Cardiovascular Embryology

R. Abdulla,
1
G. A. Blew,
2
M.J. Holterman
3
1
Pediatric Cardiology, The University of Chicago. MC4051, 5841 S. Maryland Ave., Chicago, IL 60637-1470, USA
2
School of Biomedical Visualization, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60637, USA
3
Department of Surgery, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60637, USA
Abstract. During the rst 20 days of development,
the human embryo has no cardiovascular structure.
Over the next month, the heart and great vessels
complete their development and look very much like
they will at full gestation. This amazing process
transforms isolated angiogenic cell islets into a com-
plex, four-chambered structure. During this trans-
formation, the single heart tube begins to beat at 23
days of development and by 30 days blood circulates
through the embryo.
Keywords: Heart Cardiovascular Embryology
Primitive heart Heart looping Outow tract
septation
This review of human embryology attempts to doc-
ument the many dierent, and sometimes disputing,
theories of the development of the heart and its great
vessels. The goal is to provide a broad spectrum and
detailed information for those interested in the eld
of pediatric cardiology. Many details were inten-
tionally left out, such as molecular biology issues,
because it is impossible to include this ever-expanding
topic together with morphogenesis in one article.
Many publications are available for understanding
molecular biology and neural crest involvement in the
development of the cardiovascular system [11, 12, 14,
15, 17, 23, 24, 3235, 38].
It is dicult to describe or use two-dimensional
(2-D) imagery when describing a three-dimensional
(3-D) object. Despite this fact, we continue to de-
scribe in our literature, lectures, and conferences the
heart using 2-D terminology and illustrations, ex-
pecting the audience to recreate a mental 3-D gure.
Unfortunately, the inability to conceive what is being
described is frequent, leading to confusion, the need
for repetition and elaboration, or, worse, misunder-
standing and error.
Pediatric cardiologists, particularly those in
training, frequently realize when examining a heart
from an autopsy that their understanding of spatial
relationship of cardiac structures of that particular
lesion was wrong. This diculty becomes even more
immense when dealing with a 3-D object in a state of
continual and complex change, such as that of the
cardiovascular system during its embryological de-
velopment. Therefore, it becomes increasingly useful
to depict these changes with four-dimensional im-
agery (i.e., computer animations depicting 3-D
structures changing over time). The task of preparing
these animations is enormous, requiring expertise in
computer medical illustration and mastery over user-
hostile software. This is possible for only a few of us,
and even then it is time-consuming and costly.
The use of computer-generated 3-D images and
animations in the eld of cardiac embryology is be-
coming more frequent. This technique is implemented
in research as well as to create educational images [1,
13, 1921, 45].
In the Internet version of this article, movie an-
imations demonstrating cardiovascular development
are presented. Embryonic folding, heart tube looping,
and development of systemic venous drainage are
demonstrated in dierent movie animations. These
images were created using current information about
the development of these structures. On the other
hand, a dierent animation shows a process that can
be used to create 3-D objects using histological slices
from human embryos. Stage 14 sliced embryos from
the Carnegie collection of human embryos from the
National Library of Medicine in Washington, DC,
were digitized, the cardiovascular structures were
traced, and the various slices were then stacked up
using special computer software. This animation
demonstrates how actual 3-D structures can be sci-
entically reassembled for better understanding
Correspondence to: R. Abdulla, email: rabdulla@peds.bsd.
uchicago.edu
Pediatr Cardiol 25:191200, 2004
DOI: 10.1007/s00246-003-0585-1
(Fig. 1). After 3-D cardiac structures from sequen-
tially staged embryos are created, the images can
serve as templates for the animation process. These
can then be studied from various vantage points and
provide embryologically correct teaching tools to
facilitate the comprehension of cardiac development
(Fig. 2).
Embryonic Folding
Early in the third week of development, the germ disk
has the appearance of a at oval disk and is com-
posed of two layers: the epiblast and the hypoplast.
