Embryology and Congenital Heart Disease

Denton A. Cooley's50th Anniversaryin Medicine

Paolo Angelini, MD

Thls series in recognltlonof Dr. Cooley's 50thanniversary in medicineis continued from theDecember 1994 issue.

Key words: Anatomy;embryology; heart defects,congenital

From: Texas Heart Instituteat St. Luke's EpiscopalHospital, and Baylor Collegeof Medicine, Houston, Texas77030

Section editors:Grady L. Hallman, MDRobert D. Leachman, MDJohn L. Ochsner, MD

Address for reprints:Paolo Angelini, MD,Leachman CardiologyAssociates, PO. Box 20206,Houston, 7X 77225-0206

Embryology andCongenital Heart DiseaseC ongenital heart defects can be considered the product of naturally occur-

ring experiments caused by developmental "errors."" During the pastseveral years, this concept has been used to help explain, define, and

classify congenital heart defects in teaching cardiovascular fellows and residentsat the Texas Heart Institute.

In this review, embryologic phenomena-' are described and abnormal embryo-logic events that could contribute to the morphogenesis of congenital heart de-fects are suggested. Because our current knowledge of congenital heart defects inthe developmental stage of life is limited, I offer these speculations and observa-tions, both in a didactic manner and as a stimulus to investigators who may ad-vance knowledge in this fascinating field of human pathology. The reader isreferred to basic embryology textbooks for more comprehensive descriptions ofnormal development. Nomenclature is still a confusing and inconsistent disciplinein this field, and it is not the intended focus of this paper.

The First Choice: SidednessThe early vertebrate embryo at the primitive streak stage (about 15 days after fer-tilization in humans) is morphologically symmetrical, as shown in histologic stud-ies (Fig. lA). The primordia of the cardiovascular system originate as clusters ofpaired, symmetrical mesenchymal cells in the coelomic mesoderm. Initially locatedon the cephalad and dorsal aspect of the embryo, they soon appear to migratearound the buccopharyngeal membrane of the forming foregut, and join at themidline of the ventral aspect of the embryo. The fused section of the cardiovascu-lar primordia lies within the cephalad section of the originally undivided coelo-mic cavity, which soon defines a midline thoracic cavity (the pericardium).Structures within the pericardial cavity are defined embryologically as the heart.

At first, the fused strands of cells of the primordia are arranged as a straightstructure called the straight tube heart, which traditionally has been described interms of prospective segments: atria, primitive ventricle, bulbus cordis, conus, andtruncus (Fig. 2). The heart at this stage has no inner circulation of blood, but soonbecomes hollow (tubelike). The mesenchymal cells forming the straight tube canbe visualized as continuously migrating from the dorsal and cephalic aspects ofthe embryo toward the intrapericardial structure. At the caudal extreme, the intra-pericardiac structure meets the venous system, which, at this stage, comprisesmainly the omphalomesenteric veins. From this caudal extreme, too, cells activelyreproduce and migrate into the cardiac tube.

Developmental Implications. The 2 cardiogenic areas are provided with intrin-sic differential growth characteristics and are the determinants of sidedness, whichis the first and fundamental choice that the primitive heart makes. The cardiacstructures originate by fusion of the 2 primordia, with the exception of the caudalextreme: the right atrium receives only right-sided cardiogenic cells, and the leftatrium, left-sided cardiogenic cells. The normal heart "decides" its visceral situs(pattern of asymmetry) at a very early stage of development (Fig. 1B). Fun-damental anomalies, such as situs inversus and situs ambiguus of the dexter(asplenia) and sinister (polysplenia) types, might be explained by the develop-mental errors illustrated in Figure 3. Such embryogenetic interpretation is sup-ported by reports of experimental studies in chicken embryos.9

Morphogenesis of the Ventricles: Cardiac LoopingThe embryonic heart acquires morphologic asymmetry, under the impulse ofcontinuous cellular migration and multiplication, by looping the bulboventricular

Embryology and Congenital Heart Disease 1Texas Heati Institutejournal

Pericardialcoelom7

Bk

Frontal View

Fig. 1 Situs solitus. A) Schematic dorsal view of the earlychicken embryo at the primitive streak stage (17 hours ofincubation). This stage corresponds to the end of the 2ndweek after fertilization in the human embryo. The embryonicdisc is symmetrical, with minimal organization. The cardiacprimordia are located in front of the cephalic end of theembryonic disc. Later on, the ventral formation of the foregutwill cause the cardiogenic areas to be located ventrally, on

each side of the foregut (pharynx). B) The normal situs solitusviscera are histologically symmetrical at this early stage, butthey have committed potentials to develop the asymmetricanatomic patterns shown in the lungs, atria (heart), liver,spleen, and intestines.

