Matrix metalloproteinase inhibition attenuates left ventricular remodeling and 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 observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing 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 months (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 (116+/-11 mu mol/L) reduced in vitro LV myocardial MMP-2 activity by approximate to 100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was 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 increased further by 13 months (899+/-64 mL, P less than or equal to0.05). LV myocardial 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 and 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 dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.