Ann Thorac Surg 2005;79:1797-1804
© 2005 The Society of Thoracic Surgeons
Review
Development of the Atrioventricular Valves: Clinicomorphological Correlations
Mazyar Kanani, MRCSa,*,
Antoon F.M. Moorman, PhDb,
Andrew C. Cook, PhDa,
Sandra Webb, PhDc,
Nigel A. Brown, PhDc,
Wouter H. Lamers, MD, PhDb,
Robert H. Anderson, MD, FRCPatha
a Institute of Child Health, London, United Kingdom
b Department of Anatomy and Embryology, Academic Medical Centre, Amsterdam, the Netherlands
c Department of Basic Medical Sciences, Anatomy and Developmental Biology, St. George's Hospital Medical School, London, United Kingdom
Accepted for publication June 25, 2004.
* Address reprint requests to Dr Kanani, Cardiac Unit, Institute of Child Health, 30 Guilford St, London WC1H 1EJ, UK; (E-mail: m.kanani{at}ich.ucl.ac.uk).
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Abstract
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The atrioventricular valves are formed from a complex arrangement of an annulus and leaflets, supported by a subvalvar apparatus that is composed of tendinous cords and papillary muscles. Although much has been said and written about their development, the exact nature of the process has yet to be fully elucidated. We believe that this is vital, since unraveling this complex process holds the key to the understanding of many of the congenital malformations that may afflict the valves.
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Introduction
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The atrioventricular valves are complex entities made up of the annulus, the leaflets, and the supporting tension apparatus, the latter comprising the tendinous cords and the papillary muscles. The leaflets are hinged from the annulus, which is an integral part of the atrioventricular junction. In the definitive heart, the tricuspid and mitral valves are separated by septal structures, which are absent in hearts having a common atrioventricular junction.
To understand the development of these valvar complexes, particularly the presence in malformed hearts of a common atrioventricular valve, valvar formation must be examined in the context of cardiac development as a whole. In addition to cardiac septation, interdependent and mutually generative processes closely linked to the formation of the atrioventricular valves include the mechanisms of connection of the right atrium to the right ventricle, and incorporation of the subaortic outlet into the left ventricle. In this review, we will seek to integrate these themes as we describe how an initially unseptated and valveless tube is changed into a complex four-chambered organ, with the chambers and arterial trunks separated by a system of one-way valves, concentrating attention on the atrioventricular valves. We will also speculate on how normal development can be perturbed to produce some of the lesions seen in modern surgical practice.
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Primary Heart Tube
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After the third week of gestation, a lumen forms within the primary endocardium of the heart that, when enveloped by myocardial cells formed in the primary cardiac crescent, becomes converted into the initially valveless and inverted Y-shaped tube that initiates the circulation [1]. With time, this primordium will become the larger part of the left ventricle and part of the atrial chambers. The future right ventricle and outflow tract, along with the remainder of the left ventricle and the atriums, take their origin from a spatially distinct area, known as the secondary heart field [2–4], with the cells migrating at a later stage from this area to become integrated within the arterial and venous poles of the developing heart tube [5].
The atrioventricular junction, the seat of the future atrioventricular valves, comes into prominence following rightward looping of the heart tube, after the 25th day of gestation of development. Looping occurs as the initial attachment of the tube to the body wall disappears, this connection being the so-called dorsal mesocardium [6]. The atrial remnant of this structure then serves as the site of entry of the pulmonary vein and the vestibular spine during the 7th week [7]. As we will see, the spine then plays a crucial role in atrial septation. Subsequent to looping, the developing heart takes on the more characteristic three-dimensional appearance of the mature organ. By the end of the 5th week, the developing ventricles have become visible as pouches that balloon from the primary tube, with the primordium of the muscular ventricular septum also being visible (Fig 1). At this stage of development, the primordial left ventricle supports the larger part of the circumference of the atrioventricular canal, while the developing right ventricle provides most of the muscular support for the developing ventricular outflow tract. The lumen of the atrioventricular canal is largely occupied by two large mesenchymal masses, the superior and inferior atrioventricular endocardial cushions [8, 9]. Initially unfused, the cushions face each other within the canal, leaving slits on each side between their edges and the lateral margins of the canal. These slits will eventually expand to become the right and left atrioventricular junctions. Even before fusion of the cushions, the right-sided slit provides continuity between the developing right atrium and right ventricle through the lumen of the primary heart tube, with the inner curve of the tube forming the roof of this communication, which is called the primary interventricular foramen (Fig 1). Studies of human embryos stained with an antibody raised to the nodose ganglion of the chick (GlN2 [Fig 2]), revealed that the myocardium surrounding the foramen is distinct from the remainder of the primary myocardium with part becoming transformed into the atrioventricular node and bundle [10, 11]. It is expansion and remoulding within this region of primary myocardium, known as the primary ring, that provides the substrate for formation of first the right ventricular inlet, and then the tricuspid valve.
