Controlled cell death is an important molding process in the embryonic heart. Ebstein malformation and muscular ventricular septal defect have been postulated to arise from abnormalities in cell death. The tricuspid valve cusps are almost exclusively derived from the interior of the embryonic right ventricular myocardium by a process of undermining of the right ventricular wall.
Abnormalities of this process of reabsorption of ventricular myocardium may lead to the Ebstein malformation with displacement of the functional tricuspid valve annulus into the right ventricle. The muscular ventricular septum forms early in development as trabeculations at the apex of the heart coalesce and the margins of the cardiac tube grow toward the endocardial cushions and atrioventricular orifice. Muscular ventricular septal defects may arise from abnormal trabecular organization or secondarily from foci of cellular death that occur during active cardiac remodeling.
Abnormal Targeted Growth
Anomalous pulmonary venous connections are believed to arise from abnormalities in targeted growth. The pulmonary veins form as an outpouching of endothelial-lined mesenchymal tissue from the lung buds, and coalesce into the common pulmonary vein, which bridges across the splanchnic space and fuses with the posterior wall of the primitive left atrium at 5 weeks’ gestation. By further remodeling, the common pulmonary vein is gradually absorbed into the posterior wall of the left atrium such that the four pulmonary veins enter the heart individually by eight weeks’ gestation. The mechanism is undefined but likely involves an attraction between the pulmonary veins and the left atrium. In the chick embryo, following experimental excision and reimplantation of the lung bud in an inverted orientation, venous connection from lung bud to the left atrium is established in 80% of cases. If absorption of the common pulmonary vein into the left atrium is incomplete, a membrane may persist between the pulmonary veins and the left atrium (cor triatriatum). Bleyl and colleagues have mapped a gene for familial totally anomalous pulmonary venous connection to a locus at chromosome 4q12 in large Utah kindreds, and they have preliminary evidence implicating the gene encoding platelet-derived growth factor receptor alpha (PDGFRA), which is localized in this region.