The rst faces the amniotic cavity and the latter faces
the yolk sac. A primitive groove, ending caudally
with the primitive pit surrounded by a node, rst
appears at approximately 16 days of development
and extends half the length of the embryo. The
primitive groove serves as a conduit for epiblast cells
that detach from the edge of the groove and migrate
inwards toward the hypoblast and replace it to form
the endoderm. After the endoderm is formed, cells
from the epiblast continue to migrate inwards to in-
ltrate the space between the epiblast and the endo-
derm to form the intraembryonic mesoderm. After
this process is complete, the epiblast is termed the
ectoderm [16, 25, 37] (Fig. 3).
The at germ disk transforms into a tubular
structure during the fourth week of development [16,
25, 35]. This is achieved through a process of dier-
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 rst 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
neural crest (total of four blood vessels). These blood
vessels run along the long axis of the germ disk, with
one pair of blood vessels at the lateral edge of the
embryo (one on each edge) and the other pair more
medially on either side of the neural tube. The blood
vessels on either side of the neural tube join at their
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
acquire a tubular form [16, 25]. The two outer
endocardial tubes will come close to each other in the
median of the embryo, ventral to the primitive gut,
and start fusing cranially to caudally, thus forming a
single median tubethe primitive heart tube [16, 41].
The Primitive Heart
The rst intraembryonic blood vessels are noted on
day 20, and 13 days later the formation of the single
median heart tube is complete. The heart starts to
beat on day 22, but the circulation does not start until
days 2729 [35].
The single tubular heart develops many con-
strictions outlining future structures. The cranial-
most area is the bulbus cordis, which extends crani-
ally into the truncus arteriosus. This, in turn, is
connected to the aortic sac and through the aortic
arches to the dorsal aorta [35]. The primitive ventricle
is caudal to the bulbus cordis and the primitive atri-
um is the caudal-most structure of the tubular heart.
The atrium connects to the sinus venosus, which re-
ceives the vitelline veins (from the yolk sac) and
common cardinal (from the embryo) and umbilical
(from primitive placenta) veins. The primitive atrium
and sinus venosus lay outside the caudal end of the
pericardial sac, and the truncus arteriosus is outside
the cranial end of the pericardial sac. Some publica-
tions have introduced new terminology describing the
segments of the primitive heart. Wenink and Gitten-
Fig. 1. The Carnegie collection of embryos includes various stages
of whole and sliced embryos. Digital images of slides of sliced
embryos are made, with various structures traced using specialized
software. Subsequently, 3-D images are electronically reconstruct-
ed. This image depicts a slice from a stage 14 embryo with 3-D
reconstruction, demonstrating the dorsal half of the embryo (white)
as well as a 3-D reconstruction of the heart. See animation of this
process in the Web version of this issue.
192 Pediatric Cardiology Vol. 25, No. 3, 2004
berger-deGroot [44] support the use of inlet, outlet,
and arterial segments as proposed by Anderson and
Becker [3, 4, 10] (Fig. 4).
Looping of the primitive heart occur on ap-
proximately day 23 of development [22]. It was ini-
tially suggested that this is due to faster growth of the
bulboventricular portion of the heart compared to
the pericardial sac and the rest of the embryo [35].
However, it has been shown that the heart will loop
even when the pericardial sac is removed, as seen
when the heart is cultured in vitro [24, 41]. It seems
that the process of looping is a genetic property of the
myocardium and not related to dierential growth
[41].
As the heart tube loops, the cephalic end of the
heart tube bends ventrally, caudally, and slightly to
the right. The bulboventricular sulcus becomes visible
from the outside, and from the inside a primitive
interventricular foramen forms. The internal fold
formed by the bulboventricular sulcus is known as
the bulboventricular fold. The bulboventricular seg-
ment of the heart is now U shaped; the bulbus cordis
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
cause the atrium and sinus venosus to become dorsal
to the heart loop [41]. At this stage, the paired sinus
venosus extends laterally and gives rise to the sinus
horns.
