title: Myocardial infarct expansion and matrix metalloproteinase inhibition.
abstract: 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.
  
  
  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 (n=7; PD166793, 20 mg x kg(-1) x d(-1)) or MI only (n=7) 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 (n=9) or MI only (n=8) 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 (4.7+/-0.1 versus 5.1+/-0.1 cm, P<0.05). Regional MI area was reduced with MMPi at 8 weeks after MI (1.3+/-0.1 versus 1.7+/-0.1 cm2, P<0.05). 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 attenuated the degree of post-MI LV dilation and expansion of the infarct during the late phase of MI healing. In addition, exogenous MMPi caused region-specific modulation of certain MMP and TIMP species.
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Brinsa
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Dowdy
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Scott
authors.forename: Julia M
authors.initials: JM
authors.lastname: Baskin
authors.forename: Anne M
authors.initials: AM
authors.lastname: Deschamps
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Lowry
authors.forename: G Patricia
authors.initials: GP
authors.lastname: Escobar
authors.forename: David G
authors.initials: DG
authors.lastname: Lucas
authors.forename: William M
authors.initials: WM
authors.lastname: Yarbrough
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D002908:Chronic Disease; D004108:Dilatation, Pathologic / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006877:Hydroxamic Acids / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000201:enzymology* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D013552:Swine; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D009842:Oligopeptides; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C370242:(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid