Objective: Tumor necrosis factor α (TNFα) is implicated in myocardial remodeling, a process in which activated cardiac fibroblasts (myofibroblasts) secrete matrix-degrading metalloproteinases (MMPs) and undergo increased proliferation and invasion. Statins are cholesterol-lowering drugs that also have direct cellular effects, which may underlie their ability to reduce myocardial remodeling. This study investigated the effect of TNFα on human cardiac myofibroblast proliferation, invasion and MMP-9 secretion, and determined whether these properties were modulated by simvastatin. Methods: Human cardiac myofibroblasts were cultured from right atrial appendage. TNF receptor expression was quantified by immunoblotting. Cell proliferation, invasion, MMP-9 secretion and MMP-9 mRNA expression were determined by cell counting, Matrigel-coated modified Boyden chamber assays, gelatin zymography and RT-PCR, respectively. Results: Human atrial myofibroblasts expressed the TNF-RI and TNF-RII receptor subtypes. TNFα (1 ng/ml) induced a 23.1±3.9% increase in cell number after 4 days (PPConclusions: TNFα, acting predominantly via the TNF-R1 receptor, increased human atrial myofibroblast proliferation, invasion and MMP-9 secretion, all of which were inhibited by simvastatin. Inhibition of cytokine-induced cardiac myofibroblast activation by statins provides a rationale for their use in patients with cardiac pathologies characterized by adverse myocardial remodeling.