Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. We have identified two types of sympathetic denervation that occur after MI in mice: sustained denervation of the infarct and border zone, and transient denervation of peri-infarct myocardium. These are caused by distinct molecular mechanisms and have very different impacts on arrhythmia susceptibility. We found that the extracellular matrix components chondroitin sulfate proteoglycans are produced in the cardiac scar after ischemia-reperfusion injury, where they cause sustained denervation of the infarct and border zone. They prevent axon outgrowth via protein tyrosine phosphatase receptor σ (PTPσ) on sympathetic neurons. We found that the absence of PTPσ, or pharmacologic modulation of PTPσ, in BalbC mice restored sympathetic innervation to the scar and borderzone. We tested the impact of reinnervation on arrhythmia susceptibility using ECG telemetry and optical mapping with voltage and Ca2+ sensitive dyes. Both techniques revealed a decreased number of induced arrhythmias following reinnervation. Optical mapping carried out 14-21 days after MI revealed increased dispersion of action potential duration (APD), supersensitivity to β-adrenergic receptor stimulation, and Ca2+ mishandling. Sympathetic reinnervation prevented all of these changes and rendered hearts remarkably resistant to induced arrhythmias. Conversely, transient denervation of peri-infarct myocardium is triggered by activation of the p75 neurotrophin receptor (p75NTR). The signaling events that follow ligand binding to p75NTR have been described extensively in cultured sympathetic neurons, but remain less clear in vivo. Activation of p75NTR in vitro induces axon regeneration through a mechanism that requires the expression and activity of the metalloprotease tumor necrosis factor-α converting enzyme (TACE). We investigated the role of TACE in sympathetic axon degeneration after MI in wildtype and p75NTR-/- C57Bl6 mice. We found that TACE expression was increased in cardiac sympathetic neurons 3 days after MI in a p75NTR-dependent manner. Inhibiting TACE with Marimastat (25 mg/kg/day) prevented axon degeneration outside of the infarct. Sympathetic nerves were identified by tyrosine hydroxylase (TH) immunohistochemistry and infarcts were identified by fibrinogen immunohistochemistry. However, total infarct area was increased in marimastat-treated hearts (vehicle: 6.0±0.8% vs. marimastat: 8.8±0.7 % total LV, n=5-6, p<0.05). Optical mapping was carried out 3 days after MI to determine if electrophysiological properties or calcium handling were altered by transient peri-infarct denervation. In contrast to the profound effect of sustained denervation on arrhythmia susceptibility, mapping analyses showed no difference between vehicle and marimastat treated hearts in APD, APD dispersion, Ca2+ transient duration, or the pacing frequency at which Ca2+ alternans emerged. Thus, sustained sympathetic denervation after myocardial has a profound impact on arrhythmia susceptibility in the mouse heart, but transient denervation does not.