Transcript Embryology - Conotruncal development

Dr Julian Johny Thottian
The Conus- also known as Infundibulum (Keith
1909 )
The Conotruncus comprises collectively two
myocardial sub segments,
the Bulbus cordis and the Truncus arteriosus
BULBUS CORDIS –refers to the ventricular outflow
tract
TRUNCUS ARTERIOSUS- embryologic precursor of
great arteries.
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D A Goor etal
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Conotruncus -The conotruncus is the outflow
region of the developing heart.
It consists of:
Conus cordis and Truncus Arteriosis.
Conus- Inferior to the aortic and pulmonary
valves .
Truncus- Superior to the valves that is
continuous with the ventral aorta (aortic sac).
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Bulbus cordis- also known as the conotruncus
lies ventral to primitive ventricle.
Together with primitive ventricle it forms the
ventricle of the formed heart. Keith (1909)
The developing two main truncal cushions and
the underlying two conal cushions are perfectly
aligned and no line of demarcation between the
two is identifiable in mammals
(Van Mierop and Patterson, 1980)
Proper alignment of the outlet septum with
ventricular trabecular septum with
membraneous septum in between.
 Proper posterior alignment of left outflow tract
with left ventricle and aorto mitral continuity.
Mechanism – differential growth and apoptosis.
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Area of the ventral pharyngeal mesoderm
(Kelly et al, 2001; Mjaadvedt et al, 2001; Waldo
et al, 2001) - Pre cardiac Splanchnic
Mesodermic -region providing myocardial
precursor cells, which migrate to the Out flow
Tract area of the developing cardiac tube,
where they build up the Conotruncal
myocardium as well as smooth muscle cells
joining the caudal portion of the aortic sac
(Waldo et al, 2005).
The topography of the SHF
Rochais F et al. Circulation Research 2009;104:933-942
Copyright © American Heart Association
.
SHF expressed NKx2.5 and Gata4 transcription
factors.
NKx2.5- and Gata4 SHF-committed cells join and
incorporate themselves into the outflow tract of
the primary heart tube, these cells undergo
terminal myocardial differentiation under the
induction of the local primary myocardial
Bmp2 factor (Waldo et al 2001)
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Wnt, fibroblast growth factor, bone
morphogenetic protein, Hedgehog, and
retinoic acid are all involved in signalling.
SHF contributes to the outflow tract (OFT),
right ventricle, and inflow region
Illustration showing the core features of the Wnt, Fgf, Bmp, Hh, and Notch signaling
pathways.
Rochais F et al. Circulation Research 2009;104:933-942
Copyright © American Heart Association
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Crest develops from - Dorsal neural tube.
It overlaps the vagal neural crest and migrates to
populate the pharyngeal arches 3, 4 and 6
(producing structures in the head) and to the heart,
forming connective tissue that separates the great
vessels of the heart.
Other Migration Locations: Pharyngeal arches and
Truncus arteriosus , aorticopulmonary septum
and the smooth muscle of great arteries.
Anterior of the aorta to become the four pre-aortic
ganglia (celiac ganglion, superior mesenteric
ganglion, inferior mesenteric ganglion and aortical
renal ganglia)
Neural crest cells modulate the SHF cells.
 It plays a role in elongation of the OFT.
Ablation of these cells cause failure of
migration of SHF cells to conotruncus. (Kelly et
al 2002)
They provide the cells for entire conotruncal
septum
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The heart tube is convoluted to forms five
straight segments (limbs), and in-between
them, four curves.
The proximal segment of the heart tube
(starting at the venous end) is the A-V
canal. It is oriented posteroanteriorly.
First curve or proximal bend- the heart tube
makes a 90 degree turn toward the right to
become the proximal transverse limb, or the
interventricular foramen.
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Curve 2 the heart tube makes a 90° turn
cephalically to become the ascending limb .
Curve 3 the heart tube turns in 90degree
medially to form the distal transverse limb.
Curve 4 the heart tube turns in 90degree
toward the back of the embryo to form the
terminal limb, which is cephalad and parallel
to the A-V canal.
Each curve has a Greater and a Lesser
curvature.
The Lesser curvature of curve 2 is the
Conoventricular Flange
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Border between meta ampulla and conus is
the Ostium bulbi, or the conoventricular
junction.
On the right the Ostium bulbi is the transition
from the trabeculated ventricular endocardium
to the smooth conal endocardium.
On the left the Ostium bulbi is lower edge of
conoventricular flange.
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Ostium bulbi shifts toward the left to
cephalically and override the IVF. This critical
process provides the conus with an access to
the left ventricle.
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The conotruncal ridges are arranged in a spiral
course, like riflings of a gun barrel.
Two main opposing dextrosuperior and
sinistroinferior truncal endocardial cushions
appear.
 Occupying respectively a dorsal and a ventral
oblique position, these cushions extend from
the junction between the aortic sac and the
truncus arteriosus down to the beginning of the
conus, where they align with the dextrodorsal
and sinistroventral conal cushions, respectively
(Van Mierop and Patterson, 1980).
Aortic truncus
Pulmonary
truncus
The truncus rotates about 90-110° in a
counterclockwise direction.
This counterclockwise rotation (torsion) of the
truncus, which follows the earlier
counterclockwise rotation of the ostium bulbi,
unwinds the coiled course of the conotruncal
ridges .
As a result, the aortic truncus is transferred to
the same side as the aortic conus (left side) and
the aortic and pulmonary trunks become
coiled, this situation is seen in the definitive
heart.
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Marked shortening of the conus and the
equivalent lengthening of the aorta and
pulmonary arteries.
The aortic conotruncus is reduced in length
from 700 to 400 microns
The length of the pulmonary conotruncus is
reduced from 880 microns to 600 microns
D A Goor et al
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Absorption of the bilateral proximal conuses
brought the distal conus septum toward the
ventricular septum, and absorption of the
distal aortic conus accounts for the fibrous
continuity between the aortic and mitral
valves.
The truncus is continuous distally with the
aortic sac (ventral aorta) which is devoid of
endocardial cushions.
At the same time, the septum aortopulmonale
grows from the dorsal wall of the aortic sac
toward the truncal septum to fuse with it.
As a result of the fusion of these two septa the
aortic sac is divided into the ascending aorta
and the pulmonary artery .
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Muscular elements arising from the right
ventricle invade the conus septum.
 Once the conus septum is muscularized it
receives the anatomic appearance of the crista
supraventricularis.
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Effect of conus absorption1. “Migration“ of the distal conus septum
toward the heart where it assumes its definitive
position in the interventricular septum
2. Additional absorption of the distal aortic
conus accounts for the fibrous continuity seen
in the mature heart between the aortic and
mitral valves
Inversion of conotruncus- 2 stages
Stage1 – Inversion of ostium bulbi at same time of
looping
Stage 2- Rotation of truncus which occurs after the
formation of septum aortopulmonale.
 Ostium bulbar rotation causes the anatomic
concordance between the left ventricle and the
proximal aortic conus
 Truncal torsion in similar manner and bring the
semilunar valves to the same sides as their
proximal conuses and unwinding the spiral course
of the conotruncal ridges.
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Ward et al. (2005) and Ward and Kirby (2006)
emphasize that a short outflow tract,
through SHF ablation and through experimental
NC ablation and with consequent low SHF cellular
output to the conotruncal region, does not allow a
normal conotruncal rotation.
PTA, tetralogy of Fallot (TF), pulmonary atresia
with ventricular septal defect (VSD), and doubleoutlet right ventricle (DORV)
as a consequence of the primary short conotruncal
morphology.
Myocardialisation of the ridges gives a
zippering effect resulting in fusion.
Fusion occurs in a distal to proximal direction
during the sixth week, allowing for cleavage of
the aorta and pulmonary trunk.
The spiralling nature of the ridges causes the
pulmonary trunk to twist around the aorta.
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The external wall of the truncal myocardium
creates some sort of rim known as myocardial
cuff, which appears to cover the root of the
aortic sac (Thompson and Fitzharris, 1979)
Dextrosuperior and sinistroinferior truncal
endocardial cushions extend from the junction
between the aortic sac and the truncus
arteriosus down to the beginning of the conus,
where they align with the dextrodorsal and
sinistroventral conal cushions, respectively
(Van Mierop and Patterson, 1980).
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The mesenchymal truncal septum undergoes a
complex differentiation process leading to the
formation of the right and left pulmonary valve
cusps and of the right coronary and left coronary
aortic valve cusps.
Two additional intercalated truncal endocardial
swellings appear to occupy a parietal position on
the right and on the left side of the truncus
arteriosus. After the normal counterclockwise
conotruncal rotation, the right intercalated
cushion becomes the posterior noncoronary
aortic valve cusp and the left intercalated cushion
becomes the anterior pulmonary valve cusp.
Caudal elongation of the aortic sac,
concomitantly with the downward retraction
of the truncus arteriosus, is the one that allows
the development of the intrapericardial
portions of the great arteries and of the arterial
walls of the sinuses of Valsalva
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Sox4 and NF-Atc transcription factors -mainly
involved in this developmental phase
Sox4 regulates the normal development and
fusion of the truncal endocardial cushions.
[Schilham et al. (1996) and Ya et al. (1998)]
Targeted disruption of the NF-Atc gene
produced absence of both arterial valves.
