Abstract 15548: Temporal Effects of Targeted Release of Recombinant Tissue Inhibitor of Matrix Metalloproteinase Post Myocardial Infarction: Relation to Determinants of Remodeling
Background: : Changes in LV matrix structure occur following a myocardial infarction (MI) and lead to progressive LV failure. This process is accompanied by an imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs), as well as prolonged local inflammation, such as increased interleukins (ILs). This study tested the hypothesis that targeted TIMP augmentation through regional injection of a degradable hyaluronic acid (HA) based hydrogel containing recombinant TIMP-3 (HA/rTIMP-3) slowed the course of LV dysfunction and local MMP/IL levels.
Methods/Results: MI was induced in adult pigs randomized to receive targeted rTIMP-3 (HA/rTIMP-3; n=8; 9-100uL injections, 20 ug rTIMP-3/injection), HA alone (n=9), or saline (MI only; n=8) and LV function (LV ejection fraction) serially measured for 14 days post-MI. Then MMP-9, a highly expressed MMP by inflammatory cells, as well as IL-8, a marker of inflammation, were assessed by rtPCR (Figure). As a function of Day 1 Post-MI, LV ejection fraction fell in the MI only and MI/HA groups but was significantly attenuated in the MI/HA/r-TIMP-3 group. Compared to referent non-MI controls (n=5), MMP-9 and IL-8 expression was blunted within the MI region in the MI/HA/r-TIMP-3 group.
Conclusion: These unique findings demonstrated that targeting the MI region by continuous delivery of a recombinant TIMP can effectively alter the progression of LV dysfunction as well as alter adverse inflammatory programs, and thereby constitutes a specific therapeutic direction.
- © 2013 by American Heart Association, Inc.