Myocardial infarct expansion and matrix metalloproteinase inhibition.
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.
Mukherjee
Rupak
R
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Brinsa
Theresa A
TA
Dowdy
Kathryn B
KB
Scott
Amelia A
AA
Baskin
Julia M
JM
Deschamps
Anne M
AM
Lowry
Abigail S
AS
Escobar
G Patricia
GP
Lucas
David G
DG
Yarbrough
William M
WM
Zile
Michael R
MR
Spinale
Francis G
FG
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
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