nadas embryology
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2
Embryology1
RICHARD VAN PRAAGH, MD
Embryology is important to pediatric cardiology as ameans of understanding. Embryology makes possible thecomprehension of complex congenital heart disease, whichin turn facilitates its accurate clinical diagnosis. Embryology also helps to clarify both the morphogenesis (pathogenesis)and the etiology (basic causes) of cardiac malformations.
DEFINITION
In man, embryology may be defined as developmentalbiology from conception to the end of the second month of
life (i.e., from conception to the end of the eighth week).
THE FIRST WEEK OF LIFE
The salient events of the first week of life from 0 to 7 days(Fig. 2-1) are (a) ovulation, (b) fertilization, (c) segmenta-tion, (d) blastocyst formation, and (e) the beginning of implantation.
THE SECOND WEEK OF LIFE
The principle developments of the second week of life,from 8 to 14 days (Fig. 2-2), are (a) completion of the
implantation, (b) bilaminar disc formation, consisting oectoderm and endoderm, (c) development of the amnioticavity, (d) appearance of the yolk sac, and (e) the elaboration of primitive villi of the developing placenta. It is note worthy that during the first 2 weeks of life, humans havno heart and no vascular system.
THE THIRD WEEK OF LIFE
From the cardiovascular standpoint, the main events othe third week of life, from 15 to 21 days, may be summa
rized as follows (Figs. 2-3 to 2-5):
1. In humans, the mesoderm develops from the ectoderm on the 15th day of life (Fig. 2-3). It is from thmesoderm that the cardiovascular system is formed.
2. The cardiogenic crescent of precardiac mesodermthe immediate precursor of the heart, appears on th18th day of life (Fig. 2-4A).
3. The intra-embryonic celom also develops on th18th day of life (Fig. 2-5). Cavitation of the mesodermforms the intra-embryonic celom, from which arderived all of the body cavities—pericardial, pleura
and peritoneal.4. The straight heart tube, or preloop stage, normall
develops by 20 days of age (Fig. 2-4B). By analogy witchick embryos, the heartbeat in man probably beginat the straight tube stage, or at the early D-loop or L-loostage (Fig. 2-4C and 2-4D).
5. Cardiac loop formation, normally to the right (D-looformation) and abnormally to the left (L-loop formation), begins by 21 days of age (Fig. 2-4C and D).
1
1This chapter is based on personal study of embryos from the following sources: theMinot Collection, Harvard Medical School, Boston; the Carnegie Collection,Carnegie Institution, Baltimore; chick embryology, morphologic, and experimental,the Carnegie Institution, Baltimore, and The Children’s Hospital, Boston;iv/iv mouse embryology, Dartmouth Medical School, Hanover, New Hampshire;and the literature.
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Corpus Luteum
4
3
2
1Graafian Follicle
Myometrium
5
6
7
8
9
Fimbria
Endometrium (progestational stage)
FIGURE 2–1 Schematic representation of the events taking place during the first week of human development. (1) Occyte immediately after ovulation. (2) Fertilization approxi-
mately 12 to 24 hours after ovulation. (3) Stage of the male and female pronuclei. (4) Spindle
of the first mitotic division. (5) Two-cell stage (approximately 30 hours of age). (6) Morulacontaining 12 to16 blastomeres (approximately 3 days of age). (7) Advanced morula stagereaching the uterine lumen (approximately 4 days of age). (8) Early blastocyst stage (approx-
imately 41 / 2 days of age). The zona pellucida has now disappeared. (9) Early phase of implantation (blastocyst approximately 6 days of age).The ovary shows the stages of the transformation between a primary follicle and a graafian follicle as well as a corpus luteum.The uterine endometrium is depicted in the progestational stage.From Langman J. Medical Embryology, 2nd ed. Baltimore: Williams & Wilkins, 1969, with
permission.
Trophoblastic Lacunae
Syncytiotrophoblast
Cytotrophoblast
Amniotic Cavity
Exocoelomic Cavity (primitive yolk sac)Fibrin CoagulumHeuser's Membrane
FIGURE 2–2 The second week of life: the implanted bilaminar disc consisting of the ectodermand endoderm, before the appearance of the mesoderm.From Langman J. Medical Embryology, 2nd ed. Baltimore: Williams & Wilkins, 1969, with
permission.
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THE FOURTH WEEK OF LIFE
The main features of cardiovascular development from22 to 28 days are the following:
1. Normally, D-loop formation is completed (Fig. 2-6,horizon XI).
2. The development of the morphologically left ventri-cle and of the morphologically right ventricle begins(Fig. 2-6, horizon XIII).
3. The circulation commences.
4. Cardiovascular septation is initiated.
5. The evolution of the aortic arches begins (Figs. 2-7,
2-8, and 2-9).
Neural crest cells originating from the posteriorrhombencephalon (rhombomeres 6–8) begin to migrateinto pharyngeal (aortic) arches 3, 4, and 6 (Figs. 2-8 and2-9) and from there to the heart where they participate inthe formulation of conus (including the conal septum), thegreat arteries (including the aorta, the aortopulmonary
septum, the carotids, the subclavians, the ductus arteriosus), and the cardiac ganglia.1
Streeter’s horizons, now often called stages (Fig. 2-10are indicated by Roman numerals in Figure 2-6. Eachorizon is a 2-day time interval. To obtain the approximatage of the embryo, double the horizon number. For exam
ple, horizon XI indicates a time interval that begins on da22. Because each horizon is 2 days long, horizon Xextends from days 22 to 24 (Fig. 2-10). Embryonic length(in mm) are also given in Figure 2-10, and it is readipossible to convert the length of a normal human embryinto both the developmental stage (horizon) and approximate age.
The left and the right ventricles develop by evaginatioor outpouching from the primary heart tube, beginning a22 to 24 days (horizon XI, Fig. 2-6, left side). By 26 to 2days (horizon XIII, Fig. 2-6, right side), development othe left ventricle is more advanced than that of the righ
(Fig. 2-6, right side).True circulation (as opposed to the ebb and flow) ithought to begin in humans at this stage (26–28 days, horzon XIII, Fig. 2-6, right side). This is known as the in-seriecirculation because the blood goes from the morphologcally right atrium to the morphologically left atrium, to thleft ventricle, to the right ventricle, and the truncus arteriosus (arterial trunk) (Fig. 2-6, right side). The in-seriecirculation is similar to that which persists in tricuspiatresia.
At the beginning of the fourth week, the first pair oaortic arches has formed (Fig. 2-7). At this stage, th ventricle (future left ventricle) of the D-bulboventricula
loop is ventral (anterior) to the proximal bulbus cordi(future right ventricle) (Fig. 2-7, right side). Thus, early iD-loop formation, the left ventricle is anterior to (ventrato) the right ventricle. Hence, among children witcongenital heart disease, the anterior ventricle is usuallyalthough not necessarily the right ventricle.
By the 26th day of life, the first pair of aortic arches (earliemandibular arteries) has involuted completely or nearlcompletely (Fig. 2-8). The second and third aortic archehave been formed, and the fourth and sixth arches arbeginning to form (Fig. 2-8). A large communicatiobetween the respiratory and gastrointestinal tracts is presen(i.e., a large tracheoesophageal “fistula”) is normal at th
stage (Fig. 2-8, right side).By the end of the fourth week (28 days, Fig. 2-9), aort
arches 1 and 2 have involuted. Aortic arches 3 and 4 arpresent (Fig. 2-9). Aortic arches 5 are incomplete bilaterallAortic arches 6 are in the process of forming (complete othe right and incomplete on the left, Fig 2-9). Botpulmonary artery branches are present, as is the commopulmonary vein (Fig. 2-9, left side).
Embryology 1
Prochordal
Connecting
stalk
Amniotic
streak
A.
Primitive
streak
Yolk sac
Plate
FIGURE 2–3 The appearance of the mesoderm, from which thecardiovascular system will arise, at 15 days of age. The mesoderm(meaning “middle skin”) buds off from the ectoderm.From Hamilton WJ, Mossman HW. Human Embryology:Prenatal Development of Form and Function, 4th ed. Baltimore:Williams & Wilkins, 1972, with permission.
