Because of the increasing availability of tools for genetic manipulation, the mouse has become the most popular animal model for studying normal and abnormal cardiac development. However, despite the enormous advances in mouse genetics, which have led to the production of numerous mutants with cardiac abnormalities resembling those seen in human congenital heart disease, relatively little comparative work has been published to demonstrate the similarities and differences in the developmental cardiac anatomy in both species. In this review we discuss some aspects of the comparative anatomy, with emphasis on the atrial anatomy, the valvuloseptal complex, and ventricular myocardial development. From the data presented it can be concluded that, apart from the obvious differences in size, the mouse and human heart are anatomically remarkably similar throughout development. The partitioning of the cardiac chambers (septation) follows the same sequence of events, while also the maturation of the cardiac valves and myocardium is quite similar in both species. The major anatomical differences are seen in the venous pole of the heart. We conclude that, taking note of the few anatomical “variations,” the use of the mouse as a model system for the human heart is warranted. Thus the analysis of mouse mutants with impaired septation will provide valuable information on cellular mechanisms involved in valvuloseptal morphogenesis (a process often disrupted in congenital heart disease), while the study of embryonic lethal mouse mutants that present with lack of compaction of ventricular trabeculae will ultimately provide clues on the etiology of this abnormality in humans.

After its initial formation the epicardium forms the outermost cell layer of the heart. As a result of an epithelial‐to‐mesenchymal transformation (EMT) individual cells delaminate from this primitive epicardial epithelium and migrate into the subepicardial space (Pérez‐Pomares et al., Dev Dyn 1997; 210:96–105; Histochem J 1998a;30:627–634). Several studies have demonstrated that these epicardially derived cells (EPDCs) subsequently invade myocardial and valvuloseptal tissues (Mikawa and Fischman, Proc Natl Acad Sci USA 1992;89:9504–9508; Mikawa and Gourdie, Dev Biol 1996;174:221–232; Dettman et al., Dev Biol 1998;193:169–181; Gittenberger de Groot et al., Circ Res 1998;82:1043–1052; Manner, Anat Rec 1999;255:212–226; Pérez‐Pomares et al., Dev. Biol. 2002b;247:307–326). A subset of EPDCs continue to differentiate in a variety of different cell types (including coronary endothelium, coronary smooth muscle cells (CoSMCs), interstitial fibroblasts, and atrioventricular cushion mesenchymal cells), whereas other EPDCs remain in a more or less undifferentiated state. Based on its specific characteristics, we consider the EPDC as the ultimate ‘cardiac stem cell’. In this review we briefly summarize what is known about events that relate to EPDC development and differentiation while at the same time identifying some of the directions where EPDC‐related research might lead us in the near future. Anat Rec Part A 276A:43–57, 2004.