TIME-DEPENDENT CHANGES IN MATRIX METALLOPROTEINASE ACTIVITY AND EXPRESSION DURING THE PROGRESSION OF CONGESTIVE-HEART-FAILURE - RELATION TOVENTRICULAR AND MYOCYTE FUNCTION

The development of congestive heart failure (CHF) is associated with l eft ventricular (LV) dilation and myocardial remodeling. However, fund amental mechanisms that contribute to this remodeling process with the progression of CHF remain unclear. The matrix metalloproteinases (MMP s) have been demonstrated to play a significant role in tissue remodel ing in a number of pathological processes. The present project tested the hypothesis that the LV dilation and remodeling during the progress ion of CHF is associated with early changes in MMP expression and zymo graphic activity, LV and myocyte function, collagen content, and MMP e xpression and zymographic activity; were serially measured during the progression of CHF caused by pacing-induced supraventricular tachycard ia (SVT) in pigs, After 7 days of SVT, LV end-diastolic dimension and myocyte length both increased by 15% from control values, and LV fract ional shortening fell by 20%. At the level of the myocyte, percent sho rtening fell by 16% after 7 days of SVT, with no change in the steady- state velocity of shortening. Longer durations of SVT caused progressi ve LV dilation, LV pump failure, and myocyte contractile dysfunction. Specifically, 21 days of SVT resulted in a >50% increase in LV dimensi on, a 56% fall in LV fractional; shortening, and a 33% decline in myoc yte velocity of shortening. The decline in LV and myocyte function wit h 21 days of SVT was accompanied by signs and symptoms of CHF. Thus, S VT causes time-dependent changes in LV geometry and function and the s ubsequent development of CHF. LV myocardial collagen content and confl uence fell by >25% after 7 days of SVT and were accompanied by an 80% increase in LV myocardial MMP zymographic activity against the substra te gelatin. After 14 days of SVT, total LV myocardial collagen content was reduced by 24%, and LV myocardial MMP zymographic activity increa sed by >100% from control values. Interstitial collagenase (MMP-1), st romelysin (MMP-3), and 72-kD gelatinase (MMP-2) were increased by appr oximate to 2-fold after 7 days of SVT. LV MMP zymographic activity and abundance remained elevated with longer durations of SVT. The results of the present study demonstrated that in this model of CF, early cha nges in LV myocardial MMP zymographic activity and protein levels occu rred with the initiation and progression of LV dilation and dysfunctio n. These findings suggest that an early contributory mechanism for the initiation of LV remodeling that occurred in this model of developing CHF is enhanced expression and potentially increased activity of LV m yocardial MMPs.