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Fig 1. This section comes from a human embryo at Carnegie stage 14, just subsequent to looping and "ballooning" to form the apical ventricular components. The atrioventricular canal (curly bracket) is aligned predominantly with the developing left ventricle (large white arrow), albeit that there is already a direct communication from the right atrium to the developing right ventricle (small white arrow). The atrioventricular canal musculature will be sequestrated on the atrial side of the atrioventricular junctions, which form at the site of the small black arrows. Note that the right atrioventricular junction (double black arrows) is also the inner heart curvature, and forms the roof of the primary ventricular foramen. The crest of the muscular ventricular septum is noted (black star). (LV = left ventricle.)
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Fig 2. This illustration, modified from the reconstruction of a human heart at Carnegie stage 14, illustrates the location of the ring of musculature of the primary heart tube delineated by reaction to an antibody to the nodose ganglion of the chick [10]. This is the myocardium of the so-called "primary ring." (AV = atrioventricular; GIN2 = antigen to chick nodose ganglion.)
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This right side of the atrioventricular canal expands across the developing muscular ventricular septum as the superior and inferior cushions fuse within the lumen of the canal, their rightward margins then becoming draped across the crest of the septum (Fig 3). Parts of the fused cushions, nonetheless, remain to the left side of the septal crest, with their bulk protruding into the cavity of the left ventricle (Fig 4), where they will form the aortic leaflet of the mitral valve. The parts spanning the crest of the developing muscular septum, which are the first parts to fuse, will form the larger part of the membranous septum. This structure, along with contributions from the outflow cushions, will eventually partition the aorta into the left ventricle [1].
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Fig 3. The first step in remoulding of the primary ring occurs concomitant with appearance of the primary ventricular septum. As the apical parts of the ventricle balloon form the primary tube, the inferior part of the primary foramen deepens to form the right ventricular inlet component between the right atrium and the dorsal part of the developing right ventricle. At the same time, the cushions within the atrioventricular canal become draped across the inferior part of the forming ventricular septum. (GIN2 = antigen to chick nodose ganglion.)
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Fig 4. This scanning electron micrograph demonstrates the arrangement of the atrioventricular cushions at 7 weeks of development. The short-axis view of the heart from beneath depicts that the larger parts of the cushions, still unfused, are located within the left ventricle. Note also the beginning of delamination of the leaflets of the tricuspid valve from the parietal ventricular wall (dotted white line). At this stage the primary orifice of the developing tricuspid valve (double-headed arrow) is parallel to the developing ventricular septum.
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Fate of the Primitive Atrioventricular Canal
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Fusion of the atrioventricular endocardial cushions during the sixth week of development divides the atrioventricular canal into the primordiums of the right and left atrioventricular junctions, to which the developing leaflets of the mitral and tricuspid valves will eventually be anchored. Septation of the canal by the cushions goes hand in hand with the beginnings of not only ventricular, but also atrial septation. The earliest indication of atrial septation is the downgrowth of the primary septum, or "septum primum," from the atrial roof. As it grows towards the cushions within the atrioventricular canal, this primary septum carries a cap of mesenchyme on its leading edge. At the same time, contiguous with the right margin of the dorsal mesocardial; connection, a further mass of mesenchyme grows into the heart at the level of the base of the developing atrial septum (Fig 1). This latter structure is the so-called "spina vestibuli," or vestibular spine, which is separate from the mesenchymal cap [7, 12, 13].
