MYOCARDIAL EXTRACELLULAR-MATRIX REMODELING WITH THE DEVELOPMENT OF PACING-INDUCED CONGESTIVE-HEART-FAILURE - CONTRIBUTORY MECHANISMS

The myocardial fibrillar collagens ensure structural integrity of adjo ining myocytes, provide the means by which myocyte shortening is trans lated into overall left ventricular (LV) pump function, and have been postulated to be essential for maintaining alignment of myofibrils wit hin the myocyte through a collagen-integrin-cytoskeletal-myofibril rel ation. This laboratory has performed a series of studies in order to e xamine the relationship between changes in myocardial collagen matrix components to LV function and geometry which occurred in a model of co ngestive 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 reduc ed and salt extractable collagen, which reflects collagen cross-linkin g, was increased with the development of CHF. LV myocyte adhesion capa city to basement membrane substrates was reduced with pacing CHF. Resu lts from a recently completed series of studies have demonstrated alte rations in the expression and activity of the collagenases, or matrix metalloproteinases (MMPs) occur during the progression of CHF. Increas ed LV myocardial MMP abundance and activity occurred with pacing CHF a nd were associated with the development of LV dilation, wall thinning, and pump dysfunction. These results suggest that changes within the m yocardial extracellular space are a dynamic process and accompany the LV remodeling and dysfunction which occurs with the development of a C HF process. Future studies which define the contributory role of MMP s ynthesis and activation in the LV remodeling process which occurs in t he setting of CHF will likely identify unique therapeutic modalities t o slow the progression of this disease process. (C) 1998 by Elsevier S cience Inc.