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2010 1: 364World Journal for Pediatric and Congenital Heart SurgeryRichard Van Praagh

Normally and Abnormally Related Great Arteries : What Have We Learned?

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Invited Lecture

Normally and Abnormally Related GreatArteries: What Have We Learned?

Richard Van Praagh, MD1

AbstractThe conus arteriosus or infundibulum was the site of the major cardiovascular evolutionary and developmental adaptation thatmade possible air-breathing and permanent land-living for vertebrates, including mammals such as ourselves. The subarterial conalfree walls perform an embryonic aortic switch procedure by 35 to 44 days of age in utero, based on growth of the left-sidedsubpulmonary conal free wall and resorption of the right-sided subaortic conal free wall, i.e., complete right-left asymmetry inthe development of the subarterial conal free walls. There is only one way of doing the developmental aortic aortic switchprocedure right (one way in situs solitus, and its mirror-image in situs inversus), and there are many ways of doing it wrong,resulting in the conotruncal anomalies. The proximal or apical part of the conus arteriosus, the septal band, was the motherof the right ventricular sinus (the lung pump). The conus transformed the single (systemic) circulation of fish into our double(systemic and pulmonary) circulations. The right ventricle (RV) is only about 36% as old as the left ventricle (LV). Mostcongenital heart disease involves anomalies of the more recently developed RV, congenital heart disease being the mostfrequent anomaly in liveborn children — almost 1 percent (0.8%).

Keywordscardiac anatomy/pathological anatomy, congenital heart disease, embryology, great vessel anomaly

Submitted May 21, 2010; Accepted July 8, 2010.Presented at the Joint Meeting of The World Society for Pediatric and Congenital Heart Surgery Honoring Dr Aldo Castaneda; July 15-17, 2010;Antigua, Guatemala.

Introduction: the Developmental AorticSwitch

The distal or subsemilunar part of the infundibulum or conus

arteriosus performs an arterial switch procedure during cardio-

genesis. Normally, the straight heart tube loops or folds to the

right. D-loop formation places the developing right ventricle

(the bulbus cordis) to the right of the developing left ventricle

(the ventricle) of the bulboventricular D-loop. D-loop forma-

tion also places the developing ascending aorta to the right of

the developing main pulmonary artery of the truncus arteriosus.

This developmental stage is reminiscent of the Taussig-Bing

malformation; that is, potentially, there is a double-outlet right

ventricle {S,D,D} with a bilateral conus, the subaortic part to

the right and the subpulmonary part to the left, closer to the

developing ventricular septum, the interventricular foramen

(the ventricular septal defect), and the developing left ventricle.

The structural problem at this critical developmental stage is

how to avoid the Taussig-Bing type of double-outlet right

ventricle. Asymmetrical conal free wall development is the

solution. On the left side, growth of the subpulmonary conal

free wall elevates the pulmonary valve superiorly and protrudes

it anteriorly, above the anterior and right-sided right ventricle,

moving the pulmonary valve and artery away from the ventri-

cular septal defect (VSD). On the right side, resorption of the

subaortic conal free wall carries the developing aortic valve

inferiorly, posteriorly, and leftward into and partly through the

interventricular foramen, resulting in aortic-mitral approxima-

tion and direct fibrous continuity. The last step in this normal

arterial switch procedure is closure of the interventricular

foramen at its rightmost end, between the anterior and septal

leaflets of the tricuspid valve and beneath the right coronary-

noncoronary commissure of the aortic valve, by atrioventricu-

lar endocardial cushion tissue that is intimately associated with

the tricuspid valve, thereby forming the membranous septum.

1 Children’s Hospital Boston, Boston, Massachusetts

Corresponding Author:

Richard Van Praagh, MD, Children’s Hospital Boston, 300 Longwood Avenue,

Boston, MA 02115

Email: [email protected]

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Abbreviations and Acronyms

ACM anatomically corrected malposition of the greatarteries

AP aortopulmonary

AV atrioventricular

DORV double-outlet right ventricle

DOLV double-outlet left ventricle

D-TGA D-transposition of the great arteries

TGA transposition of the great arteries

TOF tetralogy of Fallot

VA ventriculoarterial

VSD ventricular septal defect

There are several ways in which the developmental arterial

switch procedure can be performed incorrectly:

1. Growth of the subaortic conal free wall and resorption of

the subpulmonary conal free wall result in transposition

of the great arteries (TGA).

2. Continued persistence and growth of both the subaortic

and the subpulmonary conal free walls, that is, failure of

subsemilunar conal free wall resorption, can result in a

double-outlet right ventricle (DORV).

3. Resorption of both the subaortic and the subpulmonary

conal free walls can rarely result in double-outlet left ven-

tricle (DOLV).

4. Abnormal development of the subaortic and subpulmonary

conal free walls, combined with ventricular loop formation

in one direction (eg, to the right) and twisting of the infun-

dibuloarterial (conotruncal) segment in the opposite direc-

tion (eg, to the left), rarely can result in anatomically

corrected malposition of the great arteries (ACM).

It is infrequently possible to have DORV with a normal type

of infundibulum and great arteries, for example, with the hypo-

plastic left heart syndrome (such as mitral atresia with a

diminutive or absent left ventricle): the subpulmonary infundi-

bulum can be well developed, and the subaortic conal free wall

can be resorbed, permitting aortic-tricuspid fibrous continuity.

Abnormally related great arteries usually have a subsemilu-

nar conal free wall malformation, but not always. Occasionally,

the atrioventricular (AV) canal (eg, the mitral valve) and the

left ventricle can be the site of the primary anomaly.

Truncus arteriosus and aortopulmonary (AP) window are

the only anomalies of which I am aware in which the great

arteries themselves are the site of primary malformation. In tet-

ralogy of Fallot (TOF), TGA, DORV, DOLV, and ACM, the

great arterial anomalies are secondary to a primary malforma-

tion of the subarterial part of the conus.

In a broader perspective, it should be understood that we are

really talking about the most important cardiovascular adapta-

tion of vertebrates to air breathing and land living. For our ver-

tebrate ancestors living in the water, a single, straight tube type

of heart was satisfactory. However, to breathe air and live

permanently on land, a double heart became advantageous. The

straight heart tube looped to the right. To avoid DORV, the

developing aorta was switched into the left ventricle by resorp-

tion of the subaortic conal free wall and by growth of the sub-

pulmonary conus to elevate the pulmonary artery superiorly

and protrude it anteriorly, getting the pulmonary artery out of

the way, that is, getting the pulmonary artery away from the

interventricular foramen (the VSD), making it possible for the

aorta to pass into the VSD and to achieve fibrous continuity

with the mitral valve. The ventricle of the bulboventricular

D-loop became the systemic ventricle. Beneath the septal band

of the proximal part of the bulbus cordis, the lung pump

evaginated or pouched out, creating the right ventricular

sinus or inflow tract and making the ventricle of the

D-bulboventricular loop the left ventricle. Hemodynamic

separation of this double heart (systemic and pulmonary) was

achieved by successful septation at all levels.

Hence, this study of normally and abnormally related great

arteries is concerned with one of the most important evolution-

ary adaptations of vertebrates to air breathing and land living:

the developmental aortic switch procedure, done by a combina-

tion of cardiac loop formation and by asymmetrical develop-

ment of the free walls of the subarterial conus arteriosus.

Normally related great arteries illustrate how the developmen-

tal aortic switch procedure is done successfully. Abnormally

related great arteries document the many ways in which the

developmental aortic switch procedure can be done

unsuccessfully.

Normally, in the developmental or biological aortic switch

procedure, as opposed to the surgical arterial switch operation,

only one great artery, the aorta, is switched, not both. This is

because developmentally, the starting position (preswitch) is

potentially a DORV of the Taussig-Bing type, which has trans-

position of the circulations because the developing pulmonary

artery is adjacent to the interventricular foramen (the VSD).

Why DORV? Because at the early straight tube stage, both

developing great arteries (the truncus arteriosus) are located

above the developing right ventricle (the bulbus cordis). How-

ever, in the normal developmental aortic switch process, both

great arteries are moved, if not switched. The pulmonary artery

has to be gotten ‘‘out of the way,’’ that is, away from the inter-

ventricular foramen (the VSD), so that the aortic valve can pass

partly through the interventricular foramen to achieve fibrous

continuity with the mitral valve. The normal growth of the sub-

pulmonary conus elevates the pulmonary valve superiorly and

protrudes it anteriorly on the left side of the developing great

arteries, thereby getting the pulmonary outflow tract ‘‘out of

the way,’’ making it physically possible for the aortic valve

to be switched partly through the interventricular foramen and

into the left ventricle. The normally related aorta sits partly

above the ventricular septum and partly above the left ventricu-

lar cavity.

So, the normal biological or developmental arterial switch

process involves both great arteries, but only one, the aorta,

is switched into the left ventricle. The normal morphogenetic

movements of both developing semilunar valves are

Van Praagh 365



reciprocals of each other: As the pulmonary valve moves super-

iorly, anteriorly, and rightward above the growing subpulmon-

ary conal free wall, the aortic valve moves inferiorly,

posteriorly, and leftward, partly through the interventricular

foramen and above the ventricular septum and the left ventricu-

lar cavity, atop the resorbed subaortic conal free wall, thereby

achieving aortic-mitral fibrous continuity via the intervalvar

fibrosa. These normal morphogenetic movements of the semi-

lunar valves and great arteries have usually been completed by

35 to 44 days of intrauterine life, when the membranous septum

typically is completed, thereby separating the morphologically

right and left ventricles. Thus, this is truly an embryonic aortic

switch procedure.

This presentation is really about our most important cardio-

vascular evolutionary adaptation that made possible air breath-

ing and land living. The evolution of the subarterial conus

arteriosus and of the right ventricular sinus made possible our

terrestrial prehistory, history, culture, and science—our

‘‘everything.’’ The many different anatomical types of abnor-

mally related great arteries document the many different ways

in which the embryonic aortic switch procedure can be done

wrong. There are only 2 ways in which this procedure can be

done right, as in solitus normally related great arteries and its

mirror image, inversus normally related great arteries.

Probably the biggest lesson that we have learned is that

abnormal relations between the great arteries have nothing pri-

marily to do with the great arteries themselves. For example, in

TGA, DORV, and DOLV, the great arteries per se typically are

normal (Figure 1). The anomaly usually involves the free walls

of the subsemilunar infundibulum or conus arteriosus (Figure

1),1,2 not the aorticopulmonary septum of the great arteries.

Abnormally related great arteries are abnormally connected

great arteries. The subsemilunar infundibulum (funnel, Latin)

or conus arteriosus (arterial cone, Latin) is the crucial connec-

tion between the great arteries above and the ventricles, ventri-

cular septum, and the AV canal and valves below.

Normally Related Great Arteries

The subsemilunar conus normally performs ‘‘Mother Nat-

ure’s’’ arterial switch operation. Here is what happens nor-

mally: At the straight tube stage and at the early D-loop

stage, a bilateral conus (subaortic and subpulmonary) is present

(Figure 2).1 Both developing great arteries are located above

the developing right ventricle, similar to the Taussig-Bing mal-

formation.3 Why? Because the truncus arteriosus, from which

the great arteries develop, is located above (cephalad to) the

bulbus cordis, from which the conus and the right ventricular

sinus develop (Figure 2). So, as ventricular D-loop formation

occurs, one potentially has DORV of the Taussig-Bing type,3

with a bilateral conus, and a subpulmonary interventricular

foramen (or VSD).

So, the developmental problem at this stage essentially is

how to avoid the Taussig-Bing malformation. The conal con-

nection holds the answer. Let us consider a bulboventricular

D-loop first (Figure 3, left panel). At the straight tube stage, the

developing subpulmonary part of the conus (main pulmonary

artery) is thought to be posterior (dorsal) relative to the subaor-

tic part of the developing conus (ascending aorta) (Figure 3).4

But looping to the right places the developing subaortic part of

the conus to the right, on the greater curvature of the D-loop,

and leaves the developing subpulmonary part of the conus to

the left, in the lesser curvature of the bulboventricular D-loop

(Figure 3).4

Then, in normal development, the subpulmonary infundibu-

lar free wall grows and expands, carrying the overlying pul-

monary valve superiorly and protruding the pulmonary valve

and main pulmonary artery anteriorly, on the left-hand side

of the great arterial outflow tracts. At the same time, on the

right-hand side of the great arterial outflow tracts, the subaortic

infundibular free wall normally undergoes resorption, permit-

ting the developing aortic valve to sink inferiorly (caudad),

posteriorly (dorsally), and to the left into the interventricular

foramen. Because of normal resorption of the subaortic infun-

dibular free wall, the noncoronary leaflet of the aortic valve and

a portion of the adjacent left coronary leaflet of the aortic valve

normally come into direct fibrous continuity with the develop-

ing mitral valve via the intervalvar fibrosa, resulting in solitus

normally related great arteries (Figure 2).1 Then, the final step

is closure of the interventricular foramen at its rightmost end,

between the anterior and septal leaflets of the tricuspid valve

and beneath the noncoronary–right coronary commissure of the

aortic valve, thereby forming the membranous septum.

