TAPVR: Molecular Pathways and Animal Models.

The venous pole of the heart where the pulmonary veins will develop encompasses the sinus venosus and the atrium. In the fourth week of development, the sinus venosus consists of a left and a right part receiving blood from the common cardinal vein, the omphalomesenteric and umbilical veins. Asymmetrical expansion of the common atrium corresponds with a rightward shift of the connection of the sinus to the atrium. The right-sided part of the sinus venosus including its tributing cardinal veins enlarges to form the right superior and inferior vena cava that will incorporate into the right atrium. The left-sided part in human development largely obliterates and remodels to form the coronary sinus in adults. In approximately the same time window (4th-fifth weeks), a splanchnic vascular plexus surrounds the developing lung buds (putative lungs) with a twofold connection. Of note, during early developmental stages, the primary route of drainage from the pulmonary plexus is toward the systemic veins and not to the heart. After lumenization of the so-called mid-pharyngeal endothelial strand (MPES), the first anlage of the pulmonary vein, the common pulmonary vein can be observed in the dorsal mesocardium, and the primary route of drainage will gradually change toward a cardiac drainage. The splanchnic pulmonary venous connections with the systemic cardinal veins will gradually disappear during normal development. In case of absence or atresia of the MPES, the pulmonary-to-systemic connections will persist, clinically resulting in total anomalous pulmonary venous return (TAPVR). This chapter describes the developmental processes and molecular pathways underlying anomalous pulmonary venous connections.