Development of the Development of the Cardiovascular SystemCardiovascular System

John M. DeSesso, Ph.D.John M. DeSesso, Ph.D.DABFM, DABFE, CHS-V, FACFEI, Fellow ATSDABFM, DABFE, CHS-V, FACFEI, Fellow ATS

Senior FellowSenior FellowNoblisNoblis

Professor of Biochemistry and Molecular & Cellular BiologyProfessor of Biochemistry and Molecular & Cellular BiologyGeorgetown University School of MedicineGeorgetown University School of Medicine

Adult ConfigurationAdult Configuration

Position of Heart in the ChestPosition of Heart in the Chest

Position of Heart in the Chest (Concluded)Position of Heart in the Chest (Concluded)

Anatomy of Anatomy of thethe Adult Heart Adult Heart

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

Review of Early DevelopmentReview of Early Development

Prior to Implantation the Zygote Prior to Implantation the Zygote Receives Nutrition by DiffusionReceives Nutrition by Diffusion

During Implantation, Most of Zygote is During Implantation, Most of Zygote is Composed of Extraembryonic TissueComposed of Extraembryonic Tissue

Langman, Medical Embryology, 4th ed (1981)

Uteroplacental Circulation Begins Before Embryonic Uteroplacental Circulation Begins Before Embryonic Cardiovascular System is EstablishedCardiovascular System is Established

Langman, Medical Embryology, 4th ed (1981)

Early Development of the ZygoteEarly Development of the Zygote

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

Induction and Early Differentiation of Induction and Early Differentiation of Cardiovascular SystemCardiovascular System

Signaling Molecules Emanate from Anterior Visceral Signaling Molecules Emanate from Anterior Visceral Endoderm and Prechordal PlateEndoderm and Prechordal Plate

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

Heart Induction Occurs during Both Heart Induction Occurs during Both Pre-streak and Ingression StagesPre-streak and Ingression Stages

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

Formation of Germ LayersFormation of Germ Layers

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

Geospatial Migration and Determination of Geospatial Migration and Determination of Cardiac Structures During Ingression Cardiac Structures During Ingression

Carlson, Human Embryology and Developmental Biology, 3rd ed

(2004)

Early Blood Vessels Form in the Yolk Sac WallEarly Blood Vessels Form in the Yolk Sac Wall

Langman, Medical Embryology, 4th ed (1981)

Establishing the Blood Vessel NetworkEstablishing the Blood Vessel Network

Cleaver and Krieg In, Heart Development, Harvey and Rosenthal, eds (1999)

Vascu

log

en

esis

Angiogenesis

Remodeling

The Heart TubeThe Heart Tube

Early Development of the Intraembryonic Early Development of the Intraembryonic Vascular SystemVascular System

Langman, Medical Embryology, 4th ed (1981)

Cephalocaudal Folding of the EmbryoCephalocaudal Folding of the Embryo

Langman, Medical Embryology, 4th ed (1981)

Formation of the Heart TubeFormation of the Heart Tube

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

Formation of the Heart Tube (Concluded)Formation of the Heart Tube (Concluded)

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

Formation of Midline Cardiac TubeFormation of Midline Cardiac Tube

Mikawa In, Heart Development, Harvey and Rosenthal, eds (1999)

Ventral View of Early Differentiation of Ventral View of Early Differentiation of Heart TubeHeart Tube

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

Folding of Heart Tube: Orientation of AtriaFolding of Heart Tube: Orientation of Atria

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

Superficial and Deep Dissection of Superficial and Deep Dissection of Developing Heart TubeDeveloping Heart Tube

Gilbert, Pictorial Human Embryology (1989)

Superficial and Deep Dissection of Superficial and Deep Dissection of Developing Heart Tube (Concluded)Developing Heart Tube (Concluded)

Gilbert, Pictorial Human Embryology (1989)

AtriaAtria

Primitive Right and Left Atria Are FormedPrimitive Right and Left Atria Are Formed

Langman, Medical Embryology, 3rd ed (1975)

Development of Interatrial SeptumDevelopment of Interatrial Septum

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

Development of the Interatrial Septum Development of the Interatrial Septum (Concluded)(Concluded)

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

Overview of Primitive Vascular SystemOverview of Primitive Vascular System

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

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

Langman, Medical Embryology, 3rd ed (1975)

