TY - JOUR T1 - Innervation and Neuronal Control of the Mammalian Sinoatrial Node: A Comprehensive Atlas JF - bioRxiv DO - 10.1101/2020.10.28.359109 SP - 2020.10.28.359109 AU - Peter Hanna AU - Michael J. Dacey AU - Jaclyn Brennan AU - Alison Moss AU - Shaina Robbins AU - Sirisha Achanta AU - Natalia P. Biscola AU - Mohammed A. Swid AU - Pradeep S. Rajendran AU - Shumpei Mori AU - Joseph E. Hadaya AU - Elizabeth H. Smith AU - Stanley G. Peirce AU - Jin Chen AU - Leif A. Havton AU - Zixi (Jack) Cheng AU - Rajanikanth Vadigepalli AU - James Schwaber AU - Robert L. Lux AU - Igor Efimov AU - John D. Tompkins AU - Donald B. Hoover AU - Jeffrey L. Ardell AU - Kalyanam Shivkumar Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/29/2020.10.28.359109.abstract N2 - 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. Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node as an initial discovery step. Here, we report an in-depth, multi-scale structural and functional characterization of the innervation of the sinoatrial node (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 electrophysiologic mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular (AV) conduction and left ventricular (LV) contractility. For the first time, we demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. This 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.Competing Interest StatementUniversity of California, Los Angeles has patents developed by K.S., J.L.A. and P.S.R. relating to cardiac neural diagnostics and therapeutics. K.S., J.L.A. and P.S.R. are co-founders of NeuCures, Inc. ER -