The development of a fully functional four-chambered heart is critically dependent on the correct formation of the structures that separate the atrial and ventricular chambers. Perturbation of this process typically results in defects that allow mixing of oxygenated and deoxygenated blood. Atrioventricular septal defects (AVSD) form a class of congenital heart malformations that are characterized by the presence of a primary atrial septal defect (pASD), a common atrioventricular valve (cAVV), and frequently also a ventricular septal defect (VSD). While AVSD were historically considered to result from failure of the endocardial atrioventricular cushions to properly develop and fuse, more recent studies have determined that inhibition of the development of other components of the atrioventricular mesenchymal complex can lead to AVSDs as well. The role of the dorsal mesenchymal protrusion (DMP) in AVSD pathogenesis has been well-documented in studies using animal models for AVSDs, and in addition, preliminary data suggest that the mesenchymal cap situated on the leading edge of the primary atrial septum may be involved in certain situations as well. In this chapter, we review what is currently known about the molecular mechanisms and animal models that are associated with the pathogenesis of AVSD.

The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.

The development of the inflow tract is undoubtedly one of the most complex remodeling events in the formation of the four-chambered heart. It involves the creation of two separate atrial chambers, the formation of an atrial/atrioventricular (AV) septal complex, the incorporation of the caval veins and coronary sinus into the right atrium, and the remodeling events that result in pulmonary venous return draining into the left atrium. In these processes, the atrioventricular mesenchymal complex, consisting of the major atrioventricular (AV) cushions, the mesenchymal cap on the primary atrial septum (pAS), and the dorsal mesenchymal protrusion (DMP), plays a crucial role.

In this publication, dedicated to Professor Robert H. Anderson and his contributions to the field of cardiac development, anatomy, and congenital heart disease, we will review some of our earlier collaborative studies. The focus of this paper is on our work on the development of the atrioventricular mesenchymal complex, studies in which Professor Anderson has played a significant role. We will revisit a number of events relevant to atrial and atrioventricular septation and present new data on the development of the mesenchymal cap of the atrial septum, a component of the atrioventricular mesenchymal complex which, thus far, has received only moderate attention.