FIGURE 4.

Changes of the extracellular matrix during reactive fibrosis leading to left ventricular stiffening. Enzymes responsible for collagen turnover are induced in both LV and RV reactive fibrosis. While studies show that collagen I cross-linking and deposition of highly cross-linked collagen I fibers impact LV function by stiffening the ECM, research is needed to understand ECM remodeling of the RV and functional consequences. Type I procollagen secreted by cardiac fibroblasts is processed to type I collagen molecules by procollagen carboxy-terminal proteinases (PCPs). Lysyl oxidases (LOXs) are enzymes that cross-link adjacent type I collagen molecules to highly cross-linked type I collagen fibers that stiffen the LV and have increased resistance to degradation by matrix metalloproteinase 1 (MMP1). MMPs, along with their inhibitors TIMPs, are responsible for ECM degradation to the carboxy-terminal telopeptide of type I collagen (CITP). While the same enzymes involved in collagen-turnover are induced in the pressure-overloaded RV, the dynamics of ECM deposition and maturation, and the extent of collagen cross-linking contributing to the severity of RV stiffness require further research.