The hemodynamic result of these developmental events is

that the posterior and left-sided left ventricle can eject only

through a posterior and right-sided aortic valve into an ascend-

ing aorta that proceeds upward (cephalad) on the right and

passes over (cephalad to) the pulmonary bifurcation because

aortic arch 4 is ventral and cephalad relative to pulmonary

arch 6. This is the fixed distal AP relationship that always

pertains (as long as an aortic arch and a pulmonary bifurcation

are present) because of this constant aortic arch 4–to–pulmonary

arch 6 relationship.

So, do you see that the development of the subsemilunar

conal free walls is performing an essential aortic switch oper-

ation? Growth of the subpulmonary conal free wall elevates the

pulmonary valve superiorly and protrudes it anteriorly, moving

it away from the interventricular foramen (the VSD). Conver-

sely, resorption of the subaortic conal free wall causes the aor-

tic valve to move in a reciprocally inferior, posterior, and

leftward direction, into the interventricular foramen, thereby

permitting normal aortic-mitral fibrous continuity. Then, the

interventricular foramen (the VSD) is closed by AV endocar-

dial cushion tissue beneath the right rim of the aortic valve and

between the anterior and septal leaflets of the tricuspid valve,

forming the membranous septum.

Conal development, growth and resorption, literally acts

like a switch in a railway track. Development of the subpul-

monary free wall switches the pulmonary valve anterosuper-

iorly, away from the interventricular foramen. Resorption of

the subaortic conal free wall switches the aortic valve into and

partly through the interventricular foramen. Growth of the

366 World Journal for Pediatric and Congenital Heart Surgery 1(3)



Figure 1. Types of human heart, with emphasis on segmental sets (or combinations), alignments, and spatial relations. Heart diagrams are viewedfrom below, as visualized with subxiphoid 2-dimensional echocardiography. Cardiotypes depicted in broken lines had not been documented whenthe diagram was made; cardiotypes shown in solid lines have all been documented. The aortic valve is indicated by the coronary ostia; thepulmonary valve is indicated by the absence of the coronary ostia. Braces {} mean ‘‘the set of.’’ Ant ¼ anterior; Inf ¼ infundibulum; LA ¼morphologically left atrium; L ¼ left; LV ¼ morphologically left ventricle; Post ¼ posterior; R ¼ right; RA ¼ morphologically right atrium; RV ¼morphologically right ventricle. The columns (1-4) are arranged in terms of atrioventricular (AV) concordance or discordance. Column 1 has AVconcordance between the situs solitus of the viscera and atria {S,-,-} and D-loop ventricles {S,D,-}. Column 2 has AV discordance between thesolitus viscera and atria {S,-,-} and L-loop ventricles {S,L,-}. Column 3 has AV concordance between the visceroatrial situs inversus {I,-,-} and L-loopventricles {I,L,-}. Column 4 has AV discordance between situs inversus of the viscera and atria {I,-.-} and D-loop ventricles {I,D,-}. Situs ambiguus{A,-,-} of the viscera and atria in the heterotaxy syndromes with congenital asplenia and polysplenia with D-loop ventricles {A,D,-} and with L-loopventricles {A,L,-} has been omitted for reasons of accuracy: when the atrial situs is uncertain or unknown {A,-,-}, one cannot say whether D-loopventricles {A,D,-} or L-loop ventricles {A,L,-} have AV concordance or discordance. To make the diagnosis of AV concordance or discordance, onemust know both the atrial situs and the ventricular situs. The rows (1-8) are arranged according to the types of ventriculoarterial (VA) alignmentthat are present. Normally related great arteries are depicted in rows 1 to 4 inclusively. Solitus normally related great arteries {-,-,S} and inversusnormally related great arteries {-,-,I} are both shown. In row 5, some types of transposition of the great arteries (TGA) are shown but by no meansall: D-TGA, that is, TGA {-,-,D} in which the transposed aortic valve lies to the right (dextro or D) relative to the transposed pulmonary valve, andL-TGA, that is, TGA {-,-,L} in which the transposed aortic valve lies to the left (levo or L) relative to the transposed pulmonary valve, are both

Van Praagh 367



subpulmonary conal free wall and resorption of the subaortic

conal free wall both are essential to the morphogenetic move-

ments of the semilunar valves. Note that truncoconal septation

appears not to be the primary development mechanism;

instead, it is subsemilunar conal free wall growth and resorption

(Figure 3).1,4

The great arteries normally do not twist around each other,

contrary to what we often say. Instead, the ascending aorta and

the main pulmonary artery normally are untwisting about each

other. Why untwisting? Because of the torsion that normally is

introduced at the semilunar valve level by the combination of

(1) ventricular D-loop formation and (2) asymmetric conal free

wall growth (subpulmonary) and resorption (subaortic).

Note how different the normal AP spatial relationship is

proximally compared with the AP spatial relationship distally.

Proximally, at the semilunar valves, the aortic valve is poster-

ior, inferior, and rightward, whereas the pulmonary valve is rel-

atively anterior, superior, and leftward. Distally, at the aortic

arch and pulmonary bifurcation, the aorta is anterior and super-

ior, while the pulmonary artery bifurcation is posterior and

inferior (Figure 2). Therefore, the fibroelastic great arteries

must untwist as they go from the semilunar valve relationship

proximally to the aortic arch–to–pulmonary bifurcation rela-

tionship distally. The latter relationship distally is fixed by the

embryonic branchial or aortic arch 4/6 relationship. This is why

the aortic arch is ‘‘always’’ anterior and superior to the pulmon-

ary bifurcation because this is the relationship of the embryonic

branchial or aortic arch 4 relative to branchial or aortic arch 6.

(The adverb ‘‘always’’ is between quotes because it is assumed

that an aortic arch and a pulmonary bifurcation are present; if

either is absent, ‘‘always’’ does not apply.) The untwisting of

the great arteries equals (in degrees) the difference between the

proximal and distal AP spatial relationships, which normally

equals approximately 150� (Figure 2).1

Transposition of the Great Arteries

Now, let us briefly consider what happens in typical D-

transposition of the great arteries (D-TGA) (Figure 3, left

panel).4 The wrong arterial switch operation is performed.

The asymmetrical conal free walls develop ‘‘backward,’’ that

is, the opposite of normal. The subpulmonary conal free wall

undergoes resorption (Figure 3), permitting pulmonary-mitral

fibrous continuity (Figure 2), and the subaortic infundibular

free wall grows, elevating the developing aortic valve super-

iorly and protruding it anteriorly (Figure 3). As a result of

reversed development of the subsemilunar conal free walls, the

aortic valve remains anteriorly above the anterior and right-

sided right ventricle, while the pulmonary artery arises poster-

iorly above the left ventricle. Thus, the arterial switch operation

of the subsemilunar conus has been done incorrectly: the pul-

monary artery (instead of the aorta) has been switched into the

left ventricle, and the aorta (instead of the pulmonary artery)

remains above the right ventricle.

This reversed or ‘‘backward’’ subsemilunar conal free wall

development may be regarded as inverted development of the

subarterial conal free walls, that is, right-left reversal or mirror

imagery, without anteroposterior or superoinferior change

(Figure 3). The concept of subsemilunar conal free wall

inverted development applies accurately after the cardiac loop

stage has been reached (Figure 3); but the concept of subsemi-

lunar infundibulum free wall developmental inversion may not

apply accurately at the straight tube stage, when these 2 devel-

oping conal free walls are thought (but not definitely known) to

be anteroposterior (Figure 3) rather than right-left. Anteropos-

terior reversal is not called inversion, whereas right-left rever-

sal is.

In D-TGA, why are the great arteries relatively parallel, or

straight and uncrossed, whereas normally great arteries are

twisted about each other, or really, untwisting above each other

(Figure 2)? Compare the proximal and distal AP relationships.

In D-TGA, proximally, the aortic valve is anterior and some-

what to the right, and the pulmonary valve is posterior and

somewhat to the left (Figure 2). Distally, the aortic arch is also

anterior and superior, and the pulmonary bifurcation is also

posterior and inferior (Figure 2). Thus, in D-TGA, both proxi-

mally at the valves and distally at the aortic arch/pulmonary

bifurcation, the aorta is anterior, and the pulmonary artery is

posterior. Consequently, in D-TGA, the great arteries are rela-

tively parallel, straight, and uncrossed because the fibroelastic

great arteries have little untwisting to do as they proceed from

the valves proximally to the aortic arch and pulmonary bifurca-

tion distally. This lack of necessary untwisting is because the

proximal and distal AP relationships are similar.

If one measures the semilunar interrelationship relative to

the sagittal plane in D-TGA, the semilunar valves often display

only about 30� dextrorotation, compared with about 150� dex-

trorotation for solitus normally related great arteries at the

Figure 1 continued. depicted. A-TGA, in which the transposed aortic valve lies directly anterior (antero or A) relative to the transposedpulmonary valve, is omitted for simplicity and clarity. In row 6, anatomically corrected malposition of the great arteries (ACM) is presented. Notethat in all anatomical types of ACM, the ventricles have looped in one direction and the infundibuloarterial segment has twisted in the oppositedirection. In ACM, the subsemilunar conus is either bilateral (subaortic and subpulmonary) or subaortic only (with pulmonary-tricuspid fibrouscontinuity). In ACM, although the great arteries are very malpositioned, nonetheless, there is VA alignment concordance by definition, hence, thename ‘‘anatomically corrected malposition of the great arteries.’’ ACM may be physiologically corrected, as in ACM {S,D,L}, because all segmentshave alignment concordance; or ACM can be physiologically uncorrected, as in ACM {S,L,D}, because there is one intersegmental alignmentdiscordance at the AV level. VA concordance is not synonymous with normally related great arteries because ACM also has VA alignmentconcordance, but the great arteries are very abnormally related in space, and the conal VA connections are also very abnormal. Row 7 depictssome anatomical types of double-outlet right ventricle (DORV), but by no means all. Similarly, row 8 shows some anatomical types of double-outletleft ventricle (DOLV) but not all. In DOLV, both parts of the subsemilunar conus may, or may not, be very deficient (absorbed or involuted).11,19,27

Reproduced with permission from Foran and colleagues.24




semilunar valves (Figure 2).1 Thus, D-TGA is characterized by

a major failure of dextrorotation at the semilunar valves

because of reversed or inverted development of the subsemilu-

nar infundibular free walls. With bulboventricular L-loops, the

same processes occur, but in mirror image, resulting in inverted

normally related great arteries or L-TGA (Figure 3, right

panel).

To generalize, normally, what happens both with ventricular

D-loops and L-loops, the initially posterior subpulmonary

conal free wall should grow. Following loop formation, the

subpulmonary conal free wall is in the lesser curvature, both

with D-loops and with L-loops (Figure 3); this is the

subpulmonary conal free wall that normally grows and

expands. The greater curvature, both of D-loops and L-loops,

is the subaortic conal free wall that normally undergoes resorp-

tion. If this subsemilunar conal free wall development is

reversed or inverted, that is, with growth of the greater curva-

ture part and resorption of the lesser curvature part, then, TGA

results, with pulmonary-mitral fibrous continuity and a right

ventricular aorta with no aortic-AV fibrous continuity because

of the presence of an interposed subsemilunar muscular conal

free wall.

