UNSW Embryology

Cardiovascular System Development

© Dr Mark Hill (2008)

Acknowledgements

Introduction

Development of the heart and vascular system begins very early in mesoderm both within (embryonic) and outside (extra embryonic) the embryo. Vascular development therefore occurs in many places, the most obvious though is the early forming heart, which grows rapidly creating an externally obvious cardiac "bulge" on the early embryo. Stage 11 embryo heart bulge The heart forms initially in the embryonic disc as a simple paired tube inside the forming pericardial cavity, which when the disc folds, gets carried into the correct anatomical position in the chest cavity.	Embryonic Heart (More? Dr ML Kirby | Heart Movies)
Throughout the mesoderm, small regions differentiate into "blood islands" which contribute both blood vessels (walls) and fetal red blood cells. These "islands" connect together to form the first vessels whcih connect with the heart tube.	Fetal blood and vessel
A key aspect of heart development is the septation of the heart into separate chambers. As the embryonic/fetal circulation is different to the neonatal circulation (lung/pulmonary activation), several defects of heart septation may only become apparent on this transition. One septal "defect" occurs in us all, the foramen ovale (between the 2 atria) which in general closes in the neonate over time.	Stage 13 heart cross-section

The peripheral vasculature can be thought of as 3 aortic/venous circulatory systems: placental (unbilical), embryonic and vitelline.

The placental system develops mainly in the extraembryonic mesoderm of the chorion, receives maternal nutrition, removes embryonic waste and is lost with the placenta at birth

The vitelline system covers the surface of the yolk sac and contributes to the portal system (between gut and liver).

The embryonic system begins symmetrically (L/R) within the embryo, and is extensively remodelled, in particular in the pharyngeal arches, to mature into our cardiovascular system.

Embryonic Heart Rate (EHR), early in development the heart starts to spontaneously beat and a recent study by Wisser and Dirschedl in dated human embryos showed an increase up to 63 postmenstrual days or 22 mm greatest length. Thereafter a steady decrease of EHR was noted. Maximal EHR is reached when morphological development of the embryonic heart is completed. (see EHR Page).

Page Links: Introduction | Reading | Computer Activities | Objectives | Learning activities | Development Overview | Cartoon Heart Development | Heart Layers | Heart Volume | Blood flow through the Embryo | Pig Overview | References | Glossary | Terms |

Related Pages: Abnormalities | Stage 13/14 | Stage 22 | Stage 22 Selected Highpower | Heart Rate | Blood | Blood Vessels | Molecular | Lymphatic | Placenta

Some Recent Findings

Molina FS, Faro C, Sotiriadis A, Dagklis T, Nicolaides KH. Heart stroke volume and cardiac output by four-dimensional ultrasound in normal fetuses. Ultrasound Obstet Gynecol. 2008 Aug;32(2):181-7.

"In normal fetuses the stroke volume and cardiac output increase between 12 and 34 weeks' gestation. The extent to which, in pathological pregnancies, possible deviations in these measurements from normal prove to be useful in the prediction of outcome remains to be determined."

Watanabe Y, Kokubo H, Miyagawa-Tomita S, Endo M, Igarashi K, Aisaki KI, Kanno J, Saga Y. Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse. Development. 2006 May;133(9):1625-34.

"...Our present study thus indicates that the Notch1 signaling pathway plays a suppressive role both in AV myocardial differentiation and the maturation of the ventricular myocardium." (More? Notch Notes)

Reading

Textbook

• Human Embryology (2nd ed.) Larson Ch7 p151-188 Heart, Ch8 p189-228 Vasculature
• The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Ch14: p304-349
• Before we Are Born (5th ed.) Moore and Persaud Ch12; p241-254
• Essentials of Human Embryology Larson Ch7 p97-122 Heart, Ch8 p123-146 Vasculature
• Human Embryology Fitzgerald and Fitzgerald Ch13-17: p77-111

