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


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


♥ 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



Morphologically left

Morphologically right


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


♥ 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


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


Left atrium

Left ventricle

Left sinus horn


♥ 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


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


♥ 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


Inferior AV cushion

Primary foramen

Mesenchymal cap

Primary septum Vestibular spine

Vestibular spine Pulmonary vein


Primary septum

Mesenchymal cap

Vestibular spine

Inferior AV cushion Superior AV cushion

Secondary foramen


Secondary septum

Breakdown

at atrial roof

Oval

foramen

Primary septum


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


♥ 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



♥ 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


Atrial component

Atrioventricular

canal

Developing left ventricle

Developing

right ventricle

Outflow tract


Left ventricle

Embryonic mouse – E10.5 Atrioventricular canal

Right ventricle

Outflow tract


♥ 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


Right atrium

Right

ventricle

Left ventricle


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


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



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


Proximal

Intermediate

Distal

Developing

right ventricle

Mouse – early E11.5

Left atrium

Left ventricle

Distal OFT

Aortic sac


Septal cushion

Parietal cushion

Non-myocardial walls

4

6


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



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


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


♥ 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 Thank you for your attention.

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