So, the first big lesson that we have learned is that the classic

truncoconal malseptation hypothesis, initially proposed by

Figure 2. The morphogenesis of normally and abnormally related great arteries. In the top row, the straight heart tube, the bulboventricularD-loop, and the bulboventricular L-loop are shown from the front (a ventral view). In the second row, the truncus arteriosus and the derivativeascending aorta (Ao) and main pulmonary artery (PA) are shown both with ventricular D-loops and L-loops, as seen from the front (a ventralview). Also depicted are the various anatomical types of conus arteriosus or infundibulum (crosshatching) that can be located beneath the PAand/or the Ao. In the third row, the aortic valve (with coronary ostia), the pulmonary valve (without coronary ostia), the subsemilunar conalmusculature (crosshatching), the mitral valve (bicuspid), and the tricuspid valve (3 leaflets) are shown as seen from below (an inferior view, ie,from caudad looking cephalad), both with ventricular D-loops and L-loops. The bottom row lists some of the relations between the greatarteries that are associated with the 4 main anatomical types of conus: subpulmonary, subaortic, bilateral (subaortic and subpulmonary), andbilaterally absent or very deficient (neither subaortic nor subpulmonary). The diagrams of the great arteries and the conus are deliberately‘‘diagrammatic’’; that is, definitive anatomy rather than developmental stages are shown, for clarity of understanding. A ¼ common (undivided)atrium; Ant ¼ anterior (ventral); AoV-TV ¼ aortic valve–to–tricuspid valve (fibrous continuity); BC ¼ bulbus cordis (from which the conusarteriosus and the right ventricular sinus develop); D-loop ¼ a bulboventricular loop that has looped or folded in a rightward (dextral or D)direction, placing the developing right ventricle to the right of the developing left ventricle; D-MGA¼ dextromalposition of the great arteries inwhich the malposed aortic valve lies dextral (or to the right) of the malposed pulmonary valve: D-MGA occurs in the double-outlet rightventricle (DORV), doublet-outlet left ventricle (DOLV), and in anatomically corrected malposition of the great arteries (ACM); D-TGA ¼dextrotransposition of the great arteries in which the transposed aortic valve lies to the right (dextro or D) relative to the transposedpulmonary valve; Inf¼ infundibulum (also known as the conus arteriosus); Lt¼ left; L-MGA¼ levomalposition of the great arteries in which themalposed aortic valve lies to the left (levo or L) relative to the malposed aortic valve: L-MGA occurs in the DORV, DOLV, and ACM (seeFigure 1); L-TGA¼ levotransposed aortic valve is to the left (levo or L) of the transposed pulmonary valve; LV¼morphologically left ventricularsinus; Post¼posterior (dorsal); PV-MV¼ pulmonary valve–to–mitral valve (fibrous continuity); RT¼ right; RV¼morphologically right ventricularsinus; Sup ¼ superior (above or cephalad); TA ¼ truncus arteriosus (from which the great arteries develop in part); V ¼ ventricle of thebulboventricular loop (from which the LV develops). Reproduced with permission from Van Praagh and colleagues.1

Van Praagh 369



Figure 3. The embryonic aortic switch procedure: how to do it right and how to do it wrong. At the straight tube stage, the future subpulmonaryconal area (stippled) is thought to be posterior (dorsal) relative to the future subaortic conal area (clear, ie, not stippled). Following D-loopformation, the future subpulmonary conal area occupies the lesser curvature of the D-loop (stippled), and the future subaortic conal area occupiesthe greater curvature of the D-loop (not stippled); the future subpulmonary conal region lies to the left, and the future subaortic conal region lies tothe right. Now, let us focus on the subsemilunar conal free walls (not the conal septum). Normally, the subpulmonary conal free wall grows andexpands, carrying the overlying developing pulmonary valve and main pulmonary artery superiorly (cephalad) and anteriorly (ventrally) on the left-hand side of the great arterial outflow tracts. At the same time, the subaortic conal free wall undergoes resorption or involution (indicated by thebroken circular line). Resorption of the subaortic infundibular free wall causes the overlying developing aortic valve and ascending aorta to sinkinferiorly (caudad), posteriorly (dorsally), and leftward. The aortic valve passes partly through the interventricular foramen and comes into fibrouscontinuity with the mitral valve via the intervalvar fibrosa. The last step in the normal morphogenesis of crossing the circulations is closure of theinterventricular foramen at its rightmost side, adjacent to the tricuspid valve. This is how the developmental arterial switch procedure is performedcorrectly in normal development. The pulmonary valve is carried up and away from the interventricular foramen, and the aortic valve passesdownward and to the left into the interventricular foramen. Formation of the membranous septum by endocardial cushion tissue of theatrioventricular canal completes the normal aortic switch procedure. D-loop formation and asymmetrical development of the subsemilunar conalfree walls result in about 150� of rotation of the semilunar valves to the right (in a counterclockwise direction), when viewed from below.Consequently, the fibroelastic ascending aorta and main pulmonary artery normally must untwist through about 150� in the opposite direction,leftward or clockwise as viewed from below, because of the fixed aortopulmonary relationship distally, where the aorta always arches anteriorly(ventrally) and superiorly (cephalad) relative to the bifurcation of the main pulmonary artery, because these are the fixed spatial relations betweenaortic arches 4 and pulmonary arches 6 in the embryonic branchial aortic arch system. So, normally related great arteries really are untwistingabout each other (not twisting about each other). D-loop formation and asymmetrical conal subsemilunar free wall development are the ‘‘engines’’that perform the aortic switch procedure, thereby normally crossing the systemic venous and the pulmonary venous circulations and achievingsolitus normally related great arteries. But look what happens when the wrong subsemilunar conal free wall grows and expands (the nonstippledsubaortic conal free wall on the greater curvature of the D-loop) and when the wrong subsemilunar conal free wall undergoes resorption (thestippled subpulmonary conal free wall in the lesser curvature of the D-loop). When subsemilunar conal free wall development is the opposite ofnormal, then, it is the aortic valve that is carried superiorly and protruded anteriorly on the right side of the great arterial outflow tracts, and it is thepulmonary valve and main pulmonary artery on the left that sink inferiorly and posteriorly, passing partly through the interventricular foramen andcoming into fibrous continuity with the mitral valve, which is made possible by the abnormal involution of the subpulmonary conal free wall (circularbroken line), resulting in D-TGA. Why are the great arteries relatively parallel, straight, or uncrossed in D-TGA? Because the aortopulmonaryrelationships both proximally at the semilunar valves and distally at the aortic arch/pulmonary artery bifurcation are very similar. Both proximallyand distally, the aorta is anterior (ventral), and the main pulmonary artery is posterior (dorsal). Consequently, in D-TGA, the great arteries haverelatively little untwisting to do as they pass from the semilunar valves proximally to the aortic arch/pulmonary bifurcation distally. An arterialswitch procedure has been performed, resulting in D-TGA, but the embryonic arterial switch procedure has been done wrong because the wrong




Quain5 (1844) and subsequently espoused by many other

authors, is not quite right.6 According to this hypothesis, nor-

mally related great arteries result from spiral downgrowth of

the truncoconal septum, whereas TGA results from straight

downgrowth of the truncoconal septum. What made us realize

that the classic malseptation hypothesis is wrong? First of all, it

was anatomically obvious that in TGA and DORV, there is

much more wrong than just an abnormally straight, relatively

nonspiral AP septum. The great arterial free walls are also ana-

tomically very abnormal. How could we tell? The coronary

arteries. The origins of the right and left coronary arteries are

very abnormally located in TGA and in DORV (Figure 2),

and the coronary arteries are the first branches of the aortic

free wall.

So, we realized that from an anatomical standpoint, TGA

and DORV are much more than just an abnormality of AP sep-

tation. The great arterial free walls are just as abnormal anato-

mically as is the AP septum. This was my first realization that

something might be wrong with the widely accepted truncal

malseptation hypothesis.5

Between 1961 and 1963, I had the good fortune to be a fel-

low in the Department of Cardiology at the Hospital for Sick

Children in Toronto, in the department headed by Dr John D.

Keith, who is widely regarded as the Canadian ‘‘father’’ of

pediatric cardiology. Dr Keith asked Dr Peter Vlad and me to

prepare the chapter on TGA for the second edition of the

renowned Keith, Rowe, and Vlad textbook on heart disease

in infancy and childhood, which would be published in

1967.7 It was my job to study all of the autopsied cases of TGA

that had been retained in their collection of pathological anat-

omy of congenital heart disease. I did so, with one question

in mind: Amid all the many differences displayed by these

heart specimens, is there a feature that they all share in com-

mon? I thought that if I could find a ‘‘common denominator,’’

this might reveal what TGA really is anatomically and

developmentally.

Then, it gradually dawned on me. All these cases of TGA do

have one feature in common, amid their myriad differences:

they all have a malformation of the subsemilunar infundibulum

or conus arteriosus.7 So, the seed of understanding had been

planted. I also had the very good fortune to spend 6 fascinating

months doing observational and experimental cardiovascular

embryology at the Carnegie Institution of Washington in the

Department of Embryology under the guidance of Dr Robert

H. DeHaan in 1966.

Also, in 1966, with Dr Stella Van Praagh, we published one

of our first discoveries in congenital heart disease: isolated ven-

tricular inversion, with a consideration of the morphogenesis,

definition, and diagnosis of nontransposed and transposed great

arteries.8 This case was an illuminating natural experiment.

The segmental anatomy was {S,L,S}. So, here was a rare

patient who had situs solitus of the viscera and atria, with a dis-

cordant ventricular L-loop with AV alignment discordance: a

right-sided right atrium opening into right-sided morphologi-

cally left ventricle, and a left-sided left atrium opening into a

left-sided morphologically right ventricle. But this patient did

not have the usual congenitally physiologically corrected TGA.

Instead, this patient had a solitus normal type of conotruncus: a

left-sided, well-developed subpulmonary muscular conus

above a left-sided and left-handed right ventricle; and on the

right side, a posterior, inferior, and right-sided aortic valve in

direct fibrous continuity with a right-sided mitral valve and

right-handed left ventricle.

So, why did this patient not have the expected corrected

TGA? An important part of the answer appeared to be

because a well-developed solitus normal type of muscular

subpulmonary conus, with resorption of the subaortic conal

free wall, was present in this patient. This was an amazing

spectacle: a solitus normal type of infundibulum and great

arteries that was related as normally as possible to the under-

lying L-loop ventricles and the inverted AV valves. Suffice it

to say that the discovery of isolated ventricular inversion

{S,L,S} strengthened our hypothesis that the subsemilunar

conus is a very important determinant of whether the great

arteries are normally or abnormally related. This case seemed

to say the following: if the conus is of the solitus normal

type, then, the great arteries are solitus normally related, even

if the ventricular loop is inverted.

There were other clues also. TGA is associated almost never

with an AP septal defect (an AP ‘‘window’’). If TGA were

really caused by an anomaly of AP septation, then, definite

malformations of the AP septum, such as an AP window,

should be relatively common with TGA; in fact, an AP window

in association with TGA is so infrequent as to be reportable.

The conal maldevelopment hypothesis also could explain

the variations in semilunar valve heights, whereas the truncal

(or truncoconal) straight septum hypothesis could not. Propo-

nents of the classic straight AP septum hypothesis tried to say

that the transposed aortic valve is higher than the transposed

pulmonary valve because the conus (beneath the transposed

Figure 3 continued. subsemilunar conal free wall grew and expanded (the subaortic) and the wrong subsemilunar conal free wall underwentresorption (the subpulmonary). When L-loop formation occurs, inverted normally related great arteries also result from subpulmonary conal freewall growth and subaortic conal free wall resorption but in a mirror image when compared with what happens to produce solitus normally relatedgreat arteries with a ventricular D-loop. Similarly, typical L-TGA results from subaortic conal free wall growth and from subpulmonary conal freewall resorption (but again, in a mirror image compared with D-TGA and a ventricular D-loop). Ao¼ ascending aorta; D-loop¼ a bulboventricularheart tube that has looped or folded in a rightward (dextral or D) direction, placing the developing right ventricle (RV) to the right of the developingleft ventricle (LV), the RV being right handed and the LV being left handed; D-TGA ¼ transposition of the great arteries in which the transposedaortic valve is to the right (dextro or D) relative to the transposed pulmonary valve; L¼ left; L-loop¼ a bulboventricular heart tube that has loopedor folded in a leftward (levo or L) direction, placing the developing RV to the left of the developing LV, RV being left handed and the LV being righthanded; PA ¼ main pulmonary artery; R ¼ right. Reproduced with permission from Van Praagh.25

Van Praagh 371



aortic valve) is part of the right ventricle and is not part of the

left ventricle. We had long known that this contention is wrong

because the semilunar part of the conus can override the ventri-

cular septum to any degree, and the subsemilunar conus can be

located mostly, if not entirely, above the morphologically left

ventricle, for example, as in ACM (Figure 1)9,10 and in DOLV

(Figure 1).11 The conal connector is not an intrinsic, insepar-

able part of either the right ventricle or the left ventricle.

Instead, the conal connector forms part of the outflow tract

of both ventricles.

The subsemilunar conus, that is, the conal septum, the par-

ietal band, and the subsemilunar free walls, ‘‘belong’’ to the

great arteries, not to the ventricles. That is why the embryolo-

gists speak of the conotruncus (ie, the subsemilunar infundibu-

lum and the great arteries). It is in this sense that the

subsemilunar conus should be regarded as ‘‘belonging to’’ the

great arteries, not to the ventricles.

