section 1 – developmental biology of the cardiovascular system

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Kliegman: Nelson Textbook of Pediatrics, 18th ed.Copyright 2007 Saunders, An Imprint of Elsevier

Part XIX The Cardiovascular System

Section 1 Developmental Biology of the Cardiovascular System

Daniel Bernstein

Chapter 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 ofatrioventricular 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 ofspecific 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 ofcardiac teratogenic effects caused by the retinoid-like drug isotretinoin.

As early as 2022 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 factordHAND is expressed in the developing right ventricle; disruption of this gene or of othertranscriptional 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

At 2224 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 mature

heart; 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 atrioventricularcanal. 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 in

development, 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 ofwhich is the primary common defect in patients with atrioventricular canal defects (see Chapter426.5 ). If the process of undermining is incomplete, one of the atrioventricular valves may notseparate normally from the ventricular myocardium, a possible cause ofEbstein anomaly (see

Chapter 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 inferiorendocardial 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 ofsmooth 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 to

fibrous continuity of the mitral and aortic valves. Defects in these processes are responsible forconotruncal and 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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423 and 424 ). The transcription factor Tbx1 has been implicated as a candidate gene, whichmay be responsible for DiGeorge syndrome.

420.4 Aortic Arch Development

The aortic arch, head and neck vessels, proximal pulmonary arteries, and ductus arteriosusdevelop 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 jointhe paired dorsal aortae ( Fig. 420-2 ). The dorsal aortae will fuse to form the descending aorta.The proximal aorta from the aortic valve to the left carotid artery arises from the aortic sac. The1st and 2nd arches largely regress by about 22 days, with the 1st aortic arch giving rise to themaxillary artery and the 2nd to the stapedial and hyoid arteries. The 3rd arches participate in theformation of the innominate artery and the common and internal carotid arteries. The right 4tharch gives rise to the innominate and right subclavian arteries, and the left 4th arch participates information of the segment of the aortic arch between the left carotid artery and the ductusarteriosus. The 5th arch does not persist as a major structure in the mature circulation. The 6tharches join the more distal pulmonary arteries, with the right 6th arch giving rise to a portion ofthe proximal right pulmonary artery and the left 6th arch giving rise to the ductus arteriosus. Theaortic arch between the ductus arteriosus and the left subclavian artery is derived from the left-

sided dorsal aorta, whereas the aortic arch distal to the left subclavian artery is derived from thefused right and left dorsal aortae. Abnormalities in development of the paired aortic arches areresponsible forright aortic arch, double aortic arch, and vascular rings (see Chapter 432.1 ).

420.5 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 musclecells with an appropriate complement of cardiac-specific contractile elements, regulatory proteins,receptors, and ion channels. Expression of the contractile protein myosin occurs at an early stageof cardiac development, even before fusion of the bilateral heart primordia. Differentiation in

Figure 420-2 Schematic drawings illustrating the changes that result during transformation of the truncus arteriosus, aortic

sac, aortic arches, and dorsal aortae into the adult arterial pattern. The vessels that are not shaded or colored are not derived

from these structures. A, Aortic arches at 6 wk; by this stage the 1st two pairs of aortic arches have largely disappeared. B,

Aortic arches at 7 wk; the parts of the dorsal aortae and aortic arches that normally disappear are indicated by broken lines. C,

Arterial vessels of a 6 mo old infant. (From Moore KL, Persaud TVN, Torchia M: The Developing Human. Philadelphia,

Elsevier, 2007.)




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these early mesodermal cells is regulated by signals from the anterior endoderm, a processknown as induction. Several putative early signaling molecules include fibroblast growth factor,activin, and insulin. 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 ofspecific gene products to regulate cardiac differentiation. Some of the primary disorders ofcardiac muscle, the cardiomyopathies, may be related to defects in some of these signaling

molecules (see Chapter 439 ).

