cardiovascular embryology

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Cardiovascular Embryology

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

1Pediatric Cardiology, The University of Chicago. MC4051, 5841 S. Maryland Ave., Chicago, IL 60637-1470, USA2School of Biomedical Visualization, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60637, USA3Department 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 vesselscomplete their development and look very much likethey will at full gestation. This amazing processtransforms isolated angiogenic cell islets into a com-plex, four-chambered structure. During this trans-formation, the single heart tube begins to beat at 23days of development and by 30 days blood circulatesthrough the embryo.

Keywords: Heart — Cardiovascular — Embryology

— Primitive heart — Heart looping — Outflow tractseptation

This review of human embryology attempts to doc-ument the many different, and sometimes disputing,theories of the development of the heart and its greatvessels. The goal is to provide a broad spectrum anddetailed information for those interested in the fieldof pediatric cardiology. Many details were inten-tionally left out, such as molecular biology issues,

because it is impossible to include this ever-expandingtopic together with morphogenesis in one article.Many publications are available for understandingmolecular biology and neural crest involvement in thedevelopment 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 theheart using 2-D terminology and illustrations, ex-

pecting the audience to recreate a mental 3-D figure.Unfortunately, the inability to conceive what is beingdescribed 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 heartfrom an autopsy that their understanding of spatialrelationship of cardiac structures of that particularlesion was wrong. This difficulty becomes even moreimmense when dealing with a 3-D object in a state of continual and complex change, such as that of thecardiovascular system during its embryological de-velopment. Therefore, it becomes increasingly usefulto depict these changes with four-dimensional im-

agery (i.e., computer animations depicting 3-Dstructures changing over time). The task of preparingthese animations is enormous, requiring expertise incomputer 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 andanimations in the field of cardiac embryology is be-coming more frequent. This technique is implementedin 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 developmentare presented. Embryonic folding, heart tube looping,and development of systemic venous drainage aredemonstrated in different movie animations. Theseimages were created using current information aboutthe development of these structures. On the otherhand, a different animation shows a process that canbe used to create 3-D objects using histological slicesfrom human embryos. Stage 14 sliced embryos from

the Carnegie collection of human embryos from theNational Library of Medicine in Washington, DC,were digitized, the cardiovascular structures weretraced, and the various slices were then stacked upusing special computer software. This animationdemonstrates how actual 3-D structures can be sci-entifically reassembled for better understanding

Correspondence to: R. Abdulla, email: [email protected].

uchicago.edu

Pediatr Cardiol 25:191–200, 2004

DOI: 10.1007/s00246-003-0585-1



Fig. 1). After 3-D cardiac structures from sequen-ally staged embryos are created, the images canrve as templates for the animation process. These

n then be studied from various vantage points andovide embryologically correct teaching tools tocilitate the comprehension of cardiac development

Fig. 2).

mbryonic Folding

arly in the third week of development, the germ diskas the appearance of a flat oval disk and is com-osed of two layers: the epiblast and the hypoplast.

he first faces the amniotic cavity and the latter facese yolk sac. A primitive groove, ending caudallyith the primitive pit surrounded by a node, first

ppears at approximately 16 days of developmentnd extends half the length of the embryo. The

imitive groove serves as a conduit for epiblast cellsat detach from the edge of the groove and migratewards toward the hypoblast and replace it to forme endoderm. After the endoderm is formed, cells

om the epiblast continue to migrate inwards to in-trate the space between the epiblast and the endo-

erm to form the intraembryonic mesoderm. Afteris process is complete, the epiblast is termed thetoderm [16, 25, 37] (Fig. 3).

The flat germ disk transforms into a tubularructure during the fourth week of development [16,, 35]. This is achieved through a process of differ-

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 toembryonic folding, angiogenic cell clusters on eitherside of the neural crest coalesce to form capillaries inthe mesoderm of the germ disk. These capillaries then

join to form a pair of blood vessels on each side of theneural crest (total of four blood vessels). These bloodvessels run along the long axis of the germ disk, with

one pair of blood vessels at the lateral edge of theembryo (one on each edge) and the other pair moremedially on either side of the neural tube. The bloodvessels on either side of the neural tube join at theircranial end.

As the embryo folds in its lateral dimension, itcauses the lateral edges of the germ disk to approacheach other until they meet, causing the embryo toacquire a tubular form [16, 25]. The two outerendocardial tubes will come close to each other in themedian of the embryo, ventral to the primitive gut,

and start fusing cranially to caudally, thus forming asingle median tube—the primitive heart tube [16, 41].

The Primitive Heart

The first intraembryonic blood vessels are noted onday 20, and 1–3 days later the formation of the singlemedian heart tube is complete. The heart starts tobeat on day 22, but the circulation does not start untildays 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, isconnected to the aortic sac and through the aorticarches to the dorsal aorta [35]. The primitive ventricleis 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) andcommon cardinal (from the embryo) and umbilical(from primitive placenta) veins. The primitive atriumand sinus venosus lay outside the caudal end of thepericardial sac, and the truncus arteriosus is outsidethe cranial end of the pericardial sac. Some publica-tions have introduced new terminology describing thesegments of the primitive heart. Wenink and Gitten-

g. 1. The Carnegie collection of embryos includes various stages

whole and sliced embryos. Digital images of slides of sliced

mbryos are made, with various structures traced using specializedftware. Subsequently, 3-D images are electronically reconstruct-

. This image depicts a slice from a stage 14 embryo with 3-D

construction, demonstrating the dorsal half of the embryo (white)

well as a 3-D reconstruction of the heart. See animation of this

ocess in the Web version of this issue.

2 Pediatric Cardiology Vol. 25, No. 3, 2004



berger-deGroot [44] support the use of inlet, outlet,and arterial segments as proposed by Anderson andBecker [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 thebulboventricular portion of the heart compared tothe pericardial sac and the rest of the embryo [35].However, it has been shown that the heart will loopeven when the pericardial sac is removed, as seenwhen the heart is cultured in vitro [24, 41]. It seemsthat the process of looping is a genetic property of themyocardium and not related to differential growth[41].

As the heart tube loops, the cephalic end of theheart tube bends ventrally, caudally, and slightly tothe right. The bulboventricular sulcus becomes visiblefrom the outside, and from the inside a primitiveinterventricular foramen forms. The internal foldformed by the bulboventricular sulcus is known asthe bulboventricular fold. The bulboventricular seg-

ment of the heart is now U shaped; the bulbus cordisforms the right arm of the U-shaped heart tube andthe primitive ventricle forms the left arm. The loopingof the bulboventricular segment of the heart willcause the atrium and sinus venosus to become dorsalto the heart loop [41]. At this stage, the paired sinusvenosus extends laterally and gives rise to the sinushorns.

As the cardiac looping progresses, the pairedatria form a common chamber and move into thepericardial sac. The atrium now occupies a moredorsal and cranial position and the common atrio-ventricular junction becomes the atrioventricular ca-nal, connecting the left side of the common atrium tothe primitive ventricle [35]. At this stage, the heart hasa smooth lining except for the area just proximal and

just distal to the bulboventricular foramen, wheretrabeculations form. The primitive ventricle willeventually develop into the left ventricle and theproximal portion of the bulbus cordis will form theright ventricle. The distal part of the bulbus cordis, anelongated structure, will form the outflow tract of both ventricles, and the truncus arteriosus will formthe roots of both great vessels. The bulbus cordisgradually 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.

R. Abdulla et al.: Cardiovascular Embryology 193



owth of the right atrium, forcing the bulbus to be ine sulcus in between the two atria [42] (Fig. 5).

ystemic Venous System

n day 21, there is a common atrium as a result of sion of the two endocardial tubes. The common

rium communicates with two sinus horns, a left andright horn, representing the unfused ends of the

ndocardial tubes [16]. These two horns will form thenus venosus.

The sinus venosus is located dorsal to the atria.he following veins drain into the sinus venosus onch side: the common cardinal vein, which drains

om the anterior cardinal vein (draining the cranialart of the embryo); the posterior cardinal veinraining the caudal part of the embryo); the umbil-al vein (connecting the heart to the primitive pla-

nta); and the vitelline vein (draining the yolk sac,astrointestinal system, and the portal circulation).

On week 4, the sinus venosus communicates withe common atrium. During week 7, the sinoatrialmmunication becomes more right sided, connectingto the right atrium. At 8 weeks, the distal end of theft cardinal vein degenerates, and the more proximalortion of it now connects through the anastomosing

in (left brachiocephalic vein) to the right anteriorrdinal vein (right brachiocephalic vein), thus form-g the superior vena cava. The left posterior cardinalin also degenerates, and the left sinus horn receivingnous blood from the heart becomes the coronary

nus. The right vitelline vein becomes the inferiorna cava, and the right posterior cardinal vein be-mes the azygos vein. All this is completed in week 8

f development. The left umbilical vein degenerates

and the right umbilical vein connects to the vitellinesystem through the ductus venosus (which is derivedfrom the vitelline veins) [26] (Fig. 6).

Pulmonary Circulation

Airways, Lung Parenchyma, and Distal Pulmonary

Arteries

On day 21 of development, a groove forms in thefloor of the foregut just dorsal to the heart. This istermed the pharyngeal groove, which develops toform the pharynx. On day 23, the laryngotrachealgroove, a median structure in the pharyngeal region,develops. The edges of the laryngotracheal tube fuseto form the larynx and trachea cranially and the rightand left main bronchi and right and left lung budsdistally. The growth and branching of the lung buds,

together with the surrounding mesoderm, form thedistal airways, lung parenchyma, and pulmonaryblood vessels. By week 16 of gestation, a full com-plement of preacinar airways and blood vessels haveformed. The pulmonary arteries in utero are muscu-lar, similar to that of the aorta. The thick, muscularwalls of pulmonary arteries extend much further intodistal arteries than what is seen in adults. Thinning of distal pulmonary arteries occurs postnatally as thepulmonary vascular resistance decreases after theonset of breathing and improved oxygenation [29].

Proximal Pulmonary Arteries

The proximal main pulmonary artery develops fromthe 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 23of development, and the four-chambered

heart is evident on day 27.




monary artery and the proximal right pulmonaryartery develop from the ventral sixth aortic arch ar-tery. The distal right pulmonary artery and the leftpulmonary 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, whichbifurcates twice to give four pulmonary veins thatgrow toward the developing lungs. The lung budsdevelop from the foregut. A plexus of veins is formedin the mesoderm enveloping the bronchial buds; theseveins will meet with the developing pulmonary veins

out of the left atrium to establish a connection duringweek 5 of gestation. As the left atrium develops, itprogressively incorporates the common pulmonaryvein into the left atrial wall until all four pulmonaryveins enter the posterior wall of the left atrium sep-arately. The incorporated pulmonary veins form thesmooth posterior wall of the left atrium, whereas thetrabeculated portion of the left atrium comes to oc-cupy a more ventral aspect [16, 35].

Atrioventricular Canal

The atrioventricular valves form during the fifth toeighth week of development [26]. Initially, endocar-dial cushion tissue forms bulges at the atrioven-tricular junction. These bulges have the appearanceof valves, and although such tissue may play an im-

portant role in the eventual formation of the atrio-ventricular valves, endocardial cushion tissues are notthe precursors of the mitral and tricuspid valves [16,43].

The atrioventricular junction is guarded by twomasses of endocardial cushions—a superior and in-

ferior cushion. These two masses will meet in themiddle, thus dividing the common atrioventricularcanal into right and left atrioventricular orifices. Theprocess through which these two cushions fuse is notclear [18], and the role of apoptosis in this process isdebatable. The fusion of the two endocardial cush-ions results in the formation of two atrioventricularorifices. In addition, the atrioventricular cushionappears to play a role in the closure of the interatrialcommunication at the edge of the primum atrialseptum. 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) lagsbehind. Such a process causes the sulcus tissue toinvaginate into the ventricular cavity, forming ahanging flap. The endocardial cushion tissue is lo-cated at the tip of this flap, which is formed fromthree layers—the outer layer from atrial tissue, theinner layer from ventricular tissue, and the middlelayer from invaginated sulcus tissue. The inlet portionof the ventricles then becomes undermined, formingthe tethering cords holding the newly formed valveleaflets. The inner sulcus tissue will eventually comein contact with the cushion tissue at the tip of valveleaflets, thus interrupting the muscular continuitybetween 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 developmentof systemic venous drainage are shown in movie

clips in the Web version of this issue. IVC , infe-

rior vena cava; SVC , superior vena cava.




he Atria and Atrial Septum

he atria of the mature heart have more than oneigin. The trabeculated portions (appendages) of the

ght and left atria are from the primitive atria,

hereas the smooth-walled posterior portions of theft and right atria originate from the incorporationf venous blood vessels. The posterior aspect of theft atrium is formed by the incorporation of theulmonary veins, whereas the posterior smooth por-on of the right atrium is derived from the sinusnosus.

The two sinus horns are initially paired struc-res; later, they fuse to give a transverse sinusnosus. The entrance of the sinus venosus shifts

ghtward to eventually enter into the right atrium

clusively. The veins draining into the left sinusnosus (left common cardinal, umbilical, and vitel-

ne veins) eventually degenerate. The left sinusnosus will become smaller because it will drain onlye venous circulation of the heart, becoming theronary sinus.

