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 effiectively spared MMP-1, -3, and -7 with effect to regional and global left ventricular remodeling in a pig model of myocardial infarction. Methods and Results: Pigs instrumented with corollary snares and radiopaque markets within the area at risk were randomized to myocardial infarction-only (n = 10) or sMMPi (PGE-530742, 1 mg/kg THD) begun 3 days prior to myocardial infarction. Ten weight-matched noninstrurnented 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 decrease 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 vas 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.