Myocardial matrix metalloproteinase expression, including an over four-fold increase in MMP-3, contributes to left ventricular remodeling in dilated cardiomyopathy and represents a therapeutic target.
Does broad-spectrum pharmacological MMP inhibition attenuate left ventricular dilation and improve pump function in the setting of developing heart failure?
Increased myocardial matrix metalloproteinase expression and activity contribute to left ventricular remodeling in cardiomyopathy, highlighting MMP inhibition as a potential therapeutic target for heart failure.
A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute 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 experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin 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 human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. 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 improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.
Francis G. Spinale (2000) conducted a review in Dilated cardiomyopathy and heart failure. Pharmacological MMP inhibitor was evaluated. Myocardial matrix metalloproteinase expression, including an over four-fold increase in MMP-3, contributes to left ventricular remodeling in dilated cardiomyopathy and represents a therapeutic target.