development of heart

1. Dr.Nandimalla Vinay kumar
Junior resident
Dept. of pediatrics
Developmental of the Heart

2. Early Cardiac Morphogenesis
 In the early presomite embryo, the first identifiable cardiac
progenitor cell clusters are arranged in the anterior lateral
plate mesoderm on both sides of the embryo’s central axis;
these clusters form paired cardiac tubes by 18 days of
gestation.
 The paired tubes fuse in the midline on the ventral surface
of the embryo to form the primitive heart tube by 22 days.
 This straight heart tube is composed of an outer
myocardial layer, an inner endocardium, and a middle layer
of extracellular matrix known as the cardiac jelly.

3. Cardiogenic Area

5.  There are 2 distinct cell lineages: the primary heart field
provides precursor cells for the left ventricle, whereas the
secondary heart field provides precursors for the atria and
right ventricle.
 Premyocardial cells, including epicardial cells and cells
derived from the neural crest, continue their migration into
the region of the heart tube.
 Regulation of this early phase of cardiac morphogenesis is
controlled in part by the interaction of specific signaling
molecules or ligands, usually expressed by 1 cell type, with
specific receptors, usually expressed by another cell type.

6.  Positional information is conveyed to the developing
cardiac mesoderm by factors such as retinoids
(isoforms of vitamin A), which bind to specific nuclear
receptors and regulate gene transcription.
 Migration of epithelial cells into the developing heart
tube is directed by extracellular matrix proteins (such as
fibronectin) interacting with cell surface receptors (the
integrins).
 Other important regulatory molecules include bone
morphogenetic protein 2 (BMP2); fibroblast growth
factor 4 (FGF4).

7.  The clinical importance of these ligands is revealed by the
spectrum of cardiac teratogenic effects caused by the
retinoid-like drug isotretinoin.
 As early as 20-22 days, before cardiac looping, the
embryonic heart begins to contract and exhibit phases of
the cardiac cycle that are surprisingly similar to those in
the mature heart.

8.  Morphologists initially identified segments of the heart tube
that were believed to correspond to structures in the
mature heart : the sinus venosus and atrium (right and left
atria), the primitive ventricle (left ventricle), the bulbus
cordis (right ventricle), and the truncus arteriosus (aorta
and pulmonary artery).
 Only the trabecular (most heavily muscularized) portions of
the left ventricular myocardium are present in the early
cardiac tube; the cells that will become the inlet portion of
the left ventricle migrate into the cardiac tube at a later
stage (after looping is initiated).

9. Five dilatations of heart tube
 Truncus Arteriosus
 Bulbus Cordis
 Primitive Ventricle
 Primitive Atrium
 Sinus Venosus

12.  Even later to appear are the primordial cells that give rise
to the great arteries (truncus arteriosus), including cells
derived from the neural crest, which are not present until
after cardiac looping is complete.
 Chamber-specific transcription factors participate in the
differentiation of the right and left ventricles.
 The basic helix-loop-helix (bHLH) transcription factor
dHAND is expressed in the developing right ventricle;
disruption of this gene or of other transcriptional factors
such as myocyte enhancer factors 2C (MEF2C) in mice
leads to hypoplasia of the right ventricle.

13.  The transcription factor eHAND is expressed in the
developing left ventricle and conotruncus and is also
critical to their development.

14. Cardiac Looping
 At approximately 22-24 days, the heart tube begins to bend
ventrally and toward the right.
 The heart is the first organ to escape from the bilateral
symmetry of the early embryo.
 Looping brings the future left ventricle leftward and in
continuity with the sinus venosus (future left and right
atria), whereas the future right ventricle is shifted rightward
and in continuity with the truncus arteriosus (future aorta
and pulmonary artery).

15. Formation of Cardiac Loop (lateral
view)

16. Formation of Cardiac Loop

17.  Potential mechanisms of cardiac looping include
differential growth rates for myocytes on the convex vs
the concave surface of the curve, differential rates of
programmed cell death (apoptosis), and mechanical
forces generated within myocardial cells via their actin
cytoskeleton.
 The signal for this directionality is contained in a
concentration gradient between the right and left sides
of the embryo in the expression of critical signaling
molecules.

18.  A number of signaling pathways have been identified
as regulators of this L-R asymmetry, including sonic
hedgehog (SHH), transforming growth factor-β, nodal,
and LR dynein.