Finally, we (Stella and I and our colleagues) were starting to

understand the so-called conotruncal or infundibuloarterial

anomalies such as D-TGA and typical DORV. It was a shock

for us to learn that these are infundibular anomalies, not great

arterial malformations. In D-TGA and typical DORV, the great

arteries per se are normal, just as in TOF, which is another

infundibular anomaly, not primarily a great arterial

malformation.

One of the great lessons was this: Abnormally related great

arteries typically are abnormally connected great arteries.

Another lesson was as follows: The abnormality involves the

subsemilunar infundibular free wall(s), not the AP septum.

The great arteries are not attached to and do not arise from

the ventricles (meaning from the ventricular sinuses). Instead,

the great arteries arise from the subsemilunar conus, be it well

developed or absorbed, and it is the conus that connects the

great arteries with the underlying ventricular sinuses, ventricu-

lar septum, AV canal, and AV valves. It is helpful to under-

stand that if the great arteries originated directly from the

ventricular sinuses or main pumping chambers, rather than

from the infundibulum or conus arteriosus, then, the many

abnormal ventriculoarterial (VA) spatial relations and connec-

tions would be developmentally impossible. The arterioventri-

cular alignments are secondary, not primary. How the great

arteries are aligned with the ventricles is secondary to infundib-

ular development and hence can be highly variable (Figure 1).

The great arteries typically arise above the ventricles, not from

the ventricles.

TOF is particularly instructive. According to the truncal

malseptation hypothesis, it used to be thought that TOF results

from truncoconal malseptation, creating an abnormally small

subpulmonary infundibulum, pulmonary valve, and main pul-

monary artery and reciprocally cutting off an abnormally large

aortic valve and ascending aorta. The disproof of this malsep-

tation hypothesis as applied to TOF is supplied by TOF with

absent pulmonary valve leaflets. In the latter anomaly, although

subpulmonary infundibular stenosis (typically moderate) is

present, the main pulmonary artery is huge, for hemodynamic

reasons (very large systolic to diastolic excursional variations,

resulting in an abnormally large main pulmonary artery). As far

as the classic malseptation hypothesis as an explanation of the

morphogenesis of TOF is concerned, we think one cannot have

it both ways, that is, infundibular stenosis favoring the aortic

outflow tract, at the expense of the pulmonary outflow tract, but

at the great arteries favoring the size of the pulmonary artery, at

the expense of the ascending aorta. We think that the size of the

great arteries in TOF is determined by hemodynamics, that is,

by the degree of obstruction of the subpulmonary conus,12 not

by truncoconal malseptation.

In TOF, why is the pulmonary valve too leftward, too pos-

terior, and too inferior compared with normal? And why is the

aortic valve reciprocally too rightward (overriding), too ante-

rior, and too superior compared with normal? We think that the

answer is because the subpulmonary conus (free wall and sep-

tum) has not grown and expanded to a normal extent. Hypopla-

sia of the subpulmonary conus is the essence of the ‘‘monology

of Stensen.’’12 This anomaly, first described by Stenson in

1671, causes the 4 malformations so well described by Fallot

in 1888 as a tetralogy. This is why, in tetralogy, the normal

developmental arterial switch procedure has been done subnor-

mally. The pulmonary valve is not as anterior, superior, and

rightward as it normally is. And reciprocally, the aortic valve

is not as posterior, inferior, and leftward as it normally is. In

TOF, resorption of the subaortic conal free wall usually is well

done, whereas subpulmonary conal expansion is subnormal,

resulting in pulmonary outflow tract stenosis or atresia. In TOF,

the subpulmonary conal septum is a variable: it can be a little

longer than normal, or normal in length, or unusually short,

or even absent (with pulmonary valve–to–aortic valve fibrous

continuity).

The aorticopulmonary septum is not always normally

formed. Truncus arteriosus13 with its AP window comes imme-

diately to mind. However, the main point is that subarterial

conal free wall development typically appears to be the princi-

pal problem in TOF, in D-TGA {S,D,D}, and in DORV

{S,D,D} (Figure 1).

It should be understood that there are 2 main parts to the

infundibulum or conus arteriosus: (1) the subsemilunar or ‘‘par-

ietal band’’ part (Figure 4A and 4B, component 4), and (2) the

‘‘septal band’’ part (Figure 4A and 4B, component 3).14,15

Component 4, the subsemilunar part of the conus, is the part

that is involved in normally and abnormally related and con-

nected great arteries. The ‘‘septal band’’ or apical part of the

conus or infundibulum can be important in anomalies such as

double-chambered right ventricle (also known as anomalous

muscle bundles of the right ventricle).

The true right ventricle is the right ventricular sinus, body,

or inflow tract, the main pumping portion of the right ventricle.

The right ventricle normally is limited by the tricuspid valve

proximally and by the conal or infundibular ring distally that

is formed by the conal septum, parietal band, septal band, and

moderator band (Figure 4A). The right ventricle sinus or inflow

tract normally is composed of 2 components: (1) the AV canal

(Figure 4A, component 1), and (2) the right ventricle sinus

(Figure 4A, component 2).14,15




Thus, both ventricles are composed of 4 developmental

components (Figure 4A and 4B). The subsemilunar or distal

part of the conus (component 4) is the ‘‘architect,’’ responsible

for crossing the circulations. But what is the proximal or apical

part (component 3) of the conus doing? What is it there for?

The lower or apical part of the conus is the ‘‘mother’’ of the

right ventricular sinus (which is, of course, the lung pump). The

septal and moderator bands never dissociate from the right ven-

tricular sinus. In other words, the right ventricle sinus always

evaginates or pouches out just beneath the septal band. By con-

trast, the conal septum and the parietal band can be ‘‘any-

where,’’ as DOLV and ACM illustrate (Figure 1).

The right ventricle is our major cardiovascular evolutionary

adaptation to air breathing and land living.16 The subsemilunar

conus normally crosses the circulations by performing the aor-

tic switch, and the right ventricle sinus is the lung pump.

Single left ventricle17,18 results from the absence of the right

ventricle sinus (Figure 4A, component 2). The associated

infundibular outlet chamber consists of components 3 and 4

in Figure 4A. Absence of the right ventricle sinus results in a

single or unpaired left ventricle, often with double-inlet left

ventricle because there is no right ventricular sinus for the tricus-

pid valve to open into. Common-inlet left ventricle also occurs,

when a common AV canal and a common AV valve coexist.

Because the anatomically right ventricle is composed partly

of the right ventricle sinus or inflow tract (Figure 4A, compo-

nents 1 and 2) and partly of the infundibulum, or conus, or out-

flow tract (Figure 4A, components 3 and 4), the composite

Figure 4. What is the subsemilunar part of the conus? Anatomically, what are we talking about? (A) This is a diagram of a normal, opened,morphologically right ventricle (RV) that shows the 4 main anatomical and developmental component of the RV. The RV inflow tract consistsof 2 components: component 1 is the atrioventricular (AV) canal contribution (the interventricular part of the AV septum, and the tricuspidvalve); and component 2 is the RV sinus, the main pumping portion of the RV. The RV outflow tract also consists of 2 components:component 3 is the proximal or apical part of the conus, which consists of the septal band and the moderator band, which is not involved in theconotruncal malformations (such as TGA, DORV, DOLV, and ACM shown in Figure 1); and component 4 is the distal or subsemilunar part ofthe conus that is involved in the above-mentioned infundibuloarterial anomalies and that consists of the conal septum, the parietal band, andthe subsemilunar conal free wall, which may be well developed, or resorbed, and which may prevent or permit semilunar-AV fibrouscontinuity, respectively. (B) This is a diagram of a normal, opened, morphologically left ventricle (LV), showing that it too consists of 4anatomical and developmental components: 1, the AV canal contribution; 2, the finely trabeculated LV sinus portion; 3, the smooth superiorleft ventricular septal surface component that is confluent with the septal band of the RV (component 3 in A); and 4, the immediately subaorticconal septum, as seen from within the LV. Again, component 4 is the subsemilunar part of the conus that we are focusing on concerninginfundibuloarterial malformations. Note the approximation of the aortic valve and the mitral valve, which is made possible by the normalresorption of the subaortic infundibular free wall. So, it is what one does not see that is most important: no subaortic conal free wallmyocardium (because it has been resorbed), making possible the normal aortic-mitral fibrous continuity. Reproduced with permission fromVan Praagh and colleagues.15

Van Praagh 373



nature of the normally right-sided ventricle often is not well

understood and hence is delineated here. Thus, normally

related and connected great arteries illustrate how the develop-

mental arterial switch should be done by the subsemilunar

infundibular free wall. Abnormally related and connected great

arteries illustrate the consequences of alterations in this devel-

opmental process.

TOF illustrates what happens when the developmental arter-

ial switch procedure is done subnormally: The pulmonary

valve remains too leftward, posterior, and inferior; the

Figure 5. The 4 main anatomical types of subsemilunar infundibulum or conus arteriosus: subpulmonary, subaortic, bilateral (subaortic andsubpulmonary), and absent or very deficient. The upper row of diagrams shows the infundibulum (crosshatched) and great arteries as seenfrom the front (frontal view). The lower row of diagrams shows the infundibulum (crosshatched), the semilunar valves—the aortic valve (AoV),indicated by the coronary arteries, and the pulmonary valve (PV), indicated by the absence of coronary arteries—and the atrioventricularvalves—the mitral valve (MV), being a 2-leaflet valve, and the tricuspid valve (TV), being a 3-leaflet valve—as seen from below (inferior view),similar to a subxiphoid 2-dimensional echocardiogram. In all diagrams, a ventricular D-loop is assumed to be present. The subpulmonary conusis normal. Resorption of the subaortic conal free wall permits aortic-mitral fibrous continuity. The presence of a subpulmonary infundibulumprevents pulmonary valve–atrioventricular valve fibrous continuity. A subpulmonary conus is associated with solitus normally related greatarteries (diagrammed here), inversus normally related great arteries (diagrammed in Figures 1-3), and in tetralogy of Fallot, both with solitusnormally related great arteries12 and with inversus normally related great arteries. A subpulmonary conus can also be associated with double-outlet right ventricle with the hypoplastic left heart syndrome (eg, with mitral atresia) and with aortic-tricuspid fibrous continuity. Thesubaortic conus is characterized by resorption of the subpulmonary conal free wall, permitting pulmonary-mitral direct fibrous continuity. Thepresence of a complete muscular subaortic conus prevents aortic-atrioventricular fibrous continuity. The subaortic conus and great arteriesshown here are associated with typical D-transposition of the great arteries, that is, TGA {S,D,D} (Figures 1-3). A subaortic conus also occurswith L-TGA, that is, TGA {S,L,L}, and with TGA {I,L,L} (Figures 1-3). A bilateral conus, being both subaortic and subpulmonary, preventssemilunar-atrioventricular fibrous continuity. A bilateral conus is associated with typical double-outlet right ventricle, both with D-loopventricles and with L-loop ventricles (Figures 1 and 2). A bilateral conus can also be associated with TGA when there is a muscularsubpulmonary outflow tract obstruction (stenosis or atresia).26 Rarely, it is possible for solitus normally great arteries to be associated with abilateral conus if the subpulmonary part of the conus is well developed and if the subaortic conal free wall is present but poorly developed, just1 or 2 mm in height between the aortic valve above and the mitral valve below; I have seen only 1 such case in my life, in a patient with theincomplete form of common AV valve canal with an ostium primum defect at the atrial level, no ventricular septal defect, and a cleft mitralvalve. So, what matters most morphogenetically is not just the anatomical type of conus that is present but rather how much the subsemilunarconal free wall is present or has been resorbed. In the rare case that I am referring to, a small amount of the subaortic conal free wall had notbeen resorbed, but not enough to disrupt the normal type of aortic valve–to–left ventricular approximation. The bilaterally absent or verydeficient conus can be associated with double-outlet left ventricle (DOLV) with aortic-mitral and pulmonary-mitral fibrous continuity, evenwith an intact ventricular septum.19 However, DOLV does not always have a bilaterally absent or very deficient conus.27 Figure 2 shows thediagram of a rare type of D-TGA with a bilaterally deficient conus, but with aortic valve–to–tricuspid valve fibrous continuity and withpulmonary valve–to–mitral valve fibrous continuity. It is also noteworthy in Figure 2 that a bilaterally absent or very deficient conus is notdiagrammed in association with L-loop ventricles. Why not? Because we have never seen this. It may occur (but I do not know that). Figure 2 isevidence based (not hypothetical, except where indicated by broken lines). AD ¼ anterior descending (coronary artery); Ant ¼ anterior(ventral); Inf ¼ inferior (caudad); Lt ¼ left; Post ¼ posterior (dorsal); Rt ¼ right; Sup ¼ superior (cephalad). Reproduced with permission fromVan Praagh.28




