Selective targeting of matrix metalloproteinase inhibition in post-infarction myocardial remodeling.
BACKGROUND
A cause-effect relationship has been established between MMP activation and left ventricular (LV) remodeling following myocardial infarction. The goal of the present study was to examine a selective MMP inhibitor (sMMPi) strategy that effectively spared MMP-1, -3, and -7 with effect to regional and global left ventricular remodeling in a pig model of myocardial infarction.


RESULTS
Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to myocardial infarction-only (n = 10) or sMMPi (PGE-530742, 1 mg/kg TID) begun 3 days prior to myocardial infarction. Ten weight-matched noninstrumented pigs served as reference controls. Left ventricular end-diastolic volume in the myocardial infarction-only group was increased from baseline (81 +/- 3 mL versus 55 +/- 4 mL, respectively, P < 0.05) but was attenuated with sMMPi (67 +/- 3 mL, P < 0.05). Fractional area of shortening of marker area was decreased in the myocardial infarction-only group (change from baseline -63 +/- 10%, P < 0.05) but this effect was attenuated with sMMPi (-28 +/- 14%, P < 0.05), indicative of less dyskinesis of the infarct region with sMMPi. Wall stress was reduced within both the septal and posterior wall regions with sMMPi. Myocardial MMP-2 activity was decreased in both remote and border areas of sMMPi-treated samples compared with myocardial infarction-only values, consistent with pharmacologic MMP inhibition.


CONCLUSIONS
Selective MMP inhibition favorably affected regional myocardial geometry and decreased left ventricular dilation post-myocardial infarction. This study suggests that a strategy of selective MMP inhibition of a limited array of MMPs may be an achievable goal in preventing pathologic left ventricular remodeling post-myocardial infarction.
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Kimberly A
KA
Apple
William M
WM
Yarbrough
Rupak
R
Mukherjee
Anne M
AM
Deschamps
Patricia G
PG
Escobar
Joseph T
JT
Mingoia
Jeffrey A
JA
Sample
Jennifer W
JW
Hendrick
Kathryn B
KB
Dowdy
Julie E
JE
McLean
Robert E
RE
Stroud
Timothy P
TP
O'Neill
Francis G
FG
Spinale
D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D005471:Fluoroscopy; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation; D013552:Swine; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases