Sudden cardiac death (SCD) from lethal heart rhythms (ventricular tachyarrhythmias; VT/VF) claims more lives each year in the United States than all disease-related causes of death combined. Patients with heart failure (HF) have the highest SCD risk. Poor understanding of underlying mechanisms linking HF and SCD preclude design of new, more effective therapies. The foremost limitation for mechanistic studies of SCD has been the lack of a suitable, non-genetic experimental model with key features of human HF. We have developed a novel model that fulfills these criteria and showed that maladaptive β-adrenergic (β-AR) responsiveness results in increased cardiac mitochondrial reactive oxygen species (ROS), leading to calcium derangement, decreased cardiac function, and increased VT/VF and SCD. Previous studies performed by our lab show that (1) failing hearts exhibit decreased β-AR responsiveness and poor electrical stability which can be reversed through activation of parasympathetic (i.e. muscarinic) receptors, and (2) increased ROS levels are directly linked to poor cardiac function and SCD can be prevented through ROS scavenging. Chronic vagus nerve stimulation (VNS) is a promising new therapy for improving left ventricular (LV) function in clinical trials of HF patients. However the underlying mechanisms for chronic VNS are largely unknown. Furthermore, the effect of chronic VNS on SCD has yet to be studied. While acute VNS terminates arrhythmia, chronic VNS may prolong cardiac repolarization and predispose to arrhythmias, especially in HF patients who typically have prolonged electrocardiographic QT intervals. Establishing whether chronic VNS is truly a safe approach for treating HF in humans remains an important task. Our preliminary findings revealed that although chronic VNS did prolong the electrocardiographic QT interval, animals treated with chronic VNS displayed decreased QT interval heterogeneity and SCD incidence. To determine if chronic VNS confers its salutary effects by way of ROS or muscarinic-related mechanisms, we will test the hypothesis that chronic VNS prevents VT/VF and SCD by reducing calcium derangement, energy demand, oxidative stress, and autonomic dysfunction in LV myocytes during pressure-overload cardiac stress. Our hypothesis will be tested pursuant to the following aims: Aim 1: Determine the effect of chronic VNS on autonomic balance, HF, VT/VF and SCD Aim 2: Determine the effect of chronic VNS on oxidative stress, energetics, and workload in failing LV myocytes Aim 3: Determine the effect of chronic VNS on electromechanical coupling and SCD risk in excised whole hearts Thus far, we have shown that chronic parasympathetic signaling represents a novel approach for treatment of SCD. This highly impactful project will allow us to (1) improve upon delivery of chronic VNS for HF treatment, (2) provide a novel, effective therapy for SCD treatment where none currently exist, and (3) generate new avenues of research through ...