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Knowledge of the role of cardiac-specific genes and their modulating factors has increased tremendously over the last decade, although 85% of human congenital cardiovascular disease is still considered to be multifactorial in origin. Advances in the molecular biology of the developing heart have greatly contributed to our understanding of cardiac morphogenesis. Manipulation of conserved genes from a variety of model organisms has increased our understanding of how genetic factors and cellular interactions contribute to cardiac development. Transgenic mouse models have allowed time-specific tracing of cells and their role in heart formation. The problem of embryo-lethality after manipulating “cardiac-specific” genes has been overcome by inducible knockout strategies. Whole genome sequencing programs have also increased understanding of mutations in humans that lead to congenital cardiovascular disease.

This chapter summarizes the initial phases of cardiac development. We then describe in more detail how cardiac morphogenesis leads to formation of the four-chambered heart and how abnormal cardiogenesis contributes to congenital cardiovascular disease.


Heart development starts with two cardiogenic plates derived from the lateral splanchnic mesoderm. These plates fuse in the midline in the anterior (cranial) region of the embryo. The crescent of the cardiogenic plates is referred to as the first heart field (FHF) and is flanked medially by the second heart field (SHF) mesoderm (Figure 1A). Upon fusion in the midline, the FHF forms the two-layered primary heart tube with myocardium on the outside lined by endocardium on the inside. The myocardium secretes a glycoprotein-rich layer, the cardiac jelly, toward the endocardium. The primary heart tube connects to the arterial pole cranially and to the venous pole caudally (Figure 1-1B) but does not contain all segments of the four-chambered heart. Venous tributaries abut on the small atrial component, followed downstream by the future atrioventricular canal and a primitive left ventricle. Finally, the outflow tract connects to the aortic sac at the arterial pole (Figure 1-1C). The various components can be distinguished soon after, as both the AV canal and the outflow tract contain an increasing amount of cardiac jelly that forms the endocardial cushions. The cushions become even more prominent as they acquire mesenchymal cells, derived from the endocardial lining as a result of endocardial-mesenchymal transition. Subsequently, the primary heart tube starts the developmentally determined rightward looping.


Cardiac development. A. Schematic depiction of the precardiac mesoderm in the primitive plate. The brown area reflects the mesoderm of the FHF, whereas the yellow area corresponds to the putative SHF mesoderm. B. Primary heart tube derived of FHF mesoderm. The tube consists of myocardium, lined by cardiac jelly. C. Heart tube after looping. The yellow areas reflect SHF-derived contributions. The SHF contributions to the outflow tract have not been depicted. Note that in this stage the atria are still positioned ...

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