Medline

• Wherefore heart thou? Embryonic origins of cardiogenic mesoderm
• The anterior heart-forming field: voyage to the arterial pole of the heart
• Development of the heart: (1) formation of the cardiac chambers and arterial trunks (2003)
• Development of the heart: (2) Septation of the atriums and ventricles (2003)

Search PubMed- Medline

(More? Additional References)

Objectives

• Describe the main features of heart development to the four-chambered system.
• Describe the development of the pericardium.
• Describe the development of primary and secondary atrial septa and the ventricular septum.
• Explain the changes occurring in the bulbis cordis and truncus arteriosus in its transformation from a single to a double tube.
• Describe the development of the aortic arches on the right and left sides from the fetus to the adult.
• Describe the development of arteries and veins.
• Describe the developmental aberrations responsible for the following malformations: patent ductus arteriosus (P.D.A.); atrial septal defects (A.S.D.) and ventricular septal defects (V.S.D.); tetralogy of Fallot.

Computer Activities

UNSW Embryology: Stage 13/14 Embryo | venous inflow to the heart | ventricles into the aortic system | caudal path of the arterial blood | embryo's venous blood | Stage 22 Embryo | Stage 22 Selected High power | Pig Systems | Human Systems (Human Cardiac) | Cardiovascular Abnormalities | Stage 16 (E12.5 Mouse vascular) | Molecular Development | Blood Development | Postnatal Heart Development | ILP Heart Tutorial

Heart Movies: Heart Development Movie Page | Heart Septation | Historic Heart Movie |

Heart Looping (451Kb)	Atrial Septation (995Kb)	Realignment (306Kb)	Ventricular Septation (646Kb)

Vasculature:

Fetal Circulation (Before Birth) (1Mb)	Circulation (After Birth) (561Kb)	Aortic Branches to Glands (Kidneys only) (1Mb)	Aortic Branches to Glands (Gonads only) (765Kb)

Embryo Images Unit: Embryo Images Online Early Cell Populations (cardiogenic section) | Cardiovascular Development | Week 3 Development | Week 4 Development | Heart Chambers and Outflow Tract | Atrioventricular Septation | Outflow Tract Septation | Ventricular Septation | Atrial Septation | Atrial Walls Aortic Arch Vessels | Changes at Birth

Learning Activities

• Review the developmental principles of the C.V.S.
• Examine the models and diagrams of the developing heart and list the main stages in heart development.
• Examine images of the 6mm pig and 8 week human embryos identifying the main features of the C.V.S.
• Relate developmental principles of the heart to the gross anatomy models.
• Introductory session on the development of blood, blood vessels and lymphatics.
• Discuss the selected malformations P.D.A., A.S.D. and V.S.D. and tetralogy of Fallot giving special reference to the developmental aberrations causing the malformations and the consequences of the malformations on the individuals.

Development Overview

• Introduction
• Below is a summary of development. Alternatively read these listed recent reviews.
  • Moorman A, Webb S, Brown NA, Lamers W, Anderson RH. Development of the heart: (1) formation of the cardiac chambers and arterial trunks. Heart. 2003 Jul;89(7):806-14.
  • Anderson RH, Webb S, Brown NA, Lamers W, Moorman A. Development of the heart: (2) Septation of the atriums and ventricles. Heart. 2003 Aug;89(8):949-58.
  • Yutzey KE, Kirby ML. Wherefore heart thou? Embryonic origins of cardiogenic mesoderm. Dev Dyn. 2002 Mar;223(3):307-20. Review.
  • Bruneau BG. Transcriptional regulation of vertebrate cardiac morphogenesis. Circ Res. 2002 Mar 22;90(5):509-19. Review.
• Timecourse
  • forms in mesenchyme of precordal plate region
  • cardiogenic region
  • growth and folding of the embryo moves heart ventrallly and downward into anatomical position
  • week 3 begins as paired heart tubes
  • fuse to form single heart tube
  • begins to beat in Humans- day 22-23
  • heart tube connects to blood vessels forming in
  • splanchnic mesoderm
  • extraembryonic mesoderm
• Week 2 pair of thin-walled tubes
• Week 3 tubes fused, truncus arteriosus outflow, heart contracting
• Week 4 heart tube continues to elongate, curving to form S shape
• Week 5 Septation starts, atrial and ventricular
• Septation continues, atrial septa remains open, foramen ovale
• Week 40 At birth pressure difference closes foramen ovale leaving a fossa ovalis

Angiogenesis

• Introduction
  • blood vessel formation
    • vasculogenesis
  • also occurs in adult and disease
  • begins week 3 in extraembryonic mesoderm
    • yolk sac
    • connecting stalk
    • chorion
  • Growth Factors
    • Vascular endothelial growth factor (VEGF), PIGF
• Angiogenesis 2
  • angioblasts form clusters - blood islands
  • blood islands extend and fuse together
  • forms a network
  • 2 populations of cells
    • peripheral- form endothelial cells
    • core- form blood cells (haemocytoblasts)
  • all vessels (arteries and veins) appear initially the same
• Blood formation
  • blood formation occurs later (week 5)
  • occurs throughout embryoic mesenchyme
  • liver
  • then spleen, bone marrow, lymph nodes
• Vascular systems
  • one vascular system with 3 components
    • vitelline
    • embryonic
    • placental
  • each component has own system of artery and vein
• Vitelline Blood vessels
  • cover entire surface of yolk sac
  • connect to embryo through yolk stalk
  • Arteries
    • arises from dorsal aorta
    • contribute to adult GIT arteries
  • Veins
    • empties into sinus venosus
    • contribute to the adult portal system
• Embryo Blood vessels (systemic)
  • will form the most of the cardiovascular system
  • some vessels have neural crest contribution
  • Arteries
    • aortic sac -> aortic arches -> dorsal aorta - umbilical artery
    • dorsal aorta
    • paired initially and fuses
    • gives off segmental arteries
  • Veins
    • 3 pairs of veins empty into the sinus venosus of the heart
    • vitelline, umbilical (only left persists), common cardinal veins
    • cardinal veins- anterior, common, posterior
    • systemic circulation
• Placental Blood vessels
  • form initially in the connecting stalk (then umbilical cord)
  • anastomose in chorioni
  • extend maternally toward chorionic villi
  • extend embryonically to the sinus venosus and dorsal aorta
  • Placental Vessels
  • Arteries
    • paired
    • carry deoxygenated blood (from dorsal aorta) and waste products to the placental villi
  • Veins
    • paired initially then only left at end of embryonic period
    • carry oxygenated blood to the embryo (sinus venosus)

Blood flow through the Embryo

Maternal Blood | -> umbilical vein -> liver -> anastomosis -> sinus venosus -> atria ventricles-> truncus arteriosus -> aortic sac -> aortic arches-> dorsal aorta-> pair of umbilical arteries | Maternal Blood

This is shown on the stage 13/14 pig G6 section.

Cartoon Heart Development

Transverse section- Heart is 2 tubes that fuse in the midline anterior to pharynx.

The pericardial cavity can be imagined as the top of the "horseshoe" of the intraembryonic coelom. (where the arms become the pleural cavity and the ends fuse anteriorly to form a single peritoneal cavity).

This view shows the initial positioning of the ventricles above the atria. The ventricles are rotated into their correct anatomical position by the growth of the heart tube, bending into an "S" shape.

Initially...

Cardiac inflow- at the bottom (sinus venosus)

Cardiac outflow- at the top (truncus arteriosus)

Heart Layers

pericardium - covers the heart. Formed by 3 layers consisting of a fibrous pericardium and a double layered serous pericardium (parietal layer and visceral epicardium layer).

myocardium - muscular wall of the heart. Thickest layer formed by spirally arranged cardiac muscle cells.

endocardium - lines the heart. Epithelial tissue lining the inner surface of heart chambers and valves.

Heart Volume

Week*	Heart Volume (ml)	Lung Volume (ml)
10	0.6	1.6
18	4.3	10.9
30	26.6	49.3

*Table data is "embryonic age" while original reference used "gestational age" (from LMP)
(Data: Peralta CF, Cavoretto P, Csapo B, Falcon O, Nicolaides KH. Lung and heart volumes by three-dimensional ultrasound in normal fetuses at 12-32 weeks' gestation. Ultrasound Obstet Gynecol. 2006 Feb;27(2):128-33.)

Stroke Volume

Week*	Left Stroke Volume (ml)	Right Stroke Volume (ml)	Cardiac Output L/R (ml/min)
10	0.02	0.01	2.39 / 1.8
18	0.32	0.30	43.46 / 46.72
32	2.07	2.67	284.71 / 365.99

*Table data is "embryonic age" while original reference used "gestational age" (from LMP). The stroke volume (SV) can be calculated from ultrasound measurement of end diastole volume (EDV) minus end systole volume (ESV); (SV = EDV - ESV).
(Data: Molina FS, Faro C, Sotiriadis A, Dagklis T, Nicolaides KH. Heart stroke volume and cardiac output by four-dimensional ultrasound in normal fetuses. Ultrasound Obstet Gynecol. 2008 Aug;32(2):181-7.

References

• Person AD, Klewer SE, Runyan RB. Cell biology of cardiac cushion development. Int Rev Cytol. 2005;243:287-335. Review.

• Matsui H, Ikeda K, Nakatani K, Sakabe M, Yamagishi T, Nakanishi T, Nakajima Y. Induction of initial cardiomyocyte alpha-actin--smooth muscle alpha-actin--in cultured avian pregastrula epiblast: a role for nodal and BMP antagonist. Dev Dyn. 2005 Aug;233(4):1419-29.
• Moorman A, Webb S, Brown NA, Lamers W, Anderson RH. Development of the heart: (1) formation of the cardiac chambers and arterial trunks. Heart. 2003 Jul;89(7):806-14.
• Anderson RH, Webb S, Brown NA, Lamers W, Moorman A. Development of the heart: (2) Septation of the atriums and ventricles. Heart. 2003 Aug;89(8):949-58.
• Brand T. Heart development: molecular insights into cardiac specification and early morphogenesis. Dev Biol. 2003 Jun 1;258(1):1-19.
• Yutzey KE, Kirby ML. Wherefore heart thou? Embryonic origins of cardiogenic mesoderm. Dev Dyn. 2002 Mar;223(3):307-20.
• Eisenberg LM. Belief vs. scientific observation: the curious story of the precardiac mesoderm. Anat Rec. 2002 Apr 1;266(4):194-7.
• Davidson AJ, Zon LI. Turning mesoderm into blood: the formation of hematopoietic stem cells during embryogenesis. Curr Top Dev Biol. 2000;50:45-60.

Selected Lists of References from PubMed March 1999 search results are available for School of Anatomy computers without internet access. Computers with internet access can search from either Page 2 or PubMed Internet Access

• Selected Research Articles and Reviews
• "Heart/review/5year limit"
• "Cardiovascular/Development/2year limit"

Search Pubmed Now

Click on the listed keywords below (used to search the external database) the most current references on Medline will be displayed.

• heart[TITL]+development[WORD]+review[WORD]

Glossary

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Cardiovascular Development Terms

For more cardiovascular term definitions and links to related topics use the glossary.

