AccScience Publishing / JCTR / Online First / DOI: 10.36922/JCTR026150025
Submit to JCTR
Cite this article
2
Download
26
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
SHORT COMMUNICATION

Npy2r-expressing postganglionic sympathetic neurons modulate cardiac functions

Sachin Sharma1,2*
Show Less
1 UCLA Neurocardiology Centre for Excellence, UCLA Health, Los Angeles, CA 90095, United States of America
2 Graphic Era University, Dehradun, India
JCTR, 026150025 https://doi.org/10.36922/JCTR026150025
Received: 11 April 2026 | Revised: 21 May 2026 | Accepted: 25 May 2026 | Published online: 12 June 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
XML
Cite
Abstract

Background: Cardiac disorders are either inherited or acquired, reflecting deformities in their structural or functional characteristics. Despite significant advances in cardiovascular drugs and surgical procedures, no breakthroughs have been achieved. The cervicothoracic ganglia, also known as stellate ganglia, located within the paravertebral chain, are known to innervate myocardial tissues in a heterogeneous manner; however, their therapeutic potential for managing myocardial diseases is not yet fully understood. Methods: Our single-cell sequencing transcriptomic data from wild-type stellate ganglia demonstrated that cardiac-innervating Npy2r-expressing neuronal subpopulations consistently innervate the myocardium. To investigate whether these neuronal subpopulations influence cardiac functions, we used the Npy2r-IRES-Cre crossed with the Ai32-(ChR2(H134R)/EYFP) strain. The offspring with genotypes Npy2r+/-::ChR2+/-, 6 to 8 weeks old littermates, were selected for optical stimulation via an optical fibre connected to the OptoEngine (473 nm, 400 mW, OptoEngine). Results: We observed a significant increase in heart rate among Npy2r+/-::Ai32+/- heterozygous mice compared to control Ai32+/- mice following optical stimulation at various frequencies: 1Hz, 5Hz, 10Hz, 15Hz, and 20Hz. Stellate ganglia isolated from Npy2r+/-::Ai9+/- heterozygote mice showed positive neuronal staining for tdTomato expression. Conclusion: These findings clearly indicate that Npy2r-expressing neuronal subpopulations in the cervicothoracic ganglia influence heart rates during in vivo optical stimulation of stellate ganglia. Relevance for Patients: The study provides novel targets for devising anti-adrenergic therapies against refractory ventricular arrhythmia. These novel targets should be used as the combinatorial therapies along with β-blockers and surgical interventions.

Graphical abstract
Keywords
Postganglionic sympathetic neurons
Optogenetic stimulation
Channelrhodopsin-2
Neuropeptide-Y
Neuropeptide-Y2r receptors
Funding
The current research has been partially funded from American Heart Association as a postdoctoral award fellowship to Sachin Sharma during his work at the UCLA Cardiac Arrhythmia Centre.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Joseph P, Lanas F, Roth G, et al. Cardiovascular disease in the Americas: the epidemiology of cardiovascular disease and its risk factors. Lancet Reg Health – Am. 2025;42:100960. doi: 10.1016/J.LANA.2024.100960

 

  1. Kumar V, Kalishwaralal K, Chauhan C, Singh G, Barnwal RP, Sharma S. AAV viral vectors as therapeutic interventions for inherited or non-inherited cardiac disorders: current aspects and future prospects. Front Med. 2025;12:1678325. doi: 10.3389/FMED.2025.1678325

 

  1. Shivkumar K, Ajijola OA, Anand I, et al. Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol. 2016;594(14):3911- 3954. doi: 10.1113/JP271870

 

  1. Ajijola OA, Aksu T, Arora R, et al. Clinical neurocardiology: defining the value of neuroscience-based cardiovascular therapeutics - 2024 update. J Physiol. 2025;603(7):1781- 1839. doi: 10.1113/JP284741

 

  1. Hanna P, Hoover DB, Kirkland LG, et al. Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy. Anat Rec. 2025;309(2):417-450. doi: 10.1002/ar.25686

 

  1. Sujith MA, Varsha Rakshitha P, Prakash VS. Bilateral stellate ganglion block calms electrical storm. IHJ Cardiovasc Rep. 2024;8(3):87-89. doi: 10.1016/J.IHJCVR.2024.09.002

 

  1. Skinner C, Ayoub M, Geara E, et al. Alternative Approaches to Bilateral Stellate Ganglion Block for Treatment of Refractory Ventricular Arrhythmia. Case Rep Anesthesiol. 2025;2025(1):2691681. doi: 10.1155/CRIA/2691681

 

  1. Ajijola OA, Yagishita D, Reddy NK, et al. Remodeling of stellate ganglion neurons after spatially targeted myocardial infarction: Neuropeptide and morphologic changes. Heart Rhythm. 2015;12(5):1027-1035. doi: 10.1016/j.hrthm.2015.01.045

