Chronic Matrix Metalloproteinase Inhibition Following Myocardial Infarction in Mice: Differential Effects on Short and Long-Term Survival

Abstract

Left ventricular (LV) remodeling occurs after myocardial infarction (MI), and the matrix metalloproteinases (MMPs) contribute to adverse LV remodeling after MI. Short-term pharmacological MMP inhibition (MMPi; days to weeks) in animal models of MI have demonstrated a reduction in adverse LV remodeling. However, the long-term effects (months) of MMPi on survival and LV remodeling after MI have not been examined. MI was induced in adult mice (n = 131) and, at 3 days post-MI, assigned to MMPi [MI-MMPi: (s)-2-(4-bromo-biphenyl-4-sulfonylamino)-3-methyl-butyric acid (PD200126), 7.5 mg/day/p.o., n = 64] or untreated (MI-only, n = 67). Unoperated mice (n = 16) served as controls. The median survival in the MI-only group was 5 days, whereas median survival was significantly greater in the MI-MMPi group at 38 days (p < 0.05). However, with prolonged MMPi (>120 days), a significant divergence in the survival curves occurred in which significantly greater mortality was observed with prolonged MMPi (p < 0.05). LV echocardiography at 6 months revealed LV dilation in the MI-only and MI-MMPi groups (154 +/- 14 and 219 +/- 24 microl) compared with control (67 +/- 4 microl, p < 0.05), with a greater degree of dilation in the MI-MMPi group (p < 0.05). MMPi conferred a beneficial effect on survival early post-MI, but prolonged MMPi (>3 months) was associated with higher mortality and adverse LV remodeling. These unique results suggest that an optimal temporal window exists with respect to pharmacological interruption of MMP activity in the post-MI period.