Figure 6. The 4 main hypotheses concerning the morphogenesis of transposition of the great arteries. (1) Malseptation of the great arteries,that is, straight (as opposed to spiral) development of the aortopulmonary septum, first proposed (to our knowledge) by Quain5 in 1844 andsubsequently espoused by many authors. Ao ¼ aorta; AoV ¼ aortic valve; PA ¼ pulmonary artery; PV ¼ pulmonary valve. The semilunar valvesare designated by conventional numbers for clarity because their relative positions are highly variable. There are 4 septal semilunar leaflets,adjacent to the aortopulmonary septum: aortic and pulmonary leaflets 1, and aortic and pulmonary leaflets 3. Pulmonary leaflet 2 is nonseptal,remote from the aortopulmonary septum. Aortic leaflet 4 is also nonseptal and normally is noncoronary. The nonseptal semilunar leaflets arealso known as the intercalated leaflets. Comparison of the semilunar leaflet numbers with normally related great arteries (NRGA) as opposedto those with transposition of the great arteries (TGA) indicates (in degrees) the morphogenetic movement that has occurred with NRGA andhas not occurred with TGA. Both with NRGA and with TGA, the distal aortopulmonary relations at the aortic arch and pulmonary bifurcationare the same: the Ao arch is ventral and cephalad to the PA bifurcation because this is the fixed aortic arch 4–to–pulmonary arch 6 relationshipdistally. The straight aortopulmonary septum hypothesis is considered to be wrong for several reasons: (a) In TGA, the free walls of the greatarteries are just as abnormal as is the aortopulmonary septum. This is indicated by the abnormal locations of the coronary ostia in TGA, the

Van Praagh 375



Figure 6 continued. coronary arteries being the first branches of the aortic free wall. So, TGA is more than an anomaly ofthe aortopulmonary septum because the great arterial free walls are also very abnormally located. (b) Definite evidence of abnormality of theaortopulmonary septum, such as AP window, is very rare in TGA. (c) The straight aortopulmonary septum hypothesis cannot explain thevariations in semilunar valve heights in the so-called conotruncal malformations, such as the aortic valve sitting high above the morphologicallyleft ventricle in anatomically corrected malposition of the great arteries {S,D,L} (Figure 1, row 6, column 1).10 (2) Conal maldevelopment. In1909, Keith23 was the first to propose that TGA results from persistence and development of the subaortic part of the conus (in white) andinvolution of the subpulmonary part of the conus (in black). In 19668 and 1967,7 we independently reached the same conclusion andsubsequently have extended the conal maldevelopment hypothesis to include all of the conotruncal anomalies (Figure 1).1-4,6-13 Note thatKeith23 and Cardell32 and many others thought that the normal semilunar relationships are pulmonary valve anterior, superior, and to the rightof the aortic valve, a frequent preangiocardiographic error. (3) Atavism. In 1923, Spitzer29,30 proposed a hypothesis of evolutionary(phylogenetic) regression to explain TGA in man, back to the cardiovascular state that is normal in higher reptiles such as crocodiles andalligators. One might suppose that such a hypothesis would strike investigators as hilariously funny. Instead, it mesmerized a generation.30,33 Myreaction (with a wink) was that our patients with TGA did not have tails, their smiles were not unusually wide, and they almost never hadichthyosis or any other features that suggested reverse evolution back to the crocodilian stage. So, I decided to study Spitzer’s theory29,30 withgreat care. Lev and Vass’s30 translation into English was very helpful. Finally, I understood what was wrong with this hypothesis in terms ofpathological anatomy. The dotted line indicates where the true ventricular septum was in TGA but has disappeared, according to Spitzer29,30

(left lower panel). Spitzer’s bicuspid, apparently stenotic, transposed pulmonary valve sits above the morphologically right ventricularmyocardium, to the right of the disappeared ventricular septum in D-loop ventricles. His diagram suggests that there is a ventricular septaldefect. Spitzer29,30 also states that the apparent ventricular septum is a hugely hypertrophied crista supraventricular (supraventricular crest),not the true interventricular septum (which has disappeared). So, in terms of pathological anatomy, what is wrong with Spitzer’sinterpretation? The anteroseptal region of the left-sided ventricle from which the transposed pulmonary artery arises in typical TGA consistsonly of the morphologically left ventricular myocardium. There is no morphologically right ventricular myocardium there to the right ofSpitzer’s dotted line. Spitzer does not explain how or why the ventricular septum routinely disappears in TGA. Crocodiles and alligatorsnormally have both a left ventricular aorta and a right ventricular aorta. Spitzer hypothesizes that human TGA represents reopening of theright ventricular aorta of the higher reptiles, plus closure of the left ventricular aorta of the higher reptile and mammals. So, Spitzer’s problemwas not to explain the right ventricular aorta in human TGA: all higher reptiles have a right ventricular aorta, as Spitzer knew. However,Spitzer’s real problem was the left ventricular pulmonary artery of human TGA because there is no animal known in which the pulmonaryartery normally originates above the morphologically left ventricle. This seems to be why Spitzer29,30 contended that the ventricular septum, tothe left of the ‘‘transposed’’ pulmonary artery, has disappeared. In this way, the pulmonary artery can be diagrammed as arising above the rightventricular myocardium, which is essential in any atavistic explanation of human TGA, because there is no animal known in which thepulmonary artery normally arises above the morphologically left ventricle. This hypothesis denies the reality of human TGA and asserts thatthe double-outlet right ventricle (DORV) is really present. The fatal flaw in Spitzer’s hypothesis29,30 of evolutionary regression to explain themorphogenesis of TGA is that in human TGA, the pulmonary artery really does arise above the morphologically left ventricle, the trueventricular septum is present and has not disappeared, and TGA (ventriculoarterial alignment discordance) really is present, not DORV. Infairness to Spitzer, it must be added that at his time (1923), what we now call DORV was then regarded as a form of TGA. Previousinvestigators have attempted to assess Spitzer’s hypothesis.30,33 It has been regarded with some doubt and skepticism. We may have been thefirst to indicate that Spitzer’s hypothesis29,30 is wrong because it is not supported by the morphological anatomical data of human TGA (asabove). (4) Fibrous malattachment. In 1962, Grant31 proposed that normally, there is a fibrous tract of low growth potential that tethers thedeveloping aortic valve (A) to the developing mitral valve (M), resulting in aortic-mitral fibrous continuity; the pulmonary valve (P) is nottethered either to the mitral valve (M) or to the tricuspid valve (T), and consequently, the pulmonary valve is normally anterior to the aorticvalve, the pulmonary valve being in communication with the anterior and right-sided ventricle (right lower panel). The fibrous tract betweenthe normally related aortic valve and the mitral valve is known as the intervalvar fibrosa. Grant’s31 hypothesis is that in TGA, this fibrous tractis shifted leftward, such that the developing pulmonary valve (P) is tethered to the developing mitral valve (M), resulting in pulmonary-mitralfibrous continuity and a left ventricular pulmonary artery. The aortic valve (A) is now untethered, and consequently, the aortic valve (A) isanterior to the pulmonary valve (P), with the aorta being above the anterior and right-sided right ventricle, as in typical TGA in man. So, thequestion becomes the following: Is there anything wrong with Grant’s31 hypothesis? Why could a fibrous tract of low growth potentialbetween the mitral valve (M) and the wrong semilunar valve, the pulmonary valve (P), not be the primary morphogenetic mechanismunderlying human TGA? This fibrous malattachment hypothesis31 cannot explain TGA with a bilateral conus (subaortic and subpulmonary).26

The presence of subpulmonary conal musculature would prevent the hypothesized abnormal pulmonary-mitral fibrous continuity that occurswhen TGA has a subaortic conus only. This fibrous malattachment hypothesis31 also cannot explain those rare cases of TGA with asubpulmonary conus,26 that is, short subpulmonary muscular conus with aortic valve–to–tricuspid valve fibrous continuity, in which thetransposed aortic valve can be posterior and inferior to the transposed pulmonary valve. This fibrous malattachment hypothesis, asproposed,31 cannot explain TGA with aortic-tricuspid fibrous continuity and a short subpulmonary conus. Grant’s hypothesis31 also does noteasily explain those rare cases of TGA with aortic-tricuspid and pulmonary-mitral fibrous continuity with a bilaterally deficient or absent conusbeneath both great arteries.26 Consequently, we prefer the view that regards subarterial conal free wall development—growth orresorption—as the primary morphogenetic mechanism. We think that semilunar-atrioventricular fibrous continuity or noncontinuity issecondary to subarterial conal free wall development (resorption or growth, respectively). The latter hypothesis can explain all of theanatomical data. The infundibuloarterial (conotruncal) anomalies (Figure 1) are appropriately named in terms of their pathological anatomy.Anatomically, both the infundibulum or conus arteriosus and the great arteries are malformed. Embryologically, or developmentally, however,the infundibuloarterial (conotruncal) anomalies are importantly misnamed. They are all infundibular or conal anomalies, like tetralogy of Fallot.The great arteries per se are normally formed. The real problem is the little hollow ‘‘platforms,’’ the coni arteriosi (arterial cones) orinfundibula (funnels) on which the great arteries stand, and which connect the great arteries above to the underlying ventricles, ventricularseptum, and atrioventricular valves below. Reproduced with permission from Van Praagh.6




subpulmonary infundibulum is obstructive (stenotic or atretic);

the aortic valve remains too rightward, anterior, and superior

(‘‘overriding’’); and a large subaortic conoventricular

malalignment type of ventricular septal defect typically results.

The fourth feature of Fallot’s tetrad, right ventricular hypertro-

phy, is not present at birth in tetralogy because right and left

ventricular pressures are essentially equal prenatally. Postna-

tally, however, right ventricular ‘‘hypertrophy’’ (compared

with normal) develops because the normal thinning of the right

ventricular free wall fails to occur, in turn because of the per-

sistence of systemic pressures in the right ventricle related to

the large subaortic VSD and right ventricular outflow tract

obstruction that are parts of the TOF. Subnormal performance

of the normal embryonic arterial switch process is what TOF

really is.

TGA {S,D,D} illustrates what happens if the arterial switch

operation is done in reverse, that is, if the pulmonary valve and

artery are approximated to the mitral valve and if the aortic

valve remains above the right ventricle. DORV {S,D,D} with

a bilateral conus illustrates what happens if the embryonic aor-

tic switch by the subsemilunar conus is not performed at all,

that is, if neither semilunar valve is switched into the left ven-

tricle and if both semilunar valves remain above the right ven-

tricle because subsemilunar conal free wall absorption has

failed to occur.

DOLV {S,D,D} (Figure 1) illustrates what can happen if

both the subaortic and the subpulmonary parts of the conus

undergo resorption, resulting in aortic-mitral and pulmonary-

mitral direct fibrous continuity.11,19 In this situation, the devel-

opmental arterial switch procedure performed by the resorption

of both parts of the subsemilunar conal free walls results in

‘‘overdoing’’ of the arterial switch procedure. Rarely, both

great arteries can come to overlie the left ventricle only, even

with an intact ventricular septum.19

Thus, there are 4 ways in which the distal or subsemilunar

infundibulum can perform the embryonic arterial switch

procedure:

1. normally;

2. in reverse (typical D-TGA);

3. not at all (typical DORV); or

4. in excess (rarely DOLV) (Figure 1).

Truncus arteriosus13,20,21 is the only infundibuloarterial

(conotruncal) anomaly in which the great arteries themselves

are primarily malformed. Again, the classic AP malseptation

hypothesis was used to explain the embryogenesis of truncus

arteriosus communis (common arterial trunk, Latin). The

classic hypothesis was that the AP septum fails to grow down-

ward (caudad) from the aortic arch 4/6 junction. Conse-

quently, it was hypothesized that the ascending aorta and

the main pulmonary artery were not completely separated

from each other and hence remained in common. Also, the

common semilunar valve was not divided into aortic and pul-

monary valves, and the conus was not septated, resulting in a

large subsemilunar VSD.

When I was working at the Congenital Heart Disease

Research and Training Center in the Hektoen Institute for Med-

ical Research at Chicago (1963-1965) with Dr Maurice Lev,

I was given truncus arteriosus as a research project. Dr Lev asked

me to figure it out: What is truncus arteriosus really? As usual,

I collaborated with Dr Stella Van Praagh.13 Fortunately, some

cases of ‘‘pseudotruncus,’’ that is, TOF with pulmonary outflow

tract atresia, had been misfiled along with the cases of ‘‘true’’ or

‘‘genuine’’ truncus arteriosus. So, I examined them all.

