DEVELOPMENT OF HEART

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DEVELOPMENT OF HEART

• Dr. Shreetal Rajan Nair

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Introduction

• Human heart starts to develop during the 3rd week
  of embryonic life. Till then the needs of the
  embryo are met through simple diffusion of blood
  between the germ layers.
• Cardiogenesis in humans is associated with
  complex morphogenetic events

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Area of discussion

• Anatomic
• Molecular
• Clinical aspects

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Cardiac development

• Early development
• Formation of the trilaminar embryo
• Origin of cardiogenic cells
• Formation of bilateral heart fields
• Formation of the heart tube
• Folding of the heart tube
• Looping of the heart tube
• Cardiac developmental abnormalities

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The Beginnings(fetal landmarks)

• Day 0 Fertilisation forming zygote initiating
  embryogenesis
• 2 cell stage 4 cell stage morula
• Week 1 implantation ( as a blastocyst)
• Week 2 bilaminar stage (epiblast,hypoblast)
• Week 3 gastrulation primitive streak,notochord
  and neural plate begin to form
• Week 4 heart begins to form.

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Week 1 beginning of development

• Day 1-Fertilisation and formation of zygote
• Day 2 2 cell blastula
• Day 3 4 cell blastula
• Day 4 morula ( 32 cell stage)
• Day 5 blastocyst ( inner cell mass of
  embryoblast and outer cell mass called
  trophoblast)
• Day 6 - implantation

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1st week
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1st week
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1st week
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BLASTOCYST FORMATION
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WEEK 2 FORMATION OF BILAMINAR EMBRYO
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Week 3
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Week 3
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Week 3
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SUMMARY- Early development

• Rule of 2s for 2nd week
• 2 germ layers (bilaminar disk) epiblast,
  hypoblast.
• 2 cavities amniotic cavity,yolk sac
• Rule of 3s for 3rd week
• 3 germ layers ( gastrula)
  ectoderm,mesoderm and endoderm

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• Cardiac Embryogenesis

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Sequence of events

• Occurs towards the end of the 3rd week
• Day I8 - cardiac precursor cells seen in the
  form of blood islands
• Day 20 - first intraembryonic blood vessels
  seen
• Day 21- Folding, heart tube formation,looping
• Day 22 heart starts to beat, ebb and flow
  initially
• Day 28 embryonic circulation established

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Cardiac development

• Early development
• Formation of trilaminar embryo
• Origin of cardiogenic cells
• Formation of bilateral heart fields
• Formation of the heart tube
• Folding of the heart tube
• Looping of the heart tube
• Cardiac developmental abnormalities

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•  The developing blood vessels and heart tube can
  be seen in an embryo at approximately 18 days .
• When looking down at this early embryo you can
  see multiple blood islands dispersed throughout
  the embryo.

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Origin of cardiac precursor cells

• The heart primordium arises predominantly from
  the mesoderm in the cardiogenic region of the
  trilaminar embryo.

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Cardiac precursor cells

• First heart field (FHF)
• Second heart field (SHF)
• Proepicardium
• Cardiac neural crest cells

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Cardiac precursor cells

• FHF
• SHF
• CNC
• Proepicardium

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Cardiac development

• Early development
• Origin of cardiogenic cells
• Formation of bilateral heart fields
• Formation of the heart tubes
• Folding of the heart tube
• Looping of the heart tube
• Cardiac development abnormalities

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The concept of heart fields

• Two distinct mesodermal heart fields that share a
  common origin appear to contribute cells to the
  developing heart in a temporally and spatially
  specific manner.
• Using special technologies to mark progenitor
  cells two heart fields (the primary and
  secondary) have been characterised.

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• The heart tube derived from the primary heart
  field may predominantly provide a scaffold that
  enables a second population of cells to migrate
  and expand into cardiac chambers .
• These additional cells arise from an area often
  referred to as the secondary heart field (SHF),
  or anterior heart field, based on its location
  anterior and medial to the crescent-shaped
  primary heart field

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HEART FIELDS

• SHF cells cross the pharyngeal mesoderm into the
  anterior and posterior portions, contributing to
  the formation of the outflow tract, future right
  ventricle, and atria

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Pathophysiology
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Cardiac development

• Early development
• Origin of cardiogenic cells
• Formation of bilateral heart fields
• Formation of the heart tube
• Folding of the heart tube
• Looping of the heart tube
• Cardiac developmental abnormalities

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• The flat germ disk transforms into a tubular
• structure during the fourth week of
  development
• This is achieved through a process of
  differential growth causing the embryo to fold in
  two different dimensions

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Formation of the endocardial tube

• The heart initially forms from two tubes located
  bilaterally (on either side) of the trilaminar
  embryo in the cranial (head)

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• This primitive, bilateral heart tubes each
  contains an inner layer of endocardium, a middle
  layer of cardiac jelly, and an outer layer of
  myocardium region

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Folding of the embryo

• 1. Craniocaudal axis due to the more rapid growth
  of the neural tube forming the brain at its
  cephalic end. Growth in this direction will cause
  the embryo to become convex shaped.
• 2.Lateral folding, causing the two lateral edges
  of the germ disk to fold forming a tube-like
  structure

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THE CARDIOGENIC AREA
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Formation of the endocardial tube

• The primitive heart tubes then fuse in the
  ventral midline to form the linear or straight
  heart tube in a cranial to caudal direction

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• Simultaneously the heart tube shows a series of
  dilatations.
• From cranial to caudal these are
• Bulbous cordis
• Ventricle
• Atrium
• Sinus venosus

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• The arterial trunk will divide to separate the
  pulmonary and systemic supply.
• The bulbus and the ventricle will later
  differentiate into the right and left ventricle

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Arterial end of the heart

• Bulbus cordis represents the arterial end of
  heart. It consists of
• proximal part called the conus
• a distal part called truncus arteriosus.
• The truncus continues distally with the aortic
  sac.

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VENOUS END OF THE HEART TUBE

• The sinus venosus represents the venous end of
  the heart. One vitelline vein from the yolksac
  one umbilical vein from the placenta and one
  common cardinal vein from the bodywall ,joins
  each horn of the sinus venosus.

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• After the formation of the head fold, this tube
  lies dorsal to the pericardial cavity and ventral
  to the foregut.
• Splanchnopleuric mesoderm lining the dorsal side
  of the pericardial cavity proliferates to forma
  thick layer called the myoepicardial mantle.

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• When the invagination is complete, the
  myoepicardial mantle completely surrounds the
  heart tube
• It gives rise to the cardiac muscle (MYOCARDIUM)
  and also to the visceral layer of the pericardium
  (EPICARDIUM)

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EXTERIOR OF THE HEART

• Heart tube is suspended from the dorsal wall of
  the pericardial cavity by 2 layers of pericardium
  that constitutes dorsal mesocardium

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• A hole forms in the dorsal mesocardium which
  increases in size.
• Gradually Mesocardium disappears and the heart
  tube lies free within the pericardial cavity
• Mesocardium disappears to form the transverse
  sinus of the pericardium

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Cardiac development

• Early development
• Origin of cardiogenic cells
• Formation of bilateral heart fields
• Formation of the heart tube
• Folding of the heart tube
• Looping of the heart tube
• Cardiac developmental abnormalities

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Cardiac looping

• Looping of the heart tube allows the straight
  heart tube to form a more complex structure
  reminiscent of the adult heart. Most cardiac
  looping occurs during the fourth week and
  completes during the fifth week of development

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• The linear heart tube develops differential
  growth of the heart tube in comparison with the
  foregut
• The direction of cardiac looping is determined by
  an asymmetric signalling system which affects
  the position of both thoracic and abdominal
  contents

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• In all vertebrates, there is differential growth
  within the heart tube itself resulting in
  posterior, leftward, slower growth and anterior,
  rightward, faster growth resulting in rightward
  looping. This positioning results in the future
  right ventricle taking an anterior and rightward
  location with reference to the future left
  ventricle

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• Further disproportionate growth of the heart tube
  in comparison to the foregut results in bending
  of the heart tube at the inflow as well as within
  the ventricular segment eventually positioning
  the inflow and future left ventricular segments
  posteriorly and to the left, with the future
  right ventricle and outflow segments anteriorly
  and to the right

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• The straight heart tube begins to elongate with
  simultaneous growth in the bulbus cordis and
  primitive ventricle
• This forces the heart to bend ventrally and
  rotate to the right, forming a C-shaped loop with
  convex side situated on the right.
• The ventricular bend moves caudally and the
  distance between the outflow and inflow tracts
  diminishes.
• The atrial and outflow poles converge and
  myocardial cells are added, forming the truncus
  arteriosus

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• Hence an S-shape is formed with the first bend of
  the 'S' being the large ventricular bend while
  the bend at the junction of the atrium and sinus
  venosus forms the second 'S' bend

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The cardiac tube grows at a greater longitudinal
rate then the rest of the embryo, causing it to
fold. As it does this it falls to the right.
This is known as d-looping. It may fall to the
left in an l-loop this will lead to a malformed
heart. Below are chick embryo dissections
showing the two types of loop.
normal d-loop l-loop
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• The fold of the loop is principally at the
  junction of bulbus cordis and ventricle. Note in
  panel C that the two end up side by side.
• The left ventricle will develop from the
  ventricle, and the right ventricle will develop
  from the bulbus cordis. (And an l-loop will
• result in ventricular inversion with the left
  ventricle on the right.
• Note also that the arterial trunk is above the
  developing right ventricle.