The sinus venosus orifice of the right atrium ist-like and to the right of the undeveloped septumimum [16]. The sinus venosus now connecting toe right atrium will assume a more vertical position.

he sinoatrial junction will become guarded by two

alve-like structures, resulting from the invaginationf the atrial wall at the right and left sinoatrialnction. This orifice enlarges, with the superior andferior vena cavae and the coronary sinus openingparately and directly into the right atrium. The

ght and left sinoatrial valves join at the top, forminge septum spurium. This septum and the two sino-rial valve-like structures obliterate and are not ap-eciated in the mature heart [41].

Atrial septation starts when the common atriumcomes indented externally by the bulbus cordis and

uncus arteriosus. This indentation will correspondternally with a thin sickle-shaped membrane devel-

ping in the common atrium on day 35 [39]. Thisembrane divides the atrium into right and left

hambers. It grows from the posterosuperior wall andtends toward the endocardial cushion of the atrio-

ventricular canal. This is the septum primum. Theseptum primum initially has a concave-shaped edgegrowing toward the atrioventricular canal. This orificeconnecting the two atria is called the ostium primum.As the superior and inferior endocardial cushionsfuse, thus dividing the atrioventricular canal into aright and left orifice, the concave lower edge of theseptum primum fuses with it, obliterating the ostiumprimum. However, just before this happens fenestra-tions appear in the posterosuperior part of the septumforming the ostium secundum, thus maintaining acommunication between the two atria [41]. The ostiumsecundum and superior vena cava later acquire a moreanterosuperior position, although they maintain theirrelationship with each other; this is achieved throughthe growth of the atria [41].

These fenestrations then coalesce and form a

larger fenestration. Meanwhile, another sickle-shapedmembrane develops on the anterosuperior wall of theright atrium, just right of the septum primum and leftof the sinus venosus valve. It grows and covers theostium secundum, which continues to allow bloodpassage since the two membranes do not fuse. Theseptum secundum grows toward the endocardialcushion, leaving only an area at the posterosuperiorpart 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 andthe edge of the septum secundum forms the rim of thefossa ovalis [44] on approximately day 42 of devel-opment (Figs. 8 and 9).

Ventricular Septation

Ventricular septation is a complex process involvingdifferent septal structures from various origins andpositioned at various planes [2, 27, 28, 31]. Thesestructures eventually meet to complete the separation

of the right and left ventricles.

Muscular Interventricular Septum

During the fifth week, on approximately day 30, amuscular fold extending from the anterior wall of theventricles to the floor appears at the middle of theventricle near the apex and grows toward the atrio-ventricular valves with a concave ridge. Most of theinitial growth is achieved by growth of the two ven-tricles on either side of the ventricular septum. Inaddition, trabeculations from the inlet region coalesceto form a septum, which grows into the ventricularcavity at a slightly different plane than that of theprimary septum; this is the inlet interventricularseptum, which is in the same plane of that of the

g. 7. Formation of atrioventricular valves.




atrial septum. The point of contact between these twosepta will cause the edge of the primary septum toprotrude slightly into the right ventricular cavity,

forming the trabecular septomarginalis. The fusion of these two septa forms the bulk of the muscularinterventricular septum. This septum will then comeinto contact with the outflow septum (Fig. 10).

The interventricular foramen, which is borderedby the concave upper ridge of the muscular inter-ventricular septum, the fused atrioventricular canalendocardial tissue, and the outflow tract septationridges, never actually closes. Instead, communicationbetween the left ventricle and the right ventricle isclosed at the end of week 7 by growth of threestructures—the right and left bulbar ridges and theposterior endocardial cushion tissue—that baffle theleft ventricular output through a newly formed leftventricular outflow tract (LVOT). The LVOT isposterior to a right ventricular outflow tract, con-necting the right ventricle to the pulmonary trunk.

Outflow Tract Septum

The cardiac outflow tract includes the ventricularoutflow tract and the aortopulmonary septum. Therehas been much debate regarding this process. Thissection provides a summary of various theories [9, 36,40].

In 1942, Kramer suggested that there are threeembryological areas: the conus, the truncus, and thepulmonary arterial segments. Each segment developstwo opposing ridges of endocardial tissue; the op-

posing pairs of ridges and those from various seg-ments meet to form a septum separating two outflowtracts and aortopulmonary trunks. The aortopulmo-nary septum is formed by ridges separating the fourth(future aortic arch) and the sixth (future pulmonaryarteries) aortic arches. The truncus ridges are formedin the area where the semilunar valves are destined tobe formed, thus forming the septum between the as-cending aorta and the main pulmonary artery. Theconus ridges form just below the semilunar valves andfrom 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, andconus regions. However, he stated that the pairs of ridges fuse independently and later on fuse with eachother to complete the septation. His theory indicatesthat the truncus ridges form first, and as they fuse theyform a truncal septum. This septum then fuses withthe aortopulmonary septum, which is formed byinvagination 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 Llorcaet al. [7], concur with Van Mierop’s theory; however,Asami believes that these ridges fuse in the oppositedirection of that indicated by Van Mierop (i.e., fromthe outflow tract to the aortopulmonary region). Onthe 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.




ere are only two septa—a conotruncal (or bulbar)nd an aortopulmonary septum.

