Myocardial Extracellular Matrix Remodeling with the Development of Pacing Induced Congestive Heart Failure: Contributory Mechanisms

The myocardial fibrillar collagens ensure structural integrity of adjoining myocytes, provide the means by which myocyte shortening is translated into overall left ventricular (LV) pump function, and have been postulated to be essential for maintaining alignment of myofibrils within the myocyte through a collagen-integrin-cytoskeletal-myofibril relation. This laboratory has performed a series of studies in order to examine the relationship between changes in myocardial collagen matrix components to LV function and geometry which occurred in a model of congestive heart failure (CHF) induced by chronic rapid pacing. In this model of CHF, indices of LV pump function are reduced and accompanied by significant dilation. LV fibrillar collagen concentration was reduced and salt extractable collagen, which reflects collagen cross-linking, was increased with the development of CHF. LV myocyte adhesion capacity to basement membrane substrates was reduced with pacing CHF. Results from a recently completed series of studies have demonstrated alterations in the expression and activity of the collagenases, or matrix metalloproteinases (MMPs) occur during the progression of CHF. Increased LV myocardial MMP abundance and activity occurred with pacing CHF and were associated with the development of LV dilation, wall thinning, and pump dysfunction. These results suggest that changes within the myocardial extracellular space are a dynamic process and accompany the LV remodeling and dysfunction which occurs with the development of a CHF process. Future studies which define the contributory role of MMP synthesis and activation in the LV remodeling process which occurs in the setting of CHF will likely identify unique therapeutic modalities to slow the progression of this disease process.