Deficiency of Tissue Inhibitor of Matrix Metalloproteinase-1 Exacerbates LV Remodeling Following Myocardial Infarction in Mice

Recent studies have directed the interests at modulating the heart failure process through inhibition of activated MMPs. We hypothesized that a loss of MMP inhibitory control by TIMP-1 deficiency alters the course of post-infarction chamber remodeling and induced chronic myocardial infarction in wild-type and TIMP-1-/-mice. LV pressure-volume loops obtained from wild-type and TIMP-1-/-mice demonstrated that LV end-diastolic volumes (LVEDV WT vs TIMP-/-: 52±4 vs 71±6µl) and LV end-diastolic pressures (LVEDP WT vs TIMP-/-: 9.0±1.2 vs 12.7±1.4mmHg) were significantly increased in the TIMP-1-/-mice 2 weeks post-MI. LV contractility was reduced to a similar degree in both the WT and TIMP-1-/-groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-1-/-indicating that the hypertrophic response was more pronounced. The observed significant loss of fibrillar collagen in the TIMP-1-/-controls may have been an important contributory factor for the observed LV alterations in the TIMP-1-/-mice after MI. These findings demonstrate that TIMP-1 deficiency amplified adverse LV remodeling following MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-1.