Investigation of Partial Electrical Nerve Block for Autonomic Regulation

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Investigation of Partial Electrical Nerve Block for Autonomic Regulation More than 600,000 people die of heart disease in the United States every year. Sudden cardiac death often occurs as a result of ventricular tachyarrhythmias (VT) in patients with coronary heart disease (CHD) and/or heart failure (HF). Autonomic dysregulation following cardiac pathology is essential to the development of HF and VT. Existing interventions are lacking in response time, reversibility, and adaptability over time. Thus, a major unmet need is to impact/regulate sympathetic neural control of cardiac function using a targeted, rapid, reversible, and gradable modality that is safe for autonomic nerves and, ultimately, can be deployed chronically. Over the last decade, advances in the field of electrical nerve block, has shown promise to be this desired therapeutic modality. Peripheral electrical nerve block has a rapid onset, is reversible and gradable. Previously nerve block has been used to completely block a nerve. This is the first study to explore the value of partially blocking a nerve. Partial electrical nerve block can mitigate autonomic reflexes without extinguishing them. However, the stability and controllability of the block at any desired level are currently unknown. Understanding the characteristics of partial block would result in far reaching contributions to the control of autonomic systems. The feasibility of closed loop control of cardiac function is highly dependent on the availability of real time feedback of autonomic parameters. Existing monitoring techniques are lacking in both responsiveness and sensitivity. To provide a real-time control source, direct recording of autonomic nerve function will be performed using real-time measurements of cardiac interstitial and vascular catecholamines. The central hypothesis of this proposal is that the autonomic system can be down regulated and the sympathetic drive to the heart maintained at a clinically relevant lower set point using DC block. The ability to maintain the autonomic system at varying specified set points based on changing cardiac function and indices of cardiac stress (e.g VT burden, heart rate) would allow for highly patient specific disease interventions. Specifically, for this proposal, the goal is to regulate functional sympathetic control of the heart and maintain a given set point for 30 minutes. Aim 1: Identify and characterize the parameters of partial nerve block needed to maintain nerve block at a given set point using an acute rodent model on the vagus (autonomic) nerve. Aim 2: Identify nerve block targets in the cardiac sympathetic pathway and characterize the effect of partial block on evoked sympathetic reflex responses, in particular the effect on block efficacy and recovery. Aim 3: Evaluate the effect of partial block on regional cardiac norepinephrine using release fast scanning cyclic voltammetry in coordination with high density assessments of regional cardiac electrical function. Aim 4: Using the neurotransmitter biosensor, develop a control paradigm to determine both when to initiate block as well as determining the block level.