CARDIAC DEVELOPMENT · human and comparative embryology is essential to an intelligent grasp of the...
Transcript of CARDIAC DEVELOPMENT · human and comparative embryology is essential to an intelligent grasp of the...
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Diane E. Spicer, BS, PA(ASCP)
University of Florida
Dept. of Pediatric Cardiology
Curator – Van Mierop Cardiac Archive
This lecture is given with special thanks to
Professor RH Anderson, my mentor and my
friend. Without his spectacular research and
images of both human and mouse embryos,
this lecture would not have been possible.
♥ “An understanding of the elementary facts of
human and comparative embryology is
essential to an intelligent grasp of the
ontogenetic problems of congenital cardiac
disease.”
♥ Maude Abbott “Atlas of Congenital Cardiac
Disease” American Heart Association, New
York, 1936
CARDIAC DEVELOPMENT
♥ What’s new?
CARDIAC DEVELOPMENT
♥ In the past, most theories of morphogenesis
were based on fanciful interpretation of
normal development
♥ We are now able to demonstrate the anatomic
and molecular changes that take place during
cardiac development
♥ This now permits us to base our inferences on
evidence, rather than speculation
CARDIAC DEVELOPMENT
♥ Do we need to change?
CARDIAC DEVELOPMENT
♥ It used to be thought that all components of
the postnatal heart were contained within the
initial linear heart tube
♥ In reality, new material is added at the
arterial and venous poles from the second
heart field. The initial tube, derived from the
first heart field, forms little more than the
definitive left ventricle
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Mouse embryo – 9 somites – Myosin LC
Putative left ventricle
Growth at venous pole
Growth at arterial pole
Mouse embryo – E8.5 – 9 somites
Atrial component
Atrioventricular
canal
Developing left ventricle
Developing
right ventricle
Outflow tract
Mouse embryo – E9.5 – 25 somites
♥ By expansion from the cavity of the
primary heart tube
♥ “Ballooning”
♥ Atrial segment – the appendages
♥ Ventricular segment – the apical
components
CARDIAC DEVELOPMENT
♥ How are the chambers formed?
CARDIAC DEVELOPMENT
♥ Does this permit us to understand the
basis of cardiac isomerism?
♥ The chambers develop under the influence of
the laterality genes
♥ Pitx2c produces morphologically leftness
♥ Lefty-1 and nodal stop this gene from
reaching the right side
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Mouse embryo – E8.5 – 9 somites
Morphologically left
Morphologically right
Mouse embryo – E9.5 – 25 somites
R L
L
R
L
R
Mouse – embryonic day 13.5
Pitx2 Knock-out mouse
Bilateral morphologically right appendages
Bilateral morphologically
left appendages
Lefty-1 Knock-out mouse
♥ Cardiac isomerism
♥ It is only the appendages that show
evidence of isomerism
♥ The venoatrial connections are variable, as
are the remainder of the cardiac
components
♥ All require description, along with the
remaining systems of organs
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
♥ What about the venoatrial connections?
♥ It is often stated that there is a common wall
between the coronary sinus and the left atrium,
which is produced by formation of a “sinuatrial
fold”
♥ In reality, the left sinus horn possesses its own
walls from the outset of development. It becomes
incorporated into the left atrioventricular groove
as it becomes the coronary sinus
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Primary atrium
Mouse embryo – 13 somites
Dorsal
mesocardium
Gut
Right
sinus
horn
Left
sinus
horn
Mouse embryo – 13 somites
Right atrium
Left atrium
Venous valves
Mouse – embryonic day 10.5
Left atrium
Left ventricle
Left sinus horn
Mouse – embryonic day 11.5
♥ Formation of the pulmonary vein
♥ It is often stated that the pulmonary vein
takes its origin from the systemic venous
sinus (or “sinus venosus”)
♥ In reality, the pulmonary vein develops
from a midline strand in the pharyngeal
mesenchyme. It canalises so as to open into
the developing left ventricle through the
remaining attachments of the dorsal
mesocardium
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Systemic venous sinus to right atrium
Opening of pulmonary vein Mouse embryo – Embryonic day 10.5
Human embryo – Carnegie stage 14 Coloured to show NKX 2.5
SVS
LSH
Human embryo – Carnegie stage 14 Coloured to show TBX 18
SVS LSH
Human embryo – Carnegie stage 14
Left atrium
Left sinus horn
Pulmonary venous component Left superior caval vein
Left atrium
Human embryo – post-septation
♥ Mechanisms of atrial septation
♥ Most textbooks still show growth of a secondary
atrial septum (the “septum secundum”) from the
atrial roof, which overlaps cranially the primary
atrial septum
♥ In reality, the so-called “septum secundum” is a
cranial interatrial fold. It is not formed until the
pulmonary veins are remodelled to form the atrial
roof. The true second septum forms the antero-
inferior buttress of the atrial septum
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
♥ Atrial septation
♥ It is transfer of the systemic venous
tributaries to the right side of the primary
atrial chamber that sets the scene for
subsequent septation
CARDIAC DEVELOPMENT
Mouse - Embryonic day 11.5
Systemic venous sinus
Secondary foramen
Primary septum
Mesenchymal cap
Primary foramen
Inferior AV cushion
Mouse - Embryonic day 11.5
Inferior AV cushion
Primary foramen
Mesenchymal cap
Primary septum Vestibular spine
Vestibular spine Pulmonary vein
Mouse - Embryonic day 11.5
Primary septum
Mesenchymal cap
Vestibular spine
Inferior AV cushion Superior AV cushion
Secondary foramen
Mouse - Embryonic day 13.5
Secondary septum
Breakdown
at atrial roof
Oval
foramen
Primary septum
Mouse - Embryonic day 14.5
Systemic venous sinus to right
Dorsal mesocardium
Primary septum & cap
Primary foramen
Pulmonary vein
Growth of
primary septum
Reducing
primary foramen
Cranial
perforations
Growth of
vestibular spine
Breakdown
cranially
Closure of
primary
foramen
Primary
septum
Oval
fossa
Oval
foramen
Superior
interatrial
fold
Antero-
inferior
buttress
CARDIAC DEVELOPMENT
Superior inter-
atrial fold
Right pulmonary veins Left pulmonary veins
Anterior-inferior
muscular buttress
Oval fossa
Tricuspid valve
Mitral valve
CARDIAC DEVELOPMENT
TV TV
MV
MV
ASD - ‘Secundum’ type Vestibular ASD
♥ The definitive atrial septum
♥ The floor of the oval fossa is derived from
the primary atrial septum
♥ The so-called “septum secundum” is the
superior interatrial fold
♥ The antero-inferior buttress is a true second
septal component
♥ Perforations within the oval fossa are
“ostium secundum” defects, but reflect
abnormal formation of the primary septum
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
♥ Ventricular septation
♥ Some suggest that the ventricular septum is
developed with a component derived from
the septum of the atrioventricular canal, and
another component representing the conal
septum
♥ In reality, the definitive ventricular septum
has only muscular and membranous
components. There are no “inlet” and
“outlet” components
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
♥ Ventricular septation
♥ The apical muscular ventricular septum
develops concomitant with the “ballooning” of
the ventricular apical components from the inlet
and outlet parts of the ventricular loop
♥ When first formed, the developing heart exhibits
double inlet to the developing left ventricle, and
double outlet from the developing right ventricle
♥ So as to close the ventricular septum, there must
be transfer of the inlet of the right ventricle, and
the outlet of the left ventricle
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Atrial component
Atrioventricular
canal
Developing left ventricle
Developing
right ventricle
Outflow tract
Mouse embryo – E9.5 – 25 somites
Left ventricle
Embryonic mouse – E10.5 Atrioventricular canal
Right ventricle
Outflow tract
♥ Ventricular septation
♥ The processes of transfer were
elucidated by a study in which it
proved possible to track the fate of a
ring of cells surrounding the initial
embryonic interventricular
communication
CARDIAC DEVELOPMENT
Lamers WH, Wessels A, Verbeek FJ, Moorman AFM, Virágh S, Wenink ACG, Gittenberger-de
Groot AC, Anderson RH. New findings concerning ventricular septation in the human heart.
Implications for maldevelopment. Circulation 1992;86:1194-1205.
CARDIAC DEVELOPMENT
Right
atrium
Left
atrium
Right
ventricle
Left
ventricle
Human embryo – Carnegie stage 13
Right atrium
Right
ventricle
Left ventricle
Human embryo – Carnegie stage 16
Part of the ring marks the
crest of the muscular
ventricular septum
Embryonic day 11.5
Right
atrium Developing
right
ventricle
Still double
outlet
CARDIAC DEVELOPMENT
♥ Atrioventricular canal initially drains exclusively to
developing left ventricle
♥ Expansion of canal produces connection between right
atrium and developing right ventricle
♥ At this stage, outflow tract is supported exclusively by
developing right ventricle
♥ Necessary to transfer aorta to left ventricle before
heart can be properly septated
♥ The story thus far
CARDIAC DEVELOPMENT
Aortic root
Left ventricle
Interventricular
communication
Line of putative
ventricular
septation
Embryonic day 12.5
Previous
interventricular
communication
Line of putative
ventricular
septation Later on embryonic day 12.5
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Aorta
RA
LA
RV
LV
Tetralogy of Fallot
Aortic root
End of embryonic day 12.5
Initial interventricular
communication is now
left ventricular
outflow tract
End of embryonic day 12.5
Tubercles fusing to wall
aorta into left ventricle
Muscularising
infundibulum
Embryonic day 15.5 Muscularised
infundibulum
Membranous
septum
♥ The definitive ventricular septum
♥ Has only apical muscular and
membranous components
♥ The postero-inferior part of the septum
separates the right ventricular inlet from
the left ventricular outlet
♥ The subpulmonary infundibulum is a
free-standing muscular sleeve
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
RA
LA
RV
LV
RV
LV
PV
AV
♥ Formation of the outflow tracts
♥ It is usual to describe the developing outflow
tract in terms of the “truncus” and “conus”
♥ It is also frequently stated that the outflow
cushions form an “aortopulmonary septal
complex”
♥ Better to analyse in tripartite fashion, showing
that the cushions separate the arterial roots
and outflow tracts, rather than the
intrapericardial arterial trunks
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Proximal
Intermediate
Distal
Developing
right ventricle
Mouse – early E11.5
Left atrium
Left ventricle
Distal OFT
Aortic sac
Mouse – early E11.5
Septal cushion
Parietal cushion
Non-myocardial walls
4
6
Mouse – early E11.5
Intrapericardial
aorta
Intrapericardial
pulm. trunk
Intrapericardial
aorta
Aortopulmonary foramen Mouse – mid E11.5
♥ The distal outflow tract
♥ Is separated to form the intrapericardial
components of the aorta and pulmonary
trunk by growth of the aortopulmonary
septum from the dorsal wall of the aortic
sac
♥ The protrusion fuses with the distal ends
of the outflow cushions to close the
embryonic aortopulmonary foramen
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
RAA
LAA
Aorta
Aortic
valve
Pulm.
valve
Pulm.
valve
Embryonic day 12.5
Oblique cut through
intermediate part of
outflow tract
Right atrium
Aortic root
Pulmonary
root
Cushions fused
centrally
Unfused peripherally
Pulmonary root
Aortic root
Embryonic day 12.5
♥ The intermediate outflow tract
♥ The distal cushions, along with the
intercalated cushions, excavate to form
the leaflets of the arterial valves
♥ The central parts of the cushions fuse to
septate the arterial roots, but then
attenuate as the roots separate one from
the other
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
Aortic root
Unfused proximal cushions
Columns of condensed
mesenchyme
Embryonic day 12.5
Right atrium
Right ventricle
Closing interventricular foramen
Aorta
Mouse – day 13.5
Aortic sac
DEVELOPMENT OF OUTFLOW TRACT
Extrapericardial
arterial trunks
Intrapericardial arterial trunks
Valves & sinuses
Ventricular outflow tracts
DEVELOPMENT OF OUTFLOW TRACT
♥ The outflow tract
♥ Is best described in terms of proximal,
intermediate, and distal components
♥ The aortopulmonary septum separates
the distal part into the intrapericardial
arterial trunks
♥ Description in terms of “truncus” and
“conus” does not legislate for formation
of arterial roots
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
♥ The bottom line
♥ The recent advances in visualising the
developing heart now permit us to
describe the changes in evidence-based
fashion
♥ The findings now provide the basis for
understanding the morphogenesis of
congenital cardiac malformations
CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT
CARDIAC DEVELOPMENT Thank you for your attention.