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Cardiogenesis involves a precisely orchestrated series of molecular and morphogenetic events that combines cell types from multiple lineages. Subtle perturbations of this process can result in life-threatening congenital heart defects (CHDs). As an organ essential for life, the heart is the first organ to form and must support the rapidly growing embryo before it has the opportunity to become a four-chambered organ. The combination of the complex morphogenetic events necessary for cardiogenesis and the superimposed hemodynamic influences may contribute to the exquisite sensitivity of the heart to perturbations as reflected in the estimated 10% incidence of severe cardiac malformations observed in early miscarriages. The fraction of congenital heart malformations that are compatible with development composes the spectrum of CHD observed clinically in nearly 1% of live births.1 An additional 1% to 2% of the population harbor more subtle cardiac developmental anomalies that only become apparent as age-dependent phenomena reveal the underlying pathology. With more than 1 million survivors of congenital heart disease (CHD) in the United States, it is becoming apparent that genetic disruptions that predispose to developmental defects can have ongoing consequences in maintenance of specific cell types and cellular processes over decades.2 A more precise understanding of the causes of CHD is imperative for the recognition and potential intervention of progressive degenerative conditions, such as heart failure, among survivors of CHD. Deciphering nature’s secrets of heart formation might lead to novel approaches to repair or regenerate damaged heart muscle. The potential of stem cells in regenerative medicine is enormous, and insights into the natural process of cardiogenesis from progenitor cells during embryogenesis will form the basis of reprogramming cells for therapeutic use.3


The anatomic features of most CHD in humans have been carefully cataloged. Although CHD was classified in the 19th century based on embryologic considerations, the advent of palliative procedures and clinical management led to a descriptive nomenclature founded on anatomic and physiologic features that governed surgical and medical therapy. However, seemingly unrelated CHD could be argued to share common embryologic origins from a mechanistic standpoint, suggesting that the etiology of CHD may be better understood by considering their developmental bases. More recent advances in genetics and molecular biology have stimulated a renaissance in seeking an embryologic framework for understanding CHD as alterations and null mutations in a wide array of genes have targeted the heart and vascular system and established abnormalities in cardiovascular ontogeny as a primary cause of embryonic demise.4,5 The ability to go beyond descriptions of the anatomic defects to developing an understanding of the genes responsible for distinct steps of cardiac morphogenesis has raised the prospects that the future of pediatric cardiology will involve more directed therapeutic and preventive measures.


Although human genetic approaches have been important in understanding CHD, detailed molecular analysis of cardiac development in humans has been difficult. The recognition that cardiac genetic pathways are highly conserved across vastly diverse species from flies to man ...

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