CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT

Transcription

1 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.

2 CARDIAC DEVELOPMENT What s new? CARDIAC DEVELOPMENT 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

3 CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT 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

4 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

5 Mouse embryo 9 somites Myosin LC

6 Growth at arterial pole Putative left ventricle Growth at venous pole Mouse embryo E8.5 9 somites

7 Outflow tract Developing left ventricle Developing right ventricle Atrioventricular canal Mouse embryo E somites Atrial component

8 CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT 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

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10 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

11 Morphologically left Morphologically right Mouse embryo E8.5 9 somites

12 L L R R R L Mouse embryo E somites

13 Mouse embryonic day 13.5

14 Pitx2 Knock-out mouse Bilateral morphologically right appendages

15 Lefty-1 Knock-out mouse Bilateral morphologically left appendages

16 CARDIAC DEVELOPMENT 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

17 What about the venoatrial connections? CARDIAC DEVELOPMENT 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

18 Mouse embryo 13 somites Primary atrium

19 Mouse embryo 13 somites Gut Dorsal mesocardium Right sinus horn Left sinus horn

20 Mouse embryonic day 10.5 Left atrium Right atrium Venous valves

21 Mouse embryonic day 11.5 Left atrium Left ventricle Left sinus horn

22 CARDIAC DEVELOPMENT 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

23 Systemic venous sinus to right atrium Mouse embryo Embryonic day 10.5 Opening of pulmonary vein

24 SVS LSH Human embryo Carnegie stage 14 Coloured to show NKX 2.5

25 SVS LSH Human embryo Carnegie stage 14 Coloured to show TBX 18

26 Human embryo Carnegie stage 14 Left atrium Left sinus horn

27 Pulmonary venous component Left superior caval vein Left atrium Human embryo post-septation

28 CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT 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 anteroinferior buttress of the atrial septum

29 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

30 Secondary foramen Primary septum Mesenchymal cap Primary foramen Systemic venous sinus Inferior AV cushion Mouse - Embryonic day 11.5

31 Vestibular spine Primary septum Mesenchymal cap Primary foramen Inferior AV cushion Mouse - Embryonic day 11.5

32 Vestibular spine Pulmonary vein Mouse - Embryonic day 11.5

33 Mouse - Embryonic day 13.5 Secondary foramen Primary septum Vestibular spine Mesenchymal cap Inferior AV cushion Superior AV cushion

34 Breakdown at atrial roof Primary septum Oval foramen Secondary septum Mouse - Embryonic day 14.5

35 Primary septum & cap Growth of primary septum Cranial perforations Primary foramen Reducing primary foramen Systemic venous sinus to right Dorsal mesocardium Pulmonary vein

36 Growth of vestibular spine Breakdown cranially Primary septum Superior interatrial fold Oval foramen Closure of primary foramen Oval fossa Anteroinferior buttress

37 CARDIAC DEVELOPMENT Right pulmonary veins Left pulmonary veins Superior interatrial fold Anterior-inferior muscular buttress Oval fossa Mitral valve Tricuspid valve

38 CARDIAC DEVELOPMENT ASD - Secundum type Vestibular ASD MV MV TV TV

39 CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT 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

40 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

41 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

42 Outflow tract Developing left ventricle Developing right ventricle Atrioventricular canal Mouse embryo E somites Atrial component

43 Embryonic mouse E10.5 Outflow tract Atrioventricular canal Right ventricle Left ventricle

44 Ventricular septation CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT 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:

45 Human embryo Carnegie stage 13 Left atrium Right atrium Left ventricle Right ventricle

46 Right atrium Part of the ring marks the crest of the muscular ventricular septum Right ventricle Left ventricle Human embryo Carnegie stage 16

47 Embryonic day 11.5 Still double outlet Right atrium Developing right ventricle

48 CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT 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

49 Interventricular communication Aortic root Line of putative ventricular septation Left ventricle Embryonic day 12.5

50 Previous interventricular communication Line of putative ventricular septation Later on embryonic day 12.5

51 CARDIAC DEVELOPMENT LA Aorta LV RA Tetralogy of Fallot RV

52 Aortic root Initial interventricular communication is now left ventricular outflow tract End of embryonic day 12.5

53 End of embryonic day 12.5 Muscularising infundibulum Tubercles fusing to wall aorta into left ventricle

54 Embryonic day 15.5 Muscularised infundibulum Membranous septum

55 CARDIAC DEVELOPMENT 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

56 CARDIAC DEVELOPMENT LA PV RV AV RA LV LV RV

57 CARDIAC DEVELOPMENT CARDIAC DEVELOPMENT 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

58 Distal Intermediate Proximal Developing right ventricle

59 Aortic sac Distal OFT Left atrium Left ventricle Mouse early E11.5

60 Mouse early E11.5 Parietal cushion 4 6 Non-myocardial walls Septal cushion

61 Mouse early E11.5 Intrapericardial aorta Intrapericardial pulm. trunk

62 Mouse mid E11.5 Aortopulmonary foramen Intrapericardial aorta

63 CARDIAC DEVELOPMENT 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

64 CARDIAC DEVELOPMENT Aorta RAA LAA Pulm. valve Aortic valve Pulm. valve

65 Embryonic day 12.5 Oblique cut through intermediate part of outflow tract Pulmonary root Aortic root Right atrium

66 Embryonic day 12.5 Pulmonary root Cushions fused centrally Unfused peripherally Aortic root

67 CARDIAC DEVELOPMENT 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

68 Aortic root Columns of condensed mesenchyme Unfused proximal cushions Embryonic day 12.5

69 Mouse day 13.5 Aorta Right atrium Right ventricle Closing interventricular foramen

70 DEVELOPMENT OF OUTFLOW TRACT Aortic sac

71 DEVELOPMENT OF OUTFLOW TRACT Intrapericardial arterial trunks Extrapericardial arterial trunks Valves & sinuses Ventricular outflow tracts

72 CARDIAC DEVELOPMENT 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

73 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

74 Thank you for your attention. CARDIAC DEVELOPMENT