Cardiac Development

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Chapter 414 Cardiac Development

Knowledge of the cellular and molecular mechanisms of cardiac development is necessary in understanding congenital heart defects and will be even more important in developing strategies for prevention, whether cell or molecular therapies or fetal cardiac interventional procedures. Cardiac defects have traditionally been grouped by common morphologic patterns: for example, abnormalities of the outflow tracts (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 be revised or eventually supplanted by new categories as our understanding of the genetic basis of congenital heart disease progresses.

414.1 Early Cardiac Morphogenesis

Daniel Bernstein

In the early presomite embryo, the 1st 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. 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. 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), the transcription factors Nkx2.5, GATA4, Mesp1, and Mesp2; and members of the Wnt/β-catenin signaling pathway. 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. Morphologists initially identified segments of the heart tube that were believed to correspond to structures in the mature heart (Web Fig. 414-1): 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). However, this model is oversimplified. 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). 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. The transcription factor eHAND is expressed in the developing left ventricle and conotruncus and is also critical to their development.

image

Web Figure 414-1 Timeline of cardiac morphogenesis.

(From Larsen WJ: Essentials of human embryology, New York, 1998, Churchill Livingstone.)

414.2 Cardiac Looping

Daniel Bernstein

At ≈22-24 days, the heart tube begins to bend ventrally and toward the right (see Web Fig. 414-1). The heart is the 1st 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). This pattern of development explains the relatively common occurrence of the cardiac anomalies double-outlet right ventricle and double-inlet left ventricle and the extreme rarity of double-outlet left ventricle and double-inlet right ventricle (Chapter 424.5). When cardiac looping is abnormal (situs inversus, heterotaxia), the incidence of serious cardiac malformations is high and there are usually associated abnormalities in the L-R patterning of the lungs and abdominal viscera.

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. A number of signaling pathways have been identified as regulators of this L-R asymmetry, including sonic hedgehog (Shh), transforming growth factor-β (TGF-β), nodal, and LR dynein. Interestingly, mice in which the LR dynein gene has been inactivated display random L-R orientation of the heart and abdominal viscera, with 50% of their hearts looping to the right and 50% looping to the left.