As the cardiac looping progresses, the paired
atria form a common chamber and move into the
pericardial sac. The atrium now occupies a more
dorsal and cranial position and the common atrio-
ventricular junction becomes the atrioventricular ca-
nal, connecting the left side of the common atrium to
the primitive ventricle [35]. At this stage, the heart has
a smooth lining except for the area just proximal and
just distal to the bulboventricular foramen, where
trabeculations form. The primitive ventricle will
eventually develop into the left ventricle and the
proximal portion of the bulbus cordis will form the
right ventricle. The distal part of the bulbus cordis, an
elongated structure, will form the outow tract of
both ventricles, and the truncus arteriosus will form
the roots of both great vessels. The bulbus cordis
gradually acquires a more medial position due to the
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 at disk(A). The lateral endo-
cardial vessels located on either side of a at embryo
disk come closer together as the embryo folds along its
long axis to transform a at structure into a tubular
shape (B). As the edges of the at 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. 3. Cells from the epiblast detach and migrate through the
primitive groove to form the endoderm and mesoderm layers.
Fig. 4. The single heart tube shows constrictions outlining future
structures.
R. Abdulla et al.: Cardiovascular Embryology 193
growth of the right atrium, forcing the bulbus to be in
the sulcus in between the two atria [42] (Fig. 5).
Systemic Venous System
On day 21, there is a common atrium as a result of
fusion of the two endocardial tubes. The common
atrium communicates with two sinus horns, a left and
a right horn, representing the unfused ends of the
endocardial tubes [16]. These two horns will form the
sinus venosus.
The sinus venosus is located dorsal to the atria.
The following veins drain into the sinus venosus on
each side: the common cardinal vein, which drains
from the anterior cardinal vein (draining the cranial
part of the embryo); the posterior cardinal vein
(draining the caudal part of the embryo); the umbil-
ical vein (connecting the heart to the primitive pla-
centa); and the vitelline vein (draining the yolk sac,
gastrointestinal system, and the portal circulation).
On week 4, the sinus venosus communicates with
the common atrium. During week 7, the sinoatrial
communication becomes more right sided, connecting
it to the right atrium. At 8 weeks, the distal end of the
left cardinal vein degenerates, and the more proximal
portion of it now connects through the anastomosing
vein (left brachiocephalic vein) to the right anterior
cardinal vein (right brachiocephalic vein), thus form-
ing the superior vena cava. The left posterior cardinal
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
vena cava, and the right posterior cardinal vein be-
comes the azygos vein. All this is completed in week 8
of development. The left umbilical vein degenerates
and the right umbilical vein connects to the vitelline
system through the ductus venosus (which is derived
from the vitelline veins) [26] (Fig. 6).
Pulmonary Circulation
Airways, Lung Parenchyma, and Distal Pulmonary
Arteries
On day 21 of development, a groove forms in the
oor of the foregut just dorsal to the heart. This is
termed the pharyngeal groove, which develops to
form the pharynx. On day 23, the laryngotracheal
groove, a median structure in the pharyngeal region,
develops. The edges of the laryngotracheal tube fuse
to form the larynx and trachea cranially and the right
and left main bronchi and right and left lung buds
distally. The growth and branching of the lung buds,
together with the surrounding mesoderm, form the
distal airways, lung parenchyma, and pulmonary
blood vessels. By week 16 of gestation, a full com-
plement of preacinar airways and blood vessels have
formed. The pulmonary arteries in utero are muscu-
lar, similar to that of the aorta. The thick, muscular
walls of pulmonary arteries extend much further into
distal arteries than what is seen in adults. Thinning of
distal pulmonary arteries occurs postnatally as the
pulmonary vascular resistance decreases after the
onset of breathing and improved oxygenation [29].
Proximal Pulmonary Arteries
The proximal main pulmonary artery develops from
the truncus arteriosus, whereas the distal main pul-
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.
194 Pediatric Cardiology Vol. 25, No. 3, 2004
monary artery and the proximal right pulmonary
artery develop from the ventral sixth aortic arch ar-
tery. The distal right pulmonary artery and the left
pulmonary arteries form from the post branchial ar-
teries, which develop from the lung buds and sur-
rounding mesoderm. The ductus arteriosus develops
from the distal left sixth aortic arch artery.
