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Cardiovascular Embryology by wulinqing

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									Pediatr Cardiol 25:191–200, 2004
DOI: 10.1007/s00246-003-0585-1

Cardiovascular Embryology

R. Abdulla,1 G. A. Blew,2 M.J. Holterman3
    Pediatric Cardiology, The University of Chicago. MC4051, 5841 S. Maryland Ave., Chicago, IL 60637-1470, USA
    School of Biomedical Visualization, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60637, USA
    Department of Surgery, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60637, USA

Abstract. During the first 20 days of development,                       for repetition and elaboration, or, worse, misunder-
the human embryo has no cardiovascular structure.                       standing and error.
Over the next month, the heart and great vessels                             Pediatric cardiologists, particularly those in
complete their development and look very much like                      training, frequently realize when examining a heart
they will at full gestation. This amazing process                       from an autopsy that their understanding of spatial
transforms isolated angiogenic cell islets into a com-                  relationship of cardiac structures of that particular
plex, four-chambered structure. During this trans-                      lesion was wrong. This difficulty becomes even more
formation, the single heart tube begins to beat at 23                   immense when dealing with a 3-D object in a state of
days of development and by 30 days blood circulates                     continual and complex change, such as that of the
through the embryo.                                                     cardiovascular system during its embryological de-
                                                                        velopment. Therefore, it becomes increasingly useful
Keywords: Heart — Cardiovascular — Embryology                           to depict these changes with four-dimensional im-
— Primitive heart — Heart looping — Outflow tract                        agery (i.e., computer animations depicting 3-D
septation                                                               structures changing over time). The task of preparing
                                                                        these animations is enormous, requiring expertise in
This review of human embryology attempts to doc-                        computer medical illustration and mastery over user-
ument the many different, and sometimes disputing,                       hostile software. This is possible for only a few of us,
theories of the development of the heart and its great                  and even then it is time-consuming and costly.
vessels. The goal is to provide a broad spectrum and                         The use of computer-generated 3-D images and
detailed information for those interested in the field                   animations in the field of cardiac embryology is be-
of pediatric cardiology. Many details were inten-                       coming more frequent. This technique is implemented
tionally left out, such as molecular biology issues,                    in research as well as to create educational images [1,
because it is impossible to include this ever-expanding                 13, 19–21, 45].
topic together with morphogenesis in one article.                            In the Internet version of this article, movie an-
Many publications are available for understanding                       imations demonstrating cardiovascular development
molecular biology and neural crest involvement in the                   are presented. Embryonic folding, heart tube looping,
development of the cardiovascular system [11, 12, 14,                   and development of systemic venous drainage are
15, 17, 23, 24, 32–35, 38].                                             demonstrated in different movie animations. These
     It is difficult to describe or use two-dimensional                   images were created using current information about
(2-D) imagery when describing a three-dimensional                       the development of these structures. On the other
(3-D) object. Despite this fact, we continue to de-                     hand, a different animation shows a process that can
scribe in our literature, lectures, and conferences the                 be used to create 3-D objects using histological slices
heart using 2-D terminology and illustrations, ex-                      from human embryos. Stage 14 sliced embryos from
pecting the audience to recreate a mental 3-D figure.                    the Carnegie collection of human embryos from the
Unfortunately, the inability to conceive what is being                  National Library of Medicine in Washington, DC,
described is frequent, leading to confusion, the need                   were digitized, the cardiovascular structures were
                                                                        traced, and the various slices were then stacked up
                                                                        using special computer software. This animation
Correspondence to: R. Abdulla, email: rabdulla@peds.bsd.                demonstrates how actual 3-D structures can be sci-                                                            entifically reassembled for better understanding
192                                                                                       Pediatric Cardiology Vol. 25, No. 3, 2004

