Aswan Heart Centre Science & Practice Series - Volume 2011, Issue 2

Cardiac malformations, most commonly valve defects, are some of the predominant causes of cardiovascular morbidity and mortality worldwide. Up to a third of all patients with complex congenital heart defects and numerous syndromic conditions, as well as a significant amount of the general population, exhibit valve defects. These observations have not only major implications in infancy; they also have a major impact on the adult population and the growing number of adults with congenital malformations. Over recent years, a large number of Mendelian inheritance patterns and syndromic causes have been identified, shedding light on the importance of genes encoding components of the extracelluar matrix in valve disease. Nevertheless, we still know little about the genetic origin of sporadic and more complex family traits. It is unclear to what extent genetic variations play a role in disease pathogenesis and influences phenotypes rooted in early development. Such knowledge would be greatly beneficial for counseling and treatment of patients. Therefore, this review summarizes the findings in human non-syndromic and syndromic valve disease with a special focus on extracellular matrix proteins, and discusses them in the context of vertebrate valve development.

The formation and remodeling of the embryonic valves is a complex and dynamic process that occurs within a constantly changing hemodynamic environment. Defects in embryonic and fetal valve remodeling are the leading cause of congenital heart defects, yet very little is known about how fibrous leaflet tissue is created from amorphous gelatinous masses called cushions. Microenvironmental cues such as mechanical forces and extracellular matrix composition play major roles in cell differentiation, but almost all research efforts in valvulogenesis center around genetics and molecular approaches. This review summarizes what is known about the dynamic mechanical and extracellular matrix microenvironment of the atrioventricular and semilunar valves during embryonic development and their possible guidance roles. A variety of new computational tools and sophisticated experimental techniques are progressing that enable precise microenvironmental alterations that are critical to complement genetic gain and loss of function approaches. Studies at the interface of mechanical and genetic signaling in embryonic valvulogenesis will likely pay significant dividends, not only in terms of increasing our mechanistic understanding, but also lead to the development of novel therapeutic strategies for patients with congenital valve abnormalities.

The embryonic heart initially consists of only two cell layers, the endocardium and the myocardium. The epicardium, which forms an epithelial layer on the surface of the heart, is derived from a cluster of mesothelial cells developing at the base of the venous inflow tract of the early embryonic heart. This cell cluster is termed the proepicardium and gives rise not only to the epicardium but also to epicardium-derived cells. These cells populate the myocardial wall and differentiate into smooth muscle cells and fibroblasts, while the contribution to the vascular endothelial lineage is uncertain. In this review we will discuss the signaling molecules involved in recruiting mesodermal cells to undergo proepicardium formation and guide these cells to the myocardial surface. Marker genes which are suitable to follow these cells during proepicardium formation and cell migration will be introduced. We will address whether the proepicardium consists of a homogenous cell population or whether different cell lineages are present. Finally the role of the epicardium as a source for cardiac stem cells and its importance in cardiac regeneration, in particular in the zebrafish and mouse model systems is discussed.