Including age and LVESD, both of which were also independent predictors of the primary endpoints in this study. Valvular tissue degeneration is characterized by fibrosis and calcification, which can cause valve dysfunction. The TIMP2 can trigger the signal cascade that instigates cardiac fibrosis, which is a characteristic of MV degeneration. The TIMP2 is also believed to act through specific, high-affinity receptors and through links to G protein and cAMP signaling pathways. Reduction and alkylation of TIMP2 produces a mitogenic and inactive mutant with an additional N-terminal alanine residue related to fibroblast growth. Lack of TIMP2 exacerbates cardiac dysfunction and impairs remodeling after pressure overload when excess membrane-type MMP activity and loss of integrin b1D degrade the uniformity of extracellular matrix remodeling and impair the myocyte�CECM interaction. The pathological findings in our patients showed more cells in the grade 2 TIMP2 section. The higher grade staining with more cells could be associated with TIMP 2 function and might play an important role in the myocardial remodeling. Our study found that lack of mitral TIMP-2 staining is associated with admission for HF and death after MV surgery. These findings suggest that TIMP2 is a prognostic indicator in patients who undergo surgical treatment for MV heart disease. Animal models have also shown the direct causal roles of TIMP2 activity in left ventricular remodeling. Heymans et al. showed that mRNA and protein levels of TIMP2 correlate with intra-cardiac fibrosis development. The MMP-inhibitory function of TIMP2 is also a key determinant of myocardial remodeling after MI, mainly due to its inhibition of MT1-MMP. Replenishing TIMP2 in diseased myocardium has shown potential as a therapeutic treatment for reducing or preventing disease progression. Our data showing that mitral TIMP 2 staining had a grade-dependent effect on the development of primary endpoints supports the continued use of TIMP2 supplement therapy. Age-dependent changes in LV structure and function may partially result from alterations in TIMP2 expression. Whereas this study showed that age is an independent risk factor for the development of primary endpoints, a previous study found thatTIMP-2 level changes as age increases. These agedependent alterations in the TIMP-2 profile favor extracellular matrix accumulation and are associated with concentric remodeling and decreased ventricular dysfunction. This association may explain the age-associated increase in the incidence of the primary endpoints in our study. Another independent predictor of the primary endpoints in this study was LVESD. Previous animal BMS-907351 849217-68-1 studies have found that, as the LV ejection fraction improves, ventricular remodeling is associated with reduced LVESD and reduced TIMP2 expression, which is consistent with our findings. Compared to the ejection fraction, LVESD may be less load-dependent and may provide a useful guide for timing MV surgery. AB1010 790299-79-5 Reports of a correlation between preoperative end-systolic diameter and prognosis after MV surgery are also consistent with our data indicating a correlation between LVESD and the occurrence of primary endpoints. Some limitations of this study are noted. First, this retrospective analysis of a single-center sample was subject to selection bias. Second, TIMP2 expression in tissues was not examined simultaneously with fibrosis-related parameters. Therefore, this study did not determine whether TIMP2 expression is simply a reactive response or a contributing factor in ventricular remodeling. However, this longitudinal study found that TIMP2 has potential use as a prognostic parameter. Third, this study only measured mitral expressions of matrix proteinases. Ventricular expression of proteinases may differ pathologically.