Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling

Abstract

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.