Activation of matrix metalloproteinases in the failing human heart: breaking the tie that binds.

Abstract

The process of left ventricular (LV) remodeling has been shown to be an important predictor of morbidity and mortality in patients with heart failure. Therefore, identifying the cascade of molecular and cellular events that contribute to LV remodeling is likely to provide new and novel targets for preventing disease progression in heart failure. In this issue of Circulation , Li and colleagues1 report that changes in the relative abundance of tissue inhibitors of the metalloproteinases (TIMPs) occur with the development of end-stage human heart failure, thus raising the important possibility that alterations in the extracellular matrix of the failing heart may contribute to disease progression in heart failure. The purpose of this editorial was to place the findings of the study by Li et al, as well as those of recently published reports, in perspective with what we know about myocardial extracellular remodeling in heart failure. The phenotype of dilated cardiomyopathic disease in humans can be characterized as a disproportionate increase in the ratio of LV ventricular chamber radius to wall thickness, with no increase in sarcomere length. The increased ratio of LV chamber radius to wall thickness is accompanied by increased myocardial wall stress, which can in turn promote further dilation and reduced pump function. Taken together, these observations would suggest that significant myocardial remodeling must occur within the LV free wall to allow for the chamber dilation and wall thinning that occur during the progression to severe LV dilation. Although the canonical view of LV remodeling has held that LV dilation occurs primarily as a result of an increase in myocyte size (hypertrophy), an increasing body of literature now suggests that the process of LV remodeling is far more complex than was once assumed and that important changes occur in the extracellular matrix components of the myocardium …