Congenital Heart Disease

Abstract

Sufficient progress has occurred in identifying, characterizing, and surgically repairing physiologically important congenital cardiac defects (which occur at the rate of 20,000/yr in the United States) that 85% of these infants can now expect to survive to adulthood. Since only the most severe structural malformations thwart current management schemes, prevention and early in utero detection are the remaining strategies to further reduce the impact of heart malformation on the health of infants and children; however, any prevention approach would depend largely on knowing the percentage of congenital heart defects that are genetic. For example, if the vast majority of congenital heart anomalies are due to intrauterine insults (infectious agents, toxins, mechanical stress, and so on) to the embryo during the first 30 days of gestation, then a prevention strategy would be ineffective; since most pregnancies are already monitored by ultrasound at least once for accurate dating, perhaps adding a “cardiac surveillance” portion to the imaging protocol would suffice to increase the chance of prenatal identification. However, evidence has begun to accumulate for the hypothesis that the majority of congenital heart malformations are due to gene alterations. Therefore, the scientific challenge of the next several decades will be to unravel the sequence of molecular decisions that result in the construction of the heart and blood vessels from the first embryonic tissue layers. Although more than 50 genes have already been reported to be involved in cardiovascular morphogenesis (Table 12-1), the way they function to form the heart and great vessels correctly (in space and time) remains obscure. Both forward and reverse genetic approaches are being tried, and a variety of organisms are being scrutinized since the underlying mechanisms of patterning appear to be widely shared among vertebrates. Murine cardiac development is difficult to study in vivo without new imaging techniques because of the relatively inaccessible embryo. Furthermore, a systematic screen of the mouse genome for embryonic lethal mutations affecting organogenesis is impractical. Other vertebrates such as the chick Gallus gallus and the African clawed frog Xenopus laevis have long generation times. The teleost fish Danio (formerly Brachydanio) rerio (zebrafish) has emerged as a model system because of its prolific egg production, rapid (90-d) generation time, optically transparent embryo, and extremely rapid heart development (48 h). Despite the advantages of the zebrafish system for mutational analysis, there are some aspects of cardiovascular construction, namely septation and pulmonary artery formation, that must be studied in higher vertebrates.