• angioblasts stem cells in blood islands generating endothelial cells
• angiogenesis the formation of blood vessels also called vasculogenesis in the embryo
• anlage (Ger. ) primordium, structure or cells which will form a future structure.
• atrial septal defects (A.S.D.)
• blood islands earliest sites of blood vessel and blood cell formation, seen mainly on yolk sac chorion
• branched villi or terminal villi, grow from sides of stem villi, region of main exchange, surrounded by maternal blood in intervillous spaces
• cardinal veins paired main systemic veins of early embryo, anterior, common, posterior.
• cardiogenic region region above precordal plate in mesoderm where ceart tube initially forms.
• cord knotting- umbilical cord knotting occurs in 1%, prevents the passage of placental blood. pseudoknots also occur usually with no effect.
• cotyledons on maternal face of placenta, form cobblestone appearance, originally placental septa formed grooves
• cytotrophoblast extraembryonic cells of trophoblastic shell surrounding embryo, contribute to villi and placental membranes.
• decidua basalis-
• decidual reaction
• ectoderm the layer (of the 3 germ cell layers) which form the nervous system from the neural tube and neural crest and also generates the epithelia covering the embryo.
• endoderm - the layer (of the 3 germ cell layers) which form the epithelial lining of the gastrointestinal tract (GIT) and accessory organs of GIT in the embryo.
• endocardium - lines the heart. Epithelial tissue lining the inner surface of heart chambers and valves.
• endothelial cells single layer of cells closest to lumen that line blood vessels
• extraembryonic mesoderm mesoderm lying outside the trilaminar embryonic disc
• fetal erythroblastosis see Haemolytic Disease of the Newborn
• haemocytoblasts stem cells for embryonic blood cell formation
• Haemolytic Disease of the Newborn fetal erythroblastosis, fetus Rh+ /maternal Rh-, fetus causes anti Rh antibodies, dangerous for 2nd child 
• anastomose-
• chorionic villi the finger-like extensions which are the functional region of the placental barrier and maternal/fetal exchange. Develop from week 2 onward as: primary, secondary, tertiary villi.
• estrogens support maternal endometrium
• fetal drug addiction occurs when drugs used maternally cross the placental barrier and can establish addiction in the unborn fetus.
• growth factor usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg VEGF, shh)
• hCG see Human chorionic gonadotrophin
• Human chorionic gonadotrophin (hCG) like leutenizing hormone, supports corpus luteum
• Human chorionic somatommotropin (hCS) or placental lactogen stimulate mammary development
• Human chorionic thyrotropin (hCT) placental derived hormone equivilant to thyroid
• Human chorionic corticotropin (hCACTH) placental derived hormone equivilant to
• maternal antibodies immune molecules capable of crossing placental barrier
• maternal decidua region of uterine endometrium where blastocyst implants. undergoes modification following implantation, decidual reaction.
• maternal sinusoids placental spaces around chorionic villi that are filled with maternal blood. Closest maternal/fetal exchange site.
• mesoderm the middle layer of the 3 germ cell layers of the embryo. Mesoderm outside the embryo and covering the amnion, yolk and chorion sacs is extraembryonic mesoderm.
• myocardium - muscular wall of the heart. Thickest layer formed by spirally arranged cardiac muscle cells.
• neural crest cell region at edge of neural plate, then atop the neural folds, that remains outside and initially dorsal to the neural tube when it forms. These paired dorsal lateral streaks of cells migrate throughout the embryo and can differentiate into many different cell types(=pluripotential). Neural crest cells also contribute to major cardiac outflow vessels.
• patent ductus arteriosus (P.D.A.)
• pericardium - covers the heart. Formed by 3 layers consisting of a fibrous pericardium and a double layered serous pericardium (parietal layer and visceral epicardium layer).
• pharyngeal arches (=branchial arches, Gk. gill) form structures of the head. Six arches form but only 4 form any structures. Each arch has a pouch, membrane and groove.
