man. Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling. Am J Physiol Heart Circ Physiol 287: H1369 -H1377, 2004; 10.1152/ajpheart.00641.2003.-The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-␣ receptor-1 (TNFR1)-mediated pathways in a murine model of myocardial infarction and remodeling. One hundred and ninety-four wild-type (WT) and TNFR1 gene-deleted (TNFR1KO) mice underwent left coronary artery ligation to induce myocardial infarction. On days 1, 3, 7, and 42, mice underwent transesophageal echocardiography. Hearts were weighed, and the left ventricle (LV) was assayed for matrix metalloproteinase (MMP)-2 and -9 activity and for tissue inhibitor of MMP (TIMP)-1 and -2 expression. Deletion of the TNFR1 gene substantially improved survival because no deaths were observed in TNFR1KO mice versus 56.4% and 18.2% in WT males and females, respectively (P Ͻ 0.002). At 42 days, LV remodeling, assessed by LV function (fractional area change of 31.9 Ϯ 7.9%, 32.2 Ϯ 7.7%, and 21.6 Ϯ 7.1% in TNFR1KO males, TNFR1KO females, and WT females, respectively, P Ͻ 0.04), and hypertrophy (heart weight-tobody weight ratios of 5.435 Ϯ 0.986, 5.485 Ϯ 0.677, and 6.726 Ϯ 0.704 mg/g, P Ͻ 0.04) were ameliorated in TNFR1KO mice. MMP-9 activity was highest at 3 days postinfarction and was highest in WT males (1.9 Ϯ 0.4 4, 3.6 Ϯ 0.24, 1.15 Ϯ 0.28, and 1.3 Ϯ 1.2 ng/100 g protein, respectively, in TNFR1KO males, WT males, TNFR1KO females, and WT females, respectively, P Ͻ 0.002), whereas at 3 days TIMP-1 mRNA fold upregulation compared with type-and sexmatched controls was lowest in WT males (138.32 Ϯ 13.05, 46.74 Ϯ 5.43, 186.09 Ϯ 28.07, and 101.76 Ϯ 22.48, respectively, P Ͻ 0.002). MMP-2 and TIMP-2 increased similarly in all infarcted groups. These findings suggest that the benefits of TNFR1 ablation might be attributable at least in part to the attenuation of cytokine-mediated imbalances in MMP-TIMP activity. extracellular matrix; left ventricular function; myocardial infarction ISCHEMIC HEART DISEASE is the major cause of congestive heart failure (CHF) in the United States. The adverse effects of left ventricular (LV) remodeling after myocardial infarction (MI) have been recognized as a primary factor in the development of ischemic cardiomyopathy and CHF (7,37,40). After the heart undergoes coronary occlusion, the infarct zone is characterized by cardiomyocyte cell death, degradation of the extracellular matrix (ECM), and neutrophil infiltration, followed by granulation tissue formation and maturation of granulation tissue into scar (6,25,30). However, remodeling also occurs in areas distant to the infarct zone and includes hypertrophy and dilatation. Recent improvements in mortality and morbidity after MI can be attributed to treatment modalities directed against late post infarction remodeling [i.e., dilation of the surviving myocardium (24)]. However, adverse outcomes, both early and late, are still common in t...