20. Cardiac Septation
 When looping is complete, the external appearance of the
heart is similar to that of a mature heart; internally, the
structure resembles a single tube, although it now has
several bulges resulting in the appearance of primitive
chambers.
 The common atrium (comprising both the right and left
atria) is connected to the primitive ventricle (future
leftventricle) via the atrioventricular canal.
 The primitive ventricle is connected to the bulbus cordis
(future right ventricle) via the bulboventricular foramen.
 The distal portion of the bulbus cordis is connected to the

21.  The heart tube now consists of several layers of
myocardium and a single layer of endocardium
separated by cardiac jelly, an acellular extracellular
matrix secreted by the myocardium.
 Septation of the heart begins at approximately day 26
with the ingrowth of large tissue masses, the
endocardial cushions, at both the atrioventricular and
conotruncal junctions.

22.  Endocardial cells dedifferentiate and migrate into the
cardiac jelly in the region of the endocardial cushions,
eventually becoming mesenchymal cells that will form
part of the atrioventricular valves.
 Complete septation of the atrioventricular canal occurs
with fusion of the endocardial cushions.
 Most of the atrioventricular valve tissue is derived from
the ventricular myocardium in a process involving
undermining of the ventricular walls.

23.  Because this process occurs asymmetrically, the tricuspid
valve annulus sits closer to the apex of the heart than the
mitral valve annulus does.
 Physical separation of these 2 valves produces the
atrioventricular septum, the absenceof which is the primary
common defect in patients with atrioventricular canal
defects .

24. FORMATION OF INTERATRIAL
SEPTUM
 Septation of the atria begins at ≈30 days with growth of the
septum primum downward toward the endocardial
cushions.The orifice that remains is the ostium primum.
 The endocardial cushions then fuse and, together with the
completed septum primum, divide the atrioventricular canal
into right and left segments.
 A 2nd opening appears in the posterior portion of the septum
primum, the ostium secundum, and it allows a portion of the
fetal venous return to the right atrium to pass across to the
left atrium.

25.  Finally, the septum secundum grows downward, just to
the right of the septum primum.
 Together with a flap of the septum primum, the ostium
secundum forms the foramen ovale, through which fetal
blood passes from the inferior vena cava to the left
atrium.

27. FORMATION OF INTERVENTRICULAR
SEPTUM
 Septation of the ventricles begins at about embryonic
day 25 .
 it consists of 3 parts -a)muscular part.-from the floor of
ventricle
b) bulbar part-from lt and rt bulbar
ridges
c)membranous part.-from av
cushions and ridges


28. interventricular septum

29. formation of aorticopulmonary
septum
 it is the spiralseptum divides aorta and pulmonary trunk.
 it develops from two truncal ridges which develop due to
proliferation of mesenchymal cells derived from neural
crest cells that migrate in the walls of truncus arteriosus
near the conus.
 these truncal ridges grow and fuse to form spiral
septum.

30. Development of Heart valves
 Atrio ventricular valves
 2 in number
 Tricuspid and mitral valves.
 formed by subendocardial mesenchyme proliferation
that project in to AV canal as swellings.
 free margins of ventricular surfaces of valves
connected to papillary muscles through chordae
tendinae.

31. formation of AV valves

32. pulmonary and aortic valves
 They develop from endocardial cushions that are
formed at the jnction of truncus and conus.

33. conducting system of the heart
 The conducting system of the heart consists of four
components:
1. SA node (pacemaker of the heart)
2. AV node.
3. Bundle of His.
4. Purkinje fibers.
1. SA node: Sinoatrial node develops during the fifth
week of IUL. Initially, it is located in the right wall of the
sinus venosus, but when the sinus venosus is
incorporated (absorbed) into the right atrium then it
comes to lie in the wall of the right atrium near the

34. AV node and AV bundle of His:
 They are derived from cells in the left wall of the
sinus venosus and AV canal.
 After incorporation of sinus venosus into the right
atrium (vide supra), these cells come to lie on the
base of interatrial septum just anterior to the opening
of coronary sinus.
 Here these cells form AV node and AV bundle of His.
purkinje fibers:
 The fibers arising from AV bundle pass from atrium
into the ventricle and split into right and left bundle
branches.
 The branches from these bundles are distributed
throughout the ventricular myocardium and are

35. Formation of Pericardium
 The pericardium consists of two components: (a)
serous pericardium and (b) fibrous pericardium.
 The serous pericardium consists of two layers: (a)
visceral layer and (b) parietal layer.
 Visceral layer of serous pericardium is derived from
splanchnopleuric mesoderm lining the dorsal side of the
pericardial cavity.
 Parietal layer of serous pericardium and fibrous
pericardium is derived from somatopleuric mesoderm
lining the ventral side of the pericardial cavity.

