Matrix metalloproteinase inhibition attenuates left ventricular remodelingand dysfunction in a rat model of progressive heart failure

Background-Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been o bserved in left ventricular (LV) failure. The present study tested the hypo thesis that MMP inhibition would influence LV remodeling and function in de veloping LV failure. Methods and Results-LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 m onths (n = 10), (2) SHHF at 13 months (n = 12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg . kg(-1) . d(-1) PO; n = 14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n = 12), and (5) WF at 13 months (n = 12). Plasma concentrations of the MMP inhibitor (1 16+/-11 mu mol/L) reduced in vitro LV myocardial MMP-2 activity by approxim ate to 100%. LV function and geometry were similar in WF rats at 9 and 13 m onths. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months wa s reduced in the SHHF group compared with WF (3578+/-477 versus 5983+/-109 mm Hg/s, P less than or equal to0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443+/-12 versus 563+/-33 mL, P less than or equal to0.05) and increase d further by 13 months (899+/-64 mL, P less than or equal to0.05). LV myoca rdial MMP-2 activity was increased by approximate to2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values an d LV volume was reduced compared with untreated SHHF values (678+/-28 mL, P less than or equal to0.05). Conclusions-MMP activity contributes to LV dilation and progression to LV d ysfunction in a rodent HF model, and direct MMP inhibition can attenuate th is process.