Published Online
on September 15, 2003

A more recent version of this article appeared on October 7, 2003

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Submitted on January 16, 2003
Revised on June 6, 2003
Accepted on June 10, 2003

Selective Targeting and Timing of Matrix Metalloproteinase Inhibition in Post-Myocardial Infarction Remodeling

William M. Yarbrough MD, Rupak Mukherjee PhD, G. Patricia Escobar DVM, Joseph T. Mingoia BS, Jeffrey A. Sample BS, Jennifer W. Hendrick BS, Kathryn B. Dowdy BS, Julie E. McLean BS, Abigail S. Lowry BS, Timothy P. O'Neill PhD, and Francis G. Spinale MD, PhD^*

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, and Procter and Gamble Pharmaceuticals, Mason, Ohio (T.P.O.).

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 (n=11) or sMMPi (PGE-530742, 10 mg/kg PO TID) begun 3 days before MI (n=11) or 3 days after MI (n=10). Eleven weight-matched noninstrumented pigs served as reference controls. At 10 days after MI, infarct size was similar between groups (47±3% of the area at risk). Marker area increased from baseline in the MI-only group (10±3%, P<0.05) but was unchanged with sMMPi. LV end-diastolic volume increased in the MI-only group (82±3 mL) compared with controls (56±3 mL, P<0.05) but was attenuated with pre-MI and post-MI sMMPi (69±3 and 69±4 mL, respectively, P<0.05). Collagen content increased in the infarct zone of the MI-only group (34±5%) compared with control (2±1%, P<0.05) but was reduced with pre-MI and post-MI sMMPi (24±1% and 23±2%, P<0.05). Collagen content increased in the border zone (12±2%) and decreased in the remote zone (3±1%) of the pre-MI sMMPi group compared with post-MI sMMPi values (7±1% and 5±1%, P<0.05).

Conclusions--Inhibition of MMP-1 and -7 is not required to favorably influence LV remodeling after MI. Moreover, a temporal difference exists with respect to the timing of sMMPi and regional and global myocardial remodeling patterns after MI.

Key words: myocardial infarction • metalloproteinases • inhibitors

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