Mechanism responsible for D‐transposition of the great arteries: Is this part of the spectrum of right isomerism?

Abstract

D-transposition of the great arteries (TGA) is one of the most common conotruncal heart defects at birth and is characterized by a discordant ventriculoarterial connection with a concordant atrioventricular connection. The morphological etiology of TGA is an inverted or arrested rotation of the heart outflow tract (OFT, conotruncus), by which the aorta is transposed in the right ventral direction to the pulmonary trunk. The rotational defect of the OFT is thought to be attributed to hypoplasia of the subpulmonic conus, which originates from the left anterior heart field (AHF) residing in the mesodermal core of the first and second pharyngeal arches. AHF, especially on the left, at the early looped heart stage (corresponding to Carnegie stage 10-11 in the human embryo) is one of the regions responsible for the impediment that causes TGA morphology. In human or experimentally produced right isomerism, malposition of the great arteries including D-TGA is frequently associated. Mutations in genes involving left-right (L-R) asymmetry, such as NODAL, ACTRIIB and downstream target FOXH1, have been found in patients with right isomerism as well as in isolated TGA. The downstream pathways of Nodal-Foxh1 play a critical role not only in L-R determination in the lateral plate mesoderm but also in myocardial specification and differentiation in the AHF, suggesting that TGA is a phenotype in heterotaxia as well as the primary developmental defect of the AHF.

Discordant ventriculo‐arterial connections, or “transposition”, are not necessarily an essential part of isomerism

“…We read with interest the suggestion of Nakajima that the mechanism responsible for discordant ventriculo‐arterial connections, or transposition, is also part of the spectrum of right isomerism (Nakajima, ). We suggest that several misconceptions were used to underscore this proposal.…”

Monthly variation in univentricular heart and transposition of the great arteries – 10–year national population-based cohort study

“…To assess the true monthly variation and factors affecting fetal development and to minimize confounders, specific timing in early pregnancy should be selected. We chose to study the variation of total prevalence at gestational age 7 + 0 weeks, as the gestational weeks 7-8 have been shown to be critical in the formation of both UVH and d-TGA [20,21]. Taken together, the obvious reasons for these conflicting results in monthly variation in prevalence include differences in populations and their case detection, differences in prenatal detection and pregnancy termination rates, and importantly, differences in the timing of assessment.…”

“…To evaluate true monthly variation, the gestational age 7 + 0 weeks was selected due to the embryological timing of heart development in both UVH and d-TGA [20,21]. Gestational age 7 + 0 weeks for cases and the total population was calculated from the estimated timing of conception based on gestational age at the end of pregnancy (Medical Birth Register or Register of Induced Abortions).…”

Role of carotenoids and retinoids during heart development

“…Recent data suggest that the level of RAR signaling in the posterior pharyngeal arches, directly modulated by HECTD1 ubiquitin ligase through RARα ubiquitination, strongly impacts the development of the aortic arch in mice [126,211]. OFT septation occurs through the fusion of the aorticopulmonary septum (cardiac neural crest cells) with the outflow cushion ridges, and the AV cushion tissue [212,213]. Post-gastrulation changes in RA-signaling lead to aortic arch defects and conotruncal heart defects: transposition of the great arteries (TGA), double outlet right ventricle (DORV), tetralogy of Fallot (TOF), and persistent truncus arteriosus (PTA).…”