IntussusceptionIntussusception

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

Pulmonary veins

Primitivepulmonary veins

Primitive left atrium

Absorbedpulmonaryvein tissue

Right and leftpulmonary veins

Left atrium

Four pulmonary veins

Smooth walled portionof left atrium

Left auricle

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

Atrioventricular SeparationAtrioventricular Separation

Atrioventricular Orifices and Atrioventricular Orifices and Endocardial CushionsEndocardial Cushions

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

Endocardial Cushions Divide theEndocardial Cushions Divide theAtrioventricular CanalAtrioventricular Canal

Larsen, Human Embryology, 3rd ed (2001)

Adherons Released by Epimyocardium Induce Adherons Released by Epimyocardium Induce the Formation of Atrioventricular Mesenchymethe Formation of Atrioventricular Mesenchyme

Carlson, Human Embryology and Developmental Biology, 3rd ed

(2004)

Ventricles and Outflow TractVentricles and Outflow Tract

Muscular Interventricular Septum Arises at the Muscular Interventricular Septum Arises at the Juncture of Bulbus Cordis and Primitive VentricleJuncture of Bulbus Cordis and Primitive Ventricle

Larsen, Human Embryology, 3rd ed (2001)

The Muscular Interventricular Septum is The Muscular Interventricular Septum is Formed by Apposition of Adjacent WallsFormed by Apposition of Adjacent Walls

septum

Langman, Medical Embryology, 3rd ed (1975)

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

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

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

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

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

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

Anatomy of the Adult HeartAnatomy of the Adult Heart

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

Formation of Atrioventricular ValvesFormation of Atrioventricular Valves

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

Anatomy of the Adult HeartAnatomy of the Adult Heart

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

Aortic ArchesAortic Arches

General Plan for Embryonic Arterial General Plan for Embryonic Arterial SystemSystem

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

Dorsal intersegmental artery

Differentiation of Aortic ArchesDifferentiation of Aortic Arches

Gilbert, Pictorial Human Embryology (1989)

Fate of Aortic ArchesFate of Aortic Arches

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

General Plan for Embryonic Arterial General Plan for Embryonic Arterial SystemSystem

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

Dorsal intersegmental artery

Venous SystemVenous System

Overview of Primitive Vascular SystemOverview of Primitive Vascular System

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

Development of Venous SystemDevelopment of Venous System

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

Development of Venous System Development of Venous System (Continued)(Continued)

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

Development of Venous System Development of Venous System (Continued)(Continued)

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

Development of Venous System Development of Venous System (Concluded)(Concluded)

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

Perinatal Circulatory ChangesPerinatal Circulatory Changes

Fetal Fetal Circulation Circulation

(Human)(Human)

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

Postnatal Postnatal Circulation Circulation

(Human)(Human)

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

Medial Umbilical

Ligaments

Congenital MalformationsCongenital Malformations

Mechanisms Driving Cardiovascular Mechanisms Driving Cardiovascular DevelopmentDevelopment

Congenital Malformations: Congenital Malformations: A Major Health IssueA Major Health Issue

• Estimated Incidence OverallEstimated Incidence Overall– Major & MinorMajor & Minor 7%7%

• Estimated Incidence of Heart Estimated Incidence of Heart MalformationsMalformations– Among LivebornAmong Liveborn 1%1%– Among StillbirthsAmong Stillbirths 10% 10%

Most Frequently Encountered Most Frequently Encountered Cardiovascular AnomaliesCardiovascular Anomalies

• Interventricular Septal DefectsInterventricular Septal Defects

• Persistent Ductus ArteriosusPersistent Ductus Arteriosus

• Interatrial Septal DefectsInteratrial Septal Defects 75%75%

• Coarctation of the AortaCoarctation of the Aorta

• Transposition of Great VesselsTransposition of Great Vessels

• Tetralogy of FallotTetralogy of Fallot 20%20%

Anatomy of the Normal HeartAnatomy of the Normal Heart

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

Malformations Related to Aberrant Malformations Related to Aberrant Cellular MigrationCellular Migration

