162
ESTABLISHMENT AND
PATTERNING OF THE PRIMARY HEART FIELD
The vascular system appears in the middle of the third week, when the embryo is no longer able to satisfy its nutritional requirements by diffu-sion alone. Progenitor heart cells lie in the epiblast, immediately adjacent to the cranial end of the primitive streak. From there, they migrate through the streak and into the splanchnic layer of lateral plate mesoderm where they form a horseshoe-shaped cluster of cells called the pri-mary heart fi eld (PHF) cranial to the neural folds (Fig. 13.1). As the progenitor heart cells
Chapter 13
Chapter 13 Cardiovascular System 163
those in the PHF, resides in splanchnic meso-derm ventral to the posterior pharynx, and is responsible for lengthening the outfl ow tract (see Fig. 13.3). Cells in the SHF also exhibit lat-erality, such that those on the right side contrib-ute to the left of the outfl ow tract region and those on the left contribute to the right. This laterality is determined by the same signaling pathway that establishes laterality for the entire embryo (Fig. 13.2) and explains the spiraling nature of the pulmonary artery and aorta and ensures that the aorta exits from the left ven-tricle and the pulmonary artery from the right ventricle.
Once cells establish the PHF, they are induced by the underlying pharyngeal endoderm to form cardiac myoblasts and blood islands that will form blood cells and vessels by the process of vasculogenesis (Chapter 6, p. 75). With time, the islands unite and form a horseshoe-shaped endothelial-lined tube surrounded by myo-blasts. This region is known as the cardiogenic region; the intraembryonic (primitive body) cavity over it later develops into the pericardial cavity (Fig. 13.1B,C).
In addition to the cardiogenic region, other blood islands appear bilaterally, parallel, and close to the midline of the embryonic shield. These islands form a pair of longitudinal vessels, the dorsal aortae.
Nodal MAO
Lefty 1
Primitive node (FGF8) Primitive
streak
Cloacal membrane Oropharyngeal
membrane
FGF8 5HT
Nodal Lefty2 PITX2
Notochord (SHH)
Figure 13.2 Dorsal view of a drawing of a 16-day embryo showing the laterality pathway. The pathway is expressed in lateral plate mesoderm on the left side and involves a number of signal-ing molecules, includsignal-ing serotonin (5HT), which result in expres-sion of the transcription factor PITX2, the master gene for left sidedness. This pathway specifi es the left side of the body and also programs heart cells in the primary and SHFs. The right side is specifi ed as well, but genes responsible for this patterning have not been completely determined. Disruption of the pathway on the left results in laterality abnormalities, including many heart defects.
Neural tube Secondary heart field
Pharyngeal arches
Outflow tract
Figure 13.3 Drawing showing the SHF that lies in splanchnic mesoderm at the posterior of the phar-ynx. The SHF provides cells that lengthen the out-flow region of the heart, which includes part of the right ventricle and the outflow tract (conus cordis and truncus arteriosus). Neural crest cells, migrat-ing from cranial neural folds to the heart through pharyngeal arches in this region, regulate the SHF by controlling FGF concentrations. Disruption of the SHF causes shortening of the outflow tract region, resulting in outflow tract defects.
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Chapter 13 Cardiovascular System 165
Ectoderm Blood islands
Oropharyngeal membrane
Amniotic cavity Endoderm
Connecting stalk
Allantois
Cloacal membrane
Foregut
Pericardial cavity Heart
tube
Hindgut
Remnant of the oropharyngeal
membrane Cloacal
membrane
Heart tube Oropharyngeal
membrane
Vitelline duct Lung bud
Liver bud
Midgut
Allantois Yolk sac
A
C
B
D
Figure 13.4 Figures showing effects of the rapid growth of the brain on positioning of the heart. Initially, the cardiogenic area and the pericardial cavity are in front of the oropharyngeal membrane. A. 18 days. B. 20 days. C. 21 days. D. 22 days.
