Enhanced Bioactive Myocardial Transforming Growth Factor-β in Advanced Human Heart Failure

Background: Transforming growth factor (TGF)-beta 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-beta activity in the myocardium of patients with advanced human heart failure. Methods and Results: Using a recently developed bioassay that measures TGF-beta bioactivity rather than TGF-beta abundance, we measured bioactive TGF-beta 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-beta were significantly increased in ICM and DCM compared with NF. Free TGF-beta had an excellent correlation with phosphorylated Smad2 (R-2=0.55, P<0.0001), a downstream marker of TGF-beta 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-beta, was significantly increased in DCM compared with NF, and the free TGF-beta level was correlated with fibulin-2 mRNA (R-2=0.24, P<0.006). Conclusions: Although both free and total soluble TGF-beta are significantly increased in ICM and DCM compared with NF, the superior correlation of free TGF-beta with downstream signaling suggests that this is the most functionally relevant form. The present findings suggest that sustained TGF-beta activation in both ICM and DCM contributes to excess myocardial fibrosis.