The tissue of the spine, together with the mesenchymal cap clothing the leading edge of the primary atrial septum, merges with the atrial margins of the fused atrioventricular endocardial cushions to close the primary atrial foramen, or "ostium primum." The vestibular spine itself then muscularizes to form the thick base of the atrial septum [13]. By this time, the initial musculature of the atrioventricular canal is becoming incorporated into the now divided atrioventricular junctions as the atrial vestibules, albeit that final separation of the musculature from the ventricular walls does not occur until much later in development, when the fibro-adipose tissues of the atrioventricular grooves separates the atrial and ventricular muscular segments at all sites other than the location of the bundle of His. The point of penetration of the bundle of His marks the site within the septal components of the initial atrioventricular canal musculature [14, 15].
Failure of fusion of the superior and inferior cushions is the process usually held responsible for producing atrioventricular septal, or "canal," defects [16]. Indeed, for many years this group of malformations was labeled as "endocardial cushion defects." Recent research, however, suggests that it is deficiency of the vestibular spine, rather than deficiency of a particular part of the muscular ventricular septum, that is responsible for the common atrioventricular junction, this feature being the hallmark of the malformations [17, 18]. Failure of this mesenchymal front to contribute to the base of the developing atrial septum permits the primary foramen to remain patent and, at the same time, ensures persistence of the common atrioventricular junction. When a valve is eventually formed in the setting of this common junction, it bears scant morphologic resemblance to the normal mitral and tricuspid valves. This is because the space between the bridging leaflets formed from the superior and inferior atrioventricular cushions is an integral part of the valvar orifice (Fig 5 [upper panel]). The location of this space reflects the arrangement seen very early during normal development (Fig 4). It is also the case that, subsequent to separation of the left atrioventricular junction, clefts of varying depth can be found in the aortic leaflet of the otherwise normally formed mitral valve (Fig 5 [lower panel]). Such clefts can also be found when the mitral valve straddles through a ventricular septal defect opening to the outlet of the right ventricle. Thus, although the zone of apposition found between the left ventricular components of the bridging leaflets in a heart with an atrioventricular septal defect with common atrioventricular junction, like the cleft of the aortic leaflet of an otherwise normal mitral valve, exists because of failure of fusion of the atrioventricular endocardial cushions, it is only the leftward tips of the cushions that have failed to fuse when there is an otherwise normally structured mitral valve.
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Fig 5. These illustrations, both taken from the apex of the left ventricle looking toward the ventricular outflow tract, contrast the morphologic arrangement of the zone of apposition (black arrow outlined in white) between the bridging leaflets in a heart with atrioventricular septal defect and common atrioventricular junction (upper panel) and the so-called "isolated cleft" (lower panel, black arrow outlined in white) in the otherwise normal mitral valve. Tendinous cords attach the edges of the "cleft" to the crest of the ventricular septum (small black arrows). The arrangement in the upper panel is comparable with the situation seen in the developing heart at 7 weeks, before formation of the discrete left atrioventricular junction.
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Development of the Mitral Valve
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Formation of the normal mitral valve not only requires division of the atrioventricular canal, but also cannot proceed until the developing aorta becomes committed to the left ventricle. In the definitive heart, almost always there is fibrous continuity between two of the leaflets of the aortic valve, and one of the leaflets of the mitral valve (Fig 6). The leaflet of the mitral valve in continuity with the aortic root can then be named the aortic leaflet, thus distinguishing it from the mural leaflet, which is hinged from the parietal atrioventricular junction. As we will see, these morphologic differences in the hinges of the leaflets reflect their developmental heritage.
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Fig 6. This section of the cardiac short axis, from a normal heart, illustrates the orientation of the definitive orifices of the mitral and tricuspid valves. Note that the septal leaflet of the tricuspid valve "hugs" the septum, while the subaortic outflow tract interposes between the septum and the aortic leaflet of the mitral valve. (TV = tricuspid valve.)
