Project Summary Heart failure (HF) is a major public health problem worldwide, especially myocardial infarction-induced HF with reduced ejection fraction (HFrEF) accounting for 50% of all HF cases. Malignant ventricular arrhythmia accounts for nearly 50-60% of mortality in HF patients. Cardiac sympathetic overactivation, a major feature of HF, could trigger malignant ventricular arrhythmias and sudden cardiac death. My research laboratory is continually focusing on the regulatory role of the peripheral nervous system in peripheral tissues (such as myocardium) in pathophysiological conditions including HF. Our recent research project found that cardiac sympathetic neuronal dysfunction contributes to cardiac sympathetic overactivation and malignant ventricular arrhythmias in advanced HF. To extend our current work, the overall vision of this R01 application is to test whether satellite glia-modulated macrophages can drive cardiac sympathetic functional and structural remodeling and be the therapeutic target for improving cardiac sympathetic function and reducing malignant ventricular arrhythmogenesis in advanced HF. To accomplish this vision, the proposal will still use myocardial infarction-induced advanced HF and sham (sham surgery) animals as the primary experimental tool to pioneer discovery in 3 Specific Aims. We will also use multifaceted approaches in this project, from conscious and anesthetized animals to cellular-molecular-genetic levels, along with some especially cutting-edge techniques (e.g., optogenetic satellite glial silencing, 3D reconstruction with tissue-maker software, cardiac slice electrochemistry recording, and a hyaluronic acid-based hydrogel delivery system). Specific Aim 1 will determine activation of satellite glia and macrophages as well as relations between satellite glia and macrophages in cardiac sympathetic ganglia in advanced HF, because there is limited information about relations among satellite glia, macrophages, and sympathetic ganglionic neurons in advanced HF. Specific Aim 2 will determine the involvement of satellite glia and macrophages in cardiac sympathetic remodeling including structural and functional alterations in cardiac sympathetic neurons located in stellate ganglia and their nerve terminals in advanced HF, because most published studies (including our work) reported the scattered information about HF-triggered cardiac sympathetic remodeling. Specific Aim 3 will provide a tight link with other Specific Aims to establish optogenetic satellite glial silencing and hydrogel-encapsulated (also macrophage-related) therapeutic approaches against sympathetic overactivation, ventricular arrhythmogenesis, and cardiac contractile dysfunction in advanced HF. Accomplishing these goals will provide major conceptual, technical, and translational advances for our understanding of the pathophysiology and related therapeutic targets of cardiac sympathetic overactivation and malignant ventricular arrhythmogenesis in advanced HF.

Project Narrative Cardiac sympathetic structural and functional changes are associated with cardiac sympathetic overactivity and arrhythmia during the progression of heart failure. This proposal will determine activation of satellite glial cells and macrophage in cardiac sympathetic ganglia and their role in cardiac sympathetic structural and functional alterations, and test the therapeutic effects of light stimulation-triggered satellite glial silencing and macrophage- related immunomodulation on ventricular arrhythmias and cardiac abnormalities in chronic heart failure. The significance of this research program is to provide the potential targets for improving cardiac sympathetic function and prognosis in patients with advanced heart failure.