Joseph Hadaya

Dysfunction of the autonomic nervous system has been implicated in the pathogenesis of cardiovascular disease, including congestive heart failure and cardiac arrhythmias. Despite advances in the medical and surgical management of these entities, progression of disease persists as does the risk for sudden cardiac death. With improved knowledge of the dynamic relationships between the nervous system and heart, neuromodulatory techniques such as cardiac sympathetic denervation and vagal nerve stimulation (VNS) have emerged as possible therapeutic approaches for the management of these disorders. In this review, we present the structure and function of the cardiac nervous system and the remodeling that occurs in disease states, emphasizing the concept of increased sympathoexcitation and reduced parasympathetic tone. We review preclinical evidence for vagal nerve stimulation, and early results of clinical trials in the setting of congestive heart failure. Vagal nerve stimulation, and other neuromodulatory techniques, may improve the management of cardiovascular disorders, and warrant further study.

Rationale: Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Objective: Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node (SAN) as an initial discovery step. Methods and Results: We report an in-depth, multiscale structural and functional characterization of the innervation of the SAN by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies, including tissue clearing, immunohistochemical, and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiological mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular conduction, and left ventricular contractility. Using this approach, we comprehensively demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. Conclusions: This report provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.