                                                                      ential growth causing the embryo to fold in two dif-
                                                                      ferent dimensions:
                                                                      1. Craniocaudal axis due to the more rapid growth of
                                                                         the neural tube forming the brain at its cephalic
                                                                         end. Growth in this direction will cause the em-
                                                                         bryo to become convex shaped.
                                                                      2. Lateral folding, causing the two lateral edges of
                                                                         the germ disk to fold forming a tube-like structure.
                                                                      The first indication of any cardiovascular develop-
                                                                      ment occurs on approximately day 18 or 19. Prior to
                                                                      embryonic folding, angiogenic cell clusters on either
                                                                      side of the neural crest coalesce to form capillaries in
                                                                      the mesoderm of the germ disk. These capillaries then
                                                                      join to form a pair of blood vessels on each side of the
Fig. 1. The Carnegie collection of embryos includes various stages    neural crest (total of four blood vessels). These blood
of whole and sliced embryos. Digital images of slides of sliced       vessels run along the long axis of the germ disk, with
embryos are made, with various structures traced using specialized    one pair of blood vessels at the lateral edge of the
software. Subsequently, 3-D images are electronically reconstruct-    embryo (one on each edge) and the other pair more
ed. This image depicts a slice from a stage 14 embryo with 3-D        medially on either side of the neural tube. The blood
reconstruction, demonstrating the dorsal half of the embryo (white)   vessels on either side of the neural tube join at their
as well as a 3-D reconstruction of the heart. See animation of this
process in the Web version of this issue.
                                                                      cranial end.
                                                                           As the embryo folds in its lateral dimension, it
                                                                      causes the lateral edges of the germ disk to approach
                                                                      each other until they meet, causing the embryo to
(Fig. 1). After 3-D cardiac structures from sequen-                   acquire a tubular form [16, 25]. The two outer
tially staged embryos are created, the images can                     endocardial tubes will come close to each other in the
serve as templates for the animation process. These                   median of the embryo, ventral to the primitive gut,
can then be studied from various vantage points and                   and start fusing cranially to caudally, thus forming a
provide embryologically correct teaching tools to                     single median tube—the primitive heart tube [16, 41].
facilitate the comprehension of cardiac development
(Fig. 2).
                                                                      The Primitive Heart

Embryonic Folding                                                     The first intraembryonic blood vessels are noted on
                                                                      day 20, and 1–3 days later the formation of the single
Early in the third week of development, the germ disk                 median heart tube is complete. The heart starts to
has the appearance of a flat oval disk and is com-                     beat on day 22, but the circulation does not start until
posed of two layers: the epiblast and the hypoplast.                  days 27–29 [35].
The first faces the amniotic cavity and the latter faces                    The single tubular heart develops many con-
the yolk sac. A primitive groove, ending caudally                     strictions outlining future structures. The cranial-
with the primitive pit surrounded by a node, first                     most area is the bulbus cordis, which extends crani-
appears at approximately 16 days of development                       ally into the truncus arteriosus. This, in turn, is
and extends half the length of the embryo. The                        connected to the aortic sac and through the aortic
primitive groove serves as a conduit for epiblast cells               arches to the dorsal aorta [35]. The primitive ventricle
that detach from the edge of the groove and migrate                   is caudal to the bulbus cordis and the primitive atri-
inwards toward the hypoblast and replace it to form                   um is the caudal-most structure of the tubular heart.
the endoderm. After the endoderm is formed, cells                     The atrium connects to the sinus venosus, which re-
from the epiblast continue to migrate inwards to in-                  ceives the vitelline veins (from the yolk sac) and
filtrate the space between the epiblast and the endo-                  common cardinal (from the embryo) and umbilical
derm to form the intraembryonic mesoderm. After                       (from primitive placenta) veins. The primitive atrium
this process is complete, the epiblast is termed the                  and sinus venosus lay outside the caudal end of the
ectoderm [16, 25, 37] (Fig. 3).                                       pericardial sac, and the truncus arteriosus is outside
     The flat germ disk transforms into a tubular                      the cranial end of the pericardial sac. Some publica-
structure during the fourth week of development [16,                  tions have introduced new terminology describing the
25, 35]. This is achieved through a process of differ-                 segments of the primitive heart. Wenink and Gitten-
R. Abdulla et al.: Cardiovascular Embryology                                                                                      193

                                                                            Fig. 2. The sequence of events resulting in the union of
                                                                            the two lateral endocardial tubes to form the single
                                                                            endocardial tube. The rest of the embryo is not shown.
                                                                            The embryo starts as a flat disk(A). The lateral endo-
                                                                            cardial vessels located on either side of a flat embryo
                                                                            disk come closer together as the embryo folds along its
                                                                            long axis to transform a flat structure into a tubular
                                                                            shape (B). As the edges of the flat embryo meet to form
                                                                            this tubular structure, the two lateral endocardial ves-
                                                                            sels unite (C), forming a single heart tube at the ventral
                                                                            aspect of the embryo (D). This process occurs on ap-
                                                                            proximately day 20 or 21 of development. See anima-
                                                                            tion of this process in the Web version of this issue.