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The building blocks of the valvar leaflets are the endocardial cushions. We have already shown how, with formation of the muscular ventricular septum, the superior and inferior atrioventricular endocardial cushions become draped across its crest, but with part of their bulk remaining as a free-standing curtain within the left ventricular cavity (Fig 4). Having fused together, it is these left ventricular components of the superior and inferior cushions that form the aortic leaflet of the definitive mitral valve, albeit still with a cleft at their parietal margin (Fig 7). The mural leaflet of the valve, in contrast, is derived from a lateral cushion that forms within the parietal part of the lumen of the newly separated left ventricular inlet component. When first formed, at 5 weeks of development in the human, this lateral cushion is related to a smaller proportion of the developing left atrioventricular junction than are the fusing left ventricular components of the superior and inferior cushions (Fig 8 [left panel]). Formation of the definitive valve, therefore, requires reorientation of the newly separated left atrioventricular junction, which expands in inferior direction. This inferior reorientation occurs concomitant with incorporation of aorta into the outlet part of the left ventricle. Blood from the left ventricle initially reaches the developing aorta through the primary interventricular foramen, with the fused atrioventricular cushions forming the left ventricular border of the roof of this pathway. As the outflow cushion fuse, and muscularize to separate the subpulmonary infundibulum from the subaortic outlet, they also fuse with the crest of the muscular ventricular septum, thus walling the developing aortic valve into left ventricle. The aortic root then occupies the space that has appeared, concomitant with the expansion and reorientation of the left atrioventricular junction, between the ventricular septum and the fused left ventricular components of the atrioventricular cushions. This space forms a bay on the ventricular aspect of the atrioventricular cushions. When the aorta is first walled into this newly created bay within the left ventricle, the myocardium of the inner heart curve continues to separate the developing aortic valvar leaflets from the cushions fusing to form the aortic leaflet of the mitral valve (Fig 7 [upper panel]). Only subsequent to the completion of septation does this muscle disappear, thus establishing the definitive arrangement of fibrous continuity (Fig 6) between the aortic leaflet of the mitral valve and the noncoronary and left coronary leaflets of the aortic valve [2].
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Fig 7. (A) A longitudinal section of the developing left ventricle after the aorta has been walled into the ventricle. Note that the musculature of the inner heart curvature continues to separate the developing leaflets of the aortic and mitral valves (bracket). This muscular fold will not disappear until after the completion of septation. The contributions from both superior and inferior atrioventricular cushions to the developing aortic leaflet of the mitral valve are clearly seen, albeit that the tips have yet to fuse (star). (B) A scanning electron micrograph illustrating the comparable arrangement, and also revealing how the papillary muscles are formed by compaction of the trabecular layer of myocardium. The unfused tip of the endocardial cushions is noted (star). (LSCV = left superior caval vein.)
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Fig 8. These diagrams, redrawn from the study of Kim and colleagues [9], indicate the change in shape and orientation of the atrioventricular cushions in the developing human heart that occurs concomitant with expansion and separation of the initially common atrioventricular junction. Initially the orifice (left) of the developing mitral valve has a trifoliate configuration (white y), which becomes bifoliate (right) subsequent to expansion of the left atrioventricular junction. The star marks the expansion of the right atrioventricular junction (dotted black line) that occurs in combination with formation of the tricuspid gully.
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Expansion of the inferior quadrants of the left atrioventricular junction of necessity also involves growth of the parietal wall of the left ventricle, with comparable growth of the lateral cushion. Thus, by 8 weeks of development, the lateral cushion has grown to occupy two thirds of the circumference of the developing mitral valve (Fig 8 [right panel]). With this remoulding, the valvar orifice changes its shape from a slit to a crescent. Within the ventricle, the two ends of this expanded crescent are associated with compacting columns in the trabecular, or spongy, layer of the ventricular muscle. These columns, which will form the papillary muscles [19], are positioned to support not only the ends of the lateral cushion, but also the distal ends of the fused atrioventricular cushions (Fig 7). Contemporaneously, there is expansion of the junction between the trabecular myocardial layer that supports the lateral cushion and the compacting external layer of the ventricular myocardium, with the curtain of myocardium thus produced being continuous with the papillary muscles that are developing by compaction of the more distal parts of the trabecular layer (Fig 9). The layer of spongy myocardium that initially supports the lateral cushion, however, will subsequently disappear. As it does so, the endothelially derived lateral cushion itself becomes transformed into the mural leaflet of the mitral valve. The liberated myocardium that initially joined the cushion to the compacting papillary muscles will also disappear with time, the myocardial cells being replaced by fibrous tissue. A similar process occurs at the interface between the edges of the developing aortic leaflet and the tips of the papillary muscles, with fibrous tension apparatus eventually replacing the myocardium.