segments inside the pericardial cavity. Differentialmigration and multiplication of cardiac primordialcells could be the original reasons for normal evolu-tion of the straight heart into a dextroverted (or right-ward) loop, called D-loop. Experimental evidence9has shown that alteration of the normal differentialgrowth pattern may result in a leftward loop, or L-loop. The direction of looping appears to establishirreversibly the relationship between the ventricles(whose primordia, originally situated in series, be-come positioned side-by-side) and the already deter-mined situs of the atrial cavities."' As shown in Figure4, the looping of the bulboventricular tube leads thebulbus cordis (prospectively, the right ventricle) to

the right (D-loop) or to the left (L-loop) of the ini-tially caudal segment, which is the primitive ventricle(prospectively, the left ventricle).

Additionally, the pattern of looping determinesthe relationship between the 4th and the 6th aorticarches. Because the 4th aortic arches are more ante-rior than the 6th, the looping of the bulboventricularsegments will also establish a slight, but definite andirreversible shift to the right (D-loop) or the left (L-loop) of the anterior aortic arches (4th) with respectto the posterior structures. Such consequential mor-

phogenetic definition results in a permanent rela-

Fig. 2 The ventral view of the 4- to 8-somite embryo showsthe formation of the straight tube heart within the pericardialcoelom. The caudal (atrial) and cephalic ends of the primitiveheart maintain the separation in 2 nearly symmetricalstructures: the right and left atria; and the right and left 1staortic arch. Embryologists12 have been able to identify theprospective regions of the heart at this early stage, as shown.Only the atria maintain strict derivation from just cardiogenicarea. The other segments combine derivatives from both theright and the left cardiogenic primordia.

tionship between the distal aortic and pulmonarytrunks (Fig. 4) that will be affected neither by theeventual inner septation of the truncoconal struc-tures nor by the shifting toward the midline of thecaudal extreme of this tube (see section on trunco-conal septation). The correlation between the posi-tion of the ventricles and the aortopulmonaryrelationship at their cephalad extreme is the basis forthe so-called loop rule of concordance of the arterio-ventricular morphologies.*ll

Developmental Implicationis. Bulboventricularlooping (to the right or the left) is a morphogeneticprocess, independent of the one that leads to thecardiac situs determination. Whereas the positions ofthe right and left atria are determined by a certaincardiac (and visceral) situs, the side-to-side relation-ship that develops between the ventricular cavitiesand the aortic and pulmonary trunks is decided bythe pattern of looping. Four basic combinations are

possible: situs solitus with D looping, situs solituswith L looping, situs inversus with D looping, or si-tus inversus with L looping. D-looping causes thecaudal segment of the loop (the primitive ventricle)to lie to the left of the cephalad segment of the bul-boventricular loop (bulbus cordis, prospectively theright ventricle). The embryologic conotruncus will

The loop rule of Van Praagh R and coworkers" describes the as-

sociation of ventricular side-to-side relationships with aorto-pulmonary relationships. When the anatomic right ventricle is onthe right side, the ascending aorta is also on the right side(both in transposition and in normally positioned great vessels).

2 Embryology and Congenital Heart Disease

Cephalad

L +R

Caudal(Truncus)

Dorsal View

Conus

Bulbuscordis

- Primitiveventricle

(Right (Leftatrium) atrium)

Iblume 22. Alumber 1, 1995

A

Situs Inversus

B

Asplenia

C

PolyspleniaFig. 3 Classic experiments in chicken embryos have shown the many potentials of the right and left cardiogenic areas, including alltypes of variations in the positions of the atria, which are the only sections of the heart that maintain the individual nature of eachcardiogenic area. A) Transplanting the right cardiogenic area in the left location and vice versa leads to the development of a mirrorimage, or situs inversus. B) Similarly, an embryo given 2 cardiogenic areas with right potentials will develop situs ambiguus dexteror asplenia syndrome (2 right atria). In naturally occurring congenital defects of the cardiogenic areas, the 2 entire hemisomas ofthe embryo commonly are affected, leading to accompanying anomalies of the situs of all viscera. C) When an embryo is trans-planted with 2 cardiogenic areas having left-sided potentials, situs ambiguus sinister or polysplenia will develop.