                                                                 Fig. 4. The single heart tube shows constrictions outlining future

                                                                 ment of the heart is now U shaped; the bulbus cordis
Fig. 3. Cells from the epiblast detach and migrate through the
primitive groove to form the endoderm and mesoderm layers.       forms the right arm of the U-shaped heart tube and
                                                                 the primitive ventricle forms the left arm. The looping
                                                                 of the bulboventricular segment of the heart will
berger-deGroot [44] support the use of inlet, outlet,            cause the atrium and sinus venosus to become dorsal
and arterial segments as proposed by Anderson and                to the heart loop [41]. At this stage, the paired sinus
Becker [3, 4, 10] (Fig. 4).                                      venosus extends laterally and gives rise to the sinus
     Looping of the primitive heart occur on ap-                 horns.
proximately day 23 of development [22]. It was ini-                   As the cardiac looping progresses, the paired
tially suggested that this is due to faster growth of the        atria form a common chamber and move into the
bulboventricular portion of the heart compared to                pericardial sac. The atrium now occupies a more
the pericardial sac and the rest of the embryo [35].             dorsal and cranial position and the common atrio-
However, it has been shown that the heart will loop              ventricular junction becomes the atrioventricular ca-
even when the pericardial sac is removed, as seen                nal, connecting the left side of the common atrium to
when the heart is cultured in vitro [24, 41]. It seems           the primitive ventricle [35]. At this stage, the heart has
that the process of looping is a genetic property of the         a smooth lining except for the area just proximal and
myocardium and not related to differential growth                 just distal to the bulboventricular foramen, where
[41].                                                            trabeculations form. The primitive ventricle will
     As the heart tube loops, the cephalic end of the            eventually develop into the left ventricle and the
heart tube bends ventrally, caudally, and slightly to            proximal portion of the bulbus cordis will form the
the right. The bulboventricular sulcus becomes visible           right ventricle. The distal part of the bulbus cordis, an
from the outside, and from the inside a primitive                elongated structure, will form the outflow tract of
interventricular foramen forms. The internal fold                both ventricles, and the truncus arteriosus will form
formed by the bulboventricular sulcus is known as                the roots of both great vessels. The bulbus cordis
the bulboventricular fold. The bulboventricular seg-             gradually acquires a more medial position due to the
194                                                                             Pediatric Cardiology Vol. 25, No. 3, 2004

                                                                              Fig. 5. Looping of the single endocardial
                                                                              heart tube transforms it into a complex four-
                                                                              chamber structure. Looping starts on day 23
                                                                              of development, and the four-chambered
                                                                              heart is evident on day 27.

growth of the right atrium, forcing the bulbus to be in     and the right umbilical vein connects to the vitelline
the sulcus in between the two atria [42] (Fig. 5).          system through the ductus venosus (which is derived
                                                            from the vitelline veins) [26] (Fig. 6).
Systemic Venous System
                                                            Pulmonary Circulation
On day 21, there is a common atrium as a result of
fusion of the two endocardial tubes. The common             Airways, Lung Parenchyma, and Distal Pulmonary
atrium communicates with two sinus horns, a left and        Arteries
a right horn, representing the unfused ends of the
endocardial tubes [16]. These two horns will form the       On day 21 of development, a groove forms in the
sinus venosus.                                              floor of the foregut just dorsal to the heart. This is
     The sinus venosus is located dorsal to the atria.      termed the pharyngeal groove, which develops to
The following veins drain into the sinus venosus on         form the pharynx. On day 23, the laryngotracheal
each side: the common cardinal vein, which drains           groove, a median structure in the pharyngeal region,
from the anterior cardinal vein (draining the cranial       develops. The edges of the laryngotracheal tube fuse
part of the embryo); the posterior cardinal vein            to form the larynx and trachea cranially and the right
(draining the caudal part of the embryo); the umbil-        and left main bronchi and right and left lung buds
ical vein (connecting the heart to the primitive pla-       distally. The growth and branching of the lung buds,
centa); and the vitelline vein (draining the yolk sac,      together with the surrounding mesoderm, form the
gastrointestinal system, and the portal circulation).       distal airways, lung parenchyma, and pulmonary
     On week 4, the sinus venosus communicates with         blood vessels. By week 16 of gestation, a full com-
the common atrium. During week 7, the sinoatrial            plement of preacinar airways and blood vessels have
communication becomes more right sided, connecting          formed. The pulmonary arteries in utero are muscu-
it to the right atrium. At 8 weeks, the distal end of the   lar, similar to that of the aorta. The thick, muscular
left cardinal vein degenerates, and the more proximal       walls of pulmonary arteries extend much further into
portion of it now connects through the anastomosing         distal arteries than what is seen in adults. Thinning of
vein (left brachiocephalic vein) to the right anterior      distal pulmonary arteries occurs postnatally as the
cardinal vein (right brachiocephalic vein), thus form-      pulmonary vascular resistance decreases after the
ing the superior vena cava. The left posterior cardinal     onset of breathing and improved oxygenation [29].
vein also degenerates, and the left sinus horn receiving
venous blood from the heart becomes the coronary
sinus. The right vitelline vein becomes the inferior        Proximal Pulmonary Arteries
vena cava, and the right posterior cardinal vein be-
comes the azygos vein. All this is completed in week 8      The proximal main pulmonary artery develops from
of development. The left umbilical vein degenerates         the truncus arteriosus, whereas the distal main pul-
R. Abdulla et al.: Cardiovascular Embryology                                                                          195

