Development of heart

development of heart

1. Dr.Nandimalla Vinay kumar Junior resident Dept. of pediatrics Developmental of the Heart

2. Early Cardiac Morphogenesis In the early presomite embryo, the first identifiable cardiac progenitor cell clusters are arranged in the anterior lateral plate mesoderm on both sides of the embryo’s central axis; these clusters form paired cardiac tubes by 18 days of gestation. The paired tubes fuse in the midline on the ventral surface of the embryo to form the primitive heart tube by 22 days . This straight heart tube is composed of an outer myocardial layer , an inner endocardium , and a middle layer of extracellular matrix known as the cardiac jelly.

3. Cardiogenic Area

4. There are 2 distinct cell lineages: the primary heart field provides precursor cells for the left ventricle , whereas the secondary heart field provides precursors for the atria and right ventricle . Premyocardial cells , including epicardial cells and cells derived from the neural crest , continue their migration into the region of the heart tube. Regulation of this early phase of cardiac morphogenesis is controlled in part by the interaction of specific signaling molecules or ligands , usually expressed by 1 cell type, with specific receptors, usually expressed by another cell type.

5. Positional information is conveyed to the developing cardiac mesoderm by factors such as retinoids ( isoforms of vitamin A), which bind to specific nuclear receptors and regulate gene transcription . Migration of epithelial cells into the developing heart tube is directed by extracellular matrix proteins (such as fibronectin ) interacting with cell surface receptors (the integrins ). Other important regulatory molecules include bone morphogenetic protein 2 (BMP2); fibroblast growth factor 4 ( FGF4).

6. The clinical importance of these ligands is revealed by the spectrum of cardiac teratogenic effects caused by the retinoid-like drug isotretinoin . As early as 20-22 days , before cardiac looping, the embryonic heart begins to contract and exhibit phases of the cardiac cycle that are surprisingly similar to those in the mature heart.

7. Morphologists initially identified segments of the heart tube that were believed to correspond to structures in the mature heart : the sinus venosus and atrium (right and left atria), the primitive ventricle (left ventricle), the bulbus cordis (right ventricle), and the truncus arteriosus (aorta and pulmonary artery ). Only the trabecular (most heavily muscularized ) portions of the left ventricular myocardium are present in the early cardiac tube; the cells that will become the inlet portion of the left ventricle migrate into the cardiac tube at a later stage (after looping is initiated).

8. Five dilatations of heart tube Truncus Arteriosus Bulbus Cordis Primitive Ventricle Primitive Atrium Sinus Venosus

9. Even later to appear are the primordial cells that give rise to the great arteries ( truncus arteriosus ), including cells derived from the neural crest, which are not present until after cardiac looping is complete. Chamber-specific transcription factors participate in the differentiation of the right and left ventricles . The basic helix-loop-helix ( bHLH ) transcription factor dHAND is expressed in the developing right ventricle; disruption of this gene or of other transcriptional factors such as myocyte enhancer factors 2C (MEF2C ) in mice leads to hypoplasia of the right ventricle.

10. The transcription factor eHAND is expressed in the developing left ventricle and conotruncus and is also critical to their development.

11. Cardiac Looping At approximately 22-24 days , the heart tube begins to bend ventrally and toward the right. The heart is the first organ to escape from the bilateral symmetry of the early embryo . Looping brings the future left ventricle leftward and in continuity with the sinus venosus (future left and right atria), whereas the future right ventricle is shifted rightward and in continuity with the truncus arteriosus (future aorta and pulmonary artery).

12. Formation of Cardiac Loop (lateral view)

13. Formation of Cardiac Loop

14. Potential mechanisms of cardiac looping include differential growth rates for myocytes on the convex vs the concave surface of the curve, differential rates of programmed cell death (apoptosis), and mechanical forces generated within myocardial cells via their actin cytoskeleton . The signal for this directionality is contained in a concentration gradient between the right and left sides of the embryo in the expression of critical signaling molecules.

15. A number of signaling pathways have been identified as regulators of this L-R asymmetry, including sonic hedgehog (SHH), transforming growth factor-β, nodal , and LR dynein .

16. Cardiac Septation When looping is complete, the external appearance of the heart is similar to that of a mature heart; internally, the structure resembles a single tube, although it now has several bulges resulting in the appearance of primitive chambers. The common atrium (comprising both the right and left atria) is connected to the primitive ventricle (future left ventricle ) via the atrioventricular canal. The primitive ventricle is connected to the bulbus cordis (future right ventricle) via the bulboventricular foramen . The distal portion of the bulbus cordis is connected to the truncus arteriosus via an outlet segment (the conus ).

17. The heart tube now consists of several layers of myocardium and a single layer of endocardium separated by cardiac jelly, an acellular extracellular matrix secreted by the myocardium . Septation of the heart begins at approximately day 26 with the ingrowth of large tissue masses , the endocardial cushions, at both the atrioventricular and conotruncal junctions.

18. Endocardial cells dedifferentiate and migrate into the cardiac jelly in the region of the endocardial cushions, eventually becoming mesenchymal cells that will form part of the atrioventricular valves . Complete septation of the atrioventricular canal occurs with fusion of the endocardial cushions . Most of the atrioventricular valve tissue is derived from the ventricular myocardium in a process involving undermining of the ventricular walls.

19. Because this process occurs asymmetrically , the tricuspid valve annulus sits closer to the apex of the heart than the mitral valve annulus does . Physical separation of these 2 valves produces the atrioventricular septum, the absenceof which is the primary common defect in patients with atrioventricular canal defects .

20. FORMATION OF INTERATRIAL SEPTUM Septation of the atria begins at ≈30 days with growth of the septum primum downward toward the endocardial cushions.The orifice that remains is the ostium primum . The endocardial cushions then fuse and, together with the completed septum primum , divide the atrioventricular canal into right and left segments. A 2 nd opening appears in the posterior portion of the septum primum , the ostium secundum , and it allows a portion of the fetal venous return to the right atrium to pass across to the left atrium.

21. Finally, the septum secundum grows downward, just to the right of the septum primum . Together with a flap of the septum primum , the ostium secundum forms the foramen ovale , through which fetal blood passes from the inferior vena cava to the left atrium.

22. FORMATION OF INTERVENTRICULAR SEPTUM Septation of the ventricles begins at about embryonic day 25 . it consists of 3 parts -a)muscular part.-from the floor of ventricle b) bulbar part-from lt and rt bulbar ridges c)membranous part.-from av cushions and ridges

23. interventricular septum

24. formation of aorticopulmonary septum it is the spiralseptum divides aorta and pulmonary trunk. it develops from two truncal ridges which develop due to proliferation of mesenchymal cells derived from neural crest cells that migrate in the walls of truncus arteriosus near the conus. these truncal ridges grow and fuse to form spiral septum.

25. Development of Heart valves Atrio ventricular valves 2 in number Tricuspid and mitral valves. formed by subendocardial mesenchyme proliferation that project in to AV canal as swellings. free margins of ventricular surfaces of valves connected to papillary muscles through chordae tendinae.

26. formation of AV valves

27. pulmonary and aortic valves They develop from endocardial cushions that are formed at the jnction of truncus and conus.

28. conducting system of the heart The conducting system of the heart consists of four components: 1. SA node (pacemaker of the heart) 2. AV node. 3. Bundle of His. 4. Purkinje fibers. 1. SA node: Sinoatrial node develops during the fifth week of IUL. Initially, it is located in the right wall of the sinus venosus, but when the sinus venosus is incorporated (absorbed) into the right atrium then it comes to lie in the wall of the right atrium near the opening of the superior vena cava.

29. AV node and AV bundle of His : They are derived from cells in the left wall of the sinus venosus and AV canal. After incorporation of sinus venosus into the right atrium (vide supra), these cells come to lie on the base of interatrial septum just anterior to the opening of coronary sinus. Here these cells form AV node and AV bundle of His. purkinje fibers : The fibers arising from AV bundle pass from atrium into the ventricle and split into right and left bundle branches. The branches from these bundles are distributed throughout the ventricular myocardium and are termed Purkinje fibers.