A

Fig. 4 The morphogenetic implications of bulboventricular looping are illustrated, showing the positions of the ventricles and ofthe cephalad extreme of the great vessels. The cephalic portion of the aorta shifts to the right in D-loop (A), and to the left in L-loop (B).LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle

Embryology and Congenital Heart Disease 3Texas Heati Iiistitiitejourtial

also be displaced to the right, since it is serially con-nected with the bulbus cordis. L-looping leads to amirror-image arrangement of the bulboventricularcomponents and their derivatives, in the frontalplane.

During the last 2 decades of experimental embry-ology and clinical anatomy studies, it has becomeapparent that other types of grossly atypical loopingare possible. These variants lead to malformations inwhich the ventricular anatomy does not conform tothe side-by-side orientation of the cavities. Rather,malformations like inferosuperior ventricles, criss-cross hearts, or dissociation between the ventric-ular morphologies and the distal truncal anatomydevelop (i.e., arterioventricular dissociation, withL-loop great arteries and D-loop ventricles). Suchatypical morphologies are most likely the result ofatypical and complex intrinsic deformities of thebulboventricular loop (i.e., double looping, as sug-gested hypothetically in Fig. 5).

Formation of the Left Ventricular OutflowTract and the Right Ventricular InflowTract: Shifting and Differential GrowthThe relationship between truncoconal outlets andventricular structures becomes established simulta-neously with another separate but equally importantmorphogenetic process: the acquisition of an inlet bythe bulbus cordis. The early, looped cardiac tube hasessentially a single inlet (the common atrioven-tricular canal), which conveys the venous blood tothe primitive ventricle. (At this time, only systemicvenous blood will be delivered, since there is no

pulmonary circulation.) This primitive ventricle hasno other outlet except a primitive ventricular septaldefect (bulboventricular defect), through whichblood is channeled into the bulbus cordis and fromthere into the common truncoconal tube (Fig. 6A).Later the atrioventricular (AV) canal grows by wid-ening rightward, and the AV cushions acquire adirect relationship to the bulbus cordis. This relation-ship leads to the maturation of the bulbus cordis intothe definitive right ventnicle (Fig. 6B).

Bulboventricularflange or spur

Truncus

Conus -

Bulbuscordis

Primitive ventricularseptal defect

(bulboventricular)Primitive

AV canal ventricle

B

Right AV canal Leftventricle ventricle

Fig. 5 The potential consequences of atypical cardiac loopingare illustrated by this theoretical example of complex (double)looping. A) The upper looping is D, leading to right-sided aorta(normal); however, the lower looping is L, leading to a rightventricle on the left. B) The result is arterioventriculardissociation (D-great vessels, L-ventricles), which constitutesan exception to the "loop rule. "

Fig. 6 The acquisition by the early loop heart (A) of the finalventricular morphologies (B) requires a widening of theatrioventricular canal to the right, and a shifting of the conusto the left, with disappearance of the bulboventricular flange.These changes occur during the 5th and 6th weeks of humanembryonic development. The arrows within these heartsrepresent blood flow patterns.


A

V'olti ine 22, Number 1. 1995

At the same time, the arterial outlet undergoes aprocess of leftward shifting and differential growththat leads to the disappearance of the bulboventric-ular flange or spur (Fig. 6B); the resorption of thecaudal extreme; and leftward shifting of the conus,closer to the anterior AV canal cushion. This processis crucial; in its absence, a double-outlet right ven-tricular defect originates.

Developmental Implications. The early heart ischaracterized by a sequential arrangement of the car-diac segments (atria -> primitive ventricle -> bulbuscordis -> single truncoconal tube). In case of persis-tence of such a primitive arrangement, the most like-ly results would include a double-inlet left ventricle(or a common AV canal entering only the left ven-tricle) and a double-outlet right ventricle of the out-let chamber variety (without an AV valve or papillarymuscles, and no inlet other than a bulboventricularcommunication).

Normally formed right and left ventricles can bedefined according to their embryologic componentsand intrinsic, anatomic features.'2 The left ventricleis characterized by a single inlet, whereas the mal-formation called double-inlet "left" ventricle is thepersistence of the embryologic primitive ventricle, amitral valve, 2 papillary muscles, and an outflowtract. In embryologic terms, the outlet portion of theleft ventricle (corresponding to the location of asupracristal ventricular septal defect) is a conal de-rivative, and not intrinsically a ventricular structure.Similarly, the right ventricle is characterized by asingle inlet with a tricuspid valve, and 1 anteriorpapillary muscle connected to the ventricular sep-tum by a moderator band. Part of the anatomic rightventricle (the outlet delineated by the crista supra-ventricularis) is a derivative of the embryologic co-nus (Fig. 7).

