Abstract 14073: Targeted Slow Release of Recombinant Tissue Inhibitor of Matrix Metalloproteinase Abrogates Adverse Post Myocardial Infarction Remodeling
Background: : A common aftermath of a myocardial infarction (MI) is left ventricular (LV) remodeling, which entails expansion of the MI region, LV dilation, and dysfunction. Past studies have established that an imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs) contribute to this process. However, translation of these observations into a clinically relevant, therapeutic strategy remains to be established. The present study utilized a large animal model of MI and targeted TIMP augmentation through regional injection of a degradable hyaluronic acid (HA) based hydrogel containing recombinant TIMP-3 (HA/rTIMP-3) and quantified indices of post-MI remodeling and biological pathways likely relevant to this process.
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 followed for 14 days where LV end-diastolic volumes, ejection fraction, and MI expansion were measured by echocardiography and radio-opaque markers with fluoroscopy. HA and rTIMP-3 formulations were developed from initial titration studies. Age-time matched controls (n=8) were included. LV dilation and pump dysfunction occurred with MI and was significantly attenuated in the HA/rTIMP-3 group (Figure). Using microdialysis and a validated MMP fluorescent substrate, in-vivo MMP activity increased by over 140% in the MI only and HA groups (p<0.05) but was normalized with HA/rTIMP-3 injections.
Conclusion: These findings provide the first proof of concept whereby regional continuous delivery of a recombinant TIMP can effectively interrupt the adverse post-MI remodeling process and thereby constitutes a novel therapeutic direction.
- © 2013 by American Heart Association, Inc.