Development of the

Cardiovascular System

John M. DeSesso, Ph.D.

DABFM, DABFE, CHS-V, FACFEI, Fellow ATS

Senior Fellow
Noblis

Professor of Biochemistry and Molecular & Cellular Biology

Georgetown University School of Medicine
Adult Configuration
Position of Heart in the Chest
Position of Heart in the Chest (Concluded)
Anatomy of the Adult Heart

Carlson, Human Embryology and Developmental Biology, 3rd ed (2004)

Review of Early Development
Prior to Implantation the Zygote
Receives Nutrition by Diffusion
 During Implantation, Most of Zygote is
Composed of Extraembryonic Tissue

Langman, Medical Embryology, 4th ed (1981)

Uteroplacental Circulation Begins Before Embryonic
Cardiovascular System is Established

Langman, Medical Embryology, 4th ed (1981)

Early Development of the Zygote

DeSesso et al., Am J Med Genet 87: 143-162 (1999)

Induction and Early Differentiation of
Cardiovascular System
 Signaling Molecules Emanate from Anterior Visceral
Endoderm and Prechordal Plate

Carlson, Human Embryology and Developmental Biology, 3rd ed (2004)

 Heart Induction Occurs during Both
Pre-streak and Ingression Stages

Brand, In Cell Signaling and Growth Factors in Development, Vol. 2, Unsicker and Krieglstein, eds (2006)
 Formation of Germ Layers

DeSesso et al., Am J Med Genet 87: 143-162 (1999)

 Geospatial Migration and Determination of
Cardiac Structures During Ingression

Carlson, Human
Embryology and
Developmental
Biology, 3rd ed
(2004)
Early Blood Vessels Form in the Yolk Sac Wall

Langman, Medical Embryology, 4th ed (1981)

 Establishing the Blood Vessel Network

s
Vasculogenesi
Angiogenesis

Remodeling
Cleaver and Krieg In, Heart
Development, Harvey and
Rosenthal, eds (1999)
The Heart Tube
Early Development of the Intraembryonic
Vascular System

Langman, Medical Embryology, 4th ed (1981)

Cephalocaudal Folding of the Embryo

Langman, Medical Embryology, 4th ed (1981)

 Formation of the Heart Tube

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology,

Vol. 2 (1972)
Formation of the Heart Tube (Concluded)

Tuchmann-Duplessis and Haegel, Illustrated Human

Embryology, Vol. 2 (1972)
 Formation of Midline Cardiac Tube

Mikawa In, Heart

Development, Harvey and
Rosenthal, eds (1999)
Ventral View of Early Differentiation of
Heart Tube

Moore, The Developing Human, 4th ed (1988)

Folding of Heart Tube: Orientation of Atria

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

 Superficial and Deep Dissection of
Developing Heart Tube

Gilbert, Pictorial Human Embryology (1989)

 Superficial and Deep Dissection of
Developing Heart Tube (Concluded)

Gilbert, Pictorial Human Embryology (1989)

Atria
Primitive Right and Left Atria Are Formed

Langman, Medical Embryology, 3rd ed (1975)

 Development of Interatrial Septum

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Development of the Interatrial Septum
(Concluded)

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Overview of Primitive Vascular System

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

 The Atria Incorporate Adjacent Structures
(dorsal view of the right atrium)

Langman, Medical Embryology, 3rd ed (1975)

Intussusception
The Atria Incorporate Adjacent Structures
(ventral view of the left atrium)

Pulmonary veins

Primitive
pulmonary veins Absorbed
pulmonary
vein tissue

Primitive left atrium

Right and left Four pulmonary veins

pulmonary veins

Smooth walled portion

of left atrium
Left atrium

Left auricle

Moore, The Developing Human, 4th ed (1988)

Atrioventricular Separation
 Atrioventricular Orifices and
Endocardial Cushions

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Endocardial Cushions Divide the
Atrioventricular Canal

Larsen, Human Embryology, 3rd ed (2001)

Adherons Released by Epimyocardium Induce
the Formation of Atrioventricular Mesenchyme

Carlson, Human
Embryology and
Developmental
Biology, 3rd ed
(2004)
Ventricles and Outflow Tract
 Muscular Interventricular Septum Arises at the
Juncture of Bulbus Cordis and Primitive Ventricle

Larsen, Human Embryology, 3rd ed (2001)

 The Muscular Interventricular Septum is
Formed by Apposition of Adjacent Walls

septum

Langman, Medical Embryology, 3rd ed (1975)

Development of Interventricular and
Spiral (Aorticopulmonary) Septa

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Development of Interventricular and Spiral
(Aorticopulmonary) Septa (Continued)

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Development of Interventricular and Spiral
(Aorticopulmonary) Septa (Concluded)

Tuchmann-Duplessis and Haegel, Illustrated Human

Embryology, Vol. 2 (1972)
 Anatomy of the Adult Heart

Carlson, Human Embryology and Developmental Biology, 3rd ed (2004)

 Formation of Atrioventricular Valves

Sadler, Langman’s Medical Embryology, 8th ed (2000)

 Anatomy of the Adult Heart

Carlson, Human Embryology and Developmental Biology, 3rd ed (2004)

Aortic Arches
General Plan for Embryonic Arterial System

Dorsal intersegmental artery

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

 Differentiation of Aortic Arches

Gilbert, Pictorial Human Embryology (1989)

