Myocardial remodeling after discrete radiofrequency injury: effects of tissue inhibitor of matrix metalloproteinase-1 gene deletion

Abstract

Discrete myocardial lesions created through the delivery of radiofrequency (RF) energy can expand; however, the mechanisms have not been established. Matrix metalloproteinases (MMPs) play an important role in myocardial remodeling, and MMP activity can be regulated by the tissue inhibitors of the metalloproteinases (TIMPs). This study examined the role of TIMP-1 in postinjury myocardial remodeling. Lesions were created on the left ventricular (LV) epicardium of wild-type (WT, 8-12 wk, 129SVE) and age-matched TIMP-1 gene-deficient (timp-1(-/-)) mice through the delivery of RF current (80 degrees C, 30 s). Heart mass, LV scar volumes, and collagen content were measured at 1 h and 3, 7, and 28 days postinjury (n = 10 each). Age-matched, nonablated mice were used as reference controls (n = 5). Heart mass indexed to tibial length increased in WT and timp-1(-/-) mice but was greater in the timp-1(-/-) mice by 7 days. Scar volumes increased in a time-dependent manner in both groups but were higher in the timp-1(-/-) mice than the WT mice at 7 days (1.48 +/- 0.09 vs. 1.20 +/- 0.11 mm(3).mg(-1).mm, P < 0.05) and remained higher at 28 days. In the remote myocardium, wall thickness was greater and relative collagen content was lower in the timp-1(-/-) mice at 28 days postinjury. Discrete myocardial RF lesions expand in a time-dependent manner associated with myocyte hypertrophy remote to the scar. Moreover, postinjury myocardial remodeling was more extensive with TIMP-1 gene deletion. Thus TIMP-1 either directly or through modulation of MMP activity may regulate myocardial remodeling following infliction of a discrete injury.

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

“…As a result, these mice exhibit reduced contact hypersensitivity response following exposure to specific antigens. In keeping with this observation, it was demonstrated that scar maturation was impaired following a discrete radiofrequency-induced myocardial injury (287). Specifically, scar volumes were increased in MMP-3 null mice at 3 days following myocardial injury and were accompanied by reduced inflammatory cell infiltration.…”

“…The effects of TIMP-1 gene deletion were likely due to loss of MMP inhibitory control, since pharmacological MMP inhibition instituted in the post-MI period yielded a myocardial phenotype similar to reference wild-type animals (173). In a discrete myocardial injury model, where significant LV dilation and dysfunction are absent, TIMP-1 null mice exhibited a greater degree of matrix remodeling within and around the site of injury (287). With respect to TIMP-3 gene deletion, a much more significant phenotype becomes manifest (106).…”

“…Murine transgenic models have been successfully constructed with either TIMP-1 or TIMP-3 gene deletion (106,173,287,369). In the TIMP-1 null mouse, no distinctive myocardial phenotype could be observed in the absence of a pathological stimulus.…”

“…In the TIMP-1 null mouse, no distinctive myocardial phenotype could be observed in the absence of a pathological stimulus. However, an accelerated LV dilation occurs following surgically induced MI, which is accompanied by worsened LV systolic performance (173,287,369). The architectural organization of the myocardial fibrillar collagen was altered in the TIMP-1 null mice and was accompanied by reduced collagen content within the remote zone post-MI (173,287,369).…”

“…However, an accelerated LV dilation occurs following surgically induced MI, which is accompanied by worsened LV systolic performance (173,287,369). The architectural organization of the myocardial fibrillar collagen was altered in the TIMP-1 null mice and was accompanied by reduced collagen content within the remote zone post-MI (173,287,369). The effects of TIMP-1 gene deletion were likely due to loss of MMP inhibitory control, since pharmacological MMP inhibition instituted in the post-MI period yielded a myocardial phenotype similar to reference wild-type animals (173).…”