 

  1. Bloxsom R, Liu K, Handford C, et al. The cardiac sympathetic co-transmitter neuropeptide-Y is pro-arrhythmic in human cardiomyocytes by lengthening activation-recovery interval. Eur Heart J. 2024;45(Supplement_1):ehae666.3774. doi: 10.1093/eurheartj/ehae666.3774

 

  1. Zaglia T, Ajijola OA. The Reappraisal of Neuropeptide Y as Biomarker and Therapeutic Target in Arrhythmic Disorders. Clin Electrophysiol. 2025;11(4):664-666. doi: 10.1016/J.JACEP.2025.01.012

 

  1. Ajijola OA, Chatterjee NA, Gonzales MJ, et al. Coronary Sinus Neuropeptide Y Levels and Adverse Outcomes in Patients With Stable Chronic Heart Failure. JAMA Cardiol. 2020;5(3):318-325. doi: 10.1001/JAMACARDIO.2019.4717

 

  1. Sharma S, Littman R, Tompkins JD, et al. Tiered sympathetic control of cardiac function revealed by viral tracing and single cell transcriptome profiling. eLife. 2023;12. doi: 10.7554/eLife.86295

 

  1. Rajendran PS, Challis RC, Fowlkes CC, et al. Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies. Nat Commun. 2019;10(1). doi: 10.1038/s41467-019-09770-1

 

  1. Sharma S. Dilated cardiomyopathy remodels cardiac neuronal subtypes in a murine model. bioRxiv. Preprint posted online August 7, 2025. doi: 10.1101/2025.08.05.668697

 

  1. Tan CMJ, Green P, Tapoulal N, Lewandowski AJ, Leeson P, Herring N. The Role of Neuropeptide Y in Cardiovascular Health and Disease. Front Physiol. 2018;9:1281. doi: 10.3389/FPHYS.2018.01281

 

  1. Berling D, Baroni L, Chaffiol A, Gauvain G, Picaud S, Antolík J. Optogenetic Stimulation Recruits Cortical Neurons in a Morphology-Dependent Manner. J Neurosci. 2024;44(49):e1215242024. doi: 10.1523/JNEUROSCI.1215-24.2024

 

  1. Samuel M, Elsokkari I, Sapp JL. Ventricular Tachycardia Burden and Mortality: Association or Causality? Can J Cardiol. 2022;38(4):454-464. doi: 10.1016/J.CJCA.2022.01.016

 

  1. Azeem B, Khurram L, Sharaf B, et al. Unmasking Arrhythmia Mortality: A 25-Year Analysis of Trends and Disparities in the United States (1999–2023). Clin Cardiol. 2025;48(3):e70109. doi: 10.1002/CLC.70109

 

  1. Tripathi R, Sullivan R, Fan THM, et al. Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy. PLoS ONE. 2017;12(12):e0189315. doi: 10.1371/journal.pone.0189315

 

  1. Lisi F, Parisi G, Gioia MI, et al. Mineralcorticoid Receptor Antagonist Withdrawal for Hyperkalemia and Mortality in Patients with Heart Failure. Cardiorenal Med. 2020;10(3). doi: 10.1159/000505286

 

  1. Armour JA. Functional anatomy of intrathoracic neurons innervating the atria and ventricles. Heart Rhythm. 2010;7(7):994-996. doi: 10.1016/J.HRTHM.2010.02.014

 

  1. Armour JA. Cardiac neuronal hierarchy in health and disease. Am J Physiol Regul Integr Comp Physiol. 2004;287(2):R262-R271. doi: 10.1152/ajpregu.00183.2004

 

  1. Shivkumar K, Ardell JL. Cardiac autonomic control in health and disease. J Physiol. 2016;594(14):3851-3852. doi: 10.1113/JP272580

 

  1. Meng L, Shivkumar K, Ajijola O. Autonomic Regulation and Ventricular Arrhythmias. Curr Treat Options Cardiovasc Med. 2018;20(5):38-. doi: 10.1007/s11936-018-0633-z

 

  1. Hanna P, Rajendran PS, Ajijola OA, et al. Cardiac neuroanatomy - Imaging nerves to define functional control. Auton Neurosci. 2017;207:48-58. doi: 10.1016/J.AUTNEU.2017.07.008

 

  1. Giannino G, Braia V, Griffith Brookles C, et al. The Intrinsic Cardiac Nervous System: From Pathophysiology to Therapeutic Implications. Biology. 2024;13(2):105. doi: 10.3390/BIOLOGY13020105

 

  1. Patsy M, Ge K, Khodabukus A, Bursac N. Development and modeling of cardiac autonomic innervation. Nat Cardiovasc Res. 2025;4(12):1598-1615. doi: 10.1038/s44161-025-00746-7

 

  1. Li YL. Stellate Ganglia and Cardiac Sympathetic Overactivation in Heart Failure. Int J Mol Sci. 2022;23(21):13311. doi: 10.3390/IJMS232113311

 

  1. Vaseghi M, Zhou W, Shi J, et al. Sympathetic innervation of the anterior left ventricular wall by the right and left stellate ganglia. Heart Rhythm. 2012;9(8):1303-1309. doi: 10.1016/j.hrthm.2012.03.052

 

  1. Higgins CB, Vatner SF, Braunwald E. Parasympathetic Control of the Heart. Pharmacol Rev. 1973;25(1):119-155. doi: 10.1016/s0031-6997(25)06588-3

 

  1. Herring N, Cranley J, Lokale MN, et al. The cardiac sympathetic co-transmitter galanin reduces acetylcholine release and vagal bradycardia: Implications for neural control of cardiac excitability. J Mol Cell Cardiol. 2012;52(3):667- 676. doi: 10.1016/j.yjmcc.2011.11.016

 

  1. Shanks J, Herring N. Peripheral cardiac sympathetic hyperactivity in cardiovascular disease: role of neuropeptides. Am J Physiol Regul Integr Comp Physiol. 2013;305(12):R1411-R1420. doi: 10.1152/ajpregu.00118.2013

 

  1. Jani N, Weperen V Van, Emamimeybodi M, et al. Neuropeptide Y Receptor Inhibitor Enhances Effects of Vagal Nerve Stimulation and Reduces Effects of Sympathetic Activation: Assessments Using Real-Time Electrophysiological and Myocardial Neuropeptide Measurements. J Am Coll Cardiol. 2023;81(8):55. doi: 10.1016/S0735-1097(23)00499-0

 

  1. Chottová Dvoráková M, Wiegand S, Pesta M, et al. Expression of neuropeptide Y and its receptors Y1 and Y2 in the rat heart and its supplying autonomic and spinal sensory ganglia in experimentally induced diabetes. Neuroscience. 2008;151(4):1016-1028. doi: 10.1016/j.neuroscience.2007.07.069

 

  1. Jönsson-Rylander AC, Nordlander M, Svindland A, Ilebekk A. Distribution of neuropeptide Y Y1 and Y2 receptors in the postmortem human heart. Peptides. 2003;24(2):255-262. doi: 10.1016/S0196-9781(03)00041-X

 

  1. Sharma S. Morphometric interpretation of postganglionic sympathetic neurons that innervate myocardium. bioRxiv. Preprint posted online July 29, 2025. doi: 10.1101/2025.07.27.667010

 

  1. Meng X, Murali S, Cheng YF, et al. Increasing the expression level of ChR2 enhances the optogenetic excitability of cochlear neurons. J Neurophysiol. 2019;122(5):1962. doi: 10.1152/jn.00828.2018

 

  1. Ripplinger CM. Neural Regulation of Cardiac Rhythm. In: Cardiovascular Signaling in Health and Disease. International Publishing Springer; 2022:323-340. doi: 10.1007/978-3-031-08309-9_11

 

  1. Ramirez RJ, Ajijola OA, Zhou W, et al. A new electrocardiographic marker for sympathetic nerve stimulation: modulation of repolarization by stimulation of stellate ganglia. J Electrocardiol. 2011;44(6):694-699. doi: 10.1016/J.JELECTROCARD.2011.07.030

 

  1. Ajijola OA, Lux RL, Khahera A, et al. Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis. Am J Physiol Heart Circ Physiol. 2017;312(3):H608-H621. doi: 10.1152/AJPHEART.00575.2016

 

  1. Ajijola OA, Yagishita D, Patel KJ, et al. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context. Am J Physiol Heart Circ Physiol. 2013;305(7):H1031-H1040. doi: 10.1152/AJPHEART.00434.2013

 

  1. Zhang X, Shi T, Holmberg K, et al. Expression and regulation of the neuropeptide Y Y2 receptor in sensory and autonomic ganglia. Proc Natl Acad Sci USA. 1997;94(2):729. doi: 10.1073/pnas.94.2.729

 

  1. Jani NR, Van Weperen VYH, Ayagama T, et al. Sympathovagal crosstalk: Y2-receptor blockade enhances vagal effects which in turn reduce NPY levels via muscarinic receptor activation. Cardiovasc Res. 2025;121(14):2189- 2203. doi: 10.1093/cvr/cvaf180
Next article in this issue
Share
Back to top
Journal of Clinical and Translational Research, Electronic ISSN: 2424-810X Print ISSN: 2382-6533, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept