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CARDIOVASCULAR

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

Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina (F.G.S., G.P.E., J.W.H., L.L.C., S.S.C., J.P.M, C.G.S., R.E.S., J.S.I.) and the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (F.G.S., J.S.I.)

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 µl) compared with control (67 ± 4 µl, 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.

Address correspondence to: Dr. Francis G. Spinale, Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC. E-mail: wilburnm{at}musc.edu

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