Enhanced bioactive myocardial transforming growth factor-β in advanced human heart failure

Abstract

BACKGROUND: Transforming growth factor (TGF)-β activation is known to play a central role in progressive ventricular remodeling in advanced heart failure in animal models, but there has been no direct evidence of increased TGF-β activity in the myocardium of patients with advanced human heart failure. METHODS AND RESULTS: Using a recently developed bioassay that measures TGF-β bioactivity rather than TGF-β abundance, we measured bioactive TGF-β in human myocardium from control non-failing donors (NF), and patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). Both free and total soluble TGF-β were significantly increased in ICM and DCM compared with NF. Free TGF-β had an excellent correlation with phosphorylated Smad2 (R(2)=0.55, P<0.0001), a downstream marker of TGF-β signaling. Collagen type I and type III were significantly upregulated in DCM compared with NF, consistent with histological evidence of myocardial fibrosis. Expression of fibulin-2, a positive modulator of TGF-β, was significantly increased in DCM compared with NF, and the free TGF-β level was correlated with fibulin-2 mRNA (R(2)=0.24, P<0.006). CONCLUSIONS: Although both free and total soluble TGF-β are significantly increased in ICM and DCM compared with NF, the superior correlation of free TGF-β with downstream signaling suggests that this is the most functionally relevant form. The present findings suggest that sustained TGF-β activation in both ICM and DCM contributes to excess myocardial fibrosis.