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

Tetralogy of FallotTetralogy of Fallot

CrouchingPosture

Coeur en Sabot

Blood Flow

Tetralogy of FallotTetralogy of Fallot

CrouchingPosture

Coeur en Sabot

Blood Flow

•Associated with ↓ VEGF

•? amelioration by periconceptual multivitamins

Radiographic view of a heart. Note increased transverse diameter, convexity of the inferior 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.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 Note the absence of a pulmonary conus and increased angle at the aorticopulmonary window in the upper left heart border window in the upper left heart border (arrow)(arrow)

Coeur en Sabot

Malformations Due to Extracellular Malformations Due to Extracellular Matrix AbnormalitiesMatrix Abnormalities

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

Membranous Ventricular Septal DefectMembranous Ventricular Septal Defect

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

Malformations Caused by Extracellular Malformations Caused by Extracellular Matrix Abnormalities (Concluded)Matrix Abnormalities (Concluded)

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

Malformations Related to Malformations Related to Abnormal Blood FlowAbnormal Blood Flow

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

Malformations Related to Malformations Related to Abnormal Blood Flow (Concluded)Abnormal Blood Flow (Concluded)

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

Malformation Caused by Aberrant Cell DeathMalformation Caused by Aberrant Cell Death

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

Malformation Related to Abnormal Malformation Related to Abnormal Visceral SitusVisceral Situs

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

Related LiteratureRelated LiteratureCarlson, B. M. (2004) Carlson, B. M. (2004) Human Embryology and Developmental Biology, 3Human Embryology and Developmental Biology, 3rdrd Ed. Ed., Mosby, St. Louis., Mosby, St. Louis.

Clark E. B. (1986) Mechanisms in the pathogenesis of congenital cardiac malformations. In: Pierpont ME, Moller JH eds. Clark E. B. (1986) Mechanisms in the pathogenesis of congenital cardiac malformations. In: Pierpont ME, Moller JH eds. Genetics Genetics of Cardiovascular Diseaseof Cardiovascular Disease. Boston: Martinus Nijhoff Publishing; 3-11.. 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 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. 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. DeSesso, J. M. (2006) Comparative Features of Vertebrate Development, In: Hood R. D, ed. Developmental and Reproductive Developmental and Reproductive Toxicology: A Practical Approach, 2Toxicology: A Practical Approach, 2ndnd Ed Ed., CRC Press, Boca Raton; 147-197.., CRC Press, Boca Raton; 147-197.

Gilbert, S. F. (1997) Developmental Biology, 5Gilbert, S. F. (1997) Developmental Biology, 5thth Ed., Sinauer Associates, Sunderland, MA. Ed., Sinauer Associates, Sunderland, MA.

Hamilton, W. J. and H. W. Mossman (1972) Hamilton, W. J. and H. W. Mossman (1972) Hamilton, Boyd and Mossman’s Human Embryology, 4Hamilton, Boyd and Mossman’s Human Embryology, 4thth Ed Ed., Williams and Wilkins, ., Williams and Wilkins, Baltimore.Baltimore.

Harvey, R. P. and N. Rosenthal (1999) Harvey, R. P. and N. Rosenthal (1999) Heart DevelopmentHeart Development, Academic Press, San Diego., Academic Press, San Diego.

Hebel, R. and M. W. Stromberg (1986) Hebel, R. and M. W. Stromberg (1986) Anatomy and Embryology of the Laboratory RatAnatomy and Embryology of the Laboratory Rat, BioMed Verlag, Worthsee, Germany., BioMed Verlag, Worthsee, Germany.

Larson, W. J. (2001) Larson, W. J. (2001) Human Embryology, 3rd EdHuman Embryology, 3rd Ed., Churchill Livingstone, New York.., Churchill Livingstone, New York.

O’Rahilly, R. and F. Müller (1992) O’Rahilly, R. and F. Müller (1992) Human Embryology and TeratologyHuman Embryology and Teratology, Wiley-Liss, New York., Wiley-Liss, New York.

Sadler, T. W. (2000) Sadler, T. W. (2000) Langman’s Medical Embryology, 8Langman’s Medical Embryology, 8thth Ed Ed., Lippincott Williams & Wilkins, Philadelphia., Lippincott Williams & Wilkins, Philadelphia..

Unsicker, K. and K. Krieglstein (2006) Cell Signaling and Growth Factors in Development, Wiley-VCH, Weinheim, GermanyUnsicker, K. and K. Krieglstein (2006) Cell Signaling and Growth Factors in Development, Wiley-VCH, Weinheim, Germany