Ranger et al. (1998)
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TOF
DORV
TGA
PTA
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Conal septum deviates anteriorly- faulty partition
of conotruncal septum.
Abnormal conal rotation takes place
Mal rotation of trunco-bulbar ridges causes
misalignment of septum and straddling of aorta
over VSD
Another mechanism-hypoplasia and under
development of the pulmonary infundibulum
causes infundibular hypoplasia.
Van Praagh et al {Amj Card 1970;26:25-33}
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Due to incomplete or failed septation of the
embryonic truncus arteriosus.
Aortopulmonary and interventricular defects
are believed to represent an abnormality of
conotruncal septation.
Van Praagh {Amj Card 1965 ;16;406-425}
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Arrest of both proximal & distal conal rotation
lead to the transposition group of diseases, in
which the aorta is dextroposed on the right side
of the pulmonary artery & has no continuity
with left ventricle
D A Goor et al
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Faulty absorption of the conus
Absent leftward shift of the conoventricular
junction account for the variability of
transposition
Impaired morphogenesis of either the outflow
portion (conotruncus) or the conoventricular
flange
 Abnormal connection between the muscular
ventricular septum and the conus septum
And hence sub aortic flow path from right
ventricle
Originally both vessels arise from RV and if no
conoventricular shifting occurs then DORV
(Manner et al , Thorac cardiovasc surg 1995 )
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THANK YOU
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Moss & Adams` Heart Disease in infants,
children and adolescents. Vol 2 Development
of conotruncus 891-892, 906,911,1040,1102
Avery Diseases of newborn. William Tauesch.
Development of conotruncus. Pg 972
Langman`s essential embryology. Thomas W
Sadler Conotruncal inversions Pg 49
Clinical recognition of congenital heart disease
by Joseph Perloff. Diagnosis of conotruncal
anomalies
1. DA Goor and Walton Lillihei Circulation
1972;46:375-384
2. Francesca Rochais et al Circulation 2009;104 :933942
3. Angelo Restivo et al THE ANATOMICAL
RECORD PART A 288A:936–943 (2006)
 4. Keith A. 1909. The Hunterian lectures on
malformations of the heart. Lancet 12:359–364.
 5. Mjaadvedt CH et al 2001. The outflow tract of
the heart is recruited from a novel heart forming
field. Dev Biol 238:97–109.
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6. Waldo K et al 2001. Conotruncal myocardium
arises from a secondary heart field. Development
128:3179–3188.
7. Ward C, Kirby ML. 2006. The secondary heart
field: understanding conotruncal defects from a
developmental perspective. Curr Cardiol Rev 2:5–
20.
8. Van Praagh {Amj Card 1965 ;16;406-425}
9. Van Mierop LHS et al 1978. Pathogenesis of
persistent truncus arteriosus in light of
observations made in a dog embryo with the
anomaly. Am J Cardiol 41:755–762.
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4.
SHF CELLS ARE DERIVED FROM
Pharyngeal ectoderm
Pharyngeal mesoderm
Pharyngeal endoderm
Dorsal pericardial wall
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NO: OF TRUNCAL AND CONAL CUSHIONS
2&4
4&2
3&4
4&3
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5.
MAIN SIGNALING PATHWAYS IN
OUTFLOW TRACT DEVELOPMENT
INCLUDE ALL EXCEPT.
WNT
FGF
SHH
NOTCH
TBX5
NUMBER OF ROTATIONS THAT TAKE PLACE
IN THE CONOTRUNCAL REGION
A. 3
B. 4
C. 2
D. 1
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3.
4.
SHF CONTRIBUTES TO ALL EXCEPT
RV
LV
OUTFLOW TRACT
INFLOW REGION
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3.
4.
WHICH GENE IS INVOLVED IN TRUNCAL
VALVE FORMATION
Sox 4
Tbx5
Fgf 10
Shh
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2.
3.
4.
SEPTUM AORTOPULMONALE IS DERIVED
FROM
Shf & Ncc
Fhf
Septum transversus
Dorsal pericardial wall
CATCH 22 INCLUDES ALL EXCEPT
1. Cardiac anomalies
2. Hyperparathyroidism
3. Thymic hypolasia
4. Cleft palate
5. Abnormal facies
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4.
DEVELOPMENT OF THE CONOTRUNCUS
OCCURS FROM
2-4 weeks
5-7 weeks
7-9 weeks
12-14 weeks
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1.
2.
3.
4.
WHICH IS NOT A NORMAL
DEVELOPMENTAL PROCESS
AV shift to right
Ostio bulbar shift to left
Clockwise rotation of truncus
Counter clockwise rotation of ostium bulbi