Development of the Cardiovascular System
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. 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. 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.
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. 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 has resulted in an explosion of information from studies in more tractable and accessible biologic models. These include fruit flies, zebrafish, chicks, and mice as model systems. Clinical lessons combined with experimental studies in mice, fish, and flies have led to a model, suggesting that unique regions of the heart have been added from distinct fields of progenitor cells in a modular fashion during evolution. In this model, defects in particular regions of the heart arise from unique genetic and environmental effects on distinct cell lineages during developmental windows of time. In addition to the classic review of cardiac development by Dehaan in 1966, more recent publications provide additional details into anatomic events that are required for normal cardiac morphogenesis.
ORIGIN OF CARDIOMYOCYTE PRECURSORS
The more recent discovery of distinct pools of progenitors that contribute to individual chambers or ...