Neuromodulatory therapies for cardiovascular diseases show great therapeutic potential. However, progress is hampered by limited in-depth knowledge of cardiac neuroanatomy. This proposal sets forth an innovative approach to characterizing the pathways at the level of the heart, focusing on the sinoatrial node (SAN). The SAN region is the site of the native, biologic pacemaker of the heart, and dysfunction of the SAN is common, particularly in the aging population. The SAN region initiates each heartbeat with robust regularity. SAN dysfunction can affect quality of life with symptoms syncope and fatigue due to chronotropic incompetence. The estimated annual incidence of SAN dysfunction in the United States is high, and the only treatment for this condition is the implantation of a pacemaker. However, pacemaker implantation is still associated with morbidity such as infection and thrombosis, mainly due to the need for lead implantation within the venous system. Leadless pacemakers have recently been developed but are still fraught with high peri-procedural complications. The autonomic nervous system plays a critical role in many facets of cardiac physiology. In recent years, increasing attention has been paid to the role of autonomic dysfunction in cardiac pathophysiology in general and arrhythmogenesis in particular. The development of therapeutics that target the cardiac autonomic nervous system could provide an effective strategy for treating arrhythmias including SAN dysfunction. Interventions of cardiac ganglia organized in ganglionated plexi (GPs) at the level of the heart have had mixed results, but improved characterization of the neuronal subpopulations may ultimately allow for less invasive therapeutics with reduced side effects. In this study, we propose to molecularly phenotype neurons in the right atrial ganglionated plexus using transcriptomic analysis. Neurons supplying the SAN will be labelled, isolated using laser capture microdissection (LCM), and analyzed using single-cell RNA sequencing to provide an unbiased approach to identifying neuronal subpopulations in the RAGP that could be potential therapeutic targets. We will also pursue an optogenetic approach to modulate intrinsic cardiac neural control of the sinoatrial node. As less invasive strategies for cardiac pacing are pursued, we propose an optogenetic approach to stimulate SAN-projecting neurons to affect SAN function. We will investigate this by using a viral vector strategy to transduce SAN-projecting RAGP neurons with an opsin that will subsequently be photostimulated to exert control of the SAN.
Sinoatrial node dysfunction significantly impacts quality of life and necessitates pacemaker implantation, which can be associated with major complications. Given the role of the cardiac autonomic nervous system in cardiovascular physiology and disease, the intrinsic cardiac nervous system may be a nexus point for intervention to improve SAN function while reducing the risk of complications to patients. Here, we propose studies to molecularly phenotype intrinsic cardiac neurons and modulate control of a subset of these intrinsic cardiac neurons that supply the sinoatrial node.
