Valvular heart diseases in the developing world: developmental biology takes center stage

Abstract

Heart valve disease is a significant and increasing global problem of which, in the developing world, the primary sufferers are the children and young adults regarded as the critical 'engine' of future economic growth. Yet, up to 10 times the current number of known sufferers remain undiagnosed in these countries. Among the most prevalent and neglected diseases are rheumatic heart disease and endomyocardial fibrosis. The etiologies of these diseases can be described in part as a dysregulation or reactivation of developmental biology pathways. Consequently, connecting mechanisms of valvulogenesis and disease etiology may represent an excellent strategy to identify therapeutic targets. These local diseases require local solutions tailored to local resources; therefore, collaboration with experienced research groups should be encouraged as a way of accelerating the creation of relevant knowledge, and its clinical translation.

Figure 1

Significantly high mortality due to RHD in developing countries compared to Western nations. The majority of sufferers in these countries are less than 15 years old [–22].

Figure 2

A) A rheumatic mitral valve showing severe thickening of the leaflet and chordae tendonae [27]. B) Hematoxylin and Eosin staining of a rheumatic mitral valve leaflet showing calcification, fibrosis, and leaflet thickening [28].

Figure 3

Pathology of endomyocardial fibrosis. (A) A fibrosed mouse heart, in which Masson’s trichrome staining illustrates excessive collagen fiber deposition (Bar = 1mm) [34]. (B) Regions of fibrosis accumulate on the myocardium, often mingling with the valve leaflets and chordae [35]. Masson’s trichrome staining of normal (C) and fibrotic (D) myocardium reveals increased collagen deposition (blue) and fiber disorganization in diseased regions (Bar = 200 um) [36].

Figure 4

Similar pathways in valve development and disease. Mechanisms such as vascularization, ECM organization, and cell migration are controlled by common molecules including, but not limited to, TGF-β, VEGF, chondromodulin-1, and tenascin-C.