In 1989, Bartlings et al. introduced a new theory.hey stated that the septation process of the ven-icular outflow tracts, pulmonary and aortic valves,

nd the great vessels is mostly caused by a singleptation complex, which they termed aortopulmo-

ary septum. This septation complex develops at thenction of the muscular ventricular outflow tract

ith the aortopulmonary vessel. This junction has addle shape, allowing the right ventricular outflowact to be long with a short main pulmonary artery,hereas the left ventricular outflow tract becomesort with a long ascending aorta (Fig. 12). Thentricular outflow septation is formed by condensedesenchyme, embedded in the endocardial cushion

ssue just proximal to the level of the aortopulmo-ary valves. The condensed mesenchyme will come inose contact with the outflow tract myocardium,om the area just above the bulboventricular fold,

nd participate in the septation of the outflow tracty providing an analogue to muscle tissue [6–9].

yocardium in contact with the mesenchymal archows rapidly and forms the bulk of the outflowptum, continuous with the primary fold on the

arietal wall of the right ventricle and the myocar-um on the right side of the primary septum.

onduction System

rimary myocardium, found in the early heart tube,ves rise to the contracting myocardium (of the atria

nd ventricles) and the conducting myocardiumodal and ventricular conducting tissue). Conduct-g myocardial tissue is frequently referred to as be-g highly specialized tissue, implying that it has a

omogenous function. In reality, some portions, such

as nodal tissue, are slow conducting and resemble lessdeveloped primary myocardium, whereas other por-tions, such as ventricular conduction tissue, are fastconducting [30].

The embryological origin and formation of thesinus and atrioventricular nodal tissue is not clear.The ventricular conduction system formation is bet-ter known. The latter starts with the formation of anencircling ring of conducting myocardial tissuearound the bulboventricular foramen. The dorsalportion of the ring will become the bundle of His. Theportion of the ring covering the septum will becomethe left and right bundle branches. The anteriorportion of the ring is called the septal branch and itdisappears during normal embryological develop-ment. Other portions of this specialized tissue thatform and later disappear are the right atrioventricularring bundle and the retroartic branch. The rightatrioventricular ring forms due to the rightward shiftof the common atrioventricular valve, which origi-nally connects the common atrium to the primitive

g. 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 specializedmyocardium rightward in a ring shape around theright atrioventricular orifice, only later to disappear.The retroarotic branch is formed as a result of theleftward 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 themidline as the two heart tubes are fusing into a me-dial tube (day 21). The two cavities approach eachother and surround the heart tube. The ventral mes-oderm is immediately absorbed and the two cavitiescommunicate. The dorsal mesoderm persists until day25. 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 theheart is four chambered, resulting in separation of atrial and ventricular myocardium. The bundle of Hisremains the only means of electrical conduction fromatria to ventricles. The sinoatrial node, atrioven-tricular node, and the bundle of His receive sympa-thetic and parasympathetic nervous supplythroughout the rest of gestation and even after birthto complete the development of the cardiac conduc-tion system.

Aortic Arches

The first pair of aortic arches is formed by the curvingof 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 arteriesappears in week 4. These regress rapidly and only aportion remains, which forms the stapedial and hyoidarteries. The third pair of the aortic arch arteriesappears at approximately the end of the fourth week;these will give rise to the common carotid arteries andthe proximal portion of the internal carotid arteries.The distal portion of the internal carotid arteries isformed by the cranial portions of the dorsal aorta.The fourth aortic arch arteries develop soon after thethird arch arteries. Their development differs on theleft from that on the right. On the left side, theypersist, connecting the ventral aorta to the dorsalaorta and forming the aortic arch. On the right, theyform the proximal portion of the right subclavianartery. 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 inmany embryo specimens. The sixth aortic arch ar-teries develop in the middle of the fifth week. Theproximal portions develop into the main and rightpulmonary arteries, whereas the distal portion of theleft aortic arch artery develops into the ductus arte-riosus (Fig. 13).

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Fig. 13. Degenerated aortic arch arteries (AAA) and the final great

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