Extracellular degradative pathways in myocardial remodeling and progression to heart failure

A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. The myocardial extracellular matrix is composed of structural proteins and biologically active molecules that contribute to the maintenance of LV myocardial architecture and function. A family of proteolytic enzymes responsible for myocardial extracellular protein degradation is the matrix metalloproteinases (MMPs). A number of MMP species have been identified within the human myocardium and are increased with the development of CHF. Certain MMPs that are expressed at very low levels in normal myocardium such as collagenase-3 (MMP-13) and the membrane-type MMPs (MT-MMPs) are substantially upregulated in CHF and likely contribute to the pathologic remodeling that occurs within the myocardium. However, not all MMP species are uniformly increased in patients with end-stage CHF, suggesting that a specific portfolio or cassette of MMPs are expressed in the failing myocardium. The necessary next steps for improving our understanding of this myocardial MMP system include (1) the identification of the MMP species that are upregulated in CHF, (2) elucidation of the upstream signaling pathways that contribute to MMP induction, (3) the development of methods to detect early myocardial MMP activation in patients with developing CHF, and (4) the examination of the effects of pharmacologic modulators of the MMP system in animal models of CHF. The results from these future studies may yield some novel therapeutic strategies by which to control myocardial extracellular remodeling and thereby slow the progression of the CHF process.