Transposition of great arteries: new insights into the pathogenesis.

Marta Unolt

doi:10.3389/fped.2013.00011

Abstract

Transposition of great arteries (TGA) is one of the most common and severe congenital heart diseases (CHD). It is also one of the most mysterious CHD because it has no precedent in phylogenetic and ontogenetic development, it does not represent an alternative physiological model of blood circulation and its etiology and morphogenesis are still largely unknown. However, recent epidemiologic, experimental, and genetic data suggest new insights into the pathogenesis. TGA is very rarely associated with the most frequent genetic syndromes, such as Turner, Noonan, Williams or Marfan syndromes, and in Down syndrome, it is virtually absent. The only genetic syndrome with a strong relation with TGA is Heterotaxy. In lateralization defects TGA is frequently associated with asplenia syndrome. Moreover, TGA is rather frequent in cases of isolated dextrocardia with situs solitus, showing link with defect of visceral situs. Nowadays, the most reliable method to induce TGA consists in treating pregnant mice with retinoic acid or with retinoic acid inhibitors. Following such treatment not only cases of TGA with d-ventricular loop have been registered, but also some cases of congenitally corrected transposition of great arteries (CCTGA). In another experiment, the embryos of mice treated with retinoic acid in day 6.5 presented Heterotaxy, suggesting a relationship among these morphologically different CHD. In humans, some families, beside TGA cases, present first-degree relatives with CCTGA. This data suggest that monogenic inheritance with a variable phenotypic expression could explain the familial aggregation of TGA and CCTGA. In some of these families we previously found multiple mutations in laterality genes including Nodal and ZIC3, confirming a pathogenetic relation between TGA and Heterotaxy. These overall data suggest to include TGA in the pathogenetic group of laterality defects instead of conotruncal abnormalities due to ectomesenchymal tissue migration.

Highlights

The embryos of mice treated with retinoic acid in day 6.5 presented Heterotaxy, suggesting a relationship among these morphologically different congenital heart diseases (CHD)
In lateralization defects (Heterotaxy or isomerisms) Transposition of great arteries (TGA) is frequently associated with complete atrioventricular canal (CAVC), mostly in asplenia syndrome
We recently obtained TGA by administration of a retinoic acid competitive antagonist in pregnant mice [60], showing that critical levels of retinoic acid must be present for normal heart and conotruncal development. These teratogenic effects may be consistently reduced by folic acid and methionine supplementation [61]. Based on these data and following the results of further experiments, we suggested that the teratogenic development of TGA was due to Hif1α down-regulation in response to blocking retinoic acid [62]

Summary

Introduction

Transposition of the great arteries (TGA) is one of the most common and severe, and one of the most mysterious, congenital heart diseases (CHD).With a prevalence of 3,54/10,000 live births in Europe, it is the fourth most common type of major cardiac defect [1], representing 5% of all CHD and 34% of conotruncal defects with situs solitus [2].It is a severe CHD: if not treated, it is the leading cause of cardiac death in neonates and infants [3].Last but not least, it is still a rather mysterious CHD: in phylogenetic and ontogenetic development it has no precedent [4]; it does not represent an alternative physiological model of blood circulation [5]; its etiology and its morphogenesis are still largely unknown [2].Over the last years, great improvements have been made in diagnosis, as well as in medical and surgical treatment of this CHD [5,6,7,8,9,10]. Transposition of great arteries (TGA) is one of the most common and severe congenital heart diseases (CHD). In lateralization defects TGA is frequently associated with asplenia syndrome.

Results

Conclusion