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Fig 9. This section, from a 6-week-old human heart, illustrates how the right ventricular inlet component (dotted line) is lined on the one side by the lateral cushion, which gives rise to the inferior leaflet of the valve, and on the other side by the septal leaflet, which is delaminating from the surface of the ventricular septum. Note the compaction of the papillary muscles of the mitral valve in the left ventricle (stars).
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Excessive or abnormal compaction of the trabecular layer of the developing ventricular myocardium is responsible for producing the so-called "parachute" deformity of the valve, either with a solitary papillary muscle supporting the entirety of the valvular complex, with a leash of cords fanning out from this single locus, or with incomplete formation of one of the two papillary trabecular columns [19, 20]. Failure of formation of the tendinous cords from the original myocardial primordiums results in the "hammock" or "arcade" lesions of the mitral valve, with the musculature extending from the edge of the leaflets to the tips of the papillary muscles. When Ebstein's malformation is seen in the setting of the morphologically mitral valve [21], it is the mural leaflet that is involved, because this is the leaflet that normally excavates from the parietal ventricular wall. Failure of excavation leaves the remnant of the mural leaflet hinged within the ventricle. The aortic leaflet is formed in normal fashion, because this leaflet is derived from the fused left ventricular components of the endocardial cushions without myocardial involvement.
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Development of the Tricuspid Valve
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When the atrioventricular canal is divided by the fusion of the atrioventricular cushions, the cavity of the left atrium is already in direct continuity with the cavity of the developing left ventricle, albeit the left junction deepens significantly subsequent with its inferior expansion. The situation is more complicated for the right atrioventricular orifice because, initially, the dorsal and right parietal margin of the atrioventricular canal has no direct connection with the parietal wall of the developing right ventricle (Fig 2). Posteroinferior expansion and remoulding of the junctional myocardium (Fig 3) is needed to bring the parietal wall of the right atrium into continuity with the parietal wall of the newly formed right ventricular inlet. As already discussed, this regional proliferation of right ventricular myocardium occurs within the area of the primary heart tube identified by Wessels and colleagues [10] as the primary ring, on account of its reaction to the GlN2 antibody raised to the nodose ganglion of the chick. The muscular conduit thus formed was initially termed the "tricuspid gully" [22], albeit that at this stage there are no leaflets of the tricuspid valve. The upstream boundary of the area in question is the developing atrioventricular junction. To one side is the developing muscular ventricular septum, with the fused atrioventricular cushions draped over its crest. The other side of the muscular valley is the newly forming parietal wall of the right ventricular inlet. As with the developing mitral valve, caudal and inferior expansion of the atrioventricular junction is associated with appearance of a new atrioventricular cushion on the parietal wall of the developing right ventricular inlet. Again replicating the changes seen on the left side, concomitant with appearance of the cushion, there is expansion of the lumen between the trabecular and compact layers of myocardium along the parietal ventricular wall. The separation of the trabecular layer sets the scene for formation of the anterosuperior and inferior leaflets of the tricuspid valve, along with their supporting tension apparatus. The third, septal, leaflet of the tricuspid valve, along with its tension apparatus, is delaminated at a much later stage from the right ventricular aspect of the developing ventricular septum.
It had initially been suggested that the proximal end of the parietal outflow cushion was involved in formation of the anterosuperior leaflet [22], but we now realize that this is not the case. It is the lateral and superior atrioventricular cushions that provide the endothelially derived tissue for both the anterosuperior and inferior leaflets. As with the mural leaflet of the mitral valve, it is the separation of the trabecular layer of myocardium from the compact layer of the ventricular inlet that lifts the cushions away from the myocardium, at the same time providing a myocardial layer connecting them to the papillary muscles, the latter structures formed by compaction within the trabecular layer. Increasing fenestration of this layer provides the scaffold for eventual formation of the tension apparatus.
The leaflets, along with their tension apparatus, are not all formed at the same time. It is the inferior and anterosuperior leaflets that emerge first, during the seventh week. The septal leaflet does not appear until appreciably later, during the tenth week, only completing its formation during the twelfth week [22]. Furthermore, when the muscular curtain forming the basis of the tricuspid valve is first seen (Fig 10 [left panel]), the orifice of the valve is no more than a slit pointing towards the subpulmonary outflow tract. Only subsequent to the excavation and delamination of the inferior and septal leaflets, and with fenestration of the trabecular musculature to produce the tension apparatus, do the definitive leaflets separate from one another, permitting the valvar orifice to expand, incorporating both primary and secondary orifices, so that it opens directly into the apical part of the right ventricle (Fig 10 [right panel]).
