Developmental basis of adult cardiovascular diseases: valvular heart diseases

Abstract

In this chapter, we review the working hypothesis that the roots of adult valvular heart disease (VHD) lie in embryonic development. Valvulogenesis is a complex process in which growth factors signal the process of endocardium-to-mesenchyme transformation (EMT) resulting in formation of prevalvular "cushions." The post-EMT processes, whereby cushions are morphogenetically remolded into valve leaflets, are less well understood, but they require periostin. Mice with targeted deletion of periostin develop degenerative changes similar to human forms of VHD. Mitral valves are also abnormally elongated in hypertrophic cardiomyopathy (HCM), which plays an important role in clinical disease expression. However, the mechanism for this is unclear, but correlates with enhanced expression of periostin in a specific population of ventricular cells derived from the embryonic proepicardial organ, which accumulate at sites where valvular endocardial EMT is reactivated. Collectively, these findings suggest that developmental mechanisms underlie adult valve responses to genetic mutations in degenerative VHD and HCM.

Figure 1

Schematic representation of valvular morhpogenesis. AV and outflow tract (semilunar) valvulogenesis commences with an EMT event, yielding cushion mesenchymal cell (blue), followed by a remodeling process whereby mesenchyme differentiates into collagen-secreting (black lines) interstitial valve fibroblasts (yellow). This remodeling event ultimately leads to leaflet compaction, attenuation, and formation of fibrous continuities that are indicative of the mature valve tissue.

Figure 2

The periostin hypothesis: Periostin expression is regulated in part by TGFβ signals and secreted by cushion mesenchymal cells (middle cell). This secretion promotes a mesenchymal to fibroblast differentiation (left cell) and is important for promoting collagen fibrillogenesis and the material properties of forming valves. In its absence, aberrant differentiation of alternative cell types (e.g., myocytes) are observed (right cell). Thus, periostin promotes differentiation of prevalvular mesenchyme into a fibroblastic lineage and/or inhibits differentiation into other mesodermal lineages.