The goal of the proposed project is to alleviate the enormous public health burden of heart failure. Heart failure leads to significant morbidity and mortality, affects almost five million Americans, and results in more than 35 billion dollars in annual healthcare costs. Current pharmacological and surgical treatments are only moderately effective and can have substantial side effects. Regardless of cause, heart failure can lead to sustained, decreased cardiac output resulting in failure of the heart to meet the perfusion demands of peripheral tissue. This decrease in cardiac output is accompanied by an imbalance in input to the heart from the autonomic nervous system. A pathological decrease in parasympathetic activity and increase in sympathetic activity further contribute to heart failure through increased oxidative stress and inflammation and predispose patients to malignant arrhythmias and sudden death. Restoration of autonomic balance would remove stress from the failing heart, and not only improve heart function but would also improve patient comfort and quality of life. The specific aim of this project is to restore autonomic balance to the failing hert through electrical stimulation of the vagus nerve using an implanted microelectrode array. The vagus nerve carries parasympathetic fibers to the heart, but also innervates the viscera and vocal cords. Therefore, electrical stimulation must be highly targeted to avoid unwanted side effects. The key innovation of this project will be to achieve the high degree of specificity required to benefit heart function without producing side effects by stimulating the vagus nerve with the micro-fabricated Utah electrode array. The Utah electrode array is comprised of 96 individual microelectrodes designed to penetrate into nerve fascicles, thus placing the conductive tip of each electrode in close proximity to small independent groups of nerve axons. This fine access to the nerve provides the ability to stimulate small groups of axons while allowing the rest of the nerve to function normally. The specific aims of this project include 1) modify the Utah electrode array from its current dimensions to a size specific to the vagus nerve, 2) demonstrate that stimulation delivered via the appropriate electrodes can activate vagus nerve fibers innervating the heart without producing unwanted side effects, and 3) show that this activation will have beneficial effects on the symptoms of heart failure. This Phase I STTR will accomplish the above aims in short-term canine experiments. Deliverables from the successful completion of these aims will be an electrode array optimized for use in the vagus nerve, the surgical strategy for implantation into the vagus nerve, and stimulation parameters optimized for producing beneficial parasympathetic effects on the heart. These outputs will support the successful transition to long- term canine experiments and subsequent clinical trials and commercialization in Phases II and III of the STTR. Because of the large number of people suffering from heart failure and the limitations of current treatments, the successful completion of this project will have a profound positive impact on public health and wellbeing.