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16 Developmental Anatomy
C B
A
D
FIGURE 2–4 Cardiac loop formation.A, Cardiogenic crescent of precardiac mesoderm. B, Straightheart tube or preloop stage. C, D-loop, with solitus (noninverted) ventricles. D, L-loop with inverted(mirror-image) ventricles. A, atrium; AIP, anterior intestinal portal; Ao, aorta; BC, bulbus cordis;HF, head fold; LT, left; LV, morphologically left ventricle; NF, neural fold; PA, (main) pulmonaryartery; RT, right; RV, morphologically right ventricle; SOM, somites; TA, truncus arteriosus.From Van Praagh R, Weinberg PM, Matsuoka R et al: Malpositions of the heart. In Adams FH,Emmanouilides GC (eds.). Heart Disease in Infants, Children, and Adolescents, 3rd ed. Baltimore:Williams & Wilkins, 1983, with permission.
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Cephalic loseof Neural plate Bucco-Pharyngeal
Membrane
Somite
Amnion Neuralplate
Somatopleuricmesodern
Splanchnopleuricmesoderm
Notochord Intermediatecell mass
Somite
Yolk Sacwall
FIGURE 2–5 Schematic representation of the cranial part of a somite embryo shows the relationships of the intra-embry-onic celom, the development of the neural plate, and the conti-
nuity between the intrae-mbryonic celom and theextra-embryonic celom. The white arrows indicate the junc-
tions between the two celomata. The dotted arrows are in the intra-embryonic celom.From Hamilton WJ, Mossman HW. Human Embryology:Prenatal Development of Form and Function, 4th edBaltimore: Williams & Wilkins, 1972, with permission.
FIGURE 2–6 Formation of the ventricles. Left, Horizon XI, 22 to 24 days of age. Carnegieembryo No. 2053, original reconstruction of cardiovascular lumen × 60 magnification. Right,Horizon XIII, 26 to 28 days of age, Carnegie embryo No. 836, original reconstruction of cardio-
vascular luman × 60 magnification. ANT. CARD. V., anterior cardiac vein; ATR.-Ventr. J’CT.,atrioventricular junction; L. ATR., morphologically left atrium; LT. Ao. ARCH, left aortic arch;
L. UMB. V., left umbilical vein; L. VENTR., morphologically left ventricle; O-M VV.,omphalomesentric veins; P. CARD. V., posterior cardiac vein; PRIM., primitive; RT. AO., rightaorta; R. ATR., morphologically right atrium; RT. VENTR, morphologically right ventricle; RT.UMBIL. V., right umbilical vein; SIN. VENOSUS, sinus venosus.From Streeter GL. Developmental horizons in human embryos, age groups XI to XXIII, vol II.Embryology Reprint. Washington, DC: Carnegie Institution, 1951, with permission.
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18 Developmental Anatomy
FIGURE 2–7 First pair of aortiarches arching over (cephalad to
first pair of pharyngeal pouche Left, ventral view. Right, Lelateral view. Carnegie embry
2053, horizon XI, 22 to 24 dayof age.From Congdon ED. Transfor
mation of the aortic-arch system during the development of thuman embryo. Contrib EmbryoCarnegie Institution 14:47, 1922
with permission.
FIGURE 2–8 Second and thir pairs of aortic aches. LeVentral view. Right, Left latera
view. Carnegie embryo 83early horizon XIII, 26 days oage. Each aortic arch passecephalad to its pharyngeal pouch
Arch 1 is involuting. Arches
and 6 are just forming.From Congdon ED. Transformation of the aortic-arch system
during the development of thhuman embryo. Contrib EmbryoCarnegie Institution 14:47, 1922
with permission.
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THE FIFTH WEEK OF LIFE
The major cardiovascular developments between days
29 and 35 may be summarized as follows:
1. The left ventricle, right ventricle, and ventricularseptum continue to grow and develop (Fig. 2-11).
2. There is approximation of the aorta to the interven-tricular foraman, mitral valve, and left ventricle(Figs. 2-11 and 2-12).
3. Separation of the ascending aorta and mainpulmonary artery occurs (Fig. 2-12, horizon XVIa,i.e., days 32–33).
4. Separation of the mitral and tricuspid valves isaccomplished (Fig. 2-12, horizon XVII, i.e., days
34–36).5. The right ventricle enlarges (compare Fig. 2-11, leftside, with Fig. 2-11, right side).
6. In association with right ventricular enlargement, themuscular ventricular septum moves from right to leftbeneath the atrioventricular canal (compare Fig. 2-11,left side, with Fig. 2-11, right side).
