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The wide spectrum of congenital cardiovascular anomalies found from the prenatal period into adulthood has challenged clinicians and scientists for centuries.1-6 The goal of this chapter is to present a highly condensed overview of our current understanding of the normal development of the vertebrate heart and vasculature and to illustrate how this knowledge allows us to begin to define the pathogenesis of congenital cardiovascular malformations. Critical insights into the molecular regulation of vertebrate heart development and the origins of congenital heart disease have come from the investigation of species with much simpler "cardiac" structures, including the pulsatile dorsal vessel in the fly, the two-chambered hearts of zebrafish, and the three-chambered hearts of amphibians. The evolutionary addition of critical cardiac features, including cardiac valves, a high-pressured ventricle, and septation of the atria, ventricles, and outflow tract, is associated with expanded molecular complexity and redundancy.7 Although many of the mechanisms that lead to the fully septated, four-chambered vertebrate heart are interdependent, they are presented in separate sections for clarity. This chapter focuses on human development; however, numerous lower vertebrate and invertebrate animal models are accelerating our identification of the genetic and epigenetic regulation of normal and aberrant cardiovascular morphogenesis.7-12

Embryo Patterning and Laterality

The initial molecular programming for cardiac morphogenesis is thought to be established at the earliest stage of development with determination of the three axes of the embryo: anteroposterior, dorsoventral, and left-right. Specific genes have been identified that alter axis determination in a range of species including the mouse, frog, and chicken.13,14 After determination of the embryo axes, subpopulations of cells (somites) are programmed in a segmental body plan controlled at the molecular level by a segmentation clock and gradients of signaling molecules.15-18 In mammals, maternal gene products control the cell through the first two cell cycles; then control switches to the embryonic genome.

The process of mesoderm formation is integral to the organization of the primary axis of the embryo and the differentiation of right and left sides. At the blastodisk stage of development, there are two primitive germ layers: endoderm and ectoderm. The endoderm layer then splits into splanchnic and visceral layers, with interposed mesodermal cells (Fig. 9–1). Mesoderm is formed as ectodermal cells migrate through the primitive streak coursing adjacent to the Hensen node, and lateral plate precardiac mesodermal cells migrate to form the heart and great vessels. The Hensen node contains retinoic acid and serves as an embryonic organizer that confers information required to direct the ultimate fate of these mesodermal cells.19 At this critical phase in cell determination, exogenous retinoic acid is extremely teratogenic, with the greatest effect at the arterial pole and the least effect at the venous pole.20

Figure 9–1.

This figure illustrates the postgastrulation morphogenetic events involved in the formation of the tubular heart. ...

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