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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
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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.
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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 ...