Background-A potential mechanism for left ventricular (LV) remodeling after myocardial infarction (MI) is activation of the matrix metalloproteinases (MMPs). This study examined the effects of MMP inhibition (MMPi) on regional LV geometry and MMP levels after MI. Methods and Results-In pigs instrumented with radiopaque markers to measure regional myocardial geometry, MI was created by ligating the obtuse marginals of the circumflex artery. In the first study, pigs were randomized to MMPi (nϭ7; PD166793, 20 mg · kg Ϫ1 · d Ϫ1 ) or MI only (nϭ7) at 5 days after MI, and measurements were performed at 2 weeks. Regional MI areas were equivalent at randomization and were increased in the MI-only group at 2 weeks after MI compared with the MMPi group. In the second study, pigs randomized to MMPi (nϭ9) or MI only (nϭ8) were serially followed up for 8 weeks. At 8 weeks after MI, LV end-diastolic dimension was lower with MMPi than in the MI-only group (4.7Ϯ0.1 versus 5.1Ϯ0.1 cm, PϽ0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3Ϯ0.1 versus 1.7Ϯ0.1 cm 2 , PϽ0.05). MMPi reduced ex vivo MMP proteolytic activity. In the MI region, membrane-type MMP levels were normalized and levels of the endogenous tissue inhibitor of MMPs (TIMP-1) were increased compared with normal levels with MMPi. These effects were not observed in the MI-only group. Conclusions-MMPi

Background-Induction of matrix metalloproteinases (MMPs) contributes to adverse remodeling after myocardial infarction (MI). Whether a region-and type-specific distribution of MMPs occurs within the post-MI myocardium remained unknown. Methods and Results-Ten sheep were instrumented with a sonomicrometry array to measure dimensions in 7 distinct regions corresponding to the remote, transition, and MI regions. Eight sheep served as reference controls. The relative abundance of representative MMP types and the tissue inhibitors of the MMPs (TIMPs) was quantified by immunoblotting. Segment length increased from baseline in the remote (24.9Ϯ5.4%), transition (18.0Ϯ2.9%), and MI (53.8Ϯ11.0%) regions at 8 weeks after MI (PϽ0.05) and was greatest in the MI region (PϽ0.05). Region-and type-specific changes in MMPs occurred after MI. For example, MMP-1 and MMP-9 abundance was unchanged in the remote, fell to 3Ϯ2% in the transition, and was undetectable in the MI region (PϽ0.05). MMP-13, MMP-8, and MT1-MMP increased by Ͼ300% in the transition and MI regions (PϽ0.05). TIMP abundance decreased significantly in the transition region after MI and fell to undetectable levels within the MI region. Conclusions-The unique findings of this study were 2-fold. First, changes in regional geometry after MI were associated with changes in MMP levels. Second, a region-specific portfolio of MMPs was induced after MI and was accompanied by a decline in TIMP levels, indicative of a loss of MMP inhibitory control. Targeting the regional imbalance between specific MMPs and TIMPs within the post-MI myocardium holds therapeutic potential.

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