ABSTRACT Autonomic remodeling is a major contributor to the initiation and maintenance of lethal ventricular arrhythmias. Following myocardial infarction (MI), sympathetic drive is increased and parasympathetic tone is reduced. There is also structural and functional remodeling of the cardiac sympathetic nerves, including regional denervation, and altered neuropeptide and neurotransmitter content. Due to the intimate relationship between cardiomyocytes and neurons, any change in nerve activity brings about adaptive changes in nearby cardio- myocytes. These changes are in addition to ischemia-driven electrophysiological and structural remodeling. The combined effects of post-MI autonomic, electrophysiological, and structural remodeling are critically important but not well understood, in part because investigating the role of the autonomic nervous system in contributing to emergent cardiac arrhythmias in the complex MI setting requires integrative, multi-scale and multi-organ approaches. Using novel methodologies developed in our lab, our goal is to determine cardiac signaling responses to normal and pathological autonomic activity, how this activity provokes arrhythmias in the post-MI heart, and the anti-arrhythmic effects of restoring nerve structure or function. We have recently developed a novel whole-heart multi-parametric optical imaging system capable of high-sensitivity fluor- escence resonance energy transfer (FRET) imaging of cardiomyocyte signaling activity in parallel with high- speed optical mapping of resulting electrophysiological responses in the intact heart. We have also generated a novel cardiomyocyte-specific cyclic AMP (cAMP) reporter mouse with a large dynamic range. We will combine these new tools with our established innervated heart approach and pharmacological and electrical neuromodulation to precisely connect physiological autonomic activity, cardiomyocyte signaling responses, and resulting arrhythmogenic behavior. Aim 1 will focus on how gradients in nerve density drive the spatio- temporal kinetics of cAMP responses throughout the heart, the effective doses of neurotransmitters required to produce nerve-evoked responses, and how cAMP activity is transduced into functional Vm and Cai changes. Aim 2 will discern cellular mechanisms responsible for denervation super-sensitivity, and the role of nerve structure vs. function in driving adrenergic responsiveness. Aim 3 will determine the mechanisms and anti- arrhythmic effects of post-MI neuromodulatory therapies. These studies will provide unprecedented insight into how autonomic dysfunction contributes to post-MI arrhythmias from cellular signaling up to macro-scale multi- organ interactions.