaflet of the tricuspid valve develops from this lower, intraventricular, part of the fused ridges septating the outflow segment. This myocardialized structure carries the tissues of the right lateral cushion, and the anterosuperior cushions are carried on the atrial surface. These conclusions are based on several further facts. First, the lower, intraventricular, part of the endocardial ridges, subsequent to fusion and apical growth, forms the new anterosuperior boundary of the tricuspid funnel. Second, via the right lateral endocardial cushion, the parietal component of the fused ridges is continuous with the anterolateral boundary of the tricuspid gully. Third, the anterolateral boundary of the tricuspid gully is marked by the position of the anterior papillary muscle, which, in turn, marks the junction between the anterosuperior and inferior leaflets.19 Temporally, the process of delamination of the anterosuperior leaflet from the developing supraventricular crest follows that of the inferior leaflet, beginning anterolaterally as a superior expansion of the space around the tricuspid gully. The medial papillary muscle develops solely from the medial (septal) margin of the septal component of the fused endocardial ridges and initially has no connection with the developing septal leaflet. The development of this topographical relation (the anteroseptal commissure) depends entirely on the completion of the process of delamination. A cleft sometimes seen between the leaflets at the site of the membranous septum19 supports our interpretation that the two components derive from different sources.
Endocardial Cushion Tissue and the Formation of
the Valvar
Leaflets
Although it was initially held that the endocardial cushions
contributed markedly to the valvar leaflets, various investigators more
recently have stressed the importance of the invagination of the
atrioventricular junction in the formation of the inferior and septal
leaflets.1 5 7 23 According
to this concept, both the
epicardial tissue of the atrioventricular groove and the atrial
myocardium make contributions to the valvar leaflets. The
atrioventricular endocardial cushions, in contrast, are demoted to a
minor role, being held, at best, to form only the free edges of the
leaflets and the nodules of Albinus. Our studies show, in contrast,
that even though the wall of the atrioventricular canal continues
anteriorly into the tricuspid gully, the site of the
immunohistochemical visualization of the GlN2-positive atrioventricular
ring bundle (which identifies the ventricular boundary of the
anatomically right atrium9 ) shows unequivocally that the
tricuspid gully is made up entirely of ventricular myocardium. Our
immunohistochemical markers also show unequivocally that neither the
tissue of the atrioventricular groove nor the atrial myocardium makes
any substantial contribution to the leaflets of the tricuspid valve.
The development of the leaflets and their tension apparatus cannot,
therefore, be explained simply on the basis of invagination of the
atrioventricular junction together with undermining of the ventricular
myocardium.7 23 Without invoking this process, it is
difficult to see how it can still be argued that the cushions form only
the free edges of the leaflets. Thus, although the presently
prevailing opinion2 3 22 24
is that the cushions function
mainly as a "glue" between the muscular components of the septal
structures during cardiac septation and that their material
contribution to the valves is minimal,2 23 our study
shows
that the contributions of endocardial cushion tissue and myocardium are
approximately equal at the time of delamination, the endocardial
cushion tissue forming the atrial face of the developing leaflet.
Tricuspid Valve and Evolutionary Conservation
In
birds and in some reptiles, the inferior and anterosuperior
leaflets of the tricuspid valve together form a single, sickle-shaped,
permanently muscular structure that can be described as the "great
mural leaflet."25 26 Its anterosuperior and
inferior
portions are demarcated by the position of the anterior papillary
muscle. In these species, the septal leaflet is hardly developed. This
arrangement is remarkably reminiscent of the architecture of the
tricuspid gully as it is seen in the mammalian embryo toward the end of
the embryonic period. The developmental formation of the components of
the tricuspid valve in chicks is also very similar to that in mammalian
embryos (Lamers, unpublished observations). The fact that the formation
of the tricuspid valve in higher vertebrates follows an evolutionarily
conserved pattern, therefore, further strengthens our earlier
conclusion, based on the comparison of cardiac septation,9
that morphogenetic programs in the heart are basically similar in all
higher vertebrates. This is particularly relevant for the use of either
mammalian or avian embryos as models in experimental studies.