7. The tricuspid valve now opens into the right ventricle(Fig. 2-11, right, and Fig. 2-12, horizon XVII).
8. The ostium primum is closed by tissue from thendocardial cushions of the atrioventricular cana(Fig. 2-13), thereby separating the atria.
9. The ventricular apex swings horizontally leftward.10. From days 30 to 36, the pulmonary valve movefrom posterior and to the left of the developinaortic valve (30–32 days, horizon XV, Fig. 2-12), ta position beside and to the left of the aorti valve (days 32–33, horizon XVIa, Fig. 2-12), thesomewhat anterior and to the left of the aorti valve (days 33–34, horizon XVIb, Fig. 2-12), anfinally to its normal anterior position to the leof the aortic valve (days 34–36, horizon XVIFig. 2-12).
Hence, the morphogenetic movement of the pulmonar
valve is from posterior to anterior, to the left of the aort valve (Fig. 2-12). The aortic valve moves virtually not at alexcept that it keeps on facing the anteriorly movinpulmonary valve (Fig. 2-12). It is thought that the reasofor the normal anterior morphogenetic movement of thpulmonary valve is the normal growth and developmenof the subpulmonary infundibulum, which carries thpulmonary valve superiorly and anteriorly. Conversely, thnormal lack of morphogenetic movement of the aorti
Embryology 1
FIGURE 2–9 Aortic arches 3
and 4. Left, Ventral view. Right, Left lateral view. Carnegieembryo 1380, late horizon XIII,
28 days of age. Aortic arches 1and 2 have involuted, 2 and 4 are
present, 5 is incomplete bilater-ally, and 6 is complete on the right
but not on the left. Right and left pulmonary artery branches and the common pulmonary vein are present.From Congdon ED. Transforma-
tion of the aortic-arch system during the development of the
human embryo. Contrib EmbryolCarnegie Institution 14:47, 1922,
with permission.
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valve appears to be due to the normal resorption of thesubaortic conal free wall.
The semilunar interrelationship at 30 to 32 days in thehuman embryo is very similar to that of D-transposition
of the great arteries (horizon XV, Fig. 2-12). At days 32to 33, the semilunar interrelationship is side-by-side, simi-lar to that of the Taussig-Bing malformation (horizon XVIa, Fig. 2-12). At days 33 to 34, the semilunar interrela-tionship is similar to that of tetralogy of Fallot (horizon XVIb, Fig. 2-12). Because the pulmonary valve has beencarried from posterior to anterior on the left-hand side of the ascending aorta, the pulmonary artery must pass in theopposite direction—from anterior to posterior on the left of
the ascending aorta—as it passes from the pulmonary valvproximally to the pulmonary bifurcation distally (horizo XVIII, Fig. 2-12). This anterior-to-posterior course of thmain pulmonary artery makes it look as though normall
related great arteries twist around each other. However, is thought that the great arteries really are passiveluntwisting about each other as the pulmonary artery passefrom the anterior pulmonary valve to the posteriopulmonary bifurcation (horizon XVIII, Fig. 2-12).
Thus, the fifth week is when the primitive, singlein-series circulation, which suffices for water-“breathingfish, is converted into the definitive, double, in-parallecirculations that characterize air-breathing mammals
20 Developmental Anatomy
FIGURE 2–10 Developmental horizons (stages) in the human embryo, modified from Streeter. Horizons are indicated at the top iRoman numerals. Embryonic ages are shown at the bottom in days. Embryonic lengths are given at the left in millimeters (mm). Salien
features of each horizon are indicated.From Neill CA. Development of the pulmonary veins with reference to the embryology of anomalies of pulmonary venous returnPediatrics 18:880, 1956, with permission.