 Fate of Aortic Arches

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

General Plan for Embryonic Arterial System

Dorsal intersegmental artery

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Venous System
Overview of Primitive Vascular System

Tuchmann-Duplessis and Haegel, Illustrated Human

Embryology, Vol. 2 (1972)
 Development of Venous System

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Development of Venous System
(Continued)

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2

(1972)
Development of Venous System
(Continued)

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology, Vol. 2 (1972)

Development of Venous System
(Concluded)

Tuchmann-Duplessis and Haegel, Illustrated Human Embryology,

Vol. 2 (1972)
Perinatal Circulatory Changes
 Fetal
Circulation
(Human)

Carlson, Human Embryology

and Developmental Biology,
3rd ed (2004)
Postnatal
Circulation
(Human)

Medial Umbilical
Ligaments
Carlson, Human Embryology
and Developmental Biology,
3rd ed (2004)
Congenital Malformations
Mechanisms Driving Cardiovascular
Development
 Congenital Malformations:
A Major Health Issue

• Estimated Incidence Overall

– Major & Minor 7%

• Estimated Incidence of Heart

Malformations
– Among Liveborn 1%
– Among Stillbirths 10%
 Most Frequently Encountered
Cardiovascular Anomalies

• Interventricular Septal Defects

• Persistent Ductus Arteriosus
• Interatrial Septal Defects 75%

• Coarctation of the Aorta

• Transposition of Great Vessels
• Tetralogy of Fallot 20%
 Anatomy of the Normal Heart

Sadler, Langman’s Medical Embryology, 8th ed (2000)

 Malformations Related to Aberrant
Cellular Migration

Sadler, Langman’s Medical Embryology, 8th ed (2000)

 Tetralogy of Fallot

Blood Flow Crouching

Posture

Coeur en Sabot
 Tetralogy of Fallot

Blood Flow Crouching

Posture

Coeur en Sabot

•Associated with ↓ VEGF

•? amelioration by periconceptual multivitamins
 Coeur en Sabot
Radiographic view of a heart. Note increased transverse
diameter, convexity of the inferior line, and elevated, rounded
apex. Its form suggests vaguely that of a wooden shoe.

Note the absence of a pulmonary conus and increased angle

at the aorticopulmonary window in the upper left heart border
(arrow)
Malformations Due to Extracellular
Matrix Abnormalities

Moore, The Developing Human, 4th ed (1988)

Membranous Ventricular Septal Defect

Sadler, Langman’s Medical Embryology, 8th ed (2000)

Malformations Caused by Extracellular
Matrix Abnormalities (Concluded)

Sadler, Langman’s Medical Embryology, 8th ed (2000)

 Malformations Related to
Abnormal Blood Flow

Moore, The Developing Human, 4th ed (1988)

 Malformations Related to
Abnormal Blood Flow (Concluded)

Sadler, Langman’s Medical Embryology, 8th ed (2000)

Malformation Caused by Aberrant Cell Death

Sadler, Langman’s Medical Embryology, 8th ed (2000)

Malformation Related to Abnormal
Visceral Situs

Moore, The Developing Human, 4th ed (1988)

 Related Literature
Carlson, B. M. (2004) Human Embryology and Developmental Biology, 3rd Ed.,
Ed., Mosby, St. Louis.
 
Clark E. B. (1986) Mechanisms in the pathogenesis of congenital cardiac malformations. In: Pierpont ME,
Moller JH eds. Genetics of Cardiovascular Disease.
Disease. Boston: Martinus Nijhoff Publishing; 3-11.
 
Clark E. B. (1992) Growth, Morphogenesis and Function: The Dynamics of Heart Development. In: Moller
JH, Neal WA and Lock JE eds. Fetal, Neonatal and Infant Heart Disease. New York: Appleton-Century-
Crofts; 1-17.
 
DeSesso, J. M. (2006) Comparative Features of Vertebrate Development, In: Hood R. D, ed. Developmental
and Reproductive Toxicology: A Practical Approach, 2nd Ed.,
Ed., CRC Press, Boca Raton; 147-197.
 
Gilbert, S. F. (1997) Developmental Biology, 5th Ed., Sinauer Associates, Sunderland, MA.
 
Hamilton, W. J. and H. W. Mossman (1972) Hamilton, Boyd and Mossman’s Human Embryology, 4th Ed.,
Ed.,
Williams and Wilkins, Baltimore.
 
Harvey, R. P. and N. Rosenthal (1999) Heart Development,
Development, Academic Press, San Diego.
 
Hebel, R. and M. W. Stromberg (1986) Anatomy and Embryology of the Laboratory Rat,
Rat, BioMed Verlag,
Worthsee, Germany.
 
Larson, W. J. (2001) Human Embryology, 3rd Ed.,
Ed., Churchill Livingstone, New York.
 
O’Rahilly, R. and F. Müller (1992) Human Embryology and Teratology,
Teratology, Wiley-Liss, New York.
 
Sadler, T. W. (2000) Langman’s Medical Embryology, 8th Ed.,
Ed., Lippincott Williams & Wilkins, Philadelphia.
 
Unsicker, K. and K. Krieglstein (2006) Cell Signaling and Growth Factors in Development, Wiley-VCH,
Weinheim, Germany