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.

Background-A cause-and-effect relationship exists between matrix metalloproteinase (MMP) induction and left ventricular (LV) remodeling after myocardial infarction (MI). Whether broad-spectrum MMP inhibition is necessary and the timing at which MMP inhibition should be instituted after MI remain unclear. This study examined the effects of MMP-1 and MMP-7-sparing inhibition (sMMPi) on regional and global LV remodeling when instituted before or after MI. Methods and Results-Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to MI only (nϭ11) or sMMPi (PGE-530742, 10 mg/kg PO TID) begun 3 days before MI (nϭ11) or 3 days after MI (nϭ10). Eleven weight-matched noninstrumented pigs served as reference controls. At 10 days after MI, infarct size was similar between groups (47Ϯ3% of the area at risk

Background-Whether

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These findings demonstrate a unique spatiotemporal pattern of MMP-9 transcriptional activation and protein content in the developing TAA. Colocalization studies suggest that early dilatation may be driven in part by MMP-9 produced by endogenous cells residing within the aortic vascular wall.

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Past studies have identified that a unique type of matrix metalloproteinase, the membrane-type-1 MMP (MT1-MMP), is increased within the left ventricle (LV) of patients with dilated cardiomyopathy (DCM). However, the cellular and molecular basis for this induction of MT1-MMP with DCM is unknown. LV myocardial biopsies from nonfailing, reference normal patients (defined as LV ejection fraction >50%, elective coronary bypass surgery, no perfusion defect at biopsy site, n = 6) and DCM patients (LV ejection fraction <20%, at transplant, n = 5) were used to establish fibroblast cultures (FIBROS). Confluent LV FIBROS from culture passages 2-5 were measured with respect to MT1-MMP mRNA and protein levels and the distribution of the MT1-MMP mRNA pool in ribosomal fractions. Total MT1-MMP mRNA within DCM FIBROS increased by over 140%, and MT1-MMP protein increased by over 190% from reference normal FIBROS (both P < 0.05). MT1-MMP mRNA in monosome fractions decreased by over twofold in DCM FIBROS compared with reference normal (P < 0.05) and remained lower in polyribosomal fractions (i.e., 15.7 +/- 5.2 vs. 1.4 +/- 0.6% in polysomal fraction 6, P < 0.05). These differences in DCM MT1-MMP FIBROS transcription and translation persisted throughout passages 2-5. The unique findings from this study demonstrated that elevated steady-state MT1-MMP mRNA and protein levels occurred in DCM FIBROS despite a decline in translational deficiency. These phenotypic changes in DCM fibroblasts may provide the basis for developing cell specific pharmacological targets for control of MT1-MMP expression.