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Embryology 2
FIGURE 2–11 Fifth week of life. Left, Horizon XV, 30 to 32 days of age, Carnegie embryo 3385, origi-
nal reconstruction of cardiovascu-lar lumen × 30. Right, Horizon
XVI, Carnegie embryo 6510, orig- inal reconstruction of cardiovas-cular lumen × 30. Abbreviationsas in previous figures.From Streeter GL. Developmentalhorizons in human embryos, age
groups XI to XXIII, vol II.Embryology Reprint. Washington,DC: Carnegie Institute, 1951, with
permission.
ao
XV
p
XVIa
XVIb
1m
XVII
XVIII
FIGURE 2–12 Dissections of human embryonic hearts, viewed from above (dorsal aspect), to show positional
changes of pulmonary valve (p) relative to aortic valve (ao) from horizons XV to XVIII. Top of figure is ventral (ante-rior), bottom of figure is dorsal (posterior), the developing
pulmonary valve (p) is to the embryo’s left, and the develop- ing aortic valve (ao) is to the embryo’s right. The atria have been removed to show partitioning of the atrioventricular canal. At the conotruncal junction, the major part of the
movement takes place on the pulmonary side of the outlet (p).The aortic valve (ao) keeps on facing the anteriorly migrating
pulmonary valve (p), but otherwise the aortic valve movesonly slightly.From Asami I. Partitioning of the arterial end of the humanheart. In Van Praagh R, Takao A (eds): Etiology andMorphogenesis of Congenital Heart Disease. Mount Kisco,
NY: Futura Publishing, 1980, p 51, with permission.
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22 Developmental Anatomy
To LA SVTT
E
SC
IC
T
CoSCPV
FIGURE 2–13 Closure of ostium primum by tissue from the endocardial cushions o the atrioventricular (AV) canal, horizo XVI, 33 days of age, Harvard embryo 736 sagittal section number 138, borcarmine and Lyons blue stain, origina
magnification×
130, right lateral viewTissue of the superior cushion (SC) an inferior cushion (IC) of the atrioventricular canal has fused with the atrial septum
which is composed of venous or sinus veno sus tissue (SVT), this fusion closing thostium primum. CoS, coronary sinusCPV, common pulmonary vein; E, esopha
gus; LA, left atrium; T, trachea.From Van Praagh R, Corsini I. Cor triatria
tum: pathologic anatomy and consideratioof morphogenesis based on 13 postmortemcases and a study of normal developmenof the pulmonary vein and atrial septum i
83 human embryos. Am Heart J 78379–405, 1969, with permission.
FIGURE 2–14 Aortic arches 3, 4and 6. Left, Ventral view. Right
Left lateral view. Carneembryo 1121, horizon XVII, 34 t36 days of age. Distal aortopul
monary separation is well see(left). Both ductus arteriosi (sixtarches) and both dorsal aortae ar
still intact.From Congdon ED. Transformation of the aortic-arch system
during the development of thhuman embryo. Contrib EmbryoCarnegie Institution 14:47, 1922
with permission.
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Cardiovascular separation is nearly completed. However,the interventricular foramen (ventricular septal defect) isstill patent.
By the end of the fifth week, aortic arches 3, 4, and 6 arepresent (Fig. 2-14). Both ductus arteriosi and both dorsalaortae are still intact. During the fifth week, neural crestcells continue to contribute to the development of theinfundibulum, the great arteries, and their branches.
THE SIXTH AND SEVENTH WEEKS
OF LIFE
The main cardiovascular developments between the36th and the 49th days of life are (a) closure of the conal(infundibular) septum and (b) closure of the membranouspart of the ventricular septum (Fig. 2-15). The ventricular
septum usually is closed between 38 and 45 days of ageClosure of the interventricular foramen can be delayeuntil after birth, when it is known as spontaneous (i.esurgically unassisted) ventricular septal defect closure.
DEVELOPMENT OF THE AORTIC
ARCHES
The evolution of the aortic arches is summarized iFigure 2-16. This diagram is helpful for the understandinof vascular rings. In diagram 8 (Fig. 2-16), the asteriskindicate the presence of fifth arches bilaterally; these arpresent in about a third of human embryos at this stage.
There are four normal interruptions of the aortiarch system: (a) involution of the right ductus arteriosus osixth arch (diagram 12, Fig. 2-16); (b) and (c) involution o
Embryology 2
FIGURE 2–15 Closure of theconal (infundibular) septum and
the interventricular foramen. A, 6 weeks. B, Beginning of seventh week. C, End of seventh week.From Langman J. Human devel-opment-normal and abnormal.
In Medical Embryology, 2nd ed.Baltimore: Williams & Wilkins,1969, with permission.
