UCLA

The autonomic nervous system (ANS) regulates normal cardiovascular function and plays a critical role in the pathophysiology of cardiovascular disease. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Further understanding of the interplay between the ANS and cardiovascular system holds promise for the development and refinement of neuroscience-based cardiovascular therapeutics. To this end, techniques to image myocardial innervation will help provide a basis for understanding the fundamental underpinnings of cardiac neural control. The evolution of gross and microscopic anatomical studies for functional mapping of cardiac neuroanatomy are reviewed here. Recognizing the major gaps in our understanding of cardiac neural control, the neural regulation of impulse initiation in the sinoatrial node as an initial discovery step is evaluated. This represents 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, a comprehensive neuroanatomic atlas of the RAGP-SAN complex is delineated. 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, intrinsic cardiac neurons’ influence on the pacemaking site in the heart is comprehensively demonstrated. 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 in mammalian hearts and for developing targeted therapies.