Developmental processes are chamber specific. Early in development, ventricular myocytesexpress 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 andexpress only a ventricular-specific MLC 2v isoform, whereas mature atrial myocytes express ANPand an atrial-specific MLC 2a isoform. Heart failure (see Chapter 442 ), volume overload (seeChapters 426 and 428 ), and pressure overload hypertrophy (see Chapter 427 ) are associatedwith a recapitulation of fetal cell phenotypes in which mature myocytes re-express fetal proteins.Because different isoforms have different contractile behavior (fast vs slow activation, high vs lowadenosine triphosphatase activity), expression of different isoforms may have importantfunctional consequences.

The extent to which stem cells can be made to differentiate into cardiac muscle cells is the focusof investigation in the field of regenerative cardiology. Some investigators believe that cardiacprecursor cells known as cardiomyoblasts can replace damaged myocytes and, if stimulated withthe proper regulatory factors, could be induced to regenerate cardiac muscle. Others believe thatcirculating stem cells or bone marrowderived cells may support cardiac regeneration.

420.6 Developmental Changes in Cardiac Function

During development, the composition of the myocardium undergoes profound changes that resultin an increase in the number and size of myocytes. During prenatal life, this process involvesmyocyte division (hyperplasia), whereas after the 1st few postnatal weeks, subsequent cardiac

growth occurs by an increase in myocyte size (hypertrophy). The myocytes themselves changeshape from round to cylindrical, the proportion of myofibrils (which contain the contractileapparatus) increases, and the myofibrils become more regular in their orientation.

The plasma membrane (known as the sarcolemma in myocytes) is the location of the ionchannels and transmembrane receptors that regulate the exchange of chemical information fromthe cell surface to the cell interior. Ion fluxes through these channels control the processes ofdepolarization and repolarization. Developmental changes have been described for the sodium-potassium pump, the sodium-hydrogen exchanger, and voltage-dependent calcium channels. Asthe myocyte matures, extensions of the sarcolemma develop toward the interior of the cell (the t-tubule system), which dramatically increases its surface area and enhances rapid activation ofthe myocyte. Regulation of the membrane's - and -adrenergic receptors with development

enhances the ability of the sympathetic nervous system to control cardiac function as the heartmatures.

The sarcoplasmic reticulum (SR), a series of tubules surrounding the myofibrils, controls theintracellular calcium concentration. A series of pumps regulate calcium release to the myofibrilsfor initiation of contraction (ryanodine-sensitive calcium channel) and calcium uptake for initiationof relaxation (adenosine triphosphatedependent SR calcium pump). In immature hearts, this SRcalcium transport system is less well developed, and such hearts consequently have anincreased dependence on transport of calcium from outside the cell for contraction. In a matureheart, the majority of the calcium to activate contraction comes from the SR. This developmentalphenomenon may explain the sensitivity of the infant heart to sarcolemmal calcium channelblockers such as verapamil, which often results in a marked depression in contractility and

cardiac arrest (see Chapter 435 ).

The major contractile proteins (myosin, actin, tropomyosin, and troponin) are organized into thefunctional unit of cardiac contraction, the sarcomere. Each has several isoforms that are




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expressed differentially by location (atrium vs ventricle) and by developmental stage (embryo,fetus, newborn, adult).

Changes in myocardial structure and myocyte biochemistry result in easily quantifiabledifferences in cardiac function with development. Fetal cardiac function is poorly responsive tochanges in both preload (filling volume) and afterload (systemic resistance). The most effectivemeans of increasing ventricular function in a fetus is through increasing the heart rate. After birth

and with further maturation, preload and afterload play an increasing role in regulating cardiacfunction. The rate of cardiac relaxation is also developmentally regulated. The decreased abilityof the immature SR calcium pump to remove calcium from the contractile apparatus ismanifested as a decreased ability of the fetal heart to enhance relaxation in response tosympathetic stimulation. This inability of the immature myocardium to use preload effectively maypartly explain the difficulty that most premature infants have in compensating for the left-to-rightshunt through a patent ductus arteriosus (see Chapters 101.4 and 426.8 ).

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section 1 – developmental biology of the cardiovascular system

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