30. Formation of Pericardium The pericardium consists of two components: (a) serous pericardium and (b) fibrous pericardium. The serous pericardium consists of two layers: (a) visceral layer and (b) parietal layer. Visceral layer of serous pericardium is derived from splanchnopleuric mesoderm lining the dorsal side of the pericardial cavity. Parietal layer of serous pericardium and fibrous pericardium is derived from somatopleuric mesoderm lining the ventral side of the pericardial cavity.

31. Aortic Arch Development The aortic arch, head and neck vessels, proximal pulmonary arteries, and ductus arteriosus develop from the aortic sac, arterial arches, and dorsal aortae . When the straight heart tube develops, the distal outflow portion bifurcates into the right and left 1st aortic arches, which join the paired dorsal aortae .

32. The left dorsal aorta will form the descending aorta. The proximal aorta from the aortic valve to the left carotid artery arises from the aortic sac. The 1st and 2nd arches largely regress by about 22 days, with the 1st aortic arch giving rise to the maxillary artery and the 2nd to the stapedial and hyoid arteries .

33. The 3rd arches participate in the formation of the innominate artery and the common and internal carotid arteries . The right 4th arch gives rise to the innominate and right subclavian arteries , and the left 4 th arch participates in formation of the segment of the aortic arch between the left carotid artery and the ductus arteriosus . The 5th arch does not persist as a major structure in the mature circulation

34. The 6th arches join the more distal pulmonary arteries, with the right 6th arch giving rise to a portion of the proximal right pulmonary artery and the left 6th arch giving rise to the ductus arteriosus .

35. Cardiac Differentiation The process by which the totipotential cells of the early embryo become committed to specific cell lineages is differentiation. Precardiac mesodermal cells differentiate into mature cardiac muscle cells with an appropriate complement of cardiac-specific contractile elements, regulatory proteins, receptors, and ion channels.

36. Expression of the contractile protein myosin occurs at an early stage of cardiac development, even before fusion of the bilateral heart primordia . Differentiation in these early mesodermal cells is regulated by signals from the anterior endoderm, a process known as induction. Several putative early signaling molecules include fibroblast growth factor, activin , and insulin.

37. Signaling molecules interact with receptors on the cell surface; thesereceptors activate 2nd messengers, which, in turn, activate specific nuclear transcription factors (GATA-4, MEF2, Nkx , bHLH , and the retinoic acid receptor family) that induce the expression of specific gene products to regulate cardiac differentiation. Some of the primary disorders of cardiac muscle, the cardiomyopathies , may be related to defects in some of these signaling molecules

38. Developmental processes are chamber specific. Early in development, ventricular myocytes express both ventricular and atrial isoforms of several proteins, such as atrial natriuretic peptide (ANP) and myosin light chain (MLC). Mature ventricular myocytes do not express ANP and express only a ventricular-specific MLC 2v isoform , whereas mature atrial myocytes express ANP and an atrial -specific MLC 2a isoform .

39. Heart failure volume overload, and pressure overload hypertrophy are associated with a recapitulation of fetal cell phenotypes in which mature myocytes reexpress fetal proteins. Because different isoforms have different contractile behavior (fast vs. slow activation, high vs. low adenosine triphosphatase activity), expression of different isoforms have important functional consequences.

40. The extent to which stem cells can be made to differentiate into cardiac muscle cells is the focus of investigation in the field of regenerative cardiology. The demonstration that fully differentiated adult cells (e.g., skin fibroblasts or peripheral blood mononuclear cells) can be reprogrammed into induced pluripotential stem cells and then differentiated into beating cardiomyocytes in vitro, has opened up many new avenues to study cardiovascular disease.

41. Some investigators believe that there are precursor cells (cardiac stem cells) reside within the myocardium that can replace damaged myocytes , although at a rate too slow to be clinically useful. Scientists are working on trying to stimulate these cells with the proper regulatory factors, thus inducing them to regenerate damaged cardiac muscle.

42. Others are investigating whether circulating stem cells, bone marrow–derived cells, or the factors they secrete can support cardiac regeneration. cells grown on biomechanical scaffolds may be used to build a replacement ventricle for patients with hypoplastic left or right heart.

43. Thank you