A B
C Endoderm
Angiogenic cell clusters
Splanchnic mesoderm
layer
Foregut Dorsal mesocardium
Intra-embryonic cavity
Neural crest Dorsal
aorta Myocardial
cells
Endocardial tube
Myocardium
Endocardial tube Cardiac
jelly Pericardial
cavity Neural crest
Figure 13.5 Transverse sections through embryos at different stages of development, showing formation of a single heart tube from paired primordia. A. Early presomite embryo (17 days). B. Late presomite embryo (18 days). C. Eight-somite stage (22 days). Fusion occurs only in the caudal region of the horseshoe-shaped tube (Fig. 12.4). The outfl ow tract and most of the ventricular region form by expansion and growth of the crescent portion of the horseshoe.
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166 Part II Systems-Based Embryology
Foregut
Endocardial heart tube
Foregut Dorsal aorta
Myocardial mantle Pericardial cavity
1st aortic arch
Oropharyngeal membrane
Dorsal mesocardium (breaking down)
Figure 13.7 Cephalic end of an early somite embryo. The developing endocardial heart tube and its investing layer bulge into the pericardial cavity. The dorsal mesocardium is breaking down.
FORMATION OF THE CARDIAC LOOP
The heart tube continues to elongate as cells are added from the SHF to its cranial end (Fig. 13.3).
This lengthening process is essential for normal formation of part of the right ventricle and the outfl ow tract region (conus cordis and truncus arteriosus that form part of the aorta and pulmo-nary artery), and for the looping process. If this lengthening is inhibited, then a variety of outfl ow tract defects occur, including DORV (both the aorta and pulmonary artery arise from the right ventricle), VSDs, tetralogy of Fallot (see Fig. 13.31), pulmonary atresia (see Fig. 13.33B), and pulmo-nary stenosis. The SHF is regulated by neural crest cells that control concentrations of FGFs in the area and pass nearby the SHF in the pharyngeal arches as they migrate from the hindbrain to septate the outfl ow tract (compare Fig. 13.3 with Fig. 13.27).
As the outfl ow tract lengthens, the cardiac tube begins to bend on day 23. The cephalic por-tion of the tube bends ventrally, caudally, and to the right (Fig. 13.8); and the atrial (caudal) por-tion shifts dorsocranially and to the left (Figs.
13.8 and 13.9A). This bending, which may be due to cell shape changes, creates the cardiac loop. It is complete by day 28. While the car-diac loop is forming, local expansions become visible throughout the length of the tube. The
Anterior intestinal portal Primitive pericardial cavity
Lateral body wall fold Septum
transversum
Hindgut
Posterior intestinal portal Intraembryonic
body cavity
Closing cranial neural fold
Figure 13.6 Frontal view of an embryo showing the heart in the pericardial cavity and the developing gut tube with the anterior and posterior intestinal portals.
The original paired tubes of the heart primordial have fused into a single tube except at their caudal ends, which remain separate. These caudal ends of the heart tube are embedded in the septum transversum, while the outfl ow tract leads to the aortic sac and aortic arches.
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Chapter 13 Cardiovascular System 167
bulboventricular sulcus (Fig. 13.8C), remains narrow. It is called the primary interventricu-lar foramen (Fig. 13.10). Thus, the cardiac tube is organized by regions along its craniocaudal axis from the conotruncus to the right ventricle to the left ventricle to the atrial region, respectively (Fig. 13.8A–C). Evidence suggests that organiza-tion of these segments is regulated by homeobox genes in a manner similar to that for the cranio-caudal axis of the embryo (see Chapter 6, p. 81).
At the end of loop formation, the smooth-walled heart tube begins to form primitive tra-beculae in two sharply defi ned areas just proximal and distal to the primary interventricular foramen (Fig. 13.10). The bulbus temporarily remains smooth walled. The primitive ventricle, which is now trabeculated, is called the primitive left atrial portion, initially a paired structure
out-side the pericardial cavity, forms a common atrium and is incorporated into the pericardial cavity (Fig. 13.8). The atrioventricular junc-tion remains narrow and forms the atrioven-tricular canal, which connects the common atrium and the early embryonic ventricle (Fig.
13.10). The bulbus cordis is narrow except for its proximal third. This portion will form the tra-beculated part of the right ventricle (Figs.
13.8 and 13.10). The midportion, the conus cordis, will form the outfl ow tracts of both ven-tricles. The distal part of the bulbus, the trun-cus arteriosus, will form the roots and proximal portion of the aorta and pulmonary artery (Fig.
