EMBRYOLOGY -

DEVELOPMENT OF
CONOTRUNCAL REGION

Dr Julian Johny Thottian

 Introduction
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.

D A Goor et al
EARLY HEART
 Definitions

Conotruncus -The conotruncus is the outflow

region of the developing heart.
It consists of:
Conus- Inferior to the
aortic and pulmonary valves .
Truncus-
Superior to the valves that is continuous with
the ventral aorta (aortic sac).
 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)
 The net result is.
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.
 Secondary heart field
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

 Molecular aspect
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)
 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

 NEURAL CREST CELLS
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)
 Role of neural crest cells
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
Cardiac neural crest cells
Sequential events related to
conotruncal septum
Embryo Aged 18-22 days
 Explanation
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.
 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
Conotruncus and ostium bulbi
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.
Shift or rotation of ostium bulbi

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.
Truncal and conal cushions
 Conotruncal ridges

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
 Truncal rotation
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.
 Absorption of conus
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
 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 .
 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.
Crista supraventricularis
 Summarize
Effect of conus absorption-
1. 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.
Basis for conotruncal defects
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 double-outlet right
ventricle (DORV)
as a consequence of the primary short
conotruncal morphology.
 Contd
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.
Formation of the Aorta and
Pulmonary Artery
 Truncal septation and
development of arterial valves
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).
 FORMATION OF SEMILUNAR
VALVES
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.
Semilunar Valve
Formation
 Development of sinus of
valsalva
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
 MOLECULAR ASPECT
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)
 Conotruncal anomalies
TOF
DORV
TGA
PTA
 TOF
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}

 Truncus arteriosus
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}

 TGA
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
 Contd..

Faulty absorption of the conus

Absent leftward shift of the conoventricular
junction account for the variability of
transposition
 DORV
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 )
THANK YOU
 Book references
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
 Article references
1. DA Goor and Walton Lillihei Circulation 1972;46:375-
384
2. Francesca Rochais et al Circulation 2009;104 :933-942
3. Angelo Restivo et al THE ANATOMICAL RECORD
PART A 288A:936943 (2006)
4. Keith A. 1909. The Hunterian lectures on

malformations of the heart. Lancet 12:359364.

5. Mjaadvedt CH et al 2001. The outflow tract of the

heart is recruited from a novel heart forming field.

Dev Biol 238:97109.
 6. Waldo K et al 2001. Conotruncal myocardium
arises from a secondary heart field. Development
128:31793188.
7. Ward C, Kirby ML. 2006. The secondary heart
field: understanding conotruncal defects from a
developmental perspective. Curr Cardiol Rev 2:520.
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 41:755762.
QUIZ
 QUESTION 1
SHF CELLS ARE DERIVED FROM
1. Pharyngeal ectoderm
2. Pharyngeal mesoderm
3. Pharyngeal endoderm
4. Dorsal pericardial wall
 QUESTION 2
NO: OF TRUNCAL AND CONAL CUSHIONS
1. 2&4
2. 4&2
3. 3&4
4. 4&3
 QUESTION 3
MAIN SIGNALING PATHWAYS IN
OUTFLOW TRACT DEVELOPMENT
INCLUDE ALL EXCEPT.
1. WNT
2. FGF
3. SHH
4. NOTCH
5. TBX5
 QUESTION 4
NUMBER OF ROTATIONS THAT TAKE PLACE
IN THE CONOTRUNCAL REGION
A. 3
B. 4
C. 2
D. 1
 QUESTION 5
SHF CONTRIBUTES TO ALL EXCEPT
1. RV
2. LV
3. OUTFLOW TRACT
4. INFLOW REGION
 QUESTION 6
WHICH GENE IS INVOLVED IN TRUNCAL
VALVE FORMATION
1. Sox 4
2. Tbx5
3. Fgf 10
4. Shh
 QUESTION 7
SEPTUM AORTOPULMONALE IS DERIVED
FROM
1. Shf & Ncc
2. Fhf
3. Septum transversus
4. Dorsal pericardial wall
 QUESTION 8
CATCH 22 INCLUDES ALL EXCEPT
1. Cardiac anomalies
2. Hyperparathyroidism
3. Thymic hypolasia
4. Cleft palate
5. Abnormal facies
 QUESTION 9
DEVELOPMENT OF THE CONOTRUNCUS
OCCURS FROM
1. 2-4 weeks
2. 5-7 weeks
3. 7-9 weeks
4. 12-14 weeks
 QUESTION 10
WHICH IS NOT A NORMAL
DEVELOPMENTAL PROCESS
1. AV shift to right
2. Ostio bulbar shift to left
3. Clockwise rotation of truncus from ventricular
side
4. Counter clockwise rotation of ostium bulbi
from ventricular side