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. CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT ♥ What’s new?
♥ “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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT ♥ Do we need to change?
♥ 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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 Growth at arterial pole
Putative left ventricle
Growth at venous pole
Mouse embryo – E8.5 – 9 somites Outflow tract
Developing left ventricle
Developing right ventricle Atrioventricular canal
Atrial component Mouse embryo – E9.5 – 25 somites CARDIACCARDIAC DEVELOPMENTDEVELOPMENT ♥ How are the chambers formed?
♥ By expansion from the cavity of the primary heart tube ♥ “Ballooning” ♥ Atrial segment – the appendages ♥ Ventricular segment – the apical components
CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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
Mouse embryo – E8.5 – 9 somites L
L
R
R
R L
Mouse embryo – E9.5 – 25 somites Mouse – embryonic day 13.5 Pitx2 Knock-out mouse
Bilateral morphologically right appendages Lefty-1 Knock-out mouse
Bilateral morphologically left appendages CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 Mouse embryo – 13 somites
Primary atrium Mouse embryo – 13 somites Gut Dorsal mesocardium
Right sinus horn Left sinus horn Mouse – embryonic day 10.5
Left atrium
Right atrium
Venous valves Mouse – embryonic day 11.5
Left atrium
Left ventricle
Left sinus horn CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 LSH SVS
Human embryo – Carnegie stage 14 Coloured to show NKX 2.5 SVS LSH
Human embryo – Carnegie stage 14 Coloured to show TBX 18 Human embryo – Carnegie stage 14
Left atrium
Left sinus horn Pulmonary venous component Left superior caval vein
Left atrium
Human embryo – post-septation CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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
♥ 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 Secondary foramen
Primary septum
Mesenchymal cap
Primary foramen
Systemic venous sinus
Inferior AV cushion
Mouse - Embryonic day 11.5 Vestibular spine Primary septum
Mesenchymal cap
Primary foramen
Inferior AV cushion
Mouse - Embryonic day 11.5 Pulmonary vein Vestibular spine
Mouse - Embryonic day 11.5 Mouse - Embryonic day 13.5
Secondary foramen
Primary septum
Mesenchymal cap Vestibular spine
Inferior AV cushion Superior AV cushion Breakdown at atrial roof
Primary septum
Oval foramen
Secondary septum
Mouse - Embryonic day 14.5 Primary septum & cap Cranial perforations Growth of primary septum
Primary foramen
Reducing primary foramen
Dorsal mesocardium Pulmonary vein Systemic venous sinus to right Growth of Breakdown Superior vestibular spine cranially interatrial fold Oval foramen Primary septum
Oval fossa Closure of primary foramen
Antero- inferior buttress CARDIAC DEVELOPMENT
Right pulmonary veins Left pulmonary veins
Superior inter- atrial fold Anterior-inferior muscular buttress
Oval fossa Mitral valve
Tricuspid valve CARDIAC DEVELOPMENT
ASD - ‘Secundum’ type Vestibular ASD
MV
MV
TV TV CARDIACCARDIAC DEVELOPMENTDEVELOPMENT ♥ 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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT ♥ 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
Outflow tract
Developing left ventricle
Developing right ventricle Atrioventricular canal
Atrial component Mouse embryo – E9.5 – 25 somites Embryonic mouse – E10.5 Atrioventricular canal Outflow tract
Right ventricle Left ventricle CARDIACCARDIAC DEVELOPMENTDEVELOPMENT ♥ 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
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. Human embryo – Carnegie stage 13 Left atrium
Right atrium
Left ventricle
Right ventricle Right atrium Part of the ring marks the crest of the muscular ventricular septum
Right ventricle Left ventricle
Human embryo – Carnegie stage 16 Embryonic day 11.5
Still double outlet
Right atrium Developing right ventricle CARDIACCARDIAC DEVELOPMENTDEVELOPMENT ♥ The story thus far
♥ 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 Interventricular communication
Aortic root
Line of putative ventricular Left ventricle septation
Embryonic day 12.5 Previous interventricular communication
Line of putative ventricular septation Later on embryonic day 12.5 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
LA
Aorta
LV
RA
RV Tetralogy of Fallot Aortic root
Initial interventricular communication is now left ventricular outflow tract
End of embryonic day 12.5 End of embryonic day 12.5 Muscularising infundibulum
Tubercles fusing to wall aorta into left ventricle Embryonic day 15.5 Muscularised infundibulum
Membranous septum CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
PV LA
AV RV
RA LV
LV
RV CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 Distal
Intermediate
Proximal
Developing right ventricle Aortic sac
Distal OFT
Left atrium
Left ventricle
Mouse – early E11.5 Mouse – early E11.5 Parietal cushion
4
6
Non-myocardial walls Septal cushion Mouse – early E11.5
Intrapericardial Intrapericardial pulm. trunk aorta Mouse – mid E11.5 Aortopulmonary foramen
Intrapericardial aorta CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
Aorta
RAA LAA
Pulm. Aortic Pulm. valve valve valve Embryonic day 12.5 Pulmonary root Oblique cut through intermediate part of outflow tract
Aortic root
Right atrium Embryonic day 12.5
Pulmonary root
Cushions fused centrally
Unfused peripherally
Aortic root CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 Columns of condensed mesenchyme
Unfused proximal cushions Embryonic day 12.5 Mouse – day 13.5
Aorta
Right atrium Right ventricle
Closing interventricular foramen DEVELOPMENT OF OUTFLOW TRACT
Aortic sac DEVELOPMENT OF OUTFLOW TRACT
Intrapericardial arterial trunks
Valves & sinuses Extrapericardial arterial trunks Ventricular outflow tracts CARDIACCARDIAC DEVELOPMENTDEVELOPMENT ♥ 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 CARDIACCARDIAC DEVELOPMENTDEVELOPMENT
♥ 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 CARDIACThank you DEVELOPMENTfor your attention.