13.10). The junction between the ventricle and the bulbus cordis, externally indicated by the
Anterior intestinal portal Primitive pericardial cavity
Septum transversum
Closing cranial neural fold Bulbus
cordis
Ventricle Atrium Sinus venosus
Aortic roots
Pericardium Pericardial cavity Bulboventricular sulcus
Left atrium
A B C
D
Figure 13.8 Formation of the cardiac loop. A. 22 days. B. 23 days. C. 24 days. D. Frontal view of the heart tube under-going looping in the pericardial cavity. The primitive ventricle is moving ventrally and to the right, while the atrial region is moving dorsally and to the left (arrows).
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Aortic roots Pericardial cavity
Bulbus cordis
Pericardium
Left ventricle Primitive left atrium
Primitive left atrium
Interventricular sulcus Trabeculated
part of right ventricle Primitive right atrium
Conus cordia
Truncus arteriosus
A B
Figure 13.9 Heart of a 5-mm embryo (28 days). A. Viewed from the left. B. Frontal view. The bulbus cordis is divided into the truncus arteriosus, conus cordis, and trabeculated part of the right ventricle. Broken line, pericardium.
Aortic arches Aortic
sac
Truncus arteriosus
II I
III IV VI
Conus cordis
Primitive right atrium
Primitive right ventricle
Primitive left atrium
Primitive left ventricle
Atrioventricular canal
Primitive interventricular
foramen Interventricular septum
Bulboventricular flange
Dorsal aorta
Figure 13.10 Frontal section through the heart of a 30-day embryo showing the primary interventricular foramen and entrance of the atrium into the primitive left ventricle. Note the bulboventricular fl ange. Arrows, direction of blood fl ow.
ventricle. Likewise, the trabeculated proximal third of the bulbus cordis is called the primitive right ventricle (Fig. 13.10).
The conotruncal portion of the heart tube, initially on the right side of the pericardial cavity,
shifts gradually to a more medial position. This change in position is the result of formation of two transverse dilations of the atrium, bulging on each side of the bulbus cordis (Figs. 13.9B, and 13.10).
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BMP 2,4 WNT inhibitors (crescent)
NKX-2.5
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170 Part II Systems-Based Embryology
(Fig. 13.12B). When the left common cardinal vein is obliterated at 10 weeks, all that remains of the left sinus horn is the oblique vein of the left atrium and the coronary sinus (Fig. 13.13).
As a result of left-to-right shunts of blood, the right sinus horn and veins enlarge greatly. The right horn, which now forms the only communication between the original sinus venosus and the atrium, is incorporated into the right atrium to form the smooth-walled part of the right atrium (Fig. 13.14).
Its entrance, the sinuatrial orifi ce, is fl anked on each side by a valvular fold, the right and left venous valves (Fig. 13.14A). Dorsocranially, the valves fuse, forming a ridge known as the septum spurium (Fig. 13.14A). Initially the valves are large, but when the right sinus horn is incorporated into the wall of the atrium, the left venous valve and the septum spurium fuse with the developing atrial septum (Fig. 13.14B). The superior portion of the right venous valve disappears entirely. The infe-rior portion develops into two parts: (1) the valve of the inferior vena cava and (2) the valve of the coronary sinus (Fig. 13.14B). The crista terminalis forms the dividing line between the original trabeculated part of the right atrium and the smooth-walled part (sinus venarum), which originates from the right sinus horn (Fig. 13.14B).
of HAND1 and HAND2, transcription factors that are expressed in the primitive heart tube and that later become restricted to the future left and right ventricles, respectively. Downstream effectors of these genes participate in the loop-ing phenomenon. HAND1 and HAND2, under the regulation of NKX2.5, also contribute to expansion and differentiation of the ventricles.
DEVELOPMENT OF THE SINUS VENOSUS
In the middle of the fourth week, the sinus veno-sus receives venous blood from the right and left sinus horns (Fig. 13.12A). Each horn receives blood from three important veins: (1) the vitelline or the omphalomesenteric vein, (2) the umbil-ical vein, and (3) the common cardinal vein.
