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Section 1 – Developmental Biology of the Cardiovascular System

Section 1 – Developmental Biology of the Cardiovascular System



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Published by Mended_Heart
A chapter in Nelson textbook of pediatrics,
Describes the development of the CVS,
it's fantastic, hOPE YOU LIKE IT.
enjoy reading.
A chapter in Nelson textbook of pediatrics,
Describes the development of the CVS,
it's fantastic, hOPE YOU LIKE IT.
enjoy reading.

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Published by: Mended_Heart on Jul 23, 2009
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Kliegman: Nelson Textbook of Pediatrics, 18thed.
Copyright ©2007 Saunders, An Imprint of Elsevier  
Part XIX – The Cardiovascular System
Section 1 – Developmental Biology of the Cardiovascular System
Daniel BernsteinChapter 420 – Cardiac Development
Knowledge of the cellular and molecular mechanisms of cardiac development is necessary inunderstanding congenital heart defects and developing strategies for prevention. Cardiac defectshave traditionally been grouped by common morphologic patterns: abnormalities of the outflowtracts (conotruncal lesions such as tetralogy of Fallot and truncus arteriosus) and abnormalities of atrioventricular septation (primum atrial septal defect, complete atrioventricular canal defect).These morphologic categories may not, however, provide an understanding of the mechanismsof genetic alterations that lead to congenital heart disease.
420.1 Early Cardiac Morphogenesis
In the early presomite embryo, the 1st identifiable cardiac precursors are angiogenetic cellclusters arranged on both sides of the embryo's central axis; these clusters form paired cardiactubes by 18 days of gestation. The paired tubes fuse in the midline on the ventral surface of theembryo to form the primitive heart tube by 22 days. Premyocardial cells, including epicardial cellsand 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 one cell type, with specificreceptors, usually expressed by another cell type. Positional information is conveyed to thedeveloping cardiac mesoderm by factors such as retinoids (isoforms of vitamin A), which bind tospecific nuclear receptors and regulate gene transcription. Migration of epithelial cells into thedeveloping heart tube is directed by extracellular matrix proteins (fibronectin) interacting with cellsurface receptors (the integrins). The importance of these ligands is noted 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 andexhibit phases of the cardiac cycle that are surprisingly similar to those in a mature heart.Morphologists have identified segments of the heart tube that were believed to correspond tostructures in a mature heart ( Fig. 420-1 ): the sinus venosus and atrium (right and left atria), theprimitive ventricle (left ventricle), the bulbus cordis (right ventricle), and the truncus arteriosus(aorta and pulmonary artery). This model is oversimplified. Only the trabecular (most heavilymuscularized) 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 alater stage (after looping is initiated). Even later to appear are the primordial cells that give rise tothe great arteries (truncus arteriosus), including cells derived from the neural crest, which are notpresent until after cardiac looping is complete. Chamber-specific transcription factors participatein the differentiation of the right and left ventricles. The basic helix-loop-helix 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 tohypoplasia of the right ventricle. The transcription factor eHAND is expressed in the developingleft ventricle and conotruncus and is also critical to their development.
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420.2 Cardiac Looping
22–24 days, the heart tube begins to bend ventrally and toward the right (see Fig. 420-1 )through as yet unknown biomechanical forces. Looping brings the future left ventricle leftwardand in continuity with the sinus venosus (future left and right atria), whereas the future rightventricle is shifted rightward and in continuity with the truncus arteriosus (future aorta andpulmonary artery). This pattern of development explains the relatively common occurrence of thecardiac anomalies double-outlet right ventricle and double-inlet left ventricle and the extremerarity of double-outlet left ventricle and double-inlet right ventricle (see Chapter 430.5 ). Cardiaclooping, one of the 1st manifestations of right-left asymmetry in the developing embryo, is criticalfor the successful completion of cardiac morphogenesis. When cardiac looping is abnormal, theincidence of serious cardiac malformations is high.Potential mechanisms of cardiac looping include differential growth rates for myocytes on theconvex 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 may be contained in a concentration gradient between the right
Figure 420-1
Timeline of cardiac morphogenesis.
(From Larsen WJ: Essentials of Human Embryology. New York, Churchill Livingstone, 1998.) 
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and left sides of the embryo by the expression of critical signaling molecules (tumor growthfactor-
family of peptide growth factors and signaling peptides such as Sonic hedgehog). Inmurine models of abnormal looping, one such defect resides in the dynein gene.
420.3 Cardiac Septation
When looping is complete, the external appearance of the heart is similar to that of a matureheart; internally, the structure resembles a single tube, although it now has several bulgesresulting in the appearance of primitive chambers. The common atrium (comprising both the rightand 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 thebulboventricular foramen. The distal portion of the bulbus cordis is connected to the truncusarteriosus via an outlet segment (the conus).The heart tube now consists of several layers of myocardium and a single layer of endocardiumseparated 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 (see Fig. 420-1 ).These cushions consist of protrusions of cardiac jelly, which, in addition to their role indevelopment, also serve a physiologic function as primitive heart valves. Endocardial cellsdedifferentiate 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 processinvolving undermining of the ventricular walls. Because this process occurs asymmetrically, thetricuspid valve annulus sits closer to the apex of the heart than the mitral valve annulus does.Physical separation of these two valves produces the atrioventricular septum, the absence of which is the primary common defect in patients with
atrioventricular canal defects
(see Chapter 426.5 ). If the process of undermining is incomplete, one of the atrioventricular valves may notseparate normally from the ventricular myocardium, a possible cause of 
Ebstein anomaly
(seeChapter 430.7 ).Septation of the atria begins at
30 days with growth of the septum primum downward toward theendocardial cushions (see Fig. 420-1 ). The orifice that remains is the ostium primum. Theendocardial cushions then fuse and, together with the completed septum primum, divide theatrioventricular canal into right and left segments. A 2nd opening appears in the posterior portionof the septum primum, the ostium secundum, and it allows a portion of the fetal venous return tothe right atrium to pass across to the left atrium. Finally, the septum secundum grows downward, just to the right of the septum primum. Together with a flap of the septum primum, the ostiumsecundum forms the foramen ovale, through which fetal blood passes from the inferior vena cavato the left atrium (see Chapter 421 ).Septation of the ventricles begins at about embryonic day 25 with protrusions of endocardium inboth the inlet (primitive ventricle) and outlet (bulbus cordis) segments of the heart. The inletprotrusions fuse into the bulboventricular septum and extend posteriorly toward the inferior endocardial cushion, where they give rise to the inlet and trabecular portions of theinterventricular septum. Ventricular septal defects can occur in any portion of the developinginterventricular septum (see Chapter 426.6 ). The outlet or conotruncal septum develops fromridges of cardiac jelly, similar to the atrioventricular cushions. These ridges fuse to form a spiralseptum that brings the future pulmonary artery into communication with the anterior andrightward right ventricle and the future aorta into communication with the posterior and leftwardleft ventricle. Differences in cell growth of the outlet septum lead to lengthening of the segment of smooth muscle beneath the pulmonary valve (conus), a process that separates the tricuspid andpulmonary valves. In contrast, disappearance of the segment beneath the aortic valve leads tofibrous continuity of the mitral and aortic valves. Defects in these processes are responsible for 
aortic arch defects
(truncus arteriosus, tetralogy of Fallot, pulmonary atresia,double-outlet right ventricle, interrupted aortic arch), a group of cardiac anomalies oftenassociated with deletions of the DiGeorge critical region of chromosome 22q11 (see Chapters
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