                                                                        Fig. 6. Development of the systemic venous
                                                                        drainage. These schematics represent dorsal
                                                                        views of the heart. (a) At week 4 of development,
                                                                        there is symmetrical systemic venous drainage
                                                                        into the two sinus venosus horns. (b) At week 7
                                                                        of development, there is degeneration of some of
                                                                        the systemic veins. (c) At week 8 of development,
                                                                        the central systemic venous anatomy as seen in a
                                                                        term infant. Normal and abnormal development
                                                                        of systemic venous drainage are shown in movie
                                                                        clips in the Web version of this issue. IVC, infe-
                                                                        rior vena cava; SVC, superior vena cava.

monary artery and the proximal right pulmonary            portant role in the eventual formation of the atrio-
artery develop from the ventral sixth aortic arch ar-     ventricular valves, endocardial cushion tissues are not
tery. The distal right pulmonary artery and the left      the precursors of the mitral and tricuspid valves [16,
pulmonary arteries form from the post branchial ar-       43].
teries, which develop from the lung buds and sur-              The atrioventricular junction is guarded by two
rounding mesoderm. The ductus arteriosus develops         masses of endocardial cushions—a superior and in-
from the distal left sixth aortic arch artery.            ferior cushion. These two masses will meet in the
                                                          middle, thus dividing the common atrioventricular
                                                          canal into right and left atrioventricular orifices. The
Pulmonary Venous System                                   process through which these two cushions fuse is not
                                                          clear [18], and the role of apoptosis in this process is
A primitive vein sprouts out of the left atrium, which    debatable. The fusion of the two endocardial cush-
bifurcates twice to give four pulmonary veins that        ions results in the formation of two atrioventricular
grow toward the developing lungs. The lung buds           orifices. In addition, the atrioventricular cushion
develop from the foregut. A plexus of veins is formed     appears to play a role in the closure of the interatrial
in the mesoderm enveloping the bronchial buds; these      communication at the edge of the primum atrial
veins will meet with the developing pulmonary veins       septum. This septum grows toward the atrioven-
out of the left atrium to establish a connection during   tricular endocardial cushion and fuses with it [41].
week 5 of gestation. As the left atrium develops, it           The formation of the atrioventricular valve starts
progressively incorporates the common pulmonary           when the atria and inlet portion of the ventricle en-
vein into the left atrial wall until all four pulmonary   large; the atrioventricular junction (or canal) lags
veins enter the posterior wall of the left atrium sep-    behind. Such a process causes the sulcus tissue to
arately. The incorporated pulmonary veins form the        invaginate into the ventricular cavity, forming a
smooth posterior wall of the left atrium, whereas the     hanging flap. The endocardial cushion tissue is lo-
trabeculated portion of the left atrium comes to oc-      cated at the tip of this flap, which is formed from
cupy a more ventral aspect [16, 35].                      three layers—the outer layer from atrial tissue, the
                                                          inner layer from ventricular tissue, and the middle
Atrioventricular Canal                                    layer from invaginated sulcus tissue. The inlet portion
                                                          of the ventricles then becomes undermined, forming
The atrioventricular valves form during the fifth to       the tethering cords holding the newly formed valve
eighth week of development [26]. Initially, endocar-      leaflets. The inner sulcus tissue will eventually come
dial cushion tissue forms bulges at the atrioven-         in contact with the cushion tissue at the tip of valve
tricular junction. These bulges have the appearance       leaflets, thus interrupting the muscular continuity
of valves, and although such tissue may play an im-       between the atria and ventricles [16] (Fig. 7).
196                                                                             Pediatric Cardiology Vol. 25, No. 3, 2004