At fi rst, communication between the sinus and the atrium is wide. Soon, however, the entrance of the sinus shifts to the right (Fig. 13.12B). This shift is caused primarily by left-to-right shunts of blood, which occur in the venous system during the fourth and fi fth weeks of development.
With obliteration of the right umbilical vein and the left vitelline vein during the fi fth week, the left sinus horn rapidly loses its importance
Sinuatrial junction
35 days
Left ventricle Right ventricle
Inferior vena cava
Right sinus horn Left
sinus horn Sinuatrial
fold Right vitelline
vein PCV ACV Sinuatrial
junction
24 days Right vitelline
vein Left umbilical
vein Left sinus
horn Common
cardinal vein
Bulbus cordis
PCV V CCV
UV VIT PCV
ACV
A
A
B
Figure 13.12 Dorsal view of two stages in the development of the sinus venosus at approximately 24 days. A and 35 days. B. Broken line, the entrance of the sinus venosus into the atrial cavity. Each drawing is accompanied by a scheme to show in transverse section the great veins and their relation to the atrial cavity. ACV, anterior cardinal vein; PCV, posterior cardinal vein; UV, umbilical vein; VIT V, vitelline vein; CCV, common cardinal vein. (See also Fig. 13.43.)
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Chapter 13 Cardiovascular System 171
Oblique vein of left atrium
Inferior vena cava Coronary sinus
Pulmonary veins Oblique vein of left atrium
Pulmonary artery
Aorta Superior vena cava
Coronary sinus
Figure 13.13 Final stage in development of the sinus venosus and great veins.
Inferior
endocardial cushion
Septum primum Septum
secundum Superior vena cava Sinus
venarum Crista terminalis
Valve of inferior vena cava Pulmonary
veins Septum
primum Interseptovalvular space
Septum spurium Right venous valve
Sinuatrial orifice Left venous
Valve of coronary sinus
A B
Figure 13.14 Ventral view of coronal sections through the heart at the level of the atrioventricular canal to show devel-opment of the venous valves. A. 5 weeks. B. Fetal stage. The sinus venarum (blue) is smooth walled; it derives from the right sinus horn. Arrows, blood fl ow.
FORMATION OF THE CARDIAC SEPTA
The major septa of the heart are formed between the 27th and 37th days of development, when the embryo grows in length from 5 mm to approxi-mately 16 to 17 mm. One method by which a septum may be formed involves two actively growing masses of tissue that approach each other until they fuse, dividing the lumen into two sepa-rate canals (Fig. 13.15A,B). Such a septum may also be formed by active growth of a single tis-sue mass that continues to expand until it reaches the opposite side of the lumen (Fig. 13.15C).
Formation of such tissue masses depends on syn-thesis and deposition of extracellular matrices and cell proliferation. The masses, known as endocar-dial cushions, develop in the atrioventricular and conotruncal regions. In these locations, they assist in formation of the atrial and ventricular
(membranous portion) septa, the atrioven-tricular canals and valves, (Fig. 13.16) and the aortic and pulmonary channels (See Fig.
13.19). Because of their key location, abnormali-ties in endocardial cushion formation may cause cardiac malformations, including atrial and ven-tricular septal defects (VSDs) and defects involv-ing the great vessels (i.e., transposition of the great vessels, common truncus arteriosus, and tetralogy of Fallot).
The other manner in which a septum is formed does not involve endocardial cushions. If, for example, a narrow strip of tissue in the wall of the atrium or ventricle should fail to grow while areas on each side of it expand rapidly, a narrow ridge forms between the two expanding portions (Fig. 13.15D,E). When growth of the expanding portions continues on either side of the narrow portion, the two walls approach each other and eventually merge, forming a septum (Fig. 13.15F).
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172 Part II Systems-Based Embryology
new crescent-shaped fold appears. This new fold, the septum secundum (Fig. 13.16C,D), never forms a complete partition in the atrial cavity (Fig. 13.16F,G). Its anterior limb extends downward to the septum in the atrioventricu-lar canal. When the left venous valve and the septum spurium fuse with the right side of the septum secundum, the free concave edge of the septum secundum begins to overlap the ostium secundum (Fig. 13.16E,F). The opening left by the septum secundum is called the oval fora-men (forafora-men ovale). When the upper part of the septum primum gradually disappears, the remaining part becomes the valve of the oval foramen. The passage between the two atrial cavities consists of an obliquely elongated cleft (Fig. 13.16E–G) through which blood from the right atrium fl ows to the left side (arrows in Figs.