Pulmonary Venous System
A primitive vein sprouts out of the left atrium, which
bifurcates twice to give four pulmonary veins that
grow toward the developing lungs. The lung buds
develop from the foregut. A plexus of veins is formed
in the mesoderm enveloping the bronchial buds; these
veins will meet with the developing pulmonary veins
out of the left atrium to establish a connection during
week 5 of gestation. As the left atrium develops, it
progressively incorporates the common pulmonary
vein into the left atrial wall until all four pulmonary
veins enter the posterior wall of the left atrium sep-
arately. The incorporated pulmonary veins form the
smooth posterior wall of the left atrium, whereas the
trabeculated portion of the left atrium comes to oc-
cupy a more ventral aspect [16, 35].
Atrioventricular Canal
The atrioventricular valves form during the fth to
eighth week of development [26]. Initially, endocar-
dial cushion tissue forms bulges at the atrioven-
tricular junction. These bulges have the appearance
of valves, and although such tissue may play an im-
portant role in the eventual formation of the atrio-
ventricular valves, endocardial cushion tissues are not
the precursors of the mitral and tricuspid valves [16,
43].
The atrioventricular junction is guarded by two
masses of endocardial cushionsa superior and in-
ferior cushion. These two masses will meet in the
middle, thus dividing the common atrioventricular
canal into right and left atrioventricular orices. The
process through which these two cushions fuse is not
clear [18], and the role of apoptosis in this process is
debatable. The fusion of the two endocardial cush-
ions results in the formation of two atrioventricular
orices. In addition, the atrioventricular cushion
appears to play a role in the closure of the interatrial
communication at the edge of the primum atrial
septum. This septum grows toward the atrioven-
tricular endocardial cushion and fuses with it [41].
The formation of the atrioventricular valve starts
when the atria and inlet portion of the ventricle en-
large; the atrioventricular junction (or canal) lags
behind. Such a process causes the sulcus tissue to
invaginate into the ventricular cavity, forming a
hanging ap. The endocardial cushion tissue is lo-
cated at the tip of this ap, which is formed from
three layersthe outer layer from atrial tissue, the
inner layer from ventricular tissue, and the middle
layer from invaginated sulcus tissue. The inlet portion
of the ventricles then becomes undermined, forming
the tethering cords holding the newly formed valve
leaets. The inner sulcus tissue will eventually come
in contact with the cushion tissue at the tip of valve
leaets, thus interrupting the muscular continuity
between the atria and ventricles [16] (Fig. 7).
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.
R. Abdulla et al.: Cardiovascular Embryology 195
The Atria and Atrial Septum
The atria of the mature heart have more than one
origin. The trabeculated portions (appendages) of the
right and left atria are from the primitive atria,
whereas the smooth-walled posterior portions of the
left and right atria originate from the incorporation
of venous blood vessels. The posterior aspect of the
left atrium is formed by the incorporation of the
pulmonary veins, whereas the posterior smooth por-
tion of the right atrium is derived from the sinus
venosus.
The two sinus horns are initially paired struc-
tures; later, they fuse to give a transverse sinus
venosus. The entrance of the sinus venosus shifts
rightward to eventually enter into the right atrium
exclusively. The veins draining into the left sinus
venosus (left common cardinal, umbilical, and vitel-
line veins) eventually degenerate. The left sinus
venosus will become smaller because it will drain only
the venous circulation of the heart, becoming the
coronary sinus.
The sinus venosus orice of the right atrium is
slit-like and to the right of the undeveloped septum
primum [16]. The sinus venosus now connecting to
the right atrium will assume a more vertical position.
The sinoatrial junction will become guarded by two
valve-like structures, resulting from the invagination
of the atrial wall at the right and left sinoatrial
junction. This orice enlarges, with the superior and
inferior vena cavae and the coronary sinus opening
separately and directly into the right atrium. The
right and left sinoatrial valves join at the top, forming
the septum spurium. This septum and the two sino-
atrial valve-like structures obliterate and are not ap-
preciated in the mature heart [41].
