Involvement of transforming growth factor-beta in the formation of fibrotic lesions in carcinoid heart disease

Abstract

Carcinoid heart disease is a complication of a neuroendocrine carcinoid tumor. Morphologically, it is characterized by the formation of fibrotic plaques with deposition of extracellular matrix in the subendocardium, frequently causing heart valve dysfunction and cardiac failure. Because members of the transforming growth factor-beta (TGF-beta) family are known to stimulate fibroblasts in their production of extracellular matrix, we investigated the expression of the three isoforms of TGF-beta and the binding protein for latent TGF-beta 1 (LTBP) in carcinoid plaques of the right side of the heart, as well as from control tissue, using immunohistochemistry. Tissue specimens were obtained intraoperatively from nine consecutive patients undergoing valve replacement surgery. TGF-beta 1 and TGF-beta 3 were detected in the fibroblasts of all plaques analyzed, whereas TGF-beta 2 was only rarely expressed. The localization of LTBP was partly concordant with that of TGF-beta 1, but the positive staining for LTBP was extracellular. Sections from unaffected heart tissue contained few fibroblasts in the subendocardium, showing only weak or no immunostaining for TGF-beta 1, -beta 2, and -beta 3 and no staining for LTBP. These results suggest that TGF-beta may play a role in the proliferation of fibroblasts and their matrix production in carcinoid heart lesions.