Implications for Cardiac Malformations
If developmental
arrest by a perturbation of the morphogenetic
program is to be considered a frequent cause of congenital
malformations,9 27 then the developmental pathology
of the
tricuspid valve should be understandable on the basis of relatively few
developmental disruptions. Perturbations of the development of the
inlet to the right ventricle have already been discussed.9
Our present observations, nonetheless, are relevant to both
Ebstein's malformation and the varying topography of the right
ventricular attachment of the anterosuperior bridging leaflet in
atrioventricular septal defects.
Ebstein's Malformation
In Ebstein's malformation, the attached margin of the septal and
inferior leaflets of the tricuspid valve are displaced apically, but
never beyond the junction of the ventricular inlet with the apical
trabecular component. The leaflets themselves are often said to be
"plastered" onto the right ventricular myocardium. The hinge
point of the anterosuperior leaflet from the supraventricular crest, in
contrast, is only rarely affected. But with increasing degrees of
anatomic severity of malformation, the fibrous transformation of this
leaflet from its muscular precursor remains incomplete. This
developmental perturbance can transform the valvar orifice into a
keyhole.28 29 30
This part of the
spectrum of Ebstein's malformation is reminiscent of
the topography described for the developing tricuspid valve during week
8 of development (Fig 1). Although a deficiency in the process
of
delamination was previously linked to the persistent attachment of the
septal and inferior leaflets,27 28 the limitation of
the
downward "displacement" of the valvar attachment to the junction
of the inlet and the trabecular zone can now be interpreted as
representing the anterior limit of the myocardial tricuspid gully.
The pathological expansion of the space contained within the tricuspid
gully in Ebstein's malformation is known as "atrialization of the
inlet." The observed "keyhole" configuration of the
anterosuperior leaflet can be understood on the basis of persistence of
the anterior orifice of the tricuspid funnel.
Atrioventricular Septal Defects
Among the hallmarks
of the atrioventricular septal defects
("endocardial cushion defects") are the retention of a common
atrioventricular valve with five leaflets, including its characteristic
anterosuperior and posteroinferior bridging leaflets and, in some
variants, the attachment of the anterosuperior bridging leaflet within
the right ventricle to the right anterior papillary muscle. This latter
feature is one end of a spectrum of morphology, minimal bridging being
associated with attachment of the anterosuperior bridging leaflet high
on the ventricular septum and increasing bridging with a downward
movement of the site of attachment of the bridging leaflet toward the
right anterior papillary muscle and a concomitant decrease in the size
of the anterosuperior leaflet of the right
ventricle.3 31 32 Again, the basic
morphology of this
syndrome is directly comparable to our embryonic description. The
precursor of the anterosuperior bridging leaflet, the anterosuperior
endocardial cushion, initially, at week 6, guards the anterior
circumference of the tricuspid funnel (Fig 4). It becomes
attached to
the right lateral endocardial cushion and to the myocardializing part
of the fused endocardial ridges of the outflow segment in weeks 7 and 8
and via these structures, with the anterior papillary muscle complex.
If the site of its anterior attachment (the fused endocardial ridges)
is displaced to the right, then the anterosuperior cushion has to
follow this displacement. Significantly, free floating of this leaflet,
together with attachment to the anterior papillary muscle, is almost a
universal finding when atrioventricular septal defect is found with
either coexisting tetralogy of Fallot or double-outlet right ventricle,
lesions in which the fused endocardial ridges remain right ventricular
structures. It also seems to us that the morphology of the bridging
leaflets underlines the importance of the cushions as morphogenetic
structures in their own right rather than merely acting as an embryonic
"glue."2 4 24
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Acknowledgments |
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Dr Virágh was supported by TEMPUS Individual Mobility Grant HUT-218-92.
Received July 5, 1994; accepted August 9, 1994.
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References |
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