                                                            ventricular canal. This is the septum primum. The
                                                            septum primum initially has a concave-shaped edge
                                                            growing toward the atrioventricular canal. This orifice
                                                            connecting the two atria is called the ostium primum.
                                                            As the superior and inferior endocardial cushions
                                                            fuse, thus dividing the atrioventricular canal into a
                                                            right and left orifice, the concave lower edge of the
                                                            septum primum fuses with it, obliterating the ostium
                                                            primum. However, just before this happens fenestra-
Fig. 7. Formation of atrioventricular valves.               tions appear in the posterosuperior part of the septum
                                                            forming the ostium secundum, thus maintaining a
                                                            communication between the two atria [41]. The ostium
The Atria and Atrial Septum                                 secundum and superior vena cava later acquire a more
                                                            anterosuperior position, although they maintain their
The atria of the mature heart have more than one            relationship with each other; this is achieved through
origin. The trabeculated portions (appendages) of the       the growth of the atria [41].
right and left atria are from the primitive atria,               These fenestrations then coalesce and form a
whereas the smooth-walled posterior portions of the         larger fenestration. Meanwhile, another sickle-shaped
left and right atria originate from the incorporation       membrane develops on the anterosuperior wall of the
of venous blood vessels. The posterior aspect of the        right atrium, just right of the septum primum and left
left atrium is formed by the incorporation of the           of the sinus venosus valve. It grows and covers the
pulmonary veins, whereas the posterior smooth por-          ostium secundum, which continues to allow blood
tion of the right atrium is derived from the sinus          passage since the two membranes do not fuse. The
venosus.                                                    septum secundum grows toward the endocardial
      The two sinus horns are initially paired struc-       cushion, leaving only an area at the posterosuperior
tures; later, they fuse to give a transverse sinus          part of the interatrial septum where the septum pri-
venosus. The entrance of the sinus venosus shifts           mum continues to exist as the foramen ovale mem-
rightward to eventually enter into the right atrium         brane. The septum primum disappears from the
exclusively. The veins draining into the left sinus         posterosuperior portion of interatrial septation and
venosus (left common cardinal, umbilical, and vitel-        the edge of the septum secundum forms the rim of the
line veins) eventually degenerate. The left sinus           fossa ovalis [44] on approximately day 42 of devel-
venosus will become smaller because it will drain only      opment (Figs. 8 and 9).
the venous circulation of the heart, becoming the
coronary sinus.                                             Ventricular Septation
      The sinus venosus orifice of the right atrium is
slit-like and to the right of the undeveloped septum        Ventricular septation is a complex process involving
primum [16]. The sinus venosus now connecting to            different septal structures from various origins and
the right atrium will assume a more vertical position.      positioned at various planes [2, 27, 28, 31]. These
The sinoatrial junction will become guarded by two          structures eventually meet to complete the separation
valve-like structures, resulting from the invagination      of the right and left ventricles.
of the atrial wall at the right and left sinoatrial
junction. This orifice enlarges, with the superior and
inferior vena cavae and the coronary sinus opening          Muscular Interventricular Septum
separately and directly into the right atrium. The
right and left sinoatrial valves join at the top, forming   During the fifth week, on approximately day 30, a
the septum spurium. This septum and the two sino-           muscular fold extending from the anterior wall of the
atrial valve-like structures obliterate and are not ap-     ventricles to the floor appears at the middle of the
preciated in the mature heart [41].                         ventricle near the apex and grows toward the atrio-
      Atrial septation starts when the common atrium        ventricular valves with a concave ridge. Most of the
becomes indented externally by the bulbus cordis and        initial growth is achieved by growth of the two ven-
truncus arteriosus. This indentation will correspond        tricles on either side of the ventricular septum. In
internally with a thin sickle-shaped membrane devel-        addition, trabeculations from the inlet region coalesce
oping in the common atrium on day 35 [39]. This             to form a septum, which grows into the ventricular
membrane divides the atrium into right and left             cavity at a slightly different plane than that of the
chambers. It grows from the posterosuperior wall and        primary septum; this is the inlet interventricular
extends toward the endocardial cushion of the atrio-        septum, which is in the same plane of that of the
R. Abdulla et al.: Cardiovascular Embryology                                                                                        197