In anomalies like tricuspid or mitral atresia, the AVcanal is normally aligned with the ventricular sep-tum. Therefore, these anomalies are not related somuch to the abnormal widening of the AV canal, asto the intrinsic defects in the differentiation of eachAV canal subdivision. Such defects lead to atresia ofeither orifice, usually after normal closure of the in-let ventricular septum. Hence tricuspid atresia is nota form of double-inlet left ventricle, although, func-tionally, mixed venous blood enters only the leftventricle in both malformations. Tricuspid atresia canoccur both with atresia of the annulus (in which theinlet of the right ventricle is also atretic) and with anormal (or only hypoplastic) tricuspid annulus withimperforated AV leaflets (in which case the inlet isvariably but distinctly preserved).

In the development of double-outlet left ventricle,the leftward shifting of the conus evidently exceedsthe normal shifting, leading to the inclusion of mostof the conal derivatives into the left ventricular out-

Texas Heart InstituteJournal

Primitiveventricularseptum

Septalrband

Anterior Moderatorpapillary muscle band

Bulbus cordis ° AV canal

§******!a Conus Primitive ventricle

Fig. 7 The definitive right ventricle is not made only from thebulbus cordis; it is also composed of tissues of the conus, theatrioventricular (AV) canal, and the primitive ventricle. Shownhere is a cross-section of a right ventricle and its embryologiccomponents.

flow tract. In contrast, cases of double-outlet rightventricle suggest an incomplete left shifting of theconal derivatives. The occurrence of double-outletright ventricle in conjunction with so many variants(for example, double side-by-side muscular coni,transposition, normally crossed great vessels, com-mon truncus, and tetralogy of Fallot'3) suggests thatseptation of the conus is a process independent ofits leftward shifting.

Atrial SeptationThe normal, complete separation of the 2 atrial cavi-ties is a complex process, involving ingrowths of tis-sue from different sources; duplication; fusion; andresorption. Figure 8 illustrates the essential mor-phologic stages. First, a membranous structure ap-pears on the posterosuperior aspect of the commonprimitive atrium medially to the entrance of the com-mon venous sinus. This membrane, called the sep-tum primum, grows caudally and anteriorly until itmeets outgrowths of the medial AV cushions. Thetransient defect of the septum primum that is nor-mally present in early embryos is called the ostiumprimum, which is closed when 3 structures con-verge and fuse: the septum primum, and the ante-rior and the posterior medial AV cushions. Before

Embryology and Congenital Heart Disease 5

Anterior medialAV cushion

Septum secundumOstium secundum

it\ /Septum primum

L:\

/ \

B Fossa ovalis Ostium primum

Svc._- n /,Fossa

ovalis

lvc

C

Membranousseptum

Fig. 8 During the 5th and 6th weeks of human development,the essential stages in the septation of the atria are com-pleted (see text). A) Arrows indicate the direction of growthof the septum primum. B) Arrows indicate the direction ofgrowth of the septum secundum. C) The fetal heart is leftwith a functionally patent foramen ovale that allows preferen-tial flow of highly oxygenated blood from the placenta throughthe IVC (arrow indicates flow pattern). Also noted are thelocations of the atrioventricular and ventricular sections ofthe membranous septum.

IVC = inferior vena cava; SVC = superior vena cava

such convergence is completed, a new membrane,the septum secundum, appears just to the right of theseptum primum, possibly as a duplication of themedial valve of the common sinus venosus. The sep-

tum secundum grows to cover the septum primumon the right side, with the exception of a round cen-

tral area. This defect is called the fossa ovalis; itsfloor, as seen from the right side of the atrial septum,is composed of septum primum. Normally, the sep-

tum primum also has or acquires a defect in itssuperoposterior section, called the ostium secun-

dum. Such a defect is not a true atrial septal defect(ASD), because it is covered on the right side by theseptum secundum; however, it functions during fe-tal life as an obligatory escape valve, allowing highlyoxygenated blood from the inferior vena cava (um-bilical veins) to leak through the fossa ovalis andthe ostium secundum into the left atrium. Only afterbirth do the septum primum and the septum sec-

undum completely coalesce, so that the normal fetalpatent foramen ovale disappears, usually during the1st 30 days of life. In a limited percentage of other-wise normal hearts (5% to 20%), this defect remainspotentially open (probe patent) for several years.

Developmental Implications. Defects of the atrialseptum typically occur at certain sites, in variablesizes (Fig. 9):

1) Ostium prnmum ASD is a defect of the caudalaspect of both the septum primum and the septumsecundum, usually caused by or concomitant with a

lack of fusion of the 2 medial AV cushions. This lackof fusion leads to the concurrent presence, in mostostium primum ASDs, of a cleft in the mitral and tri-cuspid septal leaflets or some type of AV canal de-fect. (See section on ventricular septal defects.)

