Abstract 17066: Intracoronary Delivery of Recombinant TIMP-3 Following Myocardial Infarction: Effects of Myocardial Remodeling and Function
Background and Significance: Ischemia-reperfusion (IR) and myocardial infarction (MI) are causes of adverse LV remodeling and heart failure (HF) and are facilitated by an imbalance in matrix metalloproteinase (MMP) activation and the endogenous tissue inhibitors of MMPs (TIMPs). We have identified that myocardial injections of a recombinant TIMP-3 (rTIMP-3; human full length) can interrupt post-MI remodeling. However, whether and to what degree intracoronary delivery of rTIMP-3 post-IR is feasible and effective remained to be established.
Methods and Results: Pigs (25 kg) underwent coronary catheterization and balloon occlusion of the left anterior descending (LAD) for 90 minutes, whereby at the final 4 minutes, rTIMP-3 (n=9; 30 mg) or saline was infused in the distal LAD. LV echocardiography was performed at 3-28 days post-IR and LV ejection fraction (EF) and LV end-diastolic volume (LVEDV) measured. LV EF fell and LVEDV increased from Baseline (pre-IR) values (66±1%, 40±1 mL, respectively) in both groups, but the extent of LV dilation was reduced in the rTIMP-3 group (Table). Despite equivalent plasma troponin levels (14±3 ng/mL), computed MI size (planimetry) at 28 days was reduced by over 45% in the rTIMP-3 group (p<0.05), indicating rTIMP-3 treatment abrogated MI expansion post-IR. Plasma NT-BNP levels, an index of HF progression, was reduced by 25% in the rTIMP-3 group compared to MI saline values (p<0.05).
Summary: While the imbalance between MMPs and TIMPs has been recognized as a contributory factor for post-MI remodeling, therapeutic strategies targeting this imbalance have not been forthcoming. This study is the first to demonstrate that a relevant delivery approach (intracoronary) using a recombinant TIMP can alter the course of post-MI remodeling.
Author Disclosures: S. Barlow: None. H. Doviak: None. J. Jacobs: None. C.B. Logdon: None. P.E. Perreault: None. K.N. Zellars: None. K. Moreau: None. C.F. Villacreses: None. S. Smith: None. A.Y. Khakoo: Employment; Significant; Amgen. T. Lee: Employment; Significant; Amgen. F.G. Spinale: Research Grant; Significant; NIH. Consultant/Advisory Board; Modest; Boston Scientific, Novartis, Acorda.
- © 2016 by American Heart Association, Inc.