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Time line of cardiogenesis
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MOLECULAR ASPECTS IN CARDIOGENESIS

• Transcriptional regulators
• Epigenetic regulation by microRNAs (miRNA)

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ROLE OF RETINOIC ACID

• HENSONS NODE which contains retinoic acid,
  serves as an embryonic organizer that confers
  information required to direct the ultimate fate
  of mesodermal cells during early embryogenesis.
• Exogenous retinoic acid is extremely teratogenic
  at that stage
• Greatest effect is on the arterial pole.

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Cardiac development

• Early development
• Origin of cardiogenic cells
• Formation of bilateral heart fields
• Formation of the heart tubes
• Folding of the heart tube
• Looping of the heart tube
• Cardiac development abnormalities

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Pathophysiology

• Abnormal left-right signalling
• Looping defects
• Defects due to abnormal migration of cells of
  primary and secondary heart fields and of cardiac
  neural crest

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One disease several mechanisms several genes
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TRANSCRIPTIONAL REGULATORS
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ABNORMALITIES OF DEVELOPMENT

• From Fertilization to Primitive Heart Tube
• Abnormal development at this stage of
• embryogenesis almost always results in
  embryonic death because of the critical nature
  of the early circulation to the further growth
  and development of the embryo and fetus.

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DEFECTIVE EXPRESSION OF TRANSCRIPTIONAL FACTORS

• Absence of Hand2 (dHAND) results in
• RV HYPOPLASIA or ABSENT RV

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Abnormalities due to abnormal left-right
signalling and dorso ventral polarity

• HETEROTAXY SYNDROMES
• DORV
• DILV

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Pathophysiology
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• In humans, mirror-image reversal of left-right
• asymmetry is often associated with normal
  organ development ( simple dextrocardia or situs
  inversus totalis) but discordance of thoracic and
  visceral asymmetry universally results in
  defective organogenesis, the most common being
  heterotaxy syndrome.

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HETEROTAXY SYNDROMES
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Abnormalities of looping

• Ventricular Inversion with Transposition of the
  Great Arteries

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• There is currently considerable research in
  animate models on the genes known to control
  left-right development. Similarly, congenitally
  corrected transposition of the great arteries is
  thought to result from both an abnormality of
  looping and of outflow tract development.
• Many other complex abnormalities involving both
  ventricles and outflow tract are thought to have
  at least some abnormality in the looping process.

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Defective migration of cells

• HYPOPLASIA OF RVOT/MPA - TOF
• ABSENCE OF RVOT/MPA- TA
• ABSENCE OF AORTO-PULMONARY SEPTUM TA
• MALALINGMENT OF AORTA AND LV ABNORMAL WEDGING
  -TOF
• ABNORMAL MYOCARDIAL TRABECULATION- LV/RV NON
  COMPACTION

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DEVELOPMENT ABNORMALITIES
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BIBLIOGRAPHY

• Braunwalds Heart Disease 9th edition
• Hursts THE HEART 13th edition, chapter 9.
• Moss and Adams Heart Disease , 7th edition
• Harrisons Text Book of Internal Medicine,18th
  edition
• Embryology and Congenital Heart Disease,Paolo
  Angelini, MD
• Cardiac Chamber FormationDevelopment, Genes,
  and Evolution
• ANTOON F. M. MOORMAN AND VINCENT M.
  CHRISTOFFELS 83 12231267, 2003
  10.1152/physrev.00006.2003
• 7. Regulation of myocardial gene
  expression during heart development
• Diego Franco ,Jorge Domínguez , María
  del Pilar de Castro , Amelia Aránega
• Rev Esp Cardiol. 200255167-84. - Vol.
  55 Núm.02
• Molecular embryology for an understanding of
  congenital heart diseases Hiroyuk i Yamagishi
  et al. Anat Sci Int (2009) 848894 Received
  27 May 2008 / Accepted 16 June 2008 /
  Published online 7 April 2009 Japanese
  Association of Anatomists 2009
• 9. Cardiovascular Embryology R. Abdulla,G.
  A. Blew,M.J. Holterman Pediatr Cardiol
  25191200, 2004

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Bibliography

• 10. Wherefore heart thou? Embryonic origins of
  cardiogenic mesoderm Katherine E. Yutzey
  ,Margaret L. Kirby , Developmental Dynamics ,
  volume 223 issue 3pages 307320, March 2002

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• Quiz

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Cardiac precursors develop from all except1.
FHF2. SHF3. NEURAL CREST4. PROEPICARDIUM5.NONE
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Atria receives contributions from

• 1 FHF
• 2. SHF
• 3.BOTH
• 4.NEURAL CREST

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BLOOD ISLANDS SEEN ON DAY

• 1. 17
• 2. 18
• 3. 19
• 4.20

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RIGHT VENTRICLE DEVELOPS FROM1.FHF2.SHF3.CNC4
.PROEPICARDIUM
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CORONARY VESSELS DEVELOP FROM

• 1. FHF
• 2.SHF
• 3.CNC
• 4.PROEPICARDIUM

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