spectrum of malformations, ranging from severe anomalies incompatible with intrauterine or perinatal survival, to lesions that produce few or no symptoms, some of which go completely unrecognized during life. Congenital heart disease affects nearly 1% of newborns (or roughly 40,000 infants per year in the United States). The incidence is higher in premature infants and in stillborns, approximately one fourth of which have significant cardiac malformations. Defects that permit live birth usually involve only single chambers or regions of the heart. Twelve entities account for 85% of congenital heart disease; their frequencies are shown in
Table 11.1
Thanks to surgical advances, the number of patients surviving with congenital heart disease is increasing rapidly and is currently estimated at over 2 million individuals in the United States alone. Although surgery may correct the hemodynamic abnormalities, the repaired heart may not be completely normal, since the myocardial hypertrophy and cardiac remodeling brought about by the congenital defect may be irreversible; in addition, virtually all cardiac surgery results in some degree of myocardial scarring. Such changes can lead secondarily to arrhythmias and myocardial dysfunction, which occasionally appear many years after surgical correction.
Congenital heart disease most commonly arises from faulty embryogenesis during gestational weeks 3 through 8, when major cardiovascular structures develop. The cause is unknown in almost 90% of cases. Of the accepted etiologic factors, environmental exposures, including congenital rubella infection, teratogens, and maternal diabetes, and genetic factors are best characterized. Genetic factors include specific loci implicated in familial forms of congenital heart disease and certain chromosomal abnormalities (e.g., trisomies 13, 15, 18, and 21, and Turner syndrome).
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Cardiac morphogenesis involves multiple genes that work together to choreograph a complex series of tightly regulated events. Key steps include commitment of progenitor cells to the myocardial lineage, formation and looping of the heart tube, segmentation and growth of the cardiac chambers, cardiac valve formation, and connection of the great vessels to the heart. Proper orchestration of these remarkable transformations depends on networks of transcription factors and several signaling pathways and molecules, including the Wnt, vascular endothelial growth factor (VEGF), bone morphogenetic protein (BMP), transforming growth factor-β (TGF-β), fibroblast growth factor, and Notch pathways. Also essential for cardiac morphogenesis is the mechanical force imparted by flowing pulsatile blood, which is sensed by the cells of the developing heart and vessels.
Since crafting a normal heart involves many steps, even subtle perturbations can adversely influence the outcome. Most of the known genetic defects are autosomal dominant mutations causing loss (or sometimes gain) of function of a particular factor. Several mutations involve transcription factors. For example, atrial septal defects (ASDs) and ventricular septal defects (VSDs) and/or conduction defects may be caused by transcription factor mutations, such as TBX5 mutations in the Holt-Oram syndrome. Other disorders (e.g., Noonan syndrome) are associated with mutations in intracellular signaling cascades that cause constitutive activation. MicroRNAs, as well as epigenetic changes (e.g., DNA methylation), also are increasingly recognized as important contributors. It is likely that even transient environmental stresses at critical junctures early in pregnancy can cause subtle changes in transcription factor activity that may recapitulate defects produced by heritable mutations.
The various structural anomalies in congenital heart disease can be assigned to three major groups based on their hemodynamic and clinical consequences: (1) malformations causing a left-to-right shunt; (2) malformations causing a right-to-left shunt (cyanotic congenital heart diseases); and (3) malformations causing obstruction.