Then, it struck me. I realized that I could not tell pseudotruncus

from so-called true truncus by examining the right ventricular

outflow tract anatomy unless I let myself look at the great arteries.

In other words, I was astonished to find that the right ventricular

outflow tract anatomy in truncus was identical with, or exceed-

ingly similar to, that found in typical tet-atresia (TOF with right

ventricular outflow tract atresia). I realized that was not the

way it was supposed to be in truncus. According to the classic

truncoconal malseptation hypothesis, truncus was thought to

result from absence of truncoconal septation, but the truncoconal

free walls were thought to be normal (uninvolved).

But that is not what I saw in truncus. The whole semilunar

infundibulum was involved: the conal septum and free wall

were both anomalous. Very similar to tet-atresia, the conus in

truncus appeared to be atretic, unexpanded, with no infundibu-

lar lumen. I realized that if the classic nonseptation hypothesis

were correct in truncus, at the level of the right ventricular out-

flow tract, I should be looking at an infundibular or conal septal

defect only, with a normally formed infundibular free wall.

Instead, in truncus arteriosus, the whole subsemilunar infundi-

bulum appeared to be involved, septum and free wall, resulting

in an unexpanded, or very poorly expanded, subpulmonary

infundibulum, as in TOF with pulmonary outflow tract atresia.

I realized that if the problem in truncus were just a conal septal

defect (at the level of the right ventricle outflow tract), then,

there should be no right ventricle outflow tract obstruction

(no stenosis nor atresia), and the overlying semilunar valve (the

pulmonary valvar component of a common semilunar valve)

should be uninvolved. I should find the expected 4-leaflet,

undivided, common semilunar valve. So, I then examined the

semilunar valves in truncus. Never was the predicted

4-leaflet semilunar valve present. Typically, the semilunar valve

in truncus arteriosus was tricuspid and tricommissural, very

similar to, if not identical, with an aortic valve.

What did the anatomical findings suggest? Typical so-called

truncus arteriosus looked like pulmonary infundibular atresia

with consequent partial or complete absence of the overlying

pulmonary valve, associated with an AP septal defect of vari-

able size, often with a right aortic arch.13 In other words, typ-

ical truncus arteriosus appears to be TOF with pulmonary

outflow tract atresia, with partial or total absence of the pul-

monary valvar leaflets, and an AP window, that is, an anomaly

closely akin to the most severe form of TOF, only even worse.

Typically, truncus arteriosus maintains a tenuous truncal

valve (ie, aortic valve)–to–mitral valve direct fibrous continu-

ity, very similar to TOF. Rarely, however, truncus arteriosus

can originate exclusively above the right ventricle, with a

Van Praagh 377



well-developed subtruncal muscular infundibulum that pre-

vents semilunar-AV fibrous continuity. We also think that in

truncus arteriosus type A213 (type A means that a VSD is pres-

ent, and type 2 means there is little or no AP septal remnant),

the main pulmonary arterial component may well be absent

(hence, no AP septal remnant).

Why do we think that? Because we have seen 2 rare cases,21

with normal {S,D,S} segmental anatomy, which had the fol-

lowing: no VSD; a main pulmonary artery arising from the

right ventricle, giving off no pulmonary artery branches and

passing through a slightly narrowed patent ductus arteriosus

into the descending thoracic aorta; and an aorta arising nor-

mally from the left ventricle, giving off coronary arteries nor-

mally and then part way up the ascending aorta, giving origin

to the right and left pulmonary artery branches, then forming

an aortic arch and giving off the brachiocephalic arteries nor-

mally, and continuing through the aortic isthmus into the des-

cending thoracic aorta.21

When one of our colleagues, an eminent cardiovascular

radiologist, saw these angiocardiograms, he quipped the fol-

lowing: ‘‘Get rid of it. It’s impossible.’’ But why is this anom-

aly21 relevant to truncus arteriosus type 2? Because the

pulmonary artery branches originate from the aorta (ie, from

the aortic sac part of the distal truncus arteriosus). In normal

development, the pulmonary artery branches then migrate

somewhat to the left, where the pulmonary artery branches then

become confluent with the main pulmonary artery. But rarely,

this normal leftward migration of the pulmonary artery

branches can fail to occur, resulting in a nonbranched main pul-

monary with both pulmonary artery branches arising from the

ascending aorta.21

Now, consider truncus type 2: there is no AP septal remnant,

and both pulmonary artery branches arise from the so-called

common arterial trunk. Is it really a common arterial trunk?

Our hypothesis is that in truncus type 2, the main pulmonary

artery component may be absent21; hence, there is no AP septal

remnant in truncus type 2. In the case of the nonbranched main

pulmonary artery described above, if there had been subpul-

monary infundibular atresia, the overlying pulmonary valve,

main pulmonary artery, and ductus arteriosus might well have

been atretic and have undergone involution. In truncus arterio-

sus type 2, we conventionally assume that a main pulmonary

artery component must be present, even though we cannot see

it and there is no AP septal remnant to indicate where this

hypothetical main pulmonary arterial component is located.

Why do we make this assumption? Because most people do

not know that the pulmonary artery branches initially arise from

the aorta (the aortic sac), and most do not wonder why there is

no AP septal remnant. In view of the hypothesis that the main pul-

monary artery component is really absent in type 2, we talk about

truncus arteriosus; that is, we omit the communis adjective. We

think that truncus arteriosus type 2 may very well be a truncus aor-

ticus solitarius, that is, a solitary aortic trunk, not a truncus arter-

iosus communis, that is, a common (AP) arterial trunk.

When we measured the right-left width of the truncus, we

found that in type 1 (that does have a main pulmonary artery

component), low down (just above the semilunar valve level),

the truncus is wider than higher up, above the origins of the pul-

monary artery branches where the truncus becomes distinctly

narrower. But in truncus type 2, the truncus is about the same

width, just above the semilunar valve level, and above the ori-

gins of the pulmonary artery branches. Why this difference in

truncal transverse dimensions between types 1 and 2? We think

that the answer is because there is a demonstrable main pul-

monary artery component in type 1 (which makes it wider low

down) but not in type 2 (hence, little or no difference between

low-down and higher-up dimensions in type 2). Were we sur-

prised by the anatomical findings in truncus arteriosus? Yes.

Briefly, truncus arteriosus is a much more interesting form of

congenital heart disease than has been generally understood.

The 5 diagnostically and surgically important cardiac seg-

ments consist of the 3 main cardiac segments (Figure 1): (1) the

visceroatrial situs, important for atrial localization; (2) the ven-

tricular loop, important for ventricular localization; and (3) the

great arteries, important hemodynamically; and 2 connecting

cardiac segments: (4) the AV canal or junction, important for

the AV valves and the AV septum; and (5) the conus arteriosus

or infundibulum, important concerning the right and left ventri-

cular outflow tracts and the alignments and connections of the

great arteries.

These 5 cardiac segments consist of 4 independent variables

and 1 dependent variable. The 4 independent variables are

(1) the visceroatrial situs, (2) the ventricular loop, (3) the conus

arteriosus, and (4) the great arteries (truncus arteriosus). The

1 dependent variable is the AV canal, in the sense that the situs

of the AV valves typically corresponds to that of the ventricular

loop and ventricles of entry, not to that of the atria of exit.

This presentation has thus far focused primarily on the sub-

semilunar part of the infundibulum and on the great arteries.

Although these 2 cardiac components are very important con-

cerning the understanding of abnormally related great arteries,

they are not the whole story. We must now widen our focus to

consider what may be called (with a wink) ‘‘the segmental situs

salad’’ of complex congenital heart disease (Figure 1). A few

examples will suffice as illustrations.

Classic congenitally physiologically corrected TGA,22 that

is, TGA {S,L,L} (Figure 1, row 5, column 2), has not only the

subsemilunar maldevelopment discussed above but also a dis-

cordant ventricular L-loop with AV and VA discordance, as is

now quite well understood.

ACM9,10 (Figure 1, row 6) is far rarer and is consequently

less well understood. In all anatomical cases of ACM that we

have examined, the ventricles have looped in one direction, and

the great arteries have twisted in the opposite direction. For

example, in ACM {S,D,L} (Figure 1, row 6, column 1), the

ventricles have looped to the right, but the infundibuloarterial

part of the heart (the conotruncus) has twisted to the left. These

opposite morphogenetic movements have resulted in the rare

VA alignments known as anatomically corrected malposition.

In ACM {S,D,L}, although the great arteries are very malposi-

tioned, they nonetheless originate above the anatomically cor-

rect ventricles: aorta above the left ventricle, and pulmonary




artery above the right ventricle (Figure 1). It is in this sense that

these malposed great arteries are anatomically corrected. ACM

{S,D,L} is also physiologically corrected because there is both

AV and VA concordance. By contrast, ACM {S,L,D} (Figure 1,

row 6, column 2) is anatomically corrected but physiologically

uncorrected because there is one intersegmental alignment

discordance, at the AV level.

It is noteworthy that ACM always has VA concordance, by

definition. Thus, VA concordance is not synonymous with nor-

mally related great arteries. In ACM, the VA alignments are

concordant, but the VA connections (the anatomical types of

conus) are always very abnormal; hence, the malposition of the

great arteries. In ACM, the conal connector is either bilateral

(subaortic and subpulmonary) or subaortic (only).

The 4 anatomical types of conus are presented in Figure 5 2:

1. subpulmonary (only), with normally related great arteries;

2. subaortic (only), with typical TGA (and other VA

alignments);

3. bilateral, that is, subaortic and subpulmonary, with DORV

and TGA (and other VA alignments); and

4. absent or very deficient, with DOLV, and rarely with TGA.

Why the ventricles loop in one direction and the great

arteries twist in the opposite direction in ACM is unknown at

present.

Is it possible to have a normal type of infundibulum and

great arteries in association with abnormally related great

arteries such as DORV? The answer is yes. For example,

when DORV is associated with mitral atresia and a diminu-

tive left ventricle, one can have DORV {S,D,‘‘S’’} with

aortic-tricuspid fibrous continuity and a well-developed

subpulmonary infundibulum. Often, the atretic mitral valve

cannot be identified anatomically, and the left ventricle may

also be unidentifiable. DORV with a unilateral conus (sub-

pulmonary only or subaortic only) is a specific anatomical

type of DORV that is associated with the hypoplastic left

heart syndrome (such as mitral atresia with a diminutive

or apparently absent left ventricle).

In the designation DORV {S,D,‘‘S’’}, the quotation marks

about the ‘‘S’’ save it from anatomical inaccuracy. Logically,

can one really have DORV if the infundibulum and great

arteries are of the normal type? Logically, one might think not.

But anatomically, it does happen. How can that be? Remember,

we are considering the spatial relations, alignments, and con-

nections between the infundibulum and great arteries above

and the ventricular septum and the AV canal and valves below.

Usually, the anomalies involve the infundibulum and occasion-

ally the great arteries above. But important malformations can

also involve the underlying ventricles and the AV valves. So,

abnormally related great arteries are not always about the

infundibulum and great arteries.

Hence, in the situation of DORV {S,D,‘‘S’’} mentioned

above, we think that the excusing quotation marks about the

‘‘S’’ are necessary to avoid anatomical inaccuracy. The spatial

relations, alignments, and connections between the solitus

normal infundibulum and great arteries cannot be entirely nor-

mal because of the anomalies involving the mitral valve and

left ventricle, which is why DORV is present (rather than nor-

mally related great arteries).

Others may prefer to designate this as DORV {S,D,D} and

state that there is aortic-tricuspid fibrous continuity with a sub-

pulmonary conus. We prefer DORV {S,D,‘‘S’’} to indicate that

the infundibulum and the great arteries really are of the normal

type and to suggest that the cause of the DORV lies elsewhere,

that is, because of the coexistence of the hypoplastic left heart

syndrome.

Perhaps the biggest lesson that we have learned is that

the classic AP malseptation hypothesis that used to be

invoked to explain the abnormal development and the

pathological anatomy of abnormally related great arteries

is incorrect, as explained above. Instead, the subsemilunar

infundibulum or conus arteriosus, which normally performs

the embryonic aortic switch procedure by growth of the sub-

pulmonary infundibular free wall and by resorption of the

subaortic infundibular free wall, is usually where the anom-

aly is located. The only relatively frequent exception of

which I am aware is truncus arteriosus, in which the great

arteries per se are also primarily malformed, as summarized

above.

Arthur Keith23 (later to become Sir Arthur Keith) was, to

my knowledge, the first to report in 1909 the concept that

TGA results from persistence and development of the subaor-

tic part of the conus and involution of the subpulmonary part

of the conus. However, the conal maldevelopment hypothesis

was subsequently ‘‘forgotten’’ in favor of the classic

AP malseptation concept.6 Based on the study of many post-

mortem cases of congenital heart disease (TGA7 and others8),

I had decided by 1967 that conal maldevelopment was the

right idea. Then, in reviewing the literature on this topic, I was

delighted to find Keith’s Hunterian lecture23 that confirmed

our conclusions.7

Discussion

What we and others have learned concerning normally and

abnormally related great arteries amounts to a general princi-

ple. As mentioned previously, the most important points are the

following. The great arteries per se are seldom the primary site

of malformation; exceptions in which the great arteries them-

selves are anomalously formed include truncus arteriosus and

AP ‘‘window.’’

In essentially all other cases, when the great arteries appear

to be malformed and anatomically are malpositioned (Figure 1),

the primary site of malformation is the subsemilunar infundibu-

lum, the hollow conical ‘‘platforms’’ on which the semilunar

valves and great arteries stand, which connect the great arteries

above to the underlying ventricles, ventricular septum, AV

canal, and AV valves.

The general principle is that both normal and abnormal rela-

tionships of the great arteries are largely determined by ventri-

cular loop formation and by asymmetrical development of the

Van Praagh 379



subsemilunar conal free walls. Normally, asymmetrical conal

development involves growth of the subpulmonary conal free

wall and resorption of the subaortic conal free wall (Figures

1-5). Abnormally, the subsemilunar conal free walls can

develop in reverse, with growth of the subaortic infundibular

free wall and resorption of the subpulmonary conal free wall,

resulting in TGA (Figures 1-3 and 5). Or both the subaortic

and the subpulmonary conal free walls can grow and expand,

typically resulting in a DORV (Figures 1, 2, and 5). Or the

opposite can happen: resorption of both the subaortic and the

subpulmonary conal free walls, which can result in a DOLV

(Figures 1 and 5).

Morphogenesis

For many years, there has been considerable interest in the

morphogenesis of TGA. Four main hypotheses have emerged

(Figure 6):

1. straight development of the AP septum, also known as the

truncal malseptation hypothesis, first proposed by Quain5

in 1844;

2. conal maldevelopment, first presented by Keith23 in 1909;

3. atavism, outlined by Spitzer29,30 in 1923; and

4. maldevelopment of the intervalvar fibrosa between the

semilunar and the AV valves, proposed by Grant31 in 1962.

Why do we think that maldevelopment of the subsemilunar

conal free walls is the correct concept concerning the morpho-

genesis of all the forms of abnormally related great arteries (not

just for TGA)? Because abnormally related great arteries

always have a malformation of the subsemilunar infundibular

free walls (Figure 1), whereas normally related great arteries8

(solitus and inversus normally related great arteries) do not

(Figure 1). This was our realization in discovering and describ-

ing isolated ventricular inversion {S,L,S}8 (Figure 1, row 3,

column 2). The lesson of this case was and still is the following:

if the subsemilunar conus is of the solitus normal type, that is, a

subpulmonary muscular conus preventing pulmonary-AV val-

var fibrous continuity, with a resorbed subaortic conal free wall

permitting aortic-mitral fibrous continuity (Figure 5), then, the

great arteries are solitus normally related, even if the ventricles

are inverted because of the coexistence of L-loop ventricles.8

This was our ‘‘ah ha!’’ moment.8 Two principles had

become clear:

1. When the great arteries are abnormally related, an anomaly

of the subsemilunar conal free walls is almost always pres-

ent (Figure 1).

2. When the great arteries are normally related, a full-blown

malformation of the subsemilunar conal free walls is never

present (Figure 1).

The above-mentioned pathological anatomical data strongly

suggest that embryological investigations should focus on the

development of the subsemilunar conal free walls (rather than

on the development of the AP septum).6

What is wrong with the straight AP septum hypothesis of

Quain5 and many subsequent investigators (Figure 6)?6 As

noted heretofore, TGA is much more than just a relatively

straight, nonspiral AP septum. In TGA, the great arterial

free walls are also very much involved, that is, positionally

abnormal anatomically. What is the proof of that? The

answer is the coronary arteries. The first branches of the

aortic free wall are the coronary arteries. The locations of

the coronary ostia in TGA are very abnormally related (Fig-

ure 6, upper left). Thus, anatomically, TGA is an anomaly

of both the AP septum and of the free walls of both great

arteries, not of the AP septum only.

If TGA were caused by anomalous septation of the great

arteries, then, definite evidence of malformation of the AP sep-

tum, such as AP septal defect (AP ‘‘window’’), would be rela-

tively common in association with TGA. In fact, however, the

association of AP window with TGA is vanishingly rare. The

straight AP septum hypothesis also cannot explain the varia-

tions in semilunar valve heights, for example, why in TGA the

aortic valve is high and the pulmonary valve is low, which is

the opposite of normally related great arteries.

Aficionados of the classic straight AP septum hypothesis

have tried to explain away this weakness of the straight AP sep-

tum concept as follows: Of course, the transposed aortic valve

is high and the transposed pulmonary valve is low (which is the

opposite of normal) because the transposed aortic valve sits on

the conus, which is a part of the morphologically right ventri-

cle, whereas the transposed pulmonary valve is low, having no

conus to sit on, and consequently, the transposed pulmonary

valve is in fibrous continuity with the mitral valve. The prob-

lem with this ‘‘explanation’’ is the assumption that the subse-

milunar part of the conus is part of the morphologically right

ventricle. In fact, it is not.

Experience has taught us that the distal or subsemilunar part

of the conus can straddle the ventricular septum, to virtually

any degree. In ACM {S,D,L}10 (Figure 1, row 6, column 1) and

in DOLV,11 for example, the subsemilunar conus arteriosus can

be mostly above the morphologically left ventricle. The first

time that one sees a well-developed left-sided left ventricle sur-

mounted by a well-formed crista supraventricularis (conal mus-

culature) leading to an L-malposed aorta10 may come as quite a

shock. Many cardiac radiology textbooks define a morphologi-

cally right ventricle as the ventricle with a crista supraventricu-

laris (supraventricular crest). The problem is that the foregoing

definition of the right ventricle is not true. Usually, the crista is

above the right ventricle, but not always.

Exceptions do not prove the rule, except in a statistical sense

of indicating what is common. Exceptions really indicate that

there is something wrong with the rule, and one better find out

what it is. This kind of case taught us that the subsemilunar

conus ‘‘belongs to’’ the great arteries and is not an intrinsic,

inseparable part of either ventricle. The conotruncus concept

of the embryologists is correct. The conal maldevelopment

hypothesis can explain the variations in semilunar valve




heights (without invoking erroneous assumptions). The subpul-

monary and the subaortic parts of the conus act as little hollow

platforms on which the great arteries stand. The better devel-

oped the subsemilunar conus (subpulmonary, or subaortic, or

both, or neither) (Figure 5) happens to be, then, the higher and

the more anterior that semilunar valve is (Figures 2, 4, and 5).

Although Keith’s23 conal maldevelopment hypothesis was,

we think, essentially correct (as above), it is noteworthy in Fig-

ure 6 (top right) that he did not get the normal semilunar inter-

relationship quite right. His drawing shows the normally

related pulmonary valve as being anteriorly and to the right

of the normally related aortic valve. As all of us who grew

up in the catheterization laboratory know, the normally related

pulmonary valve should be anterior, superior, and to the left of

the normally related aortic valve. Also, the subpulmonary part

of the conus (shown in black, Figure 6) normally ends up some-

what further to the right than it should be.

What is wrong with Spitzer’s atavistic hypothesis to explain

the morphogenesis of TGA (Figure 6, lower left)?29,30 He

called his hypothesis a phylogenetic theory. It will be recalled

that phylogeny has to do with evolution, that is, the evolution-

ary development of a phylum, for example, of a species or

genus (Greek phule, tribe, clan), whereas ontogeny has to do

with the development of an individual organism (Greek, from

on [stem ont-], the present participle of einai, to be). Thus, the

prefix onto- indicates being or existence. Consequently, phylo-

geny means evolutionary development, whereas ontogeny

denotes individual development (embryology).

In 1923, Spitzer29,30 proposed a hypothesis of evolutionary

regression, back to the stage that is normally found in higher

reptiles such as crocodiles and alligators. Such higher reptiles

have both a left ventricular aorta and a right ventricular aorta.

Spitzer’s hypothesis29,30 is that the transposed aorta of human

TGA represents the reopened right ventricular aorta of the

higher reptiles and the closure of the left ventricular aorta of

higher reptiles and mammals. However, the fatal flaw in this

atavistic hypothesis involves the transposed pulmonary artery.

Spitzer states that the anterior portion of the true interventricu-

lar septum has disappeared: the location of the absent true ven-

tricular septum he indicates by a broken line. The apparent

ventricular septum anteriorly in TGA, Spitzer says, is a false

ventricular septum, a hugely hypertrophied crista supraventri-

cularis. In this way, Spitzer claims that the transposed pulmon-

ary valve and artery are arising from above the right ventricular

myocardium, that is, originating to the right of the vanished

true ventricular septum.

Why is this contention important? Because there is no ani-

mal known in which the pulmonary artery normally originates

above the morphologically left ventricle. Unfortunately for

Spitzer’s atavistic hypothesis,29,30 and indeed for any hypoth-

esis of phylogenic regression, the left-sided ventricle above

which the transposed pulmonary artery typically arises is com-

posed entirely of morphologically left ventricular myocardium.

There is no morphologically right ventricular myocardium

anteroseptally in this left-sided ventricular chamber. The

apparent ventricular septum is indeed the true ventricular

septum. There has been no ventricular septal disappearance,

contrary to Spitzer’s diagram (Figure 6, lower left). The anato-

mical data do not support Spitzer’s hypothesis.29,30

What is wrong with Grant’s31 fibrous malattachment

hypothesis, first proposed in 1962? Grant proposed that nor-

mally, there is a fibrous tract of low growth potential that

tethers the developing aortic valve to the developing mitral

valve (Figure 6, lower right). This causes the normal aortic-

mitral fibrous continuity and permits the pulmonary valve to

be anterior to the aortic valve, and the pulmonary valve is nor-

mally not in continuity with either the mitral valve or the tricus-

pid valve (Figure 6, lower right).

In TGA, Grant proposed that this fibrous tract of low growth

potential is shifted to the left so that it lies between the mitral

valve and pulmonary valve (not between the mitral valve and

aortic valve, which is normal). This left shift of the fibrous tract

tethers the pulmonary valve to the mitral valve but leaves the

aortic valve free and not in fibrous continuity with either AV

valve (mitral valve or tricuspid valve), as in typical TGA.

What is wrong with this fibrous malattachment hypoth-

esis?31 It cannot explain all of the conal anatomical types that

are found in association with TGA.26 Specifically, it cannot

explain those cases of TGA with a bilateral subsemilunar conus

(subaortic and subpulmonary) in which there is no pulmonary-

mitral fibrous continuity.

What anatomical types of subsemilunar conus are associated

with D-loop TGA in which a VSD is present? In 1993, Pasquini

and colleagues26 tried to answer this question, based on a study

of 119 cases of D-loop TGA with VSD:

1. a subaortic conus (with no subpulmonary conal free wall)

in 88.2%;

2. a bilateral (subaortic and subpulmonary) conus in 6.7%;

3. a subpulmonary conus (with no or minimal subaortic

conus) in 3.4%; and

4. a bilateral absent conus (neither subaortic nor subpulmon-

ary) in 1.7%.

We think that semilunar-AV fibrous continuity or disconti-

nuity results from the resorption or lack of resorption of the

subsemilunar conal free walls, respectively (Figure 3).

The conal development hypothesis, ‘‘development’’ includ-

ing both subsemilunar conal free wall growth and resorption,

appears able to explain all of the above-mentioned anatomical

types of conus associated with normally and abnormally related

great arteries (Figures 1-5).

What do we still not understand concerning normally and

abnormally related great arteries? Again, the answer is much.

The development (growth and resorption) of the subsemilunar

conal free walls is not the whole story. For example, why do the

ventricles loop in one direction, while the infundibuloarterial

segment (the conotruncus) twists in the opposite direction,

resulting, admittedly rarely, in ACM (Figure 1, row 6)? At

present, we do not know.

