Pulmonary atresia or persistent truncus arteriosus: is it important to make the distinction and how do we do it?

The congenital cardiac anomaly known as tetralogy of Fallot (TOF) is characterized by right ventricular outflow tract obstruction caused by subpulmonary stenosis, dextroposition (overriding) of the aorta, a ventricular septal defect, and right ventricular hypertrophy. The right ventricular hypertrophy is secondary to the presence of right ventricular outflow obstruction (pulmonic valvar or subvalvar stenosis or in the most severe case, atresia). Cyanosis in these patients is attributable to the passage of systemic venous blood into the aorta, bypassing the lungs, with the degree of cyanosis dependent on the severity of the outflow tract obstruction. The malformations that are classified as persistent truncus arteriosus (PTA) are characterized by a single multicuspid semilunar valve with a single vessel, the truncus, arising from the ventricles and giving rise to systemic, pulmonary, and coronary circulations. Thus, both PTA and TOF with pulmonary atresia are characterized by a single vessel emanating from the heart. In PTA, the septation that would divide the common arterial trunk into an aorta and pulmonary trunk is missing, whereas in TOF with pulmonary atresia, it is unclear whether this septation is missing or misplaced. Diagnosis of TOF with pulmonary atresia relies on the presence of a pulmonary valve remnant by clinical imaging. This criterion permits differentiation of TOF with pulmonary atresia and PTA. However, if the pulmonary atresia develops embryonically before a valve is formed, then this criterion would not distinguish PTA from TOF with pulmonary atresia. New findings in experimental mouse models by Théveniau-Ruissy et al reported recently in Circulation Research shed unexpected light on the embryogenesis of these defects and may allow differentiation of the 2 defects in ways that have not been used previously.1 The myocardium and smooth muscle at the arterial pole, that is, the subaortic and subpulmonary myocardium and the smooth muscle at the base of the aortic and pulmonary arterial trunks, is added from a specific region of the ventral pharyngeal mesoderm caudal to the attachment point of the outflow tract with the pharynx that has been called secondary heart field.2,3 The secondary heart field contains the progenitors of both the myocardium and smooth muscle of the arterial pole and ablation of this region has been shown to result in pulmonary stenosis/atresia with overriding aorta.4 This implicates secondary heart field as the defining cell population associated with pulmonary stenosis/atresia. Other experimental causes of pulmonary stenosis/atresia are associated with decreased proliferation in this field of progenitors. Decreased proliferation is experimentally associated with decreased fibroblast growth factor signaling.5 Tbx1-null mice also have decreased proliferation in the secondary heart field, and this is associated with TOF.5,6 Reports from Margaret Buckingham and colleagues in the last 3 years have shown that myocardium originating from this region has unique aortic and pulmonary identity well before septation of the outflow tract. This group has identified 2 separate loci that specifically express a lacZ reporter in outflow myocardium in what will become the subaortic and subpulmonary myocardium. The first report used the y96Myf5-nlacZ-16 (96-16) transgene that marks the pulmonary aspect of the outflow myocardium. The study confirmed rotation of the outflow tract using DiI injection. The authors were also able to show that the outflow failed to rotate in Splotch, Pitx2 c mutants with persistent truncus or doubleoutlet right ventricle or transposition of the great arteries.7 A second study from this group showed another transgene, A17-Myf5-nlacZ-T55 (T55), which is expressed in the outflow myocardium in a pattern complementary to 96-16 and continues development as the subaortic myocardium. The 2 myocardial populations represented by the 96-16 (subpulmonary) and T55 (subaortic) appear from a clonal analysis to arise from distinct precursor populations.8 The article by Théveniau-Ruissy et al identifies the gene that is represented by the 96-16 transgenic as Semaphorin3C (Sema3C).1 Sema3C, a secreted growth factor associated with axonal path-finding and angiogenesis, has been reported previously to be expressed in the outflow myocardium, although not specifically identified as subpulmonary myocardium. Sema3C mutant mice have cardiovascular defects that include conotruncal malformations, although these are, unfortunately, not well described.9 Plexins are the receptors for semaphorins, and PlexinA2 is expressed by neural crest cells. In Sema3C-null embryos, distribution of the plexinA2expressing neural crest cells in the outflow tract is altered but the cells are present in the outflow tract.9 Furthermore, cardiac neural crest form the outflow septation complex The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pediatrics (Neonatology), Neonatal-Perinatal Research Institute, Duke University Medical Center, Durham, NC. Correspondence to Margaret L. Kirby, Department of Pediatrics (Neonatology), Neonatal-Perinatal Research Institute, Bell Building, Rm 157, Box 3179, Duke University Medical Center, Durham, NC 27712. E-mail [email protected] (Circ Res. 2008;103:337-339.) © 2008 American Heart Association, Inc.