Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target

A fundamental structural event in the progression of heart failure due to d ilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The m atrix metalloproteinases (MMPs) are an endogenous family of enzymes which c ontribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experim ental and clinical forms of dilated cardiomyopathy (DCM), increased express ion of certain species of myocardial MMPs have been demonstrated. Specifica lly, increased myocardial levels of the gelatinase, MMP-9 has been identifi ed in both ischemic and non-ischemic forms of human DCM. In addition, strom elysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal hum an LV myocardium, the membrane type 1 MMP(MT1-MMP) was detected. These MT-M MPs may provide important sites for local MMP activation within the myocard ium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvemen t in LV pump function. Thus, increased LV myocardial MMP expression and act ivity are contributory factors in the LV remodeling process in cardiomyopat hic disease states. Regulation of myocardial MMP expression and activity ma y be an important therapeutic target for controlling myocardial matrix remo deling in the setting of developing heart failure. (C) 2000 Elsevier Scienc e B.V. All rights reserved.