Acute stretch caused by volume overload (VO) of aorto-caval fistula (ACF) induces a variety of myocardial responses including mast cell accumulation, matrix metalloproteinase (MMP) activation, and collagen degradation, all of which are critical in dictating long-term left ventricle (LV) outcome to VO. Meanwhile, these responses can be part of myocardial inflammation dictated by tumor necrosis factor-α (TNF-α), which is elevated after acute ACF. However, it is unknown whether TNF-α mediates a major myocardial inflammatory response to stretch in early VO. In 24-h ACF and sham rats, microarray gene expression profiling and subsequent Ingenuity Pathway Analysis identified a predominant inflammatory response and a gene network of biologically interactive genes strongly linked to TNF-α. Western blot demonstrated increased local production of TNF-α in the LV (1.71- and 1.66-fold in pro- and active-TNF-α over control, respectively, P<0.05) and cardiomyocytes (2- and 4-fold in pro- and active-TNF-α over control, respectively, P<0.05). TNF-α neutralization with infliximab (5.5 mg/kg) attenuated the myocardial inflammatory response to acute VO, as indicated by inhibition of inflammatory gene upregulation, myocardial infiltration (total CD45+ cells, mast cells, and neutrophils), MMP-2 activation, collagen degradation, and cardiac cell apoptosis, without improving LV remodeling and function. These results indicate that TNF-α produced by cardiomyocytes mediates a predominant inflammatory response to stretch in the early VO in the ACF rat, suggesting an important role of TNF-α in initiating pathophysiological response of myocardium to VO. © 2009.