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Fig 10. These scanning electron micrographs depict the developing tricuspid valve at 7 weeks (left) and 8 weeks (right). Both are dissected by removing the anterior wall of the developing right ventricle. Note that the orifice of the valve initially points towards the subpulmonary infundibulum (left). Only subsequent to liberation of the anterosuperior and inferior leaflets does the valvar orifice open directly into the apical part of the right ventricle. (RV = right ventricle; Ant-sup = anterosuperior.)
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The initial relationship of the primary orifice of the valve provides an explanation for the nature of Ebstein's malformation when it afflicts the tricuspid valve (Fig 11). The hallmark of the malformation is failure of expansion of the ventricular lumen supporting, and consequent lack of delamination of, the inferior and septal leaflets from the walls of the right ventricular inlet component. The significant anatomical variations of surgical importance, nonetheless, reflect the structure of the leading edge of the anterosuperior leaflet [23]. This leaflet, in contrast to the septal and inferior leaflets, retains its normal junctional hinge from the atrioventricular junction along the supraventricular crest. In the most severe cases, however, the leading edge of the leaflet is attached in linear fashion along the distal margin of the right ventricular inlet, forming a partition, often unduly muscularized, between the inlet and the apical trabecular component. The valvar opening seen in this setting represents failure of formation of the secondary part of the valvular orifice, this being the part that provides access to the apical part of the right ventricle.
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Fig 11. A heart with the Ebstein malformation of the tricuspid valve, from the atrial and ventricular aspects. There is failure of delamination of the inferior and septal leaflets from the walls of the right ventricular inlet component. The black arrows represent the so-called keyhole orifice arising from the conjoint nature of the inferior and septal leaflets. (Left) Atrial aspect. (Right) Ventricular aspect.
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Comment
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It has long been known that the atrioventricular valves are formed in part from myocardium, and in part from mesenchymal elements [8]. Over the years, nonetheless, there has been debate about the precise contributions made by the different elements. Odgers [8] believed that the endocardial cushions were the sole source of the tissues of the leaflets and their tendinous cords. Van Mierop and coworkers [16] concurred, albeit pointing out that, although the endocardial cushions were the prime source of material, subsequent changes of the mesenchyme ensured that they made no lasting and recognizable contribution to the substance of the mature valves. Wenink and Gittenberger-de Groot [19] argued that cushions played a more passive role, acting as "glue" to hold together the delaminating myocardium. Drawing the consensus between these polarized inferences, Lamers and colleagues [22] believed that the tissue from the cushions formed the atrial side, while the myocardium gave rise to the ventricular aspect of the leaflet. This arrangement accounts well for the continuity of the leaflets with the papillary muscles, by the tendinous cords, and it is certainly the case that the tendinous cords are formed in a region that initially possessed a myocardial phenotype. The mechanisms of transformation from myocardium to fibrous tissue, nonetheless, have still to be determined. Work in our laboratories, as yet unpublished, suggests that the cells forming the definitive tendinous cords may never have possessed a myocardial phenotype. Still more work is needed, therefore, to demonstrate precisely how the layers of the developing tension apparatus become converted into fibrous tissues.
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Acknowledgments
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We are grateful to the British Heart Foundation for the support for this work. We would also like to thank Gemma Price for the preparation of the illustrations.
