Matrix metalloproteinase inhibition during the development of congestive heart failure - Effects on left ventricular dimensions and function

The development of congestive heart failure (CHF) is associated with left v entricle(LV) dilation and myocardial remodeling. The matrix metalloproteina ses (MMPs) play a significant role in extracellular remodeling, and recent studies have demonstrated increased MMP expression and activity with CHF. W hether increased MMP activity directly contributes to the LV remodeling wit h CHF remains unknown. Accordingly, this study examined the effects of chro nic MMP inhibition (MMPi) on LV size and function during the progression of CHF. Pigs were assigned to the following groups: (1) CHF, rapid pacing for 3 weeks at 240 bpm (n=12); (2) CHF/MMPi rapid pacing and concomitant MMPi (PD166793, 20 mg/kg per day [n=10]), and (3) control (n=11). With pacing CH F, LV fractional shortening was reduced (19+/-1 versus 45+/-1%), and end-di astolic dimension increased (5.67+/-0.11 versus 3.55+/-0.05 cp),compared wi th baseline values (P<0.05). In the CHF/MMPi group, LV endocardial shorteni ng increased (25+/-2%) and the end-diastolic dimension was reduced (4.92+/- 0.17 cm) compared with CHF-only values (P<0.05). LV midwall shortening was reduced to a comparable degree in the CHF-only and CHF/MMPi groups. LV peak wall stress increased 3-fold with pacing CHF compared with controls and wa s significantly reduced in the CHF/MMPi group. LV myocardial stiffness was unchanged with CHF but was increased in the CHF/MMPi group. LV myocyte leng th was increased with pacing CHF compared with controls (180+/-3 versus 125 +/-4 mu m, P<0.05) and was reduced in the CHF/MMPi group (169+/-4 mu m, P<0 .05). Basal-state myocyte shortening velocity was reduced with pacing CHF c ompared with controls (33+/-2 versus 66+/-1 mu m/s, P<0.05) and was unchang ed in the CHF/MMPi group (31+/-2 mu m/s). Using an ex vivo assay system, my ocardial MMP activity was increased with pacing CHF and was reduced with ch ronic MMPi. In summary, concomitant MMPi with developing CHF limited LV dil ation and reduced wall stress. These results suggest that increased myocard ial MMP activity contributes to LV myocardial remodeling in developing CHF.