[Show abstract][Hide abstract] ABSTRACT: Sympathetic hyperinnervation occurs in human ventricular tissue after myocardial infarction and may contribute to arrhythmias. Aberrant sympathetic sprouting is associated with elevated nerve growth factor (NGF) in many contexts, including ventricular hyperinnervation. However, it is unclear whether cardiomyocytes or other cell types are responsible for increased NGF synthesis. In this study, left coronary arteries were ligated and ventricular tissue examined in rats 1-28 days post-infarction. Infarct and peri-infarct tissue was essentially devoid of sensory and parasympathetic nerves at all time points. However, areas of increased sympathetic nerve density were observed in the peri-infarct zone between post-ligation days 4-14. Hyperinnervation occurred in regions containing accumulations of macrophages and myofibroblasts. To assess whether these inflammatory cells synthesize NGF, sections were processed for NGF in situ hybridization and immunohistochemistry. Both macrophage1 antigen-positive macrophages and alpha-smooth muscle actin-immunoreactive myofibroblasts expressed NGF in areas where they were closely proximate to sympathetic nerves. To investigate whether NGF produced by peri-infarct cells induces sympathetic outgrowth, we co-cultured adult sympathetic ganglia with peri-infarct explants. Neurite outgrowth from sympathetic ganglia was significantly greater at post-ligation days 7-14 as compared to control tissue. Addition of an NGF function-blocking antibody prevented the increased neurite outgrowth induced by peri-infarct tissue. These findings provide evidence that inflammatory cell NGF synthesis plays a causal role in sympathetic hyperinnervation following myocardial infarction.