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References
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- Moorman A, Webb S, Brown NA, Lamers W, Anderson RH. Development of the heart: (1) formation of the cardiac chambers and arterial trunks Heart 2003;89:806-814.[Free Full Text]
- Anderson RH, Webb S, Brown N, Lamers W, Moorman A. Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks Heart 2003;89:1110-1118.[Free Full Text]
- Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez RA, et al. The outflow of the heart is formed from a novel heart-forming field Dev Biol 2001;238:97-109.[Medline]
- Kelly RG, Brown NA, Buckingham ME. The arterial pole of the mouse heart forms from Fgf10 expressing cells in the pharngeal mesoderm Dev Cell 2001;1:435-440.[Medline]
- Cai CL, Liang X, Shi Y, et al. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart Dev Cell 2003;5:877-889.[Medline]
- Webb S, Brown NA, Wessels A, Anderson RH. Development of the murine pulmonary vein and its relationship to the embryonic venous sinus Anat Rec 1998;250:325-334.[Medline]
- Webbs, Brown NA, Anderson RH. Formation of the septal structures in the normal mouse Circ Res 1998;82:645-656.[Abstract/Free Full Text]
- Odgers PNB. The development of the atrioventricular valves in man J Anat 1939;73:643-657.[Medline]
- Kim JS, Viragh S, Moorman AF, Anderson RH, Lamers WH. Development of the myocardium of the atrioventricular canal and the vestibular spine in the human heart Circ Res 2001;88:395-402.[Abstract/Free Full Text]
- Wessels A, Vermeulen JL, Verbeek FJ, et al. Spatial distribution of "tissue-specific" antigens in the developing human heart and skeletal muscleIII. An immunohistochemical analysis of the distribution of the neural tissue antigen G1N2 in the embryonic heart: implications for the development of the atrioventricular conduction system. Anat Rec 1992;232:97-111.[Medline]
- Lamers WH, Moorman AF. Cardiac septation: a late contribution of the embryonic primary myocardium to heart morphogenesis Circ Res 2002;91:92-103.
- Tasaka H, Krug EL, Markwald RR. Origin of the pulmonary venous orifice in the mouse and its relation to the morphogenesis of the sinus venosus, extracardiac mesenchyme (spina vestibuli), and atrium Anat Rec 1996;246:107-113.[Medline]
- Sharratt GP, Webb S, Anderson RH. The vestibular defect: an interatrial communication due to a deficiency in the atrial septal component derived from the vestibular spine Cardiol Young 2003;13:184-190.[Medline]
- Wessels A, Markman MW, Vermeulen JL, et al. The development of the atrioventricular junction in the human heart Circ Res 1996;781:110-117.
- Anderson RH, Webb S, Brown N, Lamers W, Moorman A. Development of the heart: (2) septation of the atriums and ventricles Heart 2003;89:949-958.[Free Full Text]
- Van Mierop LH, Alley RD, Kausel HW, Stranahan A. The anatomy and embryology of endocardial cushion defects J Thorac Cardiovasc Surg 1962;43:71-83.
- Webb S, Anderson RH, Lamers WH, Brown NA. Mechanisms of deficient cardiac septation in the mouse with trisomy 16 Circ Res 1999;84:897-905.[Abstract/Free Full Text]
- Blom NA, Ottenkamp J, Wenink AG, Gittenberger-de Groot AC. Deficiency of the vestibular spine in atrioventricular septal defects in human fetuses with Down syndrome Am J Cardiol 2003;91:180-184.[Medline]
- Wenink AC, Gittenberger-de Groot AC. Embryology of the mitral valve Int J Cardiol 1986;11:75-84.[Medline]
- Wenink AC, Gittenberger-de Groot AC, Brom AG. Developmental considerations of mitral valve anomalies Int J Cardiol 1986;11:85-101.[Medline]
- Thilenius OG, Vitullo D, Bharati S, et al. Endocardial cushion defect associated with cor triatriatum sinistrum or supravalve mitral ring Am J Cardiol 1979;44:1339-1343.[Medline]
- Lamers WH, Viragh S, Wessels A, Moorman AF, Anderson RH. Formation of the tricuspid valve in the human heart Circulation 1995;91:111-121.[Abstract/Free Full Text]
- Schreiber C, Cook A, Ho SY, Augustin N, Anderson RH. Morphologic spectrum of Ebstein's malformation: revisitation relative to surgical repair J Thorac Cardiovasc Surg 1999;117:148-155.[Abstract/Free Full Text]
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J. J. Vettukattil, T. Bharucha, and R. H. Anderson
Defining Ebstein's malformation using three-dimensional echocardiography
Interactive CardioVascular and Thoracic Surgery,
December 1, 2007;
6(6):
685 - 690.
[Abstract]
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A. F. Corno, M. J. Kocica, and F. Torrent-Guasp
The helical ventricular myocardial band of Torrent-Guasp: potential implications in congenital heart defects
Eur. J. Cardiothorac. Surg.,
April 1, 2006;
29(Suppl_1):
S61 - S68.
[Abstract]
[Full Text]
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Top
Abstract
Introduction