37. Aortic Arch Development
 The aortic arch, head and neck vessels, proximal
pulmonary arteries, and ductus arteriosus develop
from the aortic sac, arterial arches, and dorsal aortae.
 When the straight heart tube develops, the distal
outflow portion bifurcates into the right and left 1st
aortic arches, which join the paired dorsal aortae.

38.  The left dorsal aorta will form the descending aorta.
 The proximal aorta from the aortic valve to the left
carotid artery arises from the aortic sac.
 The 1st and 2nd arches largely regress by about 22
days, with the 1st aortic arch giving rise to the
maxillary artery and the 2nd to the stapedial and
hyoid arteries.

39.  The 3rd arches participate in the formation of the
innominate artery and the common and internal carotid
arteries.
 The right 4th arch gives rise to the innominate and right
subclavian arteries, and the left 4th arch participates in
formation of the segment of the aortic arch between the
left carotid artery and the ductus arteriosus.
 The 5th arch does not persist as a major structure in the
mature circulation

40.  The 6th arches join the more distal pulmonary arteries, with
the right 6th arch giving rise to a portion of the proximal
right pulmonary artery and the left 6th arch giving rise to
the ductus arteriosus.

45. Cardiac Differentiation
 The process by which the totipotential cells of the early
embryo become committed to specific cell lineages is
differentiation.
 Precardiac mesodermal cells differentiate into mature
cardiac muscle cells with an appropriate complement of
cardiac-specific contractile elements, regulatory proteins,
receptors, and ion channels.

46.  Expression of the contractile protein myosin occurs at an
early stage of cardiac development, even before fusion of
the bilateral heart primordia.
 Differentiation in these early mesodermal cells is regulated
by signals from the anterior endoderm, a process known as
induction.
 Several putative early signaling molecules include
fibroblast growth factor, activin, and insulin.

47.  Signaling molecules interact with receptors on the cell
surface; thesereceptors activate 2nd messengers, which,
in turn, activate specific nuclear transcription factors
(GATA-4, MEF2, Nkx, bHLH, and the retinoic acid receptor
family) that induce the expression of specific gene products
to regulate cardiac differentiation.
 Some of the primary disorders of cardiac muscle, the
cardiomyopathies, may be related to defects in some of
these signaling molecules

48.  Developmental processes are chamber specific.
 Early in development, ventricular myocytes express both
ventricular and atrial isoforms of several proteins, such as
atrial natriuretic peptide (ANP) and myosin light chain
(MLC).
 Mature ventricular myocytes do not express ANP and
express only a ventricular-specific MLC 2v isoform,
whereas mature atrial myocytes express ANP and an
atrial-specific MLC 2a isoform.

49.  Heart failure volume overload, and pressure overload
hypertrophy are associated with a recapitulation of fetal cell
phenotypes in which mature myocytes reexpress fetal
proteins.
 Because different isoforms have different contractile
behavior (fast vs. slow activation, high vs. low adenosine
triphosphatase activity), expression of different isoforms
have important functional consequences.

50.  The extent to which stem cells can be made to differentiate
into cardiac muscle cells is the focus of investigation in the
field of regenerative cardiology.
 The demonstration that fully differentiated adult cells (e.g.,
skin fibroblasts or peripheral blood mononuclear cells) can
be reprogrammed into induced pluripotential stem cells and
then differentiated into beating cardiomyocytes in vitro, has
opened up many new avenues to study cardiovascular
disease.

51.  Some investigators believe that there are precursor cells
(cardiac stem cells) reside within the myocardium that can
replace damaged myocytes, although at a rate too slow to
be clinically useful.
 Scientists are working on trying to stimulate these cells
with the proper regulatory factors, thus inducing them to
regenerate damaged cardiac muscle.

52.  Others are investigating whether circulating stem cells,
bone marrow–derived cells, or the factors they secrete
can support cardiac regeneration.
 cells grown on biomechanical scaffolds may be used to
build a replacement ventricle for patients with
hypoplastic left or right heart.

53. Thank you