Rotation of the Myocardial Wall of the Outflow Tract Is Implicated in the Normal Positioning of the Great Arteries

Abstract

Abstract-Congenital heart defects frequently involve a failure of outflow tract (OFT) formation during development. We analyzed the remodeling of the OFT, using the y96-Myf5-nlacZ-16 transgene, which marks a subpopulation of myocardial cells of the pulmonary trunk. Expression analyses of reporter transcript and protein suggest that the myocardial wall of the OFT rotates before and during the formation of the great arteries. Rotational movement was confirmed by Di-I injection experiments with cultured embryos. We subsequently examined the expression of the transgene in mouse models for OFT defects. In hearts with persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), or transposition of the great arteries, rotation of the myocardial wall of the OFT is arrested or fails to initiate. This is observed in Splotch (Pax3) mutants with PTA or DORV and may be a result of defects in neural crest migration, known to affect OFT septation. However, in Pitx2␦c mutant embryos, where cardiac neural crest cells are present in the heart, PTA and DORV are again associated with a rotation defect. This is also seen in Pitx2␦c mutants, which have transposition of the great arteries. Because Pitx2c is involved in left-right signaling, these results suggest that embryonic laterality affects rotation of the myocardial wall during OFT maturation. We propose that failure of normal rotation of OFT myocardium may underlie major forms of congenital heart disease. (Circ Res. 2006;98:421-428.)Key Words: heart Ⅲ outflow tract Ⅲ Splotch Ⅲ Pitx2 Ⅲ transposition of the great arteries C ongenital heart defects are observed in 0.8% of children in developed countries and are responsible for more than 20% of spontaneous abortions and 10% of all stillbirths.

Morphogenesis of outflow tract rotation during cardiac development: The pulmonary push concept

“…We postulate that the dominant left-sided expression of Pitx2c induces the expression of Nkx2.5 within the anterior heart field, which might be disturbed in Pitx2c knock-out mouse embryos. In our study of the VEGF120/120 embryo, we could discern the malpositioning of the Nkx2.5-positive mesenchymal cells at the pulmonary side of the OFT in line with results of Bajolle et al (2006) that indicate a malpositioning of OFT myocardium in Pitx2c mutant hearts with double outlet right ventricle. The disorganization of the Nkx2.5-positive SHF mesenchyme in front of the pharynx is indicative of an abnormal differentiation of the SHF.…”

“…Clonal studies showed a larger number of cell clones in the subpulmonary region, indicative for a higher proliferative rate, whereas in the subaortic region clones were very small (Bajolle et al, 2008). The subpulmonary myocardium remained in a posterior position in the Pitx2c knock-out mouse that presents with OFT malformations such as transposition of the great arteries and double outlet right ventricle (Bajolle et al, 2006). We postulate that the dominant left-sided expression of Pitx2c induces the expression of Nkx2.5 within the anterior heart field, which might be disturbed in Pitx2c knock-out mouse embryos.…”

“…It is suggested that, besides lengthening, a rotational motion of the OFT is required for normal positioning of the aorta and pulmonary trunk and their respective orifices (Bajolle et al, 2006;Thompson and Fitzharris 1979;Thompson et al, 1987). Multiple developmental signaling factors such as Pitx2c and Fgf8/10, expressed in the anterior heart field in an asymmetrical fashion, have been reported as potential regulators of this rotational motion (Ai et al, 2006).…”

Le débit cardiaque, acteur majeur de la morphogenèse asymétrique des arcs aortiques

“…Ces résul-tats suggèrent que, bien que le remodelage asymétrique des arcs aortiques requière Pitx2, il ne dépend pas de sa fonction dans les arcs aortiques. Ainsi, les auteurs s'appuient sur une étude récente montrant que Pitx2 est aussi nécessaire à la rotation du myocarde à la base de la voie efférente ( Figure 1A) [6], pour avancer l'hypothèse selon laquelle la latéralisation de la crosse aortique pourrait être le résultat de la rotation de la voie efférente. Celle-ci induirait la distribution préférentielle du débit cardiaque à gauche et la réduction du débit cardiaque à droite, participant de cette manière à l'asymétrie de développement de la crosse aortique.…”

“…Une nouvelle publication vient renforcer cette idée en démontrant que l'asymétrie de la crosse aortique est déterminée par le débit cardiaque préférentiel dans les arcs aortiques gauches [5]. Elle suggère que la rotation du myocarde à la base de la voie efférente (aorte et tronc pulmonaire) [6], sous le contrôle de Pitx2, participe à cette hémodynamique particulière [5].…”