Sudden cardiac death (SCD) due to ventricular tachyarrhythmias (VT) is the leading cause of mortality in the United States, resulting in 250,000 deaths/year. Implantable cardiac defibrillators (ICD) have been the primary bailout treatment strategy for patients with VT. Despite optimum medical therapy and targeted catheter ablation, 20-50% of patients can expect to have recurrent VT and ICD shocks at one year, decreasing quality of life and increasing mortality. Cardiac autonomic dysregulation, characterized by (i) excessive sympathetic activation and (ii) diminished parasympathetic response are central to the pathogenesis of cardiomyopathy and VT. Blockade of sympathetic activation has been the focus of current therapies for cardiomyopathy and arrhythmias. However, significant abnormalities in parasympathetic activity also accompany cardiomyopathy and have been demonstrated to increase risk of arrhythmias and SCD. There is a huge knowledge gap as to why parasympathetic dysfunction occurs. Our laboratory recently has determined that the acetylcholine content in the border zones and viable regions of infarcted hearts are similar if not greater than normal hearts. Thus, the diminished parasympathetic response post myocardial infarction (MI) occurs despite ample cardiac neurotransmitter levels. The primary and unique hypothesis of this proposal is that MI leads to a decrease in central parasympathetic drive to the heart due to altered cardiac afferent signaling (caused by the infarct itself). This proposal, for he first time, will determine the maladaptive alterations in vagal afferent signaling in a conscious large animal chronic MI model and in humans with cardiomyopathy. Multi-electrode array neural recordings will be combined with simultaneous high-density electrophysiological mapping and direct neurotransmitter content measurements in basal and stressed conditions to assess autonomic remodeling and function. Based on this foundation, effects of emerging neuromodulatory therapies including vagal nerve stimulation and cardiac sympathetic denervation (which also alters cardiac afferents) can then be mechanistically evaluated. Some of the key challenges associated with human studies and conscious animal neural recordings have been overcome in my laboratory. Accomplishing the goals of this proposal will identify and classify new and traditional neural targets of therapy that are game-changing, and has the potential of presenting disease-modifying life-saving therapies to patients in the United States and around the globe.