Transposition of the great arteries (TGA) is a common conotruncal heart defect whereby abnormal development of the cardiac outflow tract results in ventriculo-arterial discordance and atrioventricular concordance. This arrangement results in the systemic and pulmonary circulations operating in parallel, rather than in series. In d-TGA with ventricular septal defect (VSD) and left ventricular outflow tract obstruction, multiple defects result from anomalies in different stages of cardiac development.

By day 16 of gestation, the developing embryo has three distinct layers: ectoderm, mesoderm, and endoderm. The anterior mesoderm ultimately gives rise to the heart. First, precardiac mesoderm cells migrate to the cephalad pole of the embryo called the first heart field.[1] There, lateral infolding creates the primitive heart tube. The inside of the heart tube is endothelium and the outside is myocardium.[2] After the formation of the primitive heart tube, three fundamental steps are responsible for ensuring proper alignment of the cardiac structures: looping, convergence, and wedging (Figure 1).[3]

Figure 1

Cartoon drawing depicting stages of cardiac development. Three fundamental steps contribute to proper alignment of the cardiac structures: looping, convergence, and wedging.

Looping

Cardiac looping describes the bending process of the endocardial tube, and it takes place from days 23 to 28. This step is critical in determining the future positions and spatial relationships of the atria, ventricles, and outflow tract (OT).[4] In the usual situation, the heart tube bends to the right (D loop), creating an “S” shape. An anomaly of cardiac looping affects the laterality of the heart.[5] Transposition is considered by many to be a laterality defect and shares some of the same genes implicated in heterotaxy syndrome.[6] At the completion of looping, the developing heart will have an inflow (proximal) limb and outflow (distal) limb in parallel.[7]

Cells at the medial and ventral part of the first heart field represent the second heart field (SHF).[8] After looping, the SHF cells migrate between the inflow and outflow limbs, and they are of major importance. The anterior cells of the SHF form both the myocytes of the right ventricle (RV) and the OT, and they form the smooth muscle cells that will form the base of the aorta and the pulmonary artery (PA).[9]Two other important cell populations contribute to the development of the OT and coronary arteries: cardiac neural crest cells (great arteries and OT) and proepicardial cells from the proepicardial organ (epicardium, which forms fibroblasts and smooth muscle cells of the coronary arteries).

Convergence

Two critical steps follow looping: convergence and wedging. Convergence is the process of alignment of the outflow tract and atrioventricular canal near the midline. A failure of fusion of the outlet septum with the primitive ventricular septum results from a malalignment between the OT and the ventricles. Disruptions during convergence contribute to the future development of malalignment VSDs.

Wedging

Until a third process, called wedging, occurs, the entire OT remains above the RV. In order to achieve ventriculo-arterial concordance, the OT undergoes counterclockwise rotation (viewed from the ventricle) to achieve: 1) movement of the future aortic valve posterior to the pulmonary trunk, and 2) formation of the proximal (conus) and distal (truncus) components of the outflow tract.[7],[10] Wedging also results in mitral-aortic continuity.[11] Proper wedging requires concomitant elongation of the OT.[12]

The cells that contribute to the development and elongation of the OT come from two places: the cardiac neural crest, and the anterior part of the SHF.[11] Cardiac neural crest cells migrate through the aortic arches and contribute smooth muscle cells to the walls of the great vessels.[10],[13] Aortic arch anomalies such as type B interruption of the aorta (IAA) are thought to relate to neural crest defects.[14],[15]

A critical role of the neural crest cells is to signal the SHF to add cardiac myocytes, and later smooth muscle cells, to the developing OT.[10] Addition of these cells permits the growth and elongation of the OT, which is a necessary process for wedging. Because the neural crest cells and the anterior heart field are so closely interlinked, if the cardiac neural crest cells fail to migrate, then the signal for other anterior heart field cells to migrate does not occur.[16] If fewer cells from the anterior heart field join the developing OT, hypoplasia of the subpulmonary conus results. The rotational defect and the VSD in d-transposition/VSD are thought to result from hypoplasia of the subpulmonic conus (a lack of wedging). This type of VSD is common to conotruncal defects and essentially results from an arrest of rotation of the OT at the base of the great arteries.[17],[18] Abnormal wedging may therefore result in interrupted aortic arch with malalignment VSD, as well as transposition of the great arteries.