                                                                                 Fig. 8. The atrial septum is formed by the septum
                                                                                 primum and septum secundum. A movie clip de-
                                                                                 picting this process can be viewed in the Web ver-
                                                                                 sion of this issue. AV, atrioventricular; IVC, inferior
                                                                                 vena cava; SVC, superior vena cava.

                                                                     Outflow Tract Septum

                                                                     The cardiac outflow tract includes the ventricular
                                                                     outflow tract and the aortopulmonary septum. There
                                                                     has been much debate regarding this process. This
                                                                     section provides a summary of various theories [9, 36,
                                                                          In 1942, Kramer suggested that there are three
                                                                     embryological areas: the conus, the truncus, and the
                                                                     pulmonary arterial segments. Each segment develops
                                                                     two opposing ridges of endocardial tissue; the op-
                                                                     posing pairs of ridges and those from various seg-
                                                                     ments meet to form a septum separating two outflow
                                                                     tracts and aortopulmonary trunks. The aortopulmo-
                                                                     nary septum is formed by ridges separating the fourth
Fig. 9. 3-D depiction of atrial septum formation. See animation in
                                                                     (future aortic arch) and the sixth (future pulmonary
Web version of this issue.                                           arteries) aortic arches. The truncus ridges are formed
                                                                     in the area where the semilunar valves are destined to
                                                                     be formed, thus forming the septum between the as-
atrial septum. The point of contact between these two                cending aorta and the main pulmonary artery. The
septa will cause the edge of the primary septum to                   conus ridges form just below the semilunar valves and
protrude slightly into the right ventricular cavity,                 from the septation between the right and left ven-
forming the trabecular septomarginalis. The fusion of                tricular outflow tracts.
these two septa forms the bulk of the muscular                            Van Mierop [41] agreed that there are three pairs
interventricular septum. This septum will then come                  of ridges forming in the aortopulmonary, truncus, and
into contact with the outflow septum (Fig. 10).                       conus regions. However, he stated that the pairs of
     The interventricular foramen, which is bordered                 ridges fuse independently and later on fuse with each
by the concave upper ridge of the muscular inter-                    other to complete the septation. His theory indicates
ventricular septum, the fused atrioventricular canal                 that the truncus ridges form first, and as they fuse they
endocardial tissue, and the outflow tract septation                   form a truncal septum. This septum then fuses with
ridges, never actually closes. Instead, communication                the aortopulmonary septum, which is formed by
between the left ventricle and the right ventricle is                invagination of the dorsal wall of the aortic sac be-
closed at the end of week 7 by growth of three                       tween the fourth and the sixth aortic arch arteries
structures—the right and left bulbar ridges and the                  (Fig. 11). Asami [7], Pexieder [36, 37], and Orts Llorca
posterior endocardial cushion tissue—that baffle the                   et al. [7], concur with Van Mierop’s theory; however,
left ventricular output through a newly formed left                  Asami believes that these ridges fuse in the opposite
ventricular outflow tract (LVOT). The LVOT is                         direction of that indicated by Van Mierop (i.e., from
posterior to a right ventricular outflow tract, con-                  the outflow tract to the aortopulmonary region). On
necting the right ventricle to the pulmonary trunk.                  the other hand, Pexieder and Orts Llorca believe that
198                                                                               Pediatric Cardiology Vol. 25, No. 3, 2004

                                                          Fig. 11. One theory of formation of the outflow tract and vascular
                                                          septation. LV, left ventricular; LVOT, left ventricular outflow
Fig. 10. Formation of ventricular septum.                 tract; RV, right ventricle; RVOT, right ventricular outflow tract.

