1. 2010. 6. 15
Cardiac
Development
관동의대 제일병원
병리과 전이경

2. Congenital Heart Disease
Frequency of Congenital Cardiac Malformations
Malformation Incidence/Million Live Births %
Ventricular septal defect (VSD) 4482 42
Atrial septal defect (ASD) 1043 10
Pulmonary stenosis (PS) 836 8
Patent ductus arteriosus (PDA) 781 7
Tetralogy of Fallot (TOF) 577 5
Coarctation of aorta (CoA) 492 5
Atrioventricular septal defect (AVSD) 396 4
Aortic stenosis (AS) 388 4
Transposition of great arteries (TGA) 388 4
Truncus arteriosus 136 1
Total anomalous pulmonary venous connection (TAPVC) 120 1
Total 9757
J Am Coll Cardiol 39:1890,2002

3. Critical periods of development for various organ
systems and the resultant malformations

4. First week of development: Second week of development:
Ovulation to implantation Bilaminar germ disc
Third week of development:
Gastrulation (trilaminar germ disc)

5. Truncus
Conus

6. Early Cardiac Morphogenesis I
(Fertilization 3rd week)
• Cardiogenic crest in
splanchnic mesoderm
in front of the neural
plate
• Bilateral endocardial
tube from angioblastic day 18
cords
• Cephalic and lateral
folding of the embryo
• Primary heart tube in
the middle thorax
day 22

7. A, day 18. B, day 20. C, day 21. D, day 22

8. Early Cardiac Morphogenesis II
(Fertilization 4th week)
• Segmentation
: SV-AT-AVC- VT-BC
• Layering
: Endocardium – Myocardium- Epicardium
Cardiac jelly
• Looping

9. AV canal Atrium Sinus
Bulbus Ventricle venosus
cordis

10. Formation of Cardiac loop
Normal D-looping
A, day 22 B, day 23 C, day 24

11. Abnormalities of cardiac looping
• Dextrocardia:
• 심장이 오른쪽 흉곽에 위치하고 심첨이 오
른쪽을 향함
• Isolated form/ situs inversus

12. Formation of cardiac septa
• Between 27th and 37th days of
development (embryo: 5mm~ 16-17mm)

17. Atrial Septation (4-6 week)
• Primary septum (septum primum)
• Secondary septum (septum secundum)
• Intermediate septum (septum
intermedium)- endocardial cushion
• Primary foramen (Foramen primum)
• Secondary foramen (Foramen secundum)
• Oval foramen (foramen oval)

18. Atrial Septal Defect
• Type
Secundum ASD (90%)
Primum ASD (5%)
Sinus venosus ASD (5%)

19. Secundum ASD (90%)

20. Endocardial cushion
• Atrioventricular and conotruncal regions
 Atrial and ventricular (membranous portion)
septa
 Atrioventricular canals and valves
 Aortic and pulmonary channels
• Abnormalities in ECC formation
 ASD, VSD, AVSD
 Defects involving great vessels (ex. TGA,
TOF)

22. Ventricular Septation

23. 30 days
Development of
conotruncal ridges
and closure of the
interventricular
foramen
35 days 7 weeks

24. Development of conotruncal ridges and
closure of the interventricular foramen
6 weeks Beginning of 7 weeks
End of 7 weeks

25. Ventricular Septation (5-8 week)
• Muscular ventricular septum
• Expansion of ventricles
• Closure of interventricular foramen
– Interventricular septum
– Atrioventricular ECC
– Outflow tract endocardial ridge

26. Ventricular Septal Defect
• Type
perimembranous (80-90%)
muscular (5-20%)
outlet or infundibular, (doubly committed) juxta-arterial (5-7%)

27. Perimembranous inlet extension
type
Muscular type
(Doubly committed) juxta-arterial type
Infundibular type
Outlet type

28. Tetralogy of Fallot
• Most common cyanotic CHD
• Conotruncal region 이상
 Unequal division of the conus
resulting from anterior
displacement of the conotruncal
septum
• Four features
1) Ventricular septal defect
2) Subpulmonary stenosis
3) Overriding of aorta
4) Right ventricular hypertrophy

29. • Essential defect : Anterosuperior displacement of outlet septum
PA

30. Persistent truncus arteriosus
• Conotruncal ridge
– fail to fuse and to
descend toward the
ventricles
– interventricular septum
형성에도 관여하므로 언제나
interventricular septal
defect동반

31. Transposition of Great Arteries
AO
PT
RV
LV
Conotruncal septum
→ fail to follow its normal spiral course and run
straight down
→ Aorta from RV, PA from LV
VSD, perimembranous type 동반하기도.

32. Neural crest cells
• Crest cells
– Vulnerable cell population
– Deficient in superoxide dismutase and catalase enzymes
that are responsible for scavenging free radicals.→ Easily
killed by compounds such as alcohol and retinoic acid.
• Essential for formation of much of the cranial region
– Disruption of crest cell development
☞ Severe craniofacial malformations
☞ Examples: Treacher-Collins' Syndrome, DiGeorge anomaly,
Robin sequence….
• Conotruncal endocardial cushions
☞ cardiac anomalies including persistent truncus arteriosus,
TOF and TGA.

33. Velocardiofacial Syndrome/DiGeorge anomaly
• 22q11.2 deletion
• “CATCH 22”
– Cardiac defects
– Abnormal face
– Thymic hypoplasia
– Cleft palate
– Hypocalcemia
• Abnormal development of
neural crest cells
• Specific facial features
– low-set ears, wide-set
eyes, a small jaw, and a
short groove in the upper
lip
• Etiology
– Genetic causes, exposure
to retinoic acids, alcohol,
and maternal DM

34. Formation of Atrioventricular Valve
• Endocardial cushion + Ventricular myocardium
• Undermining of myocardium

35. Formation of Ventriculoarterial Valve
5 weeks 6 weeks
7 weeks
6 weeks 7 weeks 9 weeks

36. Development of Conduction System
• Cardiomyogenic origin of conduction
cells
• Emergence of cardiac pacemaker in
embryonic tube heart
• Development of atrioventricular delay in
looping, tube heart
• Differentiation of fast conduction
system during chamber septation

37. Left-right Sidedness and Heart
• First organ with asymmetry
• Genetic difference between right and
left before morphologic asymmetry
• LA and RA - left-right sidedness
• LV and RV - anteroposterior axis

38. PITX2: a transcription factor responsible for
establishing left sidedness

39. Subdivision of Primary Heart Tube
Heart tube Looped heart Adult heart
Bulbus cordis OFT truncus arteriosus Great arteries
conus cordis RV
Embryonic right ventricle
Ventricle Embryonic left ventricle LV
Atrioventricular canal (AVC)
Atrium Atrium Atrium
Sinus venosus Sinus venosus
Caval veins

40. 4-mm embryo (end of the fourth week)

41. Venous system
• Vitelline system -> portal system
• Cardinal system -> caval system
• Umbilical system -> disappear after
birth

43. Double aortic arch

44. Abnormal origin of the right subclavian artery
Interruption of aortic arch

45. Normal heart
IVC