Cardiac Development

관동의대 제일병원병리과 전이경

2010. 6. 15

Congenital Heart DiseaseFrequency of Congenital Cardiac Malformations

Malformation Incidence/Million Live Births %

Ventricular septal defect (VSD) 4482 42Atrial septal defect (ASD) 1043 10Pulmonary stenosis (PS) 836 8Patent ductus arteriosus (PDA) 781 7Tetralogy of Fallot (TOF) 577 5Coarctation of aorta (CoA) 492 5Atrioventricular septal defect (AVSD) 396 4Aortic stenosis (AS) 388 4Transposition of great arteries (TGA) 388 4Truncus arteriosus 136 1Total anomalous pulmonary venous connection (TAPVC) 120 1Total 9757

J Am Coll Cardiol 39:1890,2002

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

First week of development: Ovulation to implantation

Second week of development:Bilaminar germ disc

Third week of development: Gastrulation (trilaminar germ disc)

Truncus

Conus

Early Cardiac Morphogenesis I(Fertilization 3rd week)

• Cardiogenic crest in splanchnic mesoderm in front of the neural plate

• Bilateral endocardial tube from angioblastic cords

• Cephalic and lateral folding of the embryo

• Primary heart tube in the middle thorax

day 18

day 22

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

Early Cardiac Morphogenesis II(Fertilization 4th week)

• Segmentation: SV-AT-AVC- VT-BC

• Layering: Endocardium – Myocardium- Epicardium

Cardiac jelly• Looping

AtriumBulbus cordis

VentricleSinus

venosusAV canal

A, day 22 B, day 23 C, day 24

Formation of Cardiac loop

Normal D-looping

Abnormalities of cardiac looping

• Dextrocardia:• 심장이오른쪽흉곽에위치하고심첨이오른쪽을향함

• Isolated form/ situs inversus

Formation of cardiac septa

• Between 27th and 37th days of development (embryo: 5mm~ 16-17mm)

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)

Atrial Septal Defect

• TypeSecundum ASD (90%)Primum ASD (5%)Sinus venosus ASD (5%)

Secundum ASD (90%)

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)

Ventricular Septation

35 days

30 days

7 weeks

Development of conotruncal ridges and closure of the interventricular

foramen

Development of conotruncal ridges and closure of the interventricular foramen

6 weeks Beginning of 7 weeks

End of 7 weeks

Ventricular Septation (5-8 week)• Muscular ventricular septum • Expansion of ventricles• Closure of interventricular foramen

– Interventricular septum – Atrioventricular ECC– Outflow tract endocardial ridge

Ventricular Septal Defect• Type

perimembranous (80-90%)muscular (5-20%)outlet or infundibular, (doubly committed) juxta-arterial (5-7%)

Perimembranous inlet extensiontype

Muscular type

(Doubly committed) juxta-arterial typeInfundibular typeOutlet type

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

• Essential defect : Anterosuperior displacement of outlet septum

PA

Persistent truncus arteriosus

• Conotruncal ridge– fail to fuse and to

descend toward the ventricles

– interventricular septum형성에도 관여하므로 언제나interventricular septal defect동반

PTAO

LV

RV

Conotruncal septum → fail to follow its normal spiral course and run

straight down → Aorta from RV, PA from LVVSD, perimembranous type 동반하기도.

Transposition of Great Arteries

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.

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

Formation of Atrioventricular Valve

• Endocardial cushion + Ventricular myocardium• Undermining of myocardium

Formation of Ventriculoarterial Valve

5 weeks

6 weeks

7 weeks

6 weeks

7 weeks 9 weeks

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

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

PITX2: a transcription factor responsible for establishing left sidedness

Subdivision of Primary Heart TubeHeart tube Looped heart Adult heart

truncus arteriosus Great arteriesOFT

conus cordis

Bulbus cordis

Embryonic right ventricle

RV

Ventricle Embryonic left ventricle LV

Atrioventricular canal (AVC)

Atrium Atrium Atrium

Sinus venosus Sinus venosus

Caval veins

4-mm embryo (end of the fourth week)

Venous system

• Vitelline system -> portal system• Cardinal system -> caval system• Umbilical system -> disappear after

birth

Double aortic arch

Abnormal origin of the right subclavian artery

Interruption of aortic arch

IVC

Normal heart