2) Fossa ovalis defect (also-but improperly-called secundum ASD) is the most common type ofASD and results from resorption of the septum pri-mum, which normally provides the floor of the fossaovalis. This defect should be distinguished from per-

sistence of the patent foramen ovale valve, a virtu-ally nonfunctional ASD (described above).

3) Sinus venosus ASD is located at the site of thenormal defect in the septum primum called the os-

tium secundum, which becomes a permanent defectupon the lack of formation or the reabsorption of the


Posterior medialA AV cushion

Iblume 22, Number 1, 1995

Dextro-dorsalconal ridge

Conus

|I AVcushions

01111111111111I Primitive ventricular septumCoronarysinus Tricuspid

valveFig. 9 The locations of the 4 most common types of atrialseptal defects are illustrated in a right view of the atrialseptum.

IVC = inferior vena cava; SVC = superior vena cava

Fig. 10 Illustrated here are the 5 components of the normalventricular septum that contribute to the final septal closure(at about the 7th or 8th week of development in the humanembryo). The right ventricular side is shown.

adjacent septum secundum. This defect is near thesuperior vena cava entrance into the right atrium andfrequently occurs in conjunction with anomalousdrainage of one or all the right pulmonary veins intothe superior vena cava or the right atrium. The rea-

son for this association has not been proved, but itcoulld be related to the jet effect directed at the up-

per atrial septum caused by a primarily abnormalflow from anomalous right pulmonary veins.

4) Coroncaty sinuiis ASD is a defect in the caudalposterior atrium, just above the normal site of drain-age of the coronary sinus, which, in Such cases, ismissing its terminal section. The coronary veins draindirectly into the left and right atria.

5) Sinigle-atrium ASD consists of a total absenceof the atrial septum, frequently accompanied by

clefts in the mitral and tricuspid septal leaflets or

even a coimiplete AV canal: evidence of the interde-pendence of the atrial septa and the AV cushions innormal development.

AV Canal and Ventricular SeptationTotal closure of the ventricular septum is normallyachlieved by the 45th day of developiment in the hu-man embryo and depends on the convergence andfusion of 5 different components: the primitive ven-

triculalr septuLml, the posterior and the anterior AVCushlions, and the dextro-dorsal and the sinistro-ven-

tral conal ridges (Fig. 10). The primitive ventricularseptum appears shortly after the looping of the car-

diac tube and defines the primitive ventricle as sep-

arate from the bulbus cordis. The upper edge of theprimitive ventricular septum delineates the bulbo-ventricular defect or primitive VSD, below the bul-boventricular flange (or spur). In order to enableventricular septal closing, the conus and AV canalmust duplicate, and then align with the primitiveventricular septum; their components are essential tothe definitive ventricular septum.The final section of the ventricular septum to

close is coimiposed of permanently fibrous tissue,whereas the rest of the septum is composed of thickmyocardial tissue. The normal site of the meimibra-nous (fibrous) ventricular septum is just caudal andposterior to the crista supraventricularis, overridingthe septal implantation of the tricuspid valve whenviewed from the right ventricular side (Fig. 1 lA).

From the left ventricular side, the membranous sep-

tum is located below the aortic valve, between theright and the noncoronary cusps, in front of thebundle of His and above its anterior subdivision (Fig.1 B). Part of the fibrous septum then separates theleft ventricular outflow tract from the right atrium,differentiating the implantation of the tricuspid valve(extending lower and anterior) from the mitral valve,which has a lower and posterior implantation intothe ventricular septum (Fig. 8C). The anterior seg-ment of the septal leaflet of the mitral valve consti-

Embryology and Congenital Heart Disease

svc

Sinistro-ventralN

conal ridge

Texas Heart Instilute.1ournal

BCrista

supraventricularis Pulmonicvalve/A

t Lancisi'smuscle

Left posterior fascicleof His bundle

Anterior Posteriorpapillary muscle papillary muscle

VSD Type II VSD Type III 1111 VSD Type IV

Fig. 11 Typical locations of the different types of ventricular septal defects and the conduction system as seen from the right sideof the septum (A) and the left side (B).

tutes the posterior wall of the left ventricular outlet.Developmental Implications. Lack of coalescence

or primary failure of any component of the ven-

tricular septum to form completely will result in a

functional communication between the 2 ventric-ular cavities.

