Cardiovascular embryology

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 primitiv

Cardiovascular Embryology

R Abdulla,1G A Blew,2M.J Holterman3

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 first 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 — Outflow tract

septation

This review of human embryology attempts to

doc-ument the many different, 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 field

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, 32–35, 38]

It is difficult 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 figure

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 difficulty 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 field of cardiac embryology is be-coming more frequent This technique is implemented

in research as well as to create educational images [1,

13, 19–21, 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 different movie animations These images were created using current information about the development of these structures On the other hand, a different 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-entifically reassembled for better understanding

Correspondence to: R Abdulla, email: rabdulla@peds.bsd.

uchicago.edu

(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 flat oval disk and is

com-posed of two layers: the epiblast and the hypoplast

The first faces the amniotic cavity and the latter faces

the yolk sac Aprimitive groove, ending caudally

with the primitive pit surrounded by a node, first

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-filtrate the space between the epiblast and the

endo-derm to form the intraembryonic mesoendo-derm After

this process is complete, the epiblast is termed the

ectoderm [16, 25, 37] (Fig 3)

The flat germ disk transforms into a tubular

structure during the fourth week of development [16,

25, 35] This is achieved through a process of

differ-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 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 tube—the primitive heart tube [16, 41] The Primitive Heart

The first intraembryonic blood vessels are noted on day 20, and 1–3 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 27–29 [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.

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 differential 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 atrioatrio-ventricular 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 outflow 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 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 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.

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 floor 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.

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

Aprimitive 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 Aplexus 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 fifth 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 cushions—a superior and in-ferior cushion These two masses will meet in the middle, thus dividing the common atrioventricular canal into right and left atrioventricular orifices 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 orifices 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 flap The endocardial cushion tissue is lo-cated at the tip of this flap, which is formed from three layers—the 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 leaflets The inner sulcus tissue will eventually come

in contact with the cushion tissue at the tip of valve leaflets, 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, supeinfe-rior vena cava.

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 orifice 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 orifice 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-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-tions appear in the posterosuperior part of the septum forming the ostium secundum, thus maintaining a communication between the two atria [41] The ostium secundum and 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 different 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 fifth week, on approximately day 30, a muscular fold extending from the anterior wall of the ventricles to the floor 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 different 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.

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 outflow septum (Fig 10)

The interventricular foramen, which is bordered

by the concave upper ridge of the muscular

inter-ventricular septum, the fused atriointer-ventricular canal

endocardial tissue, and the outflow 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

structures—the right and left bulbar ridges and the

posterior endocardial cushion tissue—that baffle the

left ventricular output through a newly formed left

ventricular outflow tract (LVOT) The LVOT is

posterior to a right ventricular outflow tract,

con-necting the right ventricle to the pulmonary trunk

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, 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 outflow 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 outflow 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 form first, 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 Mierop’s theory; however, Asami believes that these ridges fuse in the opposite direction of that indicated by Van Mierop (i.e., from the outflow 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 Amovie 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.

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,

whereas the left ventricular outflow tract becomes

short with a long ascending aorta (Fig 12) The

ventricular outflow 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 outflow tract myocardium,

from the area just above the bulboventricular fold,

and participate in the septation of the outflow tract

by providing an analogue to muscle tissue [6–9]

Myocardium in contact with the mesenchymal arch

grows rapidly and forms the bulk of the outflow

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, implybe-ing 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 latbet-ter 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 outflow tract and vascular septation LV, left ventricular; LVOT, left ventricular outflow tract; RV, right ventricle; RVOT, right ventricular outflow tract.

Fig 12 Diagram depicting the theory of ventricular outflow and great vessels’ septation by Bartlings et al [9] Numbers indicate specific aortic arch arteries.

(left) ventricle This results in a shift of the specialized

myocardium rightward in a ring shape around the

right atrioventricular orifice, only later to disappear

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

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

Aband 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 first 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 arar-teries 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 many embryo specimens The sixth aortic arch ar-teries develop in the middle of the fifth 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)

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