Background - Matrix metalloproteinases (MMPs) contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor, PG-530742 (PG), on the progression of LV dysfunction and remodeling in dogs with HF. Methods and Results - Chronic HF (LV ejection fraction [LVEF] 36%) was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 months of therapy with either high-dose PG (3.5mg/kg, n=8) (HD), low-dose PG (0.2mg/kg, n=8) (LD), or to a matched placebo (PL, n=8). PG has been shown to produce complete inhibition of MMPs 2, 3, 9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 months after initiating therapy. In PL dogs and in LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-month follow-up period. Whereas, in HD dogs, EF increased from 36±1 % to 40±1 % (p=0.003), EDV and ESV decreased (59±4 vs. 57±4 ml, p=0.02, 38±2 vs. 34±2 ml, p=0.00001). Compared to controls, treatment with HD showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD-treated dogs but not LD-treated dogs.Conclusions - In dogs with moderate heart failure, long-term monotherapy with high dose selective MMP inhibitor, PG-53072, prevents LV remodeling and the progression of global LV dysfunction.