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
illnesses in the form of congenital heart defects. As the organ
most essential for life, the heart is the first organ to form and
functions to support the rapidly growing embryo before it becomes
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.
This phenomenon is reflected in the estimated 10% incidence
of severe cardiac malformations observed in early miscarriages.
The fraction of congenital heart malformations that are capable
of supporting the intrauterine circulation comprises the spectrum
of congenital heart disease observed clinically.
Although congenital heart disease was classified in the 18th
and 19th centuries based on embryologic considerations, the advent
of palliative procedures and clinical management led to a descriptive
nomenclature founded on anatomic and physiologic features that directed
surgery and medical therapy. However, seemingly unrelated defects
may share common embryologic origins from a mechanistic standpoint,
and thus the etiology of various defects may be better understood from
a developmental standpoint. Recent advances in genetics and molecular
biology have stimulated a renaissance in studies designed to define
an embryologic framework for understanding congenital heart disease.
The ability to go beyond descriptions of the anatomical defects
to developing an understanding of the genes responsible for distinct
steps of cardiac morphogenesis is necessary for more directed therapeutic
and preventive measures.
Although human genetic approaches are important in understanding
congenital heart disease, 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 has resulted in an explosion of information from
studies in more tractable and accessible biological models. Chemical
mutagenesis studies of the fruit fly (Drosophila) and of the simple vertebrate,
zebra fish, have resulted in the identification of many genes that
are required for normal cardiac development. Although genetic approaches
are not feasible in chick embryos, they have four-chambered hearts
and the embryos are easily accessible within the egg for surgical
and molecular manipulation during cardiogenesis. Such approaches
have been useful for defining the role of populations of cells during
development. Finally, the laboratory mouse, a mammal with a cardiovascular
system nearly identical to that in humans, has been an invaluable model
system for understanding the mechanisms underlying human disease.
Advances in technology have made it possible to mutate or to delete
specific genes in the mouse genome, either globally or in a tissue-specific
manner, and to study the effects of such mutations in mice heterozygous
or homozygous for the disrupted gene of interest. Thus, each biological
system offers unique opportunities to enhance understanding of cardiogenesis.
Mapping and identification of human congenital heart disease
genes is equally important. Correlation of particular amino ...