Four types of ventricular septal defects (VSDs) are

recognized (Figs. 11 and 12):1'1) Membranous orperimembranous septal defect

(VSD type II>4 is caused by the failure of the mem-branous septum to form completely, and may occur

because of an inadequacy of any of the 5 contribu-tors. This VSD is located in the left ventricular out-flow tract, just beneath the noncoronary and rightcoronary cusps of the aorta. Less frequently, thisVSD consists of a left ventricular-to-right atrial com-munication (atrioventricular defect), typically lo-cated just above the anteromedial commissure of thetricuspid valve. From the right ventricular view, themembranous VSD is located just caudal to the cristasupraventricularis, anterior or posterior to the im-plantation of the Lancisi's papillary muscle of the tri-cuspid valve (Fig. 11A).

2) Supracnstal or conal septal defect (VSD type IP4is located in the right ventricular outflow tract justbelow the pulmonary valve. From a left ventricularview, the defect is just below the right coronary cusp,

which frequently leads to the prolapse of that cusp

into the defect and consequent functional septal clo-

sure in diastole. Because of its close relationship withthe supporting structure of the right aortic leaflet, thisVSD is often complicated by aortic regurgitation. Itis interesting to note that the location of this defectindicates the midline of the conal septum and illus-trates the contribution of this (conal) structure to theclosing of the "ventricular" (anatomically defined)septum.

3) AV canal defects (VSD type IIIY4 are the mostcomplex VSDs; they involve not only a lack of sepa-

ration of the ventricular cavities, but also some vari-able defects of AV valves. The variants range fromthe isolated cleft of the septal leaflets to a common

AV valve with varying degrees of attachment to theventricular septum and shortening of the height ofthe ventricular septum. Occasionally, subaortic ste-

nosis is also associated with an AV canal defect. It isimportant to note that this VSD is caused by a fail-ure of the uppermost component of the ventricularseptum to develop below the septal leaflets of theAV valves, most likely because of a lack in the me-

dial AV cushions. Similar to the type II VSD, themembranous septum is never present in these cases

(these defects include a component of the type II

VSD). A gooseneck appearance of the left ven-

tricular outflow tract, indicated by left ventricularangiography, is characteristic of these VSDs. Thisconfiguration, as well as the presence of subaorticstenosis, may occur because the septal leaflet (ante-


A

Hisbundle

AVnode

VSD Type I

Volume 22, Number 1, 1995

Posterior AV node Truncoconal Septation: The Formation

R<

L of the Aortic and Pulmonary TrunksThe earlier section on cardiac looping alluded to the

Anterior basic and primitive relationship of the distal portionsof the aorta and pulmonary artery (related to thedevelopment of the 4th and 6th aortic arches, respec-

/}ltzMitral \\\ tively). The separation of the conus and truncus into

/,\valve \ \ \2 channels occurs simultaneously, but indepen-dently, at each level. The truncal septation is formed/D//a 'S M 2} § Xby 2 opposite (truncal) ridges, which begin to de-

4 \ \\ \'t 2 ^ / velop from the area between the 4th and 6th aortic

l rTricuspidt \\ ' Z / arches (the aortic sac) and grow caudally in a spiralfashion during normal development. At their caudal

valve \ \\NCl//Lc^ Lextreme, the truncal ridges swell and are then called\N\\/\,icushions. They are complemented by similar inter-

calated cushions in the free wall of the commontruncus (Fig. 13). The ftirther development of such"I/semilunar" cushions leads to the formation of the

Right ,> / %u\\,W aortic and pulmonary valves. Caudal to this level, thecoronary conal segment (which is relatively longer in earlyartery / / 7 Left embryonic hearts than in end-development hearts)

Membranous coronaryventricular Aortic Pulmonic artery A Common truncusseptum valve valve

Fig. 12 The coronal section of the heart is illustrated, to show B Intercalatedthe location of the membranous ventricular septum and the cushions (semilunar)course of the coronary arteries with respect to the cardiac _valves.

LC = left coronary cusp; NC = noncoronary cusp; RC = rightcoronary cusp Truncal

ridgesrior half) of the mitral valve is usually implanted intothe outflow tract of the left ventricle, causing theoutflow chamber to be hypoplastic and sometimes Cstenotic. The AV conduction system is alsopeculiarain these cases, because the bundle of His is displaced Incompleteinferoposteriorly, and its anterior subdivision is elon- - fusiongated. The left anterior fascicular block seen electro-cardiographically in these cases is not a sign of realhistologic or functional damage to the anterior fas- D Final Stagecicle, but simply of its increased length.

4) Muscular septal defect (VSD type IV14 is caused tby 1 or multiple defects in the primitive ventricularseptum. The location is unpredictable. These VSDs -kare usually small and difficult to recognize on surgi-cal inspection from the trabeculated right ventricularaspect. In cases of tricuspid atresia, a peculiar andconsistent type of muscular VSD occurs: a fissure- Aortic Pulmonarylike, horizontal defect located inferiorly and posteri- valve valveorly to the membranous septum.Common ventricle is the case wherein little or no

residuum of the ventricular septum exists, althoughthcoa setu ma eitc.Thsmresvr Fig. 13 Formation of the pulmonary and aortic semilunar

valves, by swellings (ridges) that appear at the caudallack of ventricular septation is probably due to the extreme of the truncus (completed by the 9th week inabsence of both the primitive ventricular septum and human embryos).the AV cushion's components.

Embryology and Congenital Heart Disease 9Texas Heati Iiistitiitejozirtial

I

presents a simultaneous process of duplication ofthe inner lumen. This duplication is accomplishedby the appearance of 2 opposite ridges (the dextro-dorsal and sinistro-ventral conal ridges), whicheventually fuse in the midline, as mentioned in thesection on ventricular septation.

It is interesting to recognize that in both normaland abnormal development, the truncal and conalsepta correspond, even though they develop byseparate processes. Hemodynamic forces most likelylead to this alignment.

In experimental embryology, the factors that leadto abnormal septation of the truncoconal segmentshave not been established. Recent investigations byKirby and coworkers'" suggest the neural crest as apredominant influence. Early damage to the ceph-alad neural crest appears to result in the frequentoccurrence of common truncus or transposition ofthe great vessels.Much of the classical discussion about the mor-

phogenesis of the great vessels revolves around thefollowing questions: Is the initial implantation ofthe conal and truncal septa identical in all cases, anddo differences in the resorption of the conus intothe left ventricle generate a different rotation of thesepta? Or could the spiral rotation (or lack of it) bedetermined before leftward shifting of the conus? Atthis time, it appears that the normal embryonic hearthas a characteristic spiral rotation of the truncoconalseptum before leftward shifting and reabsorption ofthe bulboventricular flange.

Developmental Implications. The arrangeimient ofthe great vessels is traditionally described as a recip-rocal relationship in space (right to left, anterior toposterior), so that normally crossed great vessels fea-ture an anterior, muscular, pulmonary conus and aposterior, short, fibrous aortic outlet. Since the 2 coniare connected to the 4th and 6th aortic arches,whose spatial relationship is established by cardiaclooping, the normal resulting rotation of the trun-coconal septum is 1800 (Fig. 14A).

In contrast, transposition of the great vessels fea-tures an aorta that is parallel to the pulmonary ar-tery, and positioned anteriorly and to the right of it(Fig. 14B). The truncoconal septum is then straight.An intermediate rotation of the conotruncus leads tothe side-by-side arrangement of the aortic and pul-monary valves (Fig. 14C) that is seen frequently, butnot exclusively, in double-outlet right ventricle.'3 Itis interesting to note that anterior coni are charac-terized by the higher location of the related semilu-nar valves and by a muscular infundibulum, whereasa posterior conus usually features fibrous continuitybetween the related semilunar valve with the mitraland tricuspid valves. Suclh intrinsic relationships ofthe great vessels could be defined independently oftheir connections with the ventricles. All 3 basic trun-

A B

Fig. 14 Schematic representation of the rotation of the trun-coconal septum in the 3 most common morphologies of thegreat vessels: A) normal (1800), B) transposed (0°), and C)side-by-side (partial distortion or 900) rotations.

coconal morphologies can occur in double-outletright ventricles (1oth great vessels arising mainlyfroimi the right ventricle); in orthoposition (1 vesselon eaclh side of the ventricular septum, as in thenormal heart); or in double-outlet left ventricle.

Recently, some investigators'6 have found it moreconvenient to eliminate the description of the intrin-sic relationship of the great vessels and describe con-nections instead. For example, the anatomy wouldbe described as normal when the aorta arises fromthe left ventricle, and the pulmonary artery, from theright ventricle. The term transposition would be ap-plied when the aorta arises from the right ventricleand the pulmonary artery from the left ventricle.According to this approach, further descriptionsidentify the infundibular morphologies. This systempresents major difficulties because it does not iden-tify the various and somewhat confusing spatialarrangements of the great vessels that occur in suchanomalies as double-outlet right ventricle or left ven-tricle, or transposition of the great vessels. Only com-mon agreement (among international societies) willsettle these disagreements, which are only partiallya matter of semantics.

Malformations of the great vessels are not onlycharacterized by the above-discussed variations inthe orientation of the truncoconal septum, but byits lack of development or uneven septation of theconotruncus, leading to either pulmonary artery ste-nosis and atresia, or to aortic hypoplasia, stenosis,and atresia (Fig. 15). Common truncus arteriosusis, in its most complete form, the result of a lack offormation of the truncoconal septum in its entirety,which in turn leads to a single arterial trunk andsemilunar valve, a conal septal defect, and the ab-

lo Embryology and Congenital Heart Disease l'olititie 22. Number 1. 1995

geneses are compared with normal developmentand are thoroughly understood. At our institution,investigators are working on questions regarding theearly development of the heart at the cellular andmolecular level,9 in addition to the morphology ofthe heart with congenital defects. Herein I have de-scribed my observations and speculations aboutmost congenital heart malformations, their plausiblemorphogenetic mechanisms, and the forms in whichthey appear. I hope this report will provide a usefulframework through which others can achieve furtherunderstanding, both for anatomic and for clinicaldisciplines.

Acknowledgment

The author is deeply indebted to Dr. M. V. de la Cruz,National Institute of Cardiology, Mexico City, fromwhom he received formal training in the field ofembryology and anatomy of congenital heart dis-eases.

References

Fig. 15 Truncoconal septation is totally absent in commontruncus arteriosus (type 1I of Collett-Edwards illustratedin [Al) and unevenly displaced toward the pulmonary side intetralogy of Fallot (B). In the latter anomaly, not only is thepulmonary valve stenotic, but also its annulus, the infundib-ulum, and the main trunk. The anteriorly displaced conalseptum (normally completed) cannot align with the ventric-ular septum, leading to a ventricular septal defect (VSD)beneath an ectasic aorta.

sence of membranous septum. Partial truncoconalseptal defects include aortopulmonary window (alimited defect of the only truncal septum); supra-cristal VSD (a conal septal or Type I VSD); and, themost common, type II of Collett and Edwards' "com-mon truncus,"1l which has only partial septation ofthe truncus in the distal section (Fig. 15A). Tetralogyof Fallot is a typical form of uneven septation of theconotruncus at the expense of the pulmonary side,resulting in pulmonary valve stenosis; in pulmonaryhypoplasia (especially evident in the infundibulum);a VSD (because of misalignment of conal and ven-tricular septa); and aortic ectasia with dextroposition(Fig. 15B).

Conclusion

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6. De la Cruz MV, Munoz-Armas S, Munoz-Cartellanos L. De-velopment of the chick heart. Baltimore: Johns HopkinsUniversity Press, 1972.

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8. Van Mierop LHS, Alley RD. Kausel HW, Stranahan A. Patho-genesis of transposition complexes. I. Embryology of theventricles and great arteries. Am J Cardiol 1963;12:216-25.

9. McQuinn TC, Takao A. Experimental embryology and tera-tology. In: Garson A, Bricker JT, McNamara DG, eds. Thescience and practice of pediatric cardiology. Vol 1. Philadel-phia: Lea & Febiger, 1990:152-70.

10. De la Cruz MV, da Rocha JP. An ontogenetic theory for theexplanation of congenital malformations involving the trun-cus and conus. Am Heart J 1956;51:782-805.

11. Van Praagh R, Layton WM, Van Praagh S. The morphogen-esis of normal and abnormal relationships between the greatarteries and the ventricles: pathologic and experimental data.In: Van Praagh R, Takao A, eds. Etiology and morphogen-esis of congenital heart diseases. Mt. Kisco, NY: Futura,1980:271-316.

12. de la Cruz MV, Sanchez Gomez C. Cayre R. The develop-mental components of the ventricles: their significance incongenital cardiac malformations. Cardiol Young 1991:1:123-8.

13. Angelini P, Leachman RD. The spectrum of double outletright ventricle: an embryologic interpretation. CardiovascDis, Bull Tex Heart Inst 1976;3:127-49.

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A

B

The concepts of congenital heart disease can beproperly interpreted and classified if their morpho-

Texcis Hean Institute.journal

14. Becu LM, Fontana RS, DuShaneJW, KirklinJW, Burchell HB,Edwards JE. Anatomic and pathologic studies in ventricularseptal defect. Circulation 1956;14:349-64.

15. Kirby ML, Gale TF, Stewart DE. Neural crest cells contributeto normal aorticopulmonary septation. Science 1983;220:1059-61.

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arteries: types and morphogenesis of ventriculoarterial dis-cordance. Am Heart J 1981; 102:271-81.

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12 Embryology and Congenital Heart Disease Volume 22, Number 1, 1995

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