Abstract 15791: Myocardial Induction of Tissue Inhibitor of Matrix Metalloproteinase-4 Modifies Post Myocardial Infarction Left Ventricular Remodeling
Background: Alterations in the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) contribute to adverse LV remodeling following myocardial infarction (MI). In particular, TIMP-4 myocardial levels are uniformly decreased in both humans and animals post-MI, which would favor a heightened proteolytic state. Accordingly, this project tested the hypothesis that targeted upregulation of myocardial TIMP-4 either through a transgenic or through discrete adenoviral delivery following MI would alter the post-MI LV remodeling process.
Methods/Results: MI was induced in wild type mice (WT C57;n=29), in mice with cardiac restricted over-expression of TIMP-4 (full length human TIMP-4/MHC promoter; TIMP-4exp; n=17). In a matched set of experiments, MI was induced in WT mice (n=34) followed by injection of a replication deficient adenoviral construct of TIMP-4adv within the MI region (10 μL of 8X109 pfu/mL). LV diastolic volume (LVEDV), LV ejection fraction (LVEF) and LV posterior wall thickness (LVPWT; site of MI induction) were determined by echocardiography at Baseline (Pre-MI), at 5 and 21 days post-MI (Table). LVEDV increased post-MI in all groups, but was significantly reduced in the TIMP-4exp and TIMP-4adv groups and was associated with improved LVEF and LVPWT. Conclusions: Myocardial restricted overexpression of TIMP-4 attenuated LV dilation and improved function post-MI, which could be recapitulated through a targeted myocardial viral delivery of TIMP-4 following MI. These unique results demonstrated that targeted strategies which alter the endogenous balance of MMPs/TIMPs at the time of MI can interrupt the progression of post-MI remodeling.
- © 2010 by American Heart Association, Inc.