• placenta (Gk. plakuos= flat cake) refers to the discoid shape of the placenta, embryonic (villous chorion)/maternal organ (decidua basalis)
• placenta accreta abnormal adherence of placenta, with absence of decidua basalis
• placental arteries paired, carry deoxygenated blood (from dorsal aorta) and waste products to the placental villi
• placental lactogen see Human chorionic somatommotropin
• placenta percreta villi of placenta penetrate myometrium
• placenta previa placenta overlies internal os of uterus, abnormal bleeding, cesarian delivery
• placental veins paired initially then only left at end of embryonic period, carry oxygenated blood to the embryo (sinus venosus)
• primary villi week 2, first stage of chorionic villi development, trophoblastic shell cells (syncitiotrophoblasts and cytotrophoblasts) form finger-like extensions into maternal decidua.
• protein hormone usually a protein distributed in the blood that binds to membrane receptors on target cells in different tissues. Do not easliy cross placental barrier.
• relaxin hormone
• secondary villi week 3, second stage of chorionic villi development, extraembryonic mesoderm grows into villi, covers entire surface of chorionic sac
• sinus venosus cavity into which all major embryonic paired veins supply (vitelline, placental, cardinal)
• splanchnic mesoderm portion of lateral plate mesoderm closest to the endoderm when coelom forms.
• stem villi or anchoring villi, cytotrophoblast cells attached to maternal tissue.
• steroid hormone lipid soluble hormone that easily crosses membranes to bind receptors in cytoplasm or nucleus of target cells. Hormone+Receptor then binds DNA activating or suppressing gene transcription. Easliy cross placental barrier.
• syncitiotrophoblast extraembryonic cells of trophoblastic shell surrounding embryo, outside the cytotrophoblast layer, involved with implantation of the blastocyst by eroding extracellular matrix surrounding maternal endometrial cells at site of implantation, also contribute to villi. (dark staining, multinucleated)
• tetralogy of Fallot- Named after Etienne-Louis Arthur Fallot (1888) who described it as "la maladie blue". The syndrome consists of a number of a number of cardiac defects possibly stemming from abnormal neural crest migration.
• tertiary villi third stage of chorionic villi development, mesenchyme differentiates into blood vessels and cells, forms arteriocapillary network, fuse with placental vessels, developing in connecting stalk
• frondosum-
• capsularis-
• electrolytes
• drugs-
• progesterone-
• umbilical cord
• umbilical cord knotting see cord knotting
• vascular endothelial growth factor (VEGF) protein growth factor family that stimulates blood vessel growth, a similar factor can be found in the placenta (PIGF).
• ventricular septal defects (V.S.D.)
• virus small infectious agent able to cross placental barrier. Can infect embryo and cause developmental abnormalities. (e.g. cytomegalovirus, rubella, measles)
• vitelline blood vessels blood vessels associated with the yolk sac.
• waste products products of cellular metabolism and cellular debris, e.g.- urea, uric acid, bilirubin

Quick Links

Page 2 | Abnormalities | OMIM | Questions | Medline
Page 3 | Pig Stage 13/14
Page 4 | Human (Stage22) | Selected Human highpower
Molecular | Lymphatic | Blood | Text only page | WWW Links | Heart Movies | Postnatal Heart Development

Development Notes ----------------- Menstrual Cycle Week 1 Week 2 Week 3 Week 4 Placenta Serial Images Genes/DNA Molecular Dev Abnormal Dev Postnatal Dev Notes Index

System Notes ----------------- Heart/Cardiovascular Respiratory Coelomic cavity Gastrointestinal Tract Head and Neck Neural Neural Crest Eye Ear Nose Endocrine Urogenital Musculoskeletal Integumentary

Movies ----------------- Embryo Growth Ultrasound Week 1 Week 2 Week 3 Week 4 Stage 13/14 Stage 22 Neural Head and Neck Heart Vasculature Gastrointestinal Urogenital Other Embryos Larsen Internet

Other Embryos ----------------- Chicken Fly Frog Mouse Rabbit Rat Worm Zebrafish Guinea Pig

UNSW Embryology ISBN: 978 0 7334 2609 4

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