there are only two septa—a conotruncal (or bulbar)
and an aortopulmonary septum.
     In 1989, Bartlings et al. introduced a new theory.
They stated that the septation process of the ven-
tricular outflow tracts, pulmonary and aortic valves,
and the great vessels is mostly caused by a single
septation complex, which they termed aortopulmo-
nary septum. This septation complex develops at the
junction of the muscular ventricular outflow tract
with the aortopulmonary vessel. This junction has a
saddle shape, allowing the right ventricular outflow
tract to be long with a short main pulmonary artery,      Fig. 12. Diagram depicting the theory of ventricular outflow and
whereas the left ventricular outflow tract becomes         great vessels’ septation by Bartlings et al. [9]. Numbers indicate
short with a long ascending aorta (Fig. 12). The          specific aortic arch arteries.
ventricular outflow septation is formed by condensed
mesenchyme, embedded in the endocardial cushion
tissue just proximal to the level of the aortopulmo-      as nodal tissue, are slow conducting and resemble less
nary valves. The condensed mesenchyme will come in        developed primary myocardium, whereas other por-
close contact with the outflow tract myocardium,           tions, such as ventricular conduction tissue, are fast
from the area just above the bulboventricular fold,       conducting [30].
and participate in the septation of the outflow tract           The embryological origin and formation of the
by providing an analogue to muscle tissue [6–9].          sinus and atrioventricular nodal tissue is not clear.
Myocardium in contact with the mesenchymal arch           The ventricular conduction system formation is bet-
grows rapidly and forms the bulk of the outflow            ter known. The latter starts with the formation of an
septum, continuous with the primary fold on the           encircling ring of conducting myocardial tissue
parietal wall of the right ventricle and the myocar-      around the bulboventricular foramen. The dorsal
dium on the right side of the primary septum.             portion of the ring will become the bundle of His. The
                                                          portion of the ring covering the septum will become
Conduction System                                         the left and right bundle branches. The anterior
                                                          portion of the ring is called the septal branch and it
Primary myocardium, found in the early heart tube,        disappears during normal embryological develop-
gives rise to the contracting myocardium (of the atria    ment. Other portions of this specialized tissue that
and ventricles) and the conducting myocardium             form and later disappear are the right atrioventricular
(nodal and ventricular conducting tissue). Conduct-       ring bundle and the retroartic branch. The right
ing myocardial tissue is frequently referred to as be-    atrioventricular ring forms due to the rightward shift
ing highly specialized tissue, implying that it has a     of the common atrioventricular valve, which origi-
homogenous function. In reality, some portions, such      nally connects the common atrium to the primitive
R. Abdulla et al.: Cardiovascular Embryology                                                                                        199

                                                                     will eventually contribute to the external carotid ar-
                                                                     teries (Fig. 13). The second pair of aortic arch arteries
                                                                     appears in week 4. These regress rapidly and only a
                                                                     portion remains, which forms the stapedial and hyoid
                                                                     arteries. The third pair of the aortic arch arteries
                                                                     appears at approximately the end of the fourth week;
                                                                     these will give rise to the common carotid arteries and
                                                                     the proximal portion of the internal carotid arteries.
                                                                     The distal portion of the internal carotid arteries is
                                                                     formed by the cranial portions of the dorsal aorta.
                                                                     The fourth aortic arch arteries develop soon after the
                                                                     third arch arteries. Their development differs on the
                                                                     left from that on the right. On the left side, they
                                                                     persist, connecting the ventral aorta to the dorsal
                                                                     aorta and forming the aortic arch. On the right, they
                                                                     form the proximal portion of the right subclavian
                                                                     artery. The fifth pair of aortic arch arteries is rudi-
                                                                     mentary and does not develop into any known ves-
                                                                     sels; this pair of aortic arch arteries is not seen in
Fig. 13. Degenerated aortic arch arteries (AAA) and the final great   many embryo specimens. The sixth aortic arch ar-
vessels anatomy.                                                     teries develop in the middle of the fifth week. The
                                                                     proximal portions develop into the main and right
(left) ventricle. This results in a shift of the specialized         pulmonary arteries, whereas the distal portion of the
myocardium rightward in a ring shape around the                      left aortic arch artery develops into the ductus arte-
right atrioventricular orifice, only later to disappear.              riosus (Fig. 13).
The retroarotic branch is formed as a result of the
leftward shift of the outflow tract, causing some of
the specialized conducting tissue to move and to be                  References
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