Figure 2. Mechanisms for transition of fibroblasts to myofibroblasts.

The transition of fibroblasts to myofibroblasts is an early event in HHD, regulated in part by increased expression of the hormones of the RAAS system (renin, ANG II, and aldosterone), ET-1, and TGF-β1. Myofibroblasts express a gene program that contributes to a progressive profibrotic state. Changes in the ECM occur in part due to an altered balance of MMPs and their inhibitors (TIMPs). These changes lead to a stiffening of the ECM and functional alterations that cause changes in signaling to myocytes. The altered physical and functional environment of the myocytes leads to progressive cardiac dysfunction.