Project Summary Coronary heart disease is the leading cause of death in the U.S., and patients who survive a coronary artery occlusion have a high risk for cardiac arrhythmias and sudden cardiac death. Spatial heterogeneity of sympathetic innervation is a major contributor to post-infarct arrhythmias and sudden cardiac death after myocardial infarction (MI), and sympathetic denervation (nerve loss) predicts arrhythmia risk in human studies. Persistent denervation is caused by chondroitin sulfate proteoglycans (CSPGs) in the scar acting on neuronal Protein Tyrosine Phosphatase Receptor Sigma (PTPσ). Targeting PTPσ with therapeutics or removing sulfation from CSPG side chains promotes post-MI reinnervation of the borderzone and infarct, preventing isoproterenol-induced arrhythmias and altering the cardiac immune response. Treatments that restore innervation shift the cardiac immune response from pro-inflammatory to reparative, but the role of reinnervation and neurotransmission in that process remains unknown. Several lines of evidence suggest that reinnervation regulates inflammation, and that noradrenergic transmission is involved. We will test that hypothesis in Aim 1. Conversely, preliminary data indicate that restoring sympathetic nerves prevents isoproterenol-induced arrhythmias even if the nerves lack norepinephrine. This surprising result suggests that another aspect of reinnervation, aside from noradrenergic transmission, is critical for normalizing cardiac β1AR signaling and electrophysiology after MI. We will test the hypothesis that post-MI reinnervation prevents arrhythmias by restoring a β1AR-SAP97 (β1 adrenergic receptor-synapse associated protein 97) signaling complex in cardiac myocytes. We hypothesize that post-MI sympathetic reinnervation regulates cardiac inflammation and electrophysiology via distinct mechanisms, and we have assembled an outstanding team of experts and innovative experimental tools to identify the mechanisms involved.