Background-The mechanisms responsible for tumor necrosis factor (TNF)-induced LV structural remodeling in the adult heart are not known. Methods and Results-We generated a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF that develop progressive LV dilation/remodeling from 4 to 12 weeks of age. During the early phases of LV structural remodeling, there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded to a decrease in total myocardial fibrillar collagen content. As the MHCsTNF mice aged, there was a significant decrease in total MMP zymographic activity that was accompanied by an increase in total fibrillar collagen content. The changes in total MMP activity and myocardial fibrillar collagen content were related to a time-dependent increase in myocardial tissue inhibitor of metalloproteinases (TIMP)-1 levels, resulting in a significant time-dependent decrease in the MMP activity/TIMP level ratio in the MHCsTNF mice. To determine a possible mechanism for the increase in myocardial fibrosis, we also measured levels of TGF-␤ 1 and TGF-␤ 2 protein levels, which were shown to be significantly elevated in the hearts of the MHCsTNF mice. Conclusions-Our results suggest that progressive time-dependent changes in the balance between MMP activity and TIMP activity are responsible, at least in part, for the spectrum of TNF-induced changes in the myofibrillar collagen content that occur during LV structural remodeling in the MHCsTNF mice.

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia͞infarction. To define the role of TNF in the setting of ischemia͞infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1͞TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1͞ TNFR2-deficient mice (77.2% ؎ 15.3%) when compared with either wild-type mice (46.8% ؎ 19.4%) or TNFR1-deficient (47.9% ؎ 10.6%) or TNFR2-deficient (41.6% ؎ 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1͞TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1͞TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1͞TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand͞receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and͞or delay the development of cardiac myocyte apoptosis after acute ischemic injury.

The utilization of CE in technically difficult cases improves endocardial visualization and impacts cardiac diagnosis, resource utilization, and patient management.

Systolic dyssynchrony occurs in 33% of DHF patients, and diastolic dyssynchrony occurs in 58%. Medical therapy results in significant shortening of the diastolic intraventricular time delay which is closely related to improvement in LV relaxation.