13.14B and 13.16E).
After birth, when lung circulation begins and pressure in the left atrium increases, the valve of the oval foramen is pressed against the sep-tum secundum, obliterating the oval foramen and separating the right and left atria. In about 20% of cases, fusion of the septum primum and septum secundum is incomplete, and a narrow oblique cleft remains between the two atria. This condition is called probe patency of the oval foramen; it does not allow intracardiac shunting of blood.
Such a septum never completely divides the orig-inal lumen but leaves a narrow communicating canal between the two expanded sections. It is usually closed secondarily by tissue contributed by neighboring proliferating tissues. Such a sep-tum partially divides the atria and ventricles.
Septum Formation in the Common Atrium
At the end of the fourth week, a sickle-shaped crest grows from the roof of the common atrium into the lumen. This crest is the fi rst portion of the septum primum (Figs. 13.14A and 13.16A,B).
The two limbs of this septum extend toward the endocardial cushions in the atrioventricular canal. The opening between the lower rim of the septum primum and the endocardial cush-ions is the ostium primum (Fig. 13.16A,B).
With further development, extensions of the superior and inferior endocardial cushions grow along the edge of the septum primum, closing the ostium primum (Fig. 13.16C,D).
Before closure is complete, however, cell death produces perforations in the upper portion of the septum primum. Coalescence of these per-forations forms the ostium secundum, ensur-ing free blood fl ow from the right to the left primitive atrium (Fig. 13.16B,D).
When the lumen of the right atrium expands as a result of incorporation of the sinus horn, a
Ridge
Ridge
Septum A
D E F
B C
Formation of septum by growth of opposite ridges
Figure 13.15 A,B. Septum formation by two actively growing ridges that approach each other until they fuse. C. Septum formed by a single actively growing cell mass. D–F. Septum formation by merging two expanding portions of the wall of the heart. Such a septum never completely separates two cavities.
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Chapter 13 Cardiovascular System 173
Ostium primum
Atrioventricular canal Right endocardial
cushion
Septum primum Left endocardial
cushion
Interventricular foramen Endocardial
cushion Septum primum
Septum secundum Ostium secundum
RA
LA
RA LV
RA
LA
RV LV
RA
RV
LA
LV
Septum primum
Interventricular septum (muscular portion)
RA
LA
RV LV
Muscular portion of the interventricular system Septum secundum
Foramen ovale Membranous portion of the interventricular
septum
Valve of oval foramen Septum primum Region of cell death
Ostium primum Posterior
endocardial cushion
Anterior endocardial
cushion Interventricular
foramen Septum secundum
Ostium secundum Anterior and posterior endocardial
cushions fused Interventricular
foramen
Superior
vena cava Septum secundum
Valve of coronary sinus Valve of inferior
vena cava Valve of the foramen ovale (septum primum)
B A
D
F
G C
E
Cut line for A and C
RA
RV
Cut line for B and D Line
of sight
RA LA
RV LV
Cut line for E and F
Cut line for G
RA
RV
RA LA
RV LV
Line
of sight Line of sight Line
of sight
Figure 13.16 Atrial septa at various stages of development. A. 30 days (6 mm). B. Same stage as A, viewed from the right. C. 33 days (9 mm). D. Same stage as C, viewed from the right. E. 37 days (14 mm). F. Newborn. G. The atrial sep-tum from the right; same stage as F.
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174 Part II Systems-Based Embryology
Septum Formation in the Atrioventricular Canal
At the end of the fourth week, two mesenchy-mal cushions, the atrioventricular endocardial cushions, appear at the anterior and posterior borders of the atrioventricular canal (Figs. 13.18 and 13.19). Initially, the atrioventricular canal gives access only to the primitive left ventricle and is separated from the bulbus cordis by the bulbo (cono) ventricular fl ange (Fig. 13.10). Near the end of the fi fth week, however, the posterior extremity of the fl ange terminates almost mid-way along the base of the superior endocardial cushion and is much less prominent than before (Fig. 13.19). Since the atrioventricular canal enlarges to the right, blood passing through the atrioventricular orifi ce now has direct access to the primitive left as well as the primitive right ventricle.
In addition to the anterior and posterior endocardial cushions, the two lateral atrio-ventricular cushions appear on the right and left borders of the canal (Figs. 13.18 and 13.19). The anterior and posterior cushions, in the meantime, project further into the lumen and fuse, resulting in a complete division of the canal into right and left atrioventricular orifi ces Further Differentiation of the Atria
While the primitive right atrium enlarges by incorporation of the right sinus horn, the primi-tive left atrium is likewise expanding. Initially, a single embryonic pulmonary vein develops as an outgrowth of the posterior left atrial wall, just to the left of the septum primum (Fig. 13.17A).
This vein gains connection with veins of the developing lung buds. During further develop-ment, the pulmonary vein and its branches are incorporated into the left atrium, forming the large smooth-walled part of the adult atrium.
Although initially one vein enters the left atrium, ultimately, four pulmonary veins enter (Fig. 13.17B) as the branches are incorporated into the expanding atrial wall.
In the fully developed heart, the original embryonic left atrium is represented by little more than the trabeculated atrial appendage, while the smooth-walled part originates from the pulmonary veins (Fig. 13.17). On the right side, the original embryonic right atrium becomes the trabeculated right atrial appendage contain-ing the pectinate muscles, and the smooth-walled sinus venarum originates from the right horn of the sinus venosus.
Septum primum Septum
secundum Superior vena cava
Sinus venarum Crista
terminalis Pulmonary
veins Septum
primum Interseptovalvular space
Septum spurium Right venous
valve Sinuatrial
orifice
A B
Left venous valve
Figure 13.17 Coronal sections through the heart to show development of the smooth-walled portions of the right and left atria. Both the wall of the right sinus horn (blue) and the pulmonary veins (red) are incorporated into the heart to form the smooth-walled parts of the atria.
Left atrioventricular canal Inferior
endocardial cushion Lateral cushion
Right atrioventricular canal Superior endocardial
cushion Common
atrioventricular canal
Figure 13.18 Formation of the septum in the atrioventricular canal. From left to right, days 23, 26, 31, and 35. The initial circular opening widens transversely.
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Chapter 13 Cardiovascular System 175
cords (Fig. 13.20B). Finally, muscular tissue in the cords degenerates and is replaced by dense connective tissue. The valves then consist of con-nective tissue covered by endocardium. They are connected to thick trabeculae in the wall of the ventricle, the papillary muscles, by means of chordae tendineae (Fig. 13.20C). In this man-ner, two valve leafl ets, constituting the bicuspid (or mitral) valve, form in the left atrioventricu-lar canal, and three, constituting the tricuspid valve, form on the right side.
by the end of the fi fth week (Figs. 13.16B,D and 13.18).
Atrioventricular Valves
After the atrioventricular endocardial cushions fuse, each atrioventricular orifi ce is surrounded by local proliferations of mesenchymal tissue (Fig. 13.20A). When the bloodstream hollows out and thins tissue on the ventricular surface of these proliferations, valves form and remain attached to the ventricular wall by muscular
Aortic sac
VI IV III
Pulmonary channel Aortic arches
Left inferior truncus swelling
Left ventral conus swelling
Left lateral cushion
Anterior endocardial cushion Interventricular septum
Right lateral cushion Bulboventricular flange
Right dorsal conus swelling Aortic channel
Right superior truncus swelling IV
Figure 13.19 Frontal section through the heart of a day-35 embryo. At this stage of development, blood from the atrial cavity enters the primitive left ventricle as well as the primitive right ventricle. Note development of the cushions in the atrioventricular canal. Cushions in the truncus and conus are also visible. Ring, primitive interventricular foramen. Arrows, blood fl ow.
C A B
Muscular chord
Papillary muscle
Chordae tendineae Antrioventricular
valves Dense
mesenchymal tissue
Myocardium
Lumen of ventricle
Figure 13.20 Formation of the atrioventricular valves and chordae tendineae. The valves are hollowed out from the ventricular side but remain attached to the ventricular wall by the chordae tendineae.
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