One of our next great challenges will be to gain a much bet-

ter understanding of the molecular genetic abnormalities and

Van Praagh 381



perhaps the environmental factors that control or influence the

development of the subsemilunar conal free walls that we have

been focusing on. This type of etiological understanding may

make possible the prediction and prevention of abnormally

related great arteries.

From a currently practical diagnostic and surgical perspec-

tive, in view of its great anatomical and developmental signif-

icance, the state of the subsemilunar conus arteriosus should be

described routinely in diagnostic imaging studies and reports

and in surgical operative notes. We need to start to understand

the subsemilunar conus arteriosus. We need to learn that the

subarterial conus is really not part of the right ventricle.

We need to understand that abnormally related great arteries

are abnormally connected great arteries; that the subsemilunar

conus is how the great arteries connect with the underlying ven-

tricles, ventricular septum, and AV valves; and that if the conal

connector has developed abnormally, the VA alignments and

other spatial relationships involving the great arteries will also

be abnormal.

Evolution and the Great Arteries

Thus far, we have considered normally and abnormally related

great arteries in terms of their normal and pathological anatomy

and embryology (ontogeny). We have barely mentioned the

probably great importance of vertebrate evolution (phylo-

geny).16 Pathological anatomy is important because it makes

possible accurate diagnosis and successful surgery; embryol-

ogy is important because it makes possible the understanding

of pathological anatomy; and evolution is important because

it makes possible the understanding of embryology.

The right ventricle (Figure 4A) is our major cardiovascular

adaptation to air breathing and land living.16 The subsemilunar

part of the conus arteriosus (Figure 4A, component 4), espe-

cially the subsemilunar conal free walls (Figure 3), normally

crosses the systemic venous and pulmonary venous circulations

by performing an embryonic aortic switch by a simultaneous

combination of subpulmonary conal free wall growth and sub-

aortic conal free wall resorption. The right ventricular sinus

(Figure 4A, component 2) evolved by evaginating or pouching

out beneath the proximal or apical portion of the conus arterio-

sus, the septal band (Figure 4A, component 3); thus, the right

ventricular sinus became the lung pump.

Who discovered evolution?16 Was it really Darwin and

Wallace, as is usually said? Fascinating to relate, the answer

is no. Evolution was in fact discovered by Empedocles, a

brilliant pre-Socratic physicist who lived from 495 to 435 BC

in Acragas (now Agrigento) in Sicily, which at that time was

part of Magna Graecia (Great Greece). Evolution may have

been understood even earlier by the Syrian brothers, who,

because of skeletal similarities, worshipped fish as the ancestor

of man. But Empedocles realized not only the existence of

evolution but how it works: by the chance occurrence of

favorable changes that then persist. Some 2300 years later, this

is what Darwin called natural selection (in 1859) and that

somewhat later Herbert Spencer termed survival of the fittest.

Homo sapiens sapiens, our modest scientific name for our-

selves (meaning ‘‘man wise wise’’), belongs to the phylum

Chordata, which includes all animals with a notochord (back

cord, Greek). The notochord early marks the long axis of the

embryo, indicating where the brain and the vertebrae will

later develop. The chordates are synonymous with the

vertebrates.

Phylogeny16

From an evolutionary (phylogenetic) standpoint, our remote

ancestors were the ancient fish of the Ordovician period and the

upper Devonian period, 500 million to 345 million years ago. In

craniate vertebrates, the heart began as a specialized part of the

primary longitudinal ventral blood vessel that pumped venous

blood from the ducts of Cuvier and the hepatic veins forward and

upward through the gills, where oxygenation took place. As long

as our vertebrate ancestors ‘‘breathed’’ water, there was a single

systemic circulation and no need for lungs or a right ventricle.

However, about 325 million years ago in the early Carboni-

ferous period, amphibians evolved. These animals evolved

lungs and so could breathe air, but they still had to breed in the

water like modern frogs. From these primitive amphibians, not

only modern amphibians evolved but also fully terrestrial ani-

mals that did not need to breed in the water. These were the

Amniota, all animals with an amniotic sac. The amniotic sac

surrounds a ‘‘mare internum’’ (internal sea) of amniotic fluid

in which the embryo and later the fetus floats, like our aquatic

vertebrate ancestors. The terrestrial Amniota then evolved into

reptiles, birds (feathered reptiles), and mammals (furry or hairy

reptiles). Mammals evolved during the Jurassic period, some

180 million years ago, when reptiles, including the giant dino-

saurs, were the lords of the earth.

Although fish and amphibians do not have a right ventricle,

higher reptiles (such as crocodiles and alligators), birds, and

mammals do. The evolution of the right ventricle was part of

the development of a double circulation—pulmonary and sys-

temic—in fully terrestrial vertebrates. In aquatic and semiaqua-

tic vertebrates, there is only a single circulation, the systemic,

that also supplies the organs of respiration (gills, lungs, and

skin).

But why is the right ventricle the right-sided ventricle?

Because D-loop formation (Figures 2 and 3), which is normal

in higher vertebrates, places the conus arteriosus, from which

the right ventricular sinus develops, to the right of the ventricle

of the bulboventricular loop, which therefore becomes the left-

sided ventricle and remains the systemic pump.

Ontogeny16

From the embryological (ontogenetic) standpoint, the salient

stages of normal human cardiogenesis are as follows:

1. The cardiogenic crescent of the precardiac mesoderm

occurs from 16 to 20 days following ovulation.




2. The straight tube or preloop stage follows from 20 to 22

days of age (Figure 2).

3. D-loop formation then occurs from 22 to 24 days of age

(Figure 2). This is when the human heart beat is thought

to begin. There is a single, in-series circulation, reminis-

cent of the circulation of a fish: from right atrium, to left

atrium, to future left ventricle, to future right ventricle,

to future great arteries. Left-sided juxtaposition of the

atrial appendages is present. The developing ventricular

apex points to the right; that is, dextrocardia is present. The

circulation resembles that in tricuspid atresia and in

double-inlet or common-inlet left ventricle. Both develop-

ing great arteries are above the future right ventricular

sinus; that is, DORV is potentially present. The aortic

switch process has not as yet occurred.

4. By 26 to 28 days of age in utero, both ventricular sinuses

are beginning to evaginate or pouch out from the greater

curvature of the bulboventricular D-loop. The left ventri-

cular sinus develops faster than the right ventricular sinus.

The right ventricular sinus is still somewhat posterior to

the left ventricular sinus because the developing ventricu-

lar apex is still pointing rightward. The right atrial appen-

dage is starting to bulge out to the right of the great arterial

outflow tracts; that is, left-sided juxtaposition of the atrial

appendages is beginning to be ‘‘cured.’’

5. By 30 to 32 days of age, much more evagination or out-

pouching of both the ventricular sinuses has occurred.

Although the right ventricular sinus is still smaller than the

left ventricular sinus, the growth of the right ventricular

sinus is catching up to that of the left ventricular sinus. The

ventricles are swinging horizontally leftward so that the

developing ventricular septum now occupies an approxi-

mately sagittal plane; that is, mesocardia is now present.

Left-sided juxtaposition of the atrial appendages has now

completely disappeared because the right atrial appendage

now lies entirely to the right of the great arterial outflow

tracts.

6. By 32 to 34 days of age, the ostium primum has almost

been closed by growth of the endocardial cushions of the

AV canal. The ostium primum normally is closed com-

pletely between 34 and 36 days of age. The tricuspid valve

is now opening into the right ventricle. The right ventricu-

lar sinus is now almost as large as the left ventricular sinus.

But mesocardia is still present.

7. By 38 to 40 days of age in utero, the ventricular apex nor-

mally points leftward; that is, levocardia has been

achieved. The right ventricular sinus is now as large as the

left ventricular sinus. The normal aortic switch procedure

has been performed developmentally (as described hereto-

fore). Cardiac morphogenesis normally is now largely

complete, except that the interventricular foramen (the

VSD) is still open.

8. Between days 38 to 45, the interventricular foramen nor-

mally is closed at its rightmost end, adjacent to the tricus-

pid valve. However, the interventricular foramen can

remain patent until after birth. Postnatal closure of the

membranous septum is so-called spontaneous closure, if

it occurs without interventional or surgical assistance. The

membranous septum is superior endocardial cushion tissue

of the AV canal that is intimately related to the tricuspid

valve (between the anterior and septal leaflets) and is also

closely related to the recently switched aortic valve

(beneath the right coronary-noncoronary commissure of

the normally located aortic valve).

As was stated by Ernst Haeckel of Jena (1834-1919) in his

biogenic law, the developmental history of the individual (onto-

geny or embryology) does tend to recapitulate the developmen-

tal history of our phylum Chordata (phylogeny or evolution).

Thus, the approximately 29-day history of human cardiac devel-

opment, from day 16 when the cardiogenic crescent is appearing

to day 45 when the interventricular foramen usually is closing,

does indeed recapitulate or summarize the 500 million–year

cardiovascular history of our phylum Chordata. The genes, with

their many favorable mutations, have an amazingly long and

accurate ‘‘memory.’’

But our genetic ‘‘memory’’ is far from perfect because of

mutations (copying errors). Now, have another look at Figure 1,

which documents many, but not all, of the unsuccessful ways in

which the embryonic aortic switch procedure can be per-

formed. This is what abnormally related great arteries really

are: unsuccessful attempts to perform the embryonic aortic

switch from the developing right to the developing left

ventricle.

Phylogeny and Ontogeny of Congenital Heart Disease16

Examining the normal morphologically right ventricle (Figure

4A) and solitus normally related great arteries (Figure 2), many

well-informed observers may not realize that they are looking

at the cardiovascular adaptations that made possible air breath-

ing and permanent land living for vertebrates, including mam-

mals such as ourselves. Just imagine that! The evolution

(phylogeny) and the embryology (ontology) of the right ventri-

cle (both parts of the conus arteriosus) and the great arteries

made possible ‘‘everything’’ for Homo sapiens sapiens—our

terrestrial prehistory, history, culture, and science.

In our phylum Chordata, the morphologically left ventricle

is the ancient professional pump. It is at least 500 million years

old and is seldom involved in primary malformation. By con-

trast, the right ventricle, including its 4 component parts (Fig-

ure 4A), is a ‘‘Johnny-come-lately,’’ a relative newcomer, only

about 180 million years old. The right ventricle is only about

36% as old as the left ventricle. Or, to say it another way, the

right ventricle is 64% younger than the left ventricle. As pedia-

tric cardiologists and congenital heart surgeons know, the right

ventricle is much more prone to malformation than is the left

ventricle. Congenital heart disease, that is, the structural heart

disease that one can be born with, is composed almost entirely

of right ventricular anomalies (congenital, from Latin congeni-

tus, born together with: com-, together þ genitus, born, past

participle of gignere, to beget).

Van Praagh 383



Consequently, we are still experiencing serious problems

with the phylogenetically younger part of our cardiovascular

system, that is, with the lung pump, the aortic switch, and the

septation mechanisms, examples of which follow: tricuspid

atresia; congenitally unguarded tricuspid orifice (ie, absence

of tricuspid leaflets, but with a patent tricuspid orifice); com-

mon AV canal (with or without common AV valve, with or

without AV septal defect); absence of the right ventricular

sinus (with double-inlet or common-inlet into a single or

unpaired left ventricle, with an infundibular outlet chamber);

VSDs; Ebstein anomaly of the tricuspid valve and right ventri-

cular sinus; Uhl disease (ie, parchment right ventricle); hypo-

plasia of the right ventricle sinus (with straddling tricuspid

valve, or double-outlet right atrium, or superoinferior ventri-

cles, or with crisscross AV relations); double-chambered right

ventricle (also known as anomalous muscle bundles of the right

ventricle); TOF; truncus arteriosus; TGA (Figure 1); DORV

(Figure 1); DOLV (Figure 1); ACM (Figure 1); other rare seg-

mental anatomical sets (Figure 1) such as situs inversus totalis

{I,L,I}, ventricular inversion with inverted normally great

arteries in visceroatrial situs solitus {S,L,I}, isolated ventricu-

lar inversion {S,L,S}, isolated ventricular noninversion

{I,D,I}, and isolated infundibuloarterial inversion {S,D,I} with

or without TOF; and AP septal defect (also known as AP

window).

The foregoing list is not complete but does indicate the mag-

nitude of the problem posed by malformations of the right ven-

tricle and its 4 component parts, the phylogenetically ‘‘recent’’

part of the human cardiovascular system. Primary anomalies of

the great arteries themselves, such as AP window, are relatively

rare. So, too, are primary anomalies of our ancient systemic

pump, the left ventricle.

Declaration of Conflicting Interests

The author(s) declared no conflicts of interest with respect to the

authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research and/or

authorship of this article.

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