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the ductus caroticus bilaterally (i.e., involution of thedorsal aortae between arches 3 and 4, bilaterally) (diagram13, Fig. 2-16); and (d) involution of the right dorsal aortadistal to the seventh intersegmental artery (part of theembryonic right subclavian artery), resulting in a left aorticarch (diagram 14, Fig. 2-16).
What determines whether one has a left aorticarch or a right aortic arch? The answer is, whicheverdorsal aorta persists. If the left dorsal aorta persists, onehas a left aortic arch. If the right dorsal aorta persists and
the left involutes, one has a right aortic arch. If both dorsalaortae persist, a double aortic arch results.
If the right dorsal aorta involutes proximal or cephaladto the seventh intersegmental artery (instead of distal tothis artery), the result is an aberrant right subclavianartery, which arises as the last brachiocephalic artery fromthe top of the descending thoracic aorta.
It has often been said (erroneously) that whichever aorticarch is present depends on which fourth aortic arch (left or
right) persists. Therefore, it is helpful to know that bothfourth aortic arches (left and right) normally always persis(Fig. 2-16), regardless of whether a left or a right aortiarch is present. Thus, which aortic arch is present is determined not by the fourth or aortic arches per se, but b which dorsal aorta persists and which involutes (diagram14, Fig. 2-16).
Recently, there has been an explosion of moleculagenetics information that is highly relevant to the normaand abnormal development of the human cardiovascula
system.2–4 The interested reader is urged to consult ththree textbooks referred to here.2–4
SUMMARY
Cardiogenesis begins on the 18th day of life with thformation of the cardiogenic crescent of precardiac mesoderm (Fig. 2-4A) and normally is completed by the 45th da
24 Developmental Anatomy
FIGURE 2–16 Development o the aortic arches. In the earlies stage, only the first arch is presen whereas in the last (full-ter fetus), the vessels have acquire nearly their adult form.From Congdon ED. Transformation of the aortic-arch system
during the development of thhuman embryo. Contrib Embryo
Carnegie Institution 14:47, 1922 with permission.
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of life with the formation of the membranous part of the ventricular septum (Fig. 2-15). Cardiovascular maturationcontinues well after birth.
REFERENCES
1. Streeter GL. Developmental horizons in human embryos, agegroups XI to XXIII, vol II. Embryology Reprint. Washington,DC: Carnegie Institute, 1951.
2. Clark EB, Nakazawa M, Takao A (eds). Etiology andMorphogenesis of Congenital Heart Disease: Twenty Years of Progress in Genetics and Developmental Biology. Armonk,NY: Futura Publishing, 2000, pp 1–397.
3. de la Cruz MV, Markwald RR (eds). Living Morphogenesis of the Heart. Boston: Birkhäuser, 2000, pp 1–233.
4. Harvey RP, Rosenthal N (eds). Heart Development. SanDiego: Academic Press, 1999, pp 1–530.
5. Langman J: Human development-normal and abnormal.
In XXX (eds). Medical Embryology, 2nd ed. Baltimore: Williams & Wilkins, 1969.
6. Hamilton WJ, Mossman HW. Human Embryology: PrenataDevelopment of Form and Function, 4th ed. Baltimore
Williams & Wilkins, 1972.7. Van Praagh R, Weinberg PM, Matsuoka R, et a
Malpositions of the heart. In Adams FH, EmmanouilideGC (eds): Heart Disease in Infants, Children and Adolescent
4th ed. Baltimore: Williams & Wilkins, 1983, pp 422–458.8. Congdon ED. Transformation of the aortic-arch systemduring the development of the human embryo. ContriEmbryol Carnegie Institution 14:47, 1922.
9. Neill CA. Development of the pulmonary veins with reference to the embryology of anomalies of pulmonary venoureturn. Pediatrics 18:880, 1956.
10. Asami I. Partitioning of the arterial end of the embryoniheart. In Van Praagh R, Takao A (eds): Etiology anMorphogenesis of Congenital Heart Disease. Mount KiscoNY: Futura Publishing, 1980, p 51.
11. Van Praagh R, Corsini I. Cor triatriatum: pathologic anatomand consideration of morphogenesis based on 13 postmortem cases and a study of normal development of th
pulmonary vein and atrial septum in 83 human embryosAm Heart J 78:379, 1969.
Embryology 2