Time-dependent changes in myocardial structure following discrete injury in mice deficient of matrix...

Myocardial scars from radiofrequency (RF) ablation can increase in size in the post-injury period, resulting in remodeling of the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) contribute to adverse myocardial remodeling following injury. However, the role of specific MMP types in RF scar enlargement remains unclear. One MMP type, MMP-3, degrades a wide range of ECM substrates and can activate other MMPs. This project examined LV remodeling in wild type (WT) and MMP-3 deficient (mmp-3-/-) mice following RF injury. RF lesions (0.5 mm probe, 80 degrees C, 30 s) were created on the LV epicardium of WT (C57/BL6) and mmp-3-/- mice and were terminally studied at 1 h, 3, 7, and 28 days post-RF (n=10 each). Heart mass indexed to tibial length (mg/mm) was similar in the WT and mmp-3-/- mice at 1 h (8.1+/-0.3 vs. 7.6+/-0.3), but lower in the mmp-3-/- mice at 28 days post-RF (11.9+/-0.4 vs. 10.5+/-0.4, P<0.05). Scar volumes were greater in the mmp-3-/- mice at 3 days, but similar in the two groups at 28 days. Immunohistochemical localization showed fewer macrophages and lymphocytes at the scar border at 3 days in the mmp-3-/- hearts, but similar staining for these cells in WT and mmp-3-/- hearts at 7 and 28 days post-RF. Post-RF, the early increase in scar volume was accelerated in mmp-3-/- mice and associated with abnormal inflammatory cell infiltration/migration to the area of injury. These findings define a mechanistic role for MMP-3 in RF scar expansion and provide a temporal window during which interruption of MMP-3 activation may impair post-RF myocardial wound healing.