Atrial septation starts when the common atrium
becomes indented externally by the bulbus cordis and
truncus arteriosus. This indentation will correspond
internally with a thin sickle-shaped membrane devel-
oping in the common atrium on day 35 [39]. This
membrane divides the atrium into right and left
chambers. It grows from the posterosuperior wall and
extends toward the endocardial cushion of the atrio-
ventricular canal. This is the septum primum. The
septum primum initially has a concave-shaped edge
growing toward the atrioventricular canal. This orice
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 orice, the concave lower edge of the
septum primum fuses with it, obliterating the ostium
primum. However, just before this happens fenestra-
tions appear in the posterosuperior part of the septum
forming the ostium secundum, thus maintaining a
communication between the two atria [41]. The ostium
secundumand superior vena cava later acquire a more
anterosuperior position, although they maintain their
relationship with each other; this is achieved through
the growth of the atria [41].
These fenestrations then coalesce and form a
larger fenestration. Meanwhile, another sickle-shaped
membrane develops on the anterosuperior wall of the
right atrium, just right of the septum primum and left
of the sinus venosus valve. It grows and covers the
ostium secundum, which continues to allow blood
passage since the two membranes do not fuse. The
septum secundum grows toward the endocardial
cushion, leaving only an area at the posterosuperior
part of the interatrial septum where the septum pri-
mum continues to exist as the foramen ovale mem-
brane. The septum primum disappears from the
posterosuperior portion of interatrial septation and
the edge of the septum secundum forms the rim of the
fossa ovalis [44] on approximately day 42 of devel-
opment (Figs. 8 and 9).
Ventricular Septation
Ventricular septation is a complex process involving
dierent septal structures from various origins and
positioned at various planes [2, 27, 28, 31]. These
structures eventually meet to complete the separation
of the right and left ventricles.
Muscular Interventricular Septum
During the fth week, on approximately day 30, a
muscular fold extending from the anterior wall of the
ventricles to the oor appears at the middle of the
ventricle near the apex and grows toward the atrio-
ventricular valves with a concave ridge. Most of the
initial growth is achieved by growth of the two ven-
tricles on either side of the ventricular septum. In
addition, trabeculations from the inlet region coalesce
to form a septum, which grows into the ventricular
cavity at a slightly dierent plane than that of the
primary septum; this is the inlet interventricular
septum, which is in the same plane of that of the
Fig. 7. Formation of atrioventricular valves.
196 Pediatric Cardiology Vol. 25, No. 3, 2004
atrial septum. The point of contact between these two
septa will cause the edge of the primary septum to
protrude slightly into the right ventricular cavity,
forming the trabecular septomarginalis. The fusion of
these two septa forms the bulk of the muscular
interventricular septum. This septum will then come
into contact with the outow septum (Fig. 10).
The interventricular foramen, which is bordered
by the concave upper ridge of the muscular inter-
ventricular septum, the fused atrioventricular canal
endocardial tissue, and the outow tract septation
ridges, never actually closes. Instead, communication
between the left ventricle and the right ventricle is
closed at the end of week 7 by growth of three
structuresthe right and left bulbar ridges and the
posterior endocardial cushion tissuethat bae the
left ventricular output through a newly formed left
ventricular outow tract (LVOT). The LVOT is
posterior to a right ventricular outow tract, con-
necting the right ventricle to the pulmonary trunk.
Outow Tract Septum
The cardiac outow tract includes the ventricular
outow tract and the aortopulmonary septum. There
has been much debate regarding this process. This
section provides a summary of various theories [9, 36,
40].
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 outow
tracts and aortopulmonary trunks. The aortopulmo-
nary septum is formed by ridges separating the fourth
(future aortic arch) and the sixth (future pulmonary
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-
cending aorta and the main pulmonary artery. The
conus ridges form just below the semilunar valves and
from the septation between the right and left ven-
tricular outow tracts.
