Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction

In the heart, collagens are the major extracellular matrix (ECM) protein. The fibrillar collagens of the heart surround and interconnect myocytes and muscle fibers to provide for muscle fiber and myocyte alignment which imparts mechanical support to the myocardium and governs tissue stiffness. Loss of collagen fibrils and struts are said to lead to myocyte slippage, ventricular dilation, and progressive contractile dysfunction. Failed human hearts examined either at autopsy or explantation invariably exhibit alterations of the ECM primarily due to changes in collagen. Modulation of the balance between matrix synthesis and degradation is important in the process of ventricular remodeling and in the pathophysiology of chronic heart failure. Support for the importance of the ECM and activity of matrix metalloproteinases (MMP) in the development of chronic heart failure has been demonstrated both in animal models of heart disease and in humans. A causative role for the ECM in this process was recently revealed in experiments using a transgenic mouse model that expresses the specific collagen-degrading enzyme, MMP-1, in the heart. These studies demonstrated that chronic expression of MMP-1 leads to dynamic changes in the heart and ultimately results in systolic dysfunction. Multiple studies in animal models have also shown that inhibition of MMP activity in animal models of heart failure have attenuated the onset of left ventricular dilatation. Future studies will determine whether inhibition of MMP activity improves morbidity and mortality in patients with heart failure.