Van Mierop [41] agreed that there are three pairs
of ridges forming in the aortopulmonary, truncus, and
conus regions. However, he stated that the pairs of
ridges fuse independently and later on fuse with each
other to complete the septation. His theory indicates
that the truncus ridges formrst, and as they fuse they
form a truncal septum. This septum then fuses with
the aortopulmonary septum, which is formed by
invagination of the dorsal wall of the aortic sac be-
tween the fourth and the sixth aortic arch arteries
(Fig. 11). Asami [7], Pexieder [36, 37], and Orts Llorca
et al. [7], concur with Van Mierops theory; however,
Asami believes that these ridges fuse in the opposite
direction of that indicated by Van Mierop (i.e., from
the outow tract to the aortopulmonary region). On
the other hand, Pexieder and Orts Llorca believe that
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.
Fig. 9. 3-D depiction of atrial septum formation. See animation in
Web version of this issue.
R. Abdulla et al.: Cardiovascular Embryology 197
there are only two septaa 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 outow 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 outow tract
with the aortopulmonary vessel. This junction has a
saddle shape, allowing the right ventricular outow
tract to be long with a short main pulmonary artery,
whereas the left ventricular outow tract becomes
short with a long ascending aorta (Fig. 12). The
ventricular outow septation is formed by condensed
mesenchyme, embedded in the endocardial cushion
tissue just proximal to the level of the aortopulmo-
nary valves. The condensed mesenchyme will come in
close contact with the outow tract myocardium,
from the area just above the bulboventricular fold,
and participate in the septation of the outow tract
by providing an analogue to muscle tissue [69].
Myocardium in contact with the mesenchymal arch
grows rapidly and forms the bulk of the outow
septum, continuous with the primary fold on the
parietal wall of the right ventricle and the myocar-
dium on the right side of the primary septum.
Conduction System
Primary myocardium, found in the early heart tube,
gives rise to the contracting myocardium (of the atria
and ventricles) and the conducting myocardium
(nodal and ventricular conducting tissue). Conduct-
ing myocardial tissue is frequently referred to as be-
ing highly specialized tissue, implying that it has a
homogenous function. In reality, some portions, such
as nodal tissue, are slow conducting and resemble less
developed primary myocardium, whereas other por-
tions, such as ventricular conduction tissue, are fast
conducting [30].
The embryological origin and formation of the
sinus and atrioventricular nodal tissue is not clear.
The ventricular conduction system formation is bet-
ter known. The latter starts with the formation of an
encircling ring of conducting myocardial tissue
around the bulboventricular foramen. The dorsal
portion of the ring will become the bundle of His. The
portion of the ring covering the septum will become
the left and right bundle branches. The anterior
portion of the ring is called the septal branch and it
disappears during normal embryological develop-
ment. Other portions of this specialized tissue that
form and later disappear are the right atrioventricular
ring bundle and the retroartic branch. The right
atrioventricular ring forms due to the rightward shift
of the common atrioventricular valve, which origi-
nally connects the common atrium to the primitive
Fig. 10. Formation of ventricular septum.
Fig. 11. One theory of formation of the outow tract and vascular
septation. LV, left ventricular; LVOT, left ventricular outow
tract; RV, right ventricle; RVOT, right ventricular outow tract.
Fig. 12. Diagram depicting the theory of ventricular outow and
great vessels septation by Bartlings et al. [9]. Numbers indicate
specic aortic arch arteries.
198 Pediatric Cardiology Vol. 25, No. 3, 2004
(left) ventricle. This results in a shift of the specialized
myocardium rightward in a ring shape around the
right atrioventricular orice, only later to disappear.
The retroarotic branch is formed as a result of the
leftward shift of the outow tract, causing some of
the specialized conducting tissue to move and to be
situated behind the aorta.
Development of Pericardial Sac
The right and left intracelomic cavities approach the
midline as the two heart tubes are fusing into a me-
dial tube (day 21). The two cavities approach each
other and surround the heart tube. The ventral mes-
oderm is immediately absorbed and the two cavities
communicate. The dorsal mesoderm persists until day
25. After the mesoderm is absorbed, the heart be-
comes suspended from the cranial and caudal ends.
A band of connective tissue grows from the epi-
cardium into the atrioventricular junction when the
heart is four chambered, resulting in separation of
atrial and ventricular myocardium. The bundle of His
remains the only means of electrical conduction from
atria to ventricles. The sinoatrial node, atrioven-
tricular node, and the bundle of His receive sympa-
thetic and parasympathetic nervous supply
throughout the rest of gestation and even after birth
to complete the development of the cardiac conduc-
tion system.
Aortic Arches
The rst pair of aortic arches is formed by the curving
of the ventral aorta to meet the dorsal aorta; these
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 diers 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 fth 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
many embryo specimens. The sixth aortic arch ar-
teries develop in the middle of the fth week. The
proximal portions develop into the main and right
pulmonary arteries, whereas the distal portion of the
left aortic arch artery develops into the ductus arte-
riosus (Fig. 13).
References
1. Abdulla R (2000) The three dimensional heart. Pediatr Cardiol
21:409
2. Anderson RH (1986) Description of ventricular septal de-
fector how long is a piece of string? Int J Cardiol 13:267278
3. Anderson RH (1991) Simplifying the understanding of con-
genital malformation of the heart. Int J Cardiol 32:131142
4. Anderson RH, Wilkinson JL, Rosenquist GC, Bergsma D
(1978) The bulbus cordis. Morphogenesis and Malformation of
the Cardiovascular System. Liss, New York, pp 128
5. Anderson PAW (1995) The molecular genetics of cardiovas-
cular disease. Curr Opin Cardiol 10:3343
6. Bartelings MM (1989) The outow tract of the heartem-
bryologic and morphologic correlations. Int J Cardiol 22:289
300
7. Bartelings MM (1990) The Outow Tract of the Heart - em-
bryologic and morphholayre correlations. Fnt. J Condcol 22:
289300
8. Bartelings MM, Gittenberger-deGroot AC (1988) The arterial
orice level in the early human embryo. Anat Embryol 177:
537542
9. Bartelings MM, et al. (1986) Contribution of the aortopul-
monary septum to the muscular outlet septum in the human
heart. Acta Morphol Neerl-Scand 24:181192
10. Becker AE, Anderson RH (1984) Cardiac embryology. In:
Nora JJ, Talao A (Eds.), Congenital Heart Disease: Causes and
Processes. Futura, New York, pp 339358
11. Benson DW, et al. (1996) New understanding in the genetics of
congenital heart disease. Curr Opin Pediatr 8:505511
12. Bockman ED (1987) Eect of neural crest on the development
of the heart and arch arteries in the chick. Am J Anat 180:332
341
Fig. 13. Degenerated aortic arch arteries (AAA) and the nal great
vessels anatomy.
R. Abdulla et al.: Cardiovascular Embryology 199
13. Bolender D, Holterman ML (2001) Animated thoughts on
teaching human development. FASEB J 15:Abstract 793.1
14. Burn J, Goodship J (1996) Developmental genetics of the
heart. Curr Opin Genet Dev 6:322326
15. Clark EB (1984) Hemodynamic control of the chick embryo
cardiovascular system. In: Nora JJ, Talao A (Eds.), Congenital
Heart Disease: Causes and Processes. Futura, New York, pp
337386
16. Colvin EV (1998) Cardiac embryology. In: Garson A Jr (Eds.),
The Science and Practice of Pediatric Cardiology, 2nd ed.
Williams & Wilkins, Baltimore, pp 91126
17. Creazzo TL, et al. (1998) Role of cardiac neural crest in car-
diovascular development. Ann Rev Physiol 60:267286
18. Hay DA (1978) Development and fusion of the endocardial
cushion. In: Rosenquist GC, Bergsma D (Eds.), Morphogenesis
and Malformations of the Cardiovascular System. Liss, New
York, pp 6990
19. Holterman MJ, et al (1999) The Visible Embryo Project: new
approaches to embryology education [abstract]. American
Academy of Pediatrics Surgical section meeting, Washington
DC
20. Holterman MJ, Blew G, Bolender D, Abdulla R (2001) Clin-
ical education development using multimedia [abstract]. Bian-
nual meeting of the American Association of Clinical
Anatomists and the British Association of Clinical Anatomists,
Cambridge, UK
21. Holterman MJ, Oladapo A, Abdulla R (1999) Clinically rele-
vant embryology: new approach to education [abstract].
American Academy of Pediatrics, Washington, DC
22. Kathiriya IS, Srivastava D (2000) Leftright asymmetry and
cardiac looping: implications for cardiac development and
congenital heart disease. Am J Med Genet 97:271279
23. Kirby ML (1989) Plasticity and predetermination of mesence-
phalic and trunk neural crest transplanted into the region of
the cardiac neural crest. Dev Biol 134:402412
24. Kirby ML, Waldo KL (1990) Role of neural crest in congenital
heart disease. Circulation 82:232340
25. Larsen WJ (1997a) Human Embryology, 2nd edn. Churchill
Livingstone, New York, pp 4961
26. Larsen WJ (1997b) Human Embryology, 2nd edn. Churchill
Livingstone, New York, pp 151188
27. Los JA (1978) Cardiac septation and development of the aorta,
pulmonary trunk, and pulmonary veins. In: Rosenquist GC,
Bergsma D (Eds.), Morphogenesis and Malformations of the
Cardiovascular System. Liss, New York, pp 109138
28. McBride RE (1981) Development of the outow tract and
closure of the interventricular septum. Am J Anat 106:309331
29. McGowan Jr FX (1992) Cardiovascular and airway interac-
tions. Int Anesthesiol Clin 30:2144
30. Moorman AF, de Jong F, Denyn MM, et al. (1998) Devel-
opment of the cardiac conduction system. Circ Res 82:629
644
31. Morse DE (1978) Scanning electron microscopy of the devel-
oping septa in the chick heart.. In: Rosenquist GC, Bergsma D
(Eds.), Morphogenesis and Malformations of the Cardiovascular
System. Liss, New York, pp 91107
32. Nadal-Ginard B, Mahdavi V (1993) Basic mechanism of car-
diac gene expression. Eur Heart J 14:suppl211
33. Nora J, Berg K, Nora AH (1991) Cardiovascular Disease:
Genetics, Epidemiology and Prevention. Oxford University
Press, New York
34. Olson EN, Srivastava D (1996) Molecular pathways control-
ling heart development. Science 272:671675
35. Pensky B (1982) Review of Medical Embryology. McMillan,
New York, pp 291355
36. Pexieder T (1978) Development of the outow tract of the
embryonic heart. In: Rosenquist GC, Bergsma D (Eds.),
Morphogenesis and Malformation of the Cardiovascular System.
Liss, New York, pp 2968
37. Pexieder T, Janecek P (1984) Organogenesis of the human
embryonic and early fetal heart as studied by microdissection
and SEM. In: Nora JJ, Talao A (Eds.), Congenital Heart
Disease: Causes and Processes. Futura, New York, pp 401
422
38. Srivastava D (2001) Genetic assembly of the heart: implica-
tions for congenital heart disease. Annu Rev Physiol 63:451
469
39. Steding G, Seidl W (1984) Cardiac septation in normal devel-
opment. In: Nora JJ, Talao A (Eds.), Congenital Heart
Disease: Causes and Processes. Futura, New York, pp 481
500
40. Thompson RP (1985) Morphogenesis of human cardiac out-
ow. Anat Rec 213:578586
41. Van Mierop LHS (1979) Morphological development of the
heart. In: Berne RM (Eds.), Handbook of Physiology, the
Cardiovascular System. American Physiology Society, Beth-
esda, MD, pp 128
42. Van Mierop LHS (1986) Cardiovascular anomalies in DiGe-
orge syndrome and importance of neural crest as a possible
pathogenetic factor. Am J Cardiol 58:133137
43. Wenink ACG (1986) Embryology of the mitral valve. Int J
Cardiol 11:7584
44. Wenink ACG, Gittenberger-deGroot AC (1985) The role of
atrioventricular endocardial cushion in the septation of the
heart. Int J Cardiol 8:2544
45. Whiten S, Smart SD, McLachlan JC, Aiton JF (1998) Com-
puter-aided interactive three-dimensional reconstruction of the
embryonic human